Clinical trial NCT03472326
Conditions: HIV-1-infection
Sponsor: Gilead Sciences
Start date: 2018-04-03; Completion date: 2019-12-09
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the short-term antiviral potency of GS-9131 functional monotherapy compared to placebo-to-match (PTM) GS-9131, each administered once daily with the existing failing antiretroviral (ARV) regimen as demonstrated by the proportion of participants achieving human immunodeficiency virus ribonucleic acid (HIV-1 RNA) \> 0.5 log10 decreases from baseline after up to 14 days of therapy in HIV-1 positive, ARV treatment experienced adult participants with nucleos(t)ide resistant virus.

This is a two-part study. Part 1 consists of three cohorts: 2 Sentinel Cohorts and 1 Randomized Cohort. Eligible participants from Part 1 will proceed to Part 2 followed by an optional open-label extension.

Detailed description:

Arms: arm 1: Treatment experienced participants will receive GS-9131 60 mg in addition to their current failing ARV regimen for a period of 10 days. arm 2: Treatment experienced participants will receive GS-9131 180 mg in addition to their current failing ARV regimen for a period of 14 days. arm 3: Participants will be randomized in 1:1:1:1 so as to receive GS-9131 in 3 active dose levels up to a maximum of 180 mg or Placebo to match GS-9131 in addition to their current failing ARV regimen for a period of 14 days in Part 1. arm 4: Participants who complete dosing in Sentinel Cohort 1 of Part 1 and show a reduction in plasma HIV RNA \> 0.5 log10 from their pre-GS-9131 baseline value at Day 11 and discontinue their current failing regimen will receive an optimized regimen consisting of GS-9131 60 mg + bictegravir (BIC) 30 mg + darunavir (DRV) 800 mg + ritonavir (RTV) 100 mg for a period of 24 weeks. After Week 24, participants will be given the option to participate in an open label extension and receive GS-9131 60 mg + BIC 75 mg + tenofovir alafenamide (TAF) 25 mg, for an additional 24 weeks or until Gilead Sciences elects to discontinue the study drug in that country, whichever occurs first. arm 5: Participants who complete dosing in Sentinel Cohort 2 of Part 1 and show a reduction in plasma HIV RNA \> 0.5 log10 from their pre-GS-9131 baseline value at Day 15 and discontinue their current failing regimen will receive an optimized regimen consisting of GS-9131 180 mg + BIC 75 mg + TAF 25 mg, for a period of 24 weeks. After Week 24, participants will be given the option to participate in an open label extension and receive GS-9131 180 mg + BIC 75 mg + TAF 25 mg, for an additional 24 weeks or until Gilead Sciences elects to discontinue the study drug in that country, whichever occurs first.
Interventions: intervention 1: GS-9131 intervention 2: BIC intervention 3: TAF intervention 4: ARV regimen intervention 5: DRV intervention 6: RTV
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily intervention 2: Tablet(s) administered orally once daily intervention 3: Tablet(s) administered orally once daily intervention 4: ARV regimen may consist of the ARV agents containing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) intervention 5: Tablet(s) administered orally once daily intervention 6: Tablet(s) administered orally once daily

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2 Study to Evaluate the Efficacy of GS-9131 Functional 
Monotherapy in HIV-I-Infected Adults Failing a Nucleos(t)ide 
Reverse Transcriptase Inhibitor-Containing Regimen with 
Nucleos(t)ide Reverse Transcriptase Inhibitor Resistant Vims 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
132376 
Not Applicable 
NCT03472324 
HIV-1 infection 
GS-US-442-4148 
Gilead Clinical 
Name: 
PD 
PD 
PD 
Program Manager: 
Telephone: 
Fax: 
Gilead Medical 
Name: 
Monitor: 
Telephone: 
Fax: 
Protocol Version/Date: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
PD 
PD 
PD 
15 June 2017 
24 August 2017 
12 October 2018 
01 November 2018 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paii icularly unpublished data, is the prope1iy 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 18 
1. 
INTRODUCTION .............................................................................................................................................. 21 
1.1. 
Background ............................................................................................................................................ 21 
1.2. 
GS-9131 ................................................................................................................................................. 21 
1. 2 .1. 
General Infonnation ............................................................................................................. 21 
1.2.2. 
Nonclinical Phrumacology and Toxicology ......................................................................... 22 
1.2.3. 
Clinical Trials ofGS-9131 ................................................................................................... 24 
1. 3. 
Bictegravir .............................................................................................................................................. 3 2 
1.3.1. 
General Infonnation ............................................................................................................. 32 
1.3.2. 
Nonclinical Pha1macology, Pha1macokinetics and Toxicology ........................................... 32 
1.3.3. 
Clinical Studies ofBictegravir ............................................................................................. 33 
1.4. 
Tenofovir Alafena1nide (TAF) ............................................................................................................... 36 
1.5. 
Danmavir (DRV, Prezista®) ................................................................................................................... 36 
1.6. 
Ritonavir (RTV, Norvir®) ...................................................................................................................... 37 
1.7. 
Rationale for This Study ........................................................................................................................ 37 
1.8. 
Rationale for the Dose Selection ............................................................................................................ 38 
1.8.1. 
GS-9131 ............................................................................................................................... 38 
1.8.2. 
Bictegravir (BIC) .................................................................................................................. 39 
1.8.3. 
Ritonavir-Boosted Damnavir (DRV + RTV) ....................................................................... 39 
1.8.4. 
Tenofovir Alafena1nide (TAF) ............................................................................................. 39 
1. 9. 
Risk/Benefit Assessment for the Study .................................................................................................. 40 
1.10. 
Compliance ............................................................................................................................................ 41 
2. 
OBJECTIVES ..................................................................................................................................................... 42 
3. 
STUDY DESIGN ................................................................................................................................................ 43 
3.1. 
3.2. 
3.3. 
3.4. 
Endpoints ............................................................................................................................................... 43 
Study Design .......................................................................................................................................... 43 
Study Treatments ................................................................................................................................... 44 
Duration ofTreatment ............................................................................................................................ 45 
4. 
SUBJECT POPULATION .................................................................................................................................. 49 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 49 
4.2. 
Inclusion Criteria .................................................................................................................................... 49 
4.3. 
Exclusion Criteria ................................................................................................................................... 50 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 52 
5.1. 
Rando1nization, Blinding and Treatment Codes .................................................................................... 52 
5.1.1. 
Procedures for Breaking Treatment Codes ........................................................................... 52 
5.2. 
Description and Handling of Study Drng ............................................................................................... 53 
5.2.1. 
Foimulation .......................................................................................................................... 53 
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5.2.2.
Packaging and Labeling .......................................................................................................53
5.2.3.
Storage and Handling...........................................................................................................54
5.3.
Dosage and Administration of GS-9131, BIC, DRV, RTV, TAF and PTM GS-9131...........................54
5.4.
Prior and Concomitant Medications For Subjects in Sentinel Cohort 2, Randomized Cohort 
and Part 2: GS-9131 + BIC + TAF ........................................................................................................55
5.5.
Accountability of IMP............................................................................................................................57
5.6.
Investigational Medicinal Product Return or Disposal...........................................................................57
6.
STUDY PROCEDURES ....................................................................................................................................58
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................58
6.2.
Pretreatment Assessments......................................................................................................................58
6.2.1.
Screening Visit .....................................................................................................................58
6.3.
Treatment Assessments..........................................................................................................................59
6.3.1.
Part 1 – Functional Monotherapy (Sentinel and Randomized Cohorts)...............................59
6.3.2.
Part 2 ....................................................................................................................................60
6.3.3.
Part 2 (Weeks 1-24)..............................................................................................................61
6.4.
Post-Treatment Assessments..................................................................................................................63
6.4.1.
Early Study Drug Discontinuation Visit for Premature Discontinuation 
from Study............................................................................................................................63
6.4.2.
30 Day Follow-Up Visit.......................................................................................................64
6.5.
Criteria for Discontinuation of Study Treatment....................................................................................65
6.5.1.
Study Stopping Criteria........................................................................................................65
6.6.
End of Study...........................................................................................................................................66
6.7.
Post Study Care......................................................................................................................................66
6.8.
Clinical Laboratory Assessments ...........................................................................................................66
6.8.1.
Blood Samples......................................................................................................................66
6.8.2.
Urine Samples ......................................................................................................................68
6.10.
Virologic Failure....................................................................................................................................69
6.10.1.
Suboptimal Virologic Response...........................................................................................69
6.10.2.
Virologic Rebound ...............................................................................................................71
6.10.3.
Management of Virologic Rebound .....................................................................................71
6.10.4.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Discontinuation and 
Week 24 ...............................................................................................................................72
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................73
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................73
7.1.1.
Adverse Events.....................................................................................................................73
7.1.2.
Serious Adverse Events........................................................................................................73
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................74
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................74
7.2.2.
Assessment of Severity ........................................................................................................75
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................75
7.3.1.
Adverse Events.....................................................................................................................75
7.3.2.
Serious Adverse Events........................................................................................................75
7.4.
Gilead Reporting Requirements.............................................................................................................76
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................77
7.6.
Toxicity Management ............................................................................................................................77
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................77
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................77
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................78
CCI
CCI-


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7.7.
Special Situations Reports......................................................................................................................78
7.7.1.
Definitions of Special Situations..........................................................................................78
7.7.2.
Instructions for Reporting Special Situations.......................................................................79
8.
STATISTICAL CONSIDERATIONS................................................................................................................81
8.1.
Analysis Objectives and Endpoints........................................................................................................81
8.1.1.
Analysis Objectives..............................................................................................................81
8.1.2.
Primary Endpoint .................................................................................................................81
8.1.3.
Secondary Endpoints............................................................................................................81
8.1.4.
Other Endpoints of Interest ..................................................................................................82
8.2.
Analysis Conventions.............................................................................................................................82
8.2.1.
Analysis Sets ........................................................................................................................82
8.3.
Data Handling Conventions ...................................................................................................................83
8.4.
Demographic Data and Baseline Characteristics ...................................................................................84
8.5.
Efficacy Analysis ...................................................................................................................................84
8.5.1.
Primary Analysis..................................................................................................................84
8.5.2.
Secondary Analyses .............................................................................................................84
8.6.
Safety Analysis.......................................................................................................................................85
8.6.1.
Extent of Exposure...............................................................................................................85
8.6.2.
Adverse Events.....................................................................................................................85
8.6.3.
Laboratory Evaluations ........................................................................................................86
8.6.4.
Other Safety Evaluations......................................................................................................86
8.7.
Pharmacokinetic Analysis......................................................................................................................86
8.8.
Biomarker Analysis................................................................................................................................87
8.9.
Sample Size............................................................................................................................................87
8.10.
Data Monitoring Committee ..................................................................................................................87
8.11.
Analysis Schedule ..................................................................................................................................87
9.
RESPONSIBILITIES..........................................................................................................................................88
9.1.
Investigator Responsibilities ..................................................................................................................88
9.1.1.
Good Clinical Practice..........................................................................................................88
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................88
9.1.3.
Informed Consent.................................................................................................................88
9.1.4.
Confidentiality......................................................................................................................89
9.1.5.
Study Files and Retention of Records ..................................................................................89
9.1.6.
Case Report Forms...............................................................................................................90
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................91
9.1.8.
Inspections............................................................................................................................91
9.1.9.
Protocol Compliance............................................................................................................91
9.2.
Sponsor Responsibilities ........................................................................................................................92
9.2.1.
Protocol Modifications.........................................................................................................92
9.2.2.
Study Report and Publications .............................................................................................92
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................92
9.3.1.
Payment Reporting...............................................................................................................92
9.3.2.
Access to Information for Monitoring..................................................................................93
9.3.3.
Access to Information for Auditing or Inspections ..............................................................93
9.3.4.
Study Discontinuation..........................................................................................................93
10.
REFERENCES ...................................................................................................................................................94
11.
APPENDICES ....................................................................................................................................................96
Appendix 1.
Investigator Signature Page....................................................................................................97


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Appendix 2.
Study Procedures Table – Cohort 1........................................................................................98
Appendix 3.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1 ............................101
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................105
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............106
Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines) ...........................128
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................129
Appendix 8.
Prior and Concomitant Medications For Subjects in Sentinel Cohort 1 and Sentinel 
Cohort 1 Subjects Who Go on to Part 2: bictegravir GS-9131 + BIC + DRV + RTV .........131
LIST OF IN-TEXT TABLES
Table 1.
Estimated Exposure Margins for GS-9131 and GS-9148 in Female Animals 
Relative to 180 mg GS-9131 ..................................................................................................23
Table 2.
Study GS-US-180-4149 Preliminary Plasma PK Data from Cohorts 1-5 ..............................26
Table 3.
Study GS-US-180-4149 Preliminary PBMC PK Data from Cohorts 1-5...............................28
Table 4.
Study GS-US-180-0104 Multiple Dose PK Data ...................................................................30
Table 5.
Study GS-US-442-4148 Preliminary PK Data .......................................................................31
Table 6.
Prior and Concomitant Medications*.....................................................................................56
LIST OF IN-TEXT FIGURES
Figure 1.
Study GS-US-442-4148: Changes in Viral Load by Subject and Failing ARV 
Regimen in the Sentinel Cohort..............................................................................................32
Figure 2.
Study Schema – Cohort 1.......................................................................................................46
Figure 3.
Study Schema – Cohort 2.......................................................................................................47
Figure 4.
Suboptimal Virologic Response Schema................................................................................70
Figure 5.
Virologic Rebound Schema....................................................................................................72


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404
Study Title: 
A Phase 2 Study to Evaluate the Efficacy of GS-9131 Functional 
Monotherapy in HIV-1-Infected Adults Failing a Nucleos(t)ide 
Reverse Transcriptase Inhibitor-Containing Regimen with 
Nucleos(t)ide Reverse Transcriptase Inhibitor Resistant Virus
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
132376 
Not Applicable
NCT03472324
Study Centers Planned:
Uganda, Zimbabwe
Objectives:
The primary objective of this study is as follows:

To evaluate the short-term antiviral potency of GS-9131 
functional monotherapy compared to placebo-to-match (PTM) 
GS-9131, each administered once daily with the existing failing 
antiretroviral (ARV) regimen, as demonstrated by the proportion 
of subjects achieving HIV-1 RNA > 0.5 log10 decreases from 
baseline through up to 14 days of therapy.
The secondary objectives of this study are as follows: 
Part 1

To evaluate the efficacy of GS-9131 functional monotherapy as 
determined by the change from baseline in log10 HIV-1 RNA at 
Day 11 (Sentinel Cohort 1) or Day 15 (Sentinel Cohort 2 and 
Randomized Cohort).
Part 2

To evaluate the safety and efficacy of a regimen containing 
GS-9131 (60 mg) + bictegravir (BIC) + darunavir (DRV) 
+ ritonavir (RTV) through 24 weeks of treatment in subjects 
from Sentinel Cohort 1 who switched from a failing regimen. 

To evaluate the safety and efficacy of a regimen containing 
GS-9131 + bictegravir (BIC) + tenofovir alafenamide (TAF) 
through 24 weeks of treatment in subjects from Sentinel Cohort 
2 and Randomized Cohort who switched from a failing regimen. 


GS-9131 (+BIC+TAF)
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
To characterize the pharmacokinetics (PK) of GS-9131 in 
treatment-experienced patients.

To evaluate the number of subjects with treatment-emergent 
nucleos(t)ide reverse transcriptase inhibitor (NRTI), protease 
inhibitor (PI), and integrase strand-transfer inhibitor (INSTI)
mutations at the time of virologic failure.
Study Design:
Part 1: GS-9131 Functional Monotherapy
The study will consist of 3 cohorts - Two Sentinel Cohorts and one
Randomized Cohort. 
The Sentinel Cohort 1 will enroll 10 TE viremic HIV-1 subjects to 
receive open-label GS-9131 60 mg for 10 days in addition to their 
current failing ARV regimen. 
Sentinel Cohort 2 will enroll up to 10 TE viremic HIV-1 subjects to 
receive open-label GS-9131 180 mg for 14 days in addition to their 
current failing ARV regimen. 
Sentinel cohort subjects who meet criteria for Part 2, will transition 
to Part 2 and not participate in the randomized portion of this study. 
The Sentinel Cohorts will be followed by a Randomized Cohort that 
is a double-blind comparison of the addition of GS-9131 (up to 
180 mg), or PTM to the current failing ARV regimen in viremic 
HIV-1 positive adults. Randomization and dosing into the 
Randomized Cohort will begin after review of the clinical data in the 
second Sentinel Cohort. 
In the Randomized Cohort, up to 48 subjects failing their current 
ARV regimen will be randomized 1:1:1:1 to GS-9131 (up to 
three active dose levels, up to 180 mg), or PTM. The GS-9131 dose 
for Treatment Arms A-C will be determined following review of the
safety, activity and available PK data from Sentinel Cohort 2.
GS-9131 will be added to their failing regimen for 14 days as 
follows: 
Treatment Arms A-C: GS-9131 once daily + current failing 
antiretroviral therapy (ART) regimen (n=12 per Treatment Arm)
Treatment Arm D: PTM + current failing ART regimen (n=12)
Randomization will be stratified by HIV-1 RNA level 
(≤100,000 copies/mL and > 100,000 copies/mL) at screening. 
Study medication will be administered by directly observed therapy 
(DOT).


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
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Number of Subjects 
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Part 2: GS-9131 + BIC + DRV + RTV or GS-9131 + BIC + TAF 
Combination Therapy 
GS-9131(60 mg)+ BIC (30 mg)+ DRV(800 mg)+ RTV(l 00 mg) 
Regimen (Sentinel Coho1i 1) 
Subjects who successfully complete all study doses in Sentinel 
Coho1i 1 and show a reduction in plasma HIV RNA > 0.5 log10 from 
their pre-GS-9131 baseline following functional monotherapy will 
discontinue their cmTent failing regimen and staii an optimized 
regimen consisting of GS-9131 (60 mg)+ BIC + DRV + RTV for at 
least 24 weeks. 
GS-9131(up to 180 mg)+ BIC (75 mg)+ TAF (25 mg) (Sentinel 
Coho1i 2 and Randomized Coho1i) 
Subjects who successfully complete all study doses in Sentinel 
Coho1i 2 and Randomized Cohort (A-C), and show a reduction in 
plasma HIV RNA > 0.5 log10 from their pre-GS-9131 baseline 
dming functional monotherapy will discontinue their cmTent failing 
regimen and staii an optimized regimen consisting of 
GS-9131 + BIC + T AF for at least 24 weeks. All Subjects 
randomized to the placebo ann (Coho1i D) will discontinue their 
cunent failing regimen and sta1i a regimen consisting of 
GS-9131(180 mg)+ BIC + TAF for at least 24 weeks. 
An Independent Data Monitoring Committee (IDMC) will review 
the progress, efficacy, and safety data while the study is ongoing. 
The committee will convene after all subjects in the randomized 
coho1i have completed Pa1i 1 and after approximately 50% of 
subjects in Pait 2 have completed Week 12 of Pait 2 of the study. 
Approximately 68 female subjects will be enrolled in this study. 
Replacement subjects may be enrolled for subjects who do not 
complete all procedmes in the functional monotherapy treatment for 
reasons other than discontinuation due to treatment related adverse 
events (AEs). 
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Target Population:
HIV-1 infected adult females ≥18 years of age failing a 2 nucleoside 
reverse transcriptase inhibitor (NRTI) + non-nucleoside reverse 
transcriptase inhibitor (NNRTI) containing treatment regimen with 
plasma HIV-1 RNA level 500 copies/mL, evidence of K65R or 
3 or more thymidine analog mutations (TAMs) or Q151M, and at 
least one documented primary resistance associated mutation to 
NNRTIs.
Duration of 
Treatment:
Part 1 Sentinel Cohort 1:  10 days. 
Part 1 Sentinel Cohort 2 and Randomized Cohort : 14 days each
Part 2: At least 24 weeks
Diagnosis and Main 
Eligibility Criteria:
HIV-1 infected subjects who meet the following criteria:

Non-pregnant/non-lactating females, ≥18 years of age at 
Screening. Females of childbearing potential (as defined in 
Appendix 7) must have a negative serum pregnancy test at 
Screening and Day 1.

Subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol-specified method(s) of 
contraception as described in Appendix 7.

Estimated glomerular filtration rate (eGFR) (Cockcroft-Gault 
equation) ≥70 mL/min

Currently taking a failing ARV regimen that contains an NRTI 

HIV-1 RNA 500 copies/mL at Screening

CD4 > 100 cells/μL at Screening

Have a screening genotype showing at least the following 
resistance mutation profile (a local genotype at the Screening 
visit is acceptable for enrollment upon review by the Sponsor): 
K65R or
at least 3 TAMs; TAMs are defined as: M41L, D67N, K70R, 
L210W, T215F/Y, or K219Q/E/N/R in reverse transcriptase 
(RT) or 
Q151M
and at least one primary resistance mutation to an NNRTI

No prior or current ARV regimens containing integrase inhibitor 
(INSTI) or protease inhibitor (PI)

No evidence of chronic viral hepatitis B or C infection. Note: 
Subjects with positive hepatitis C virus (HCV) antibody and 
without detectable HCV RNA are permitted to enroll. 
No evidence of active AIDS-related opportunistic infection, 
including tuberculosis. 


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Study Procedures/
Frequency:
At Screening, laboratory analyses (hematology, chemistry, 
urinalysis, and serum pregnancy test [for females of childbearing 
potential]), HIV-1 RNA, cluster determinant 4 (CD4) cell count, 
vital signs, electrocardiogram (ECG), complete physical 
examination, and eGFR will be performed.  HIV-1 protease, and 
reverse transcriptase genotype/phenotype, and hepatitis B virus 
(HBV) and HCV serologies will be analyzed. 
Part 1:
Sentinel Cohort 1 (GS-9131 60 mg plus Current Failing 
Regimen)
Following Screening and Day 1 (baseline) visits, subjects will be 
required to visit the clinic daily on Days 2-11. All study medication 
will be delivered by DOT on Days 1-10.
Laboratory analyses (hematology, chemistry, and urinalysis) will be 
performed at Day 1 (baseline), Day 7, and Day 11. A fasting 
metabolic profile will be performed on Day 1. Urine and serum 
pregnancy test (females of childbearing potential only) will be done 
at Screening and Day 1 and a urine pregnancy test on Day 11; 
positive urine pregnancy test on Day 11 will be confirmed with a 
serum pregnancy test. CD4 T cell count will be performed at 
Screening, Day 1 (baseline), and Day 11. A plasma sample for 
phenotypic and genotypic testing of HIV-1 resistance will be 
collected at Screening, Day 1, and Day 11. A complete physical 
examination will be performed at Screening, Day 1 (baseline), and 
Day 11. Symptom driven physical exam will be performed on Day 2 
and Day 7. ECGs will be performed at Screening, Day 1, and 
Day 11. 
On Day 10, all subjects will participate in a PK evaluation.
Samples for HIV-1 RNA will be collected at Screening, Day 1 
(baseline), and Days 2, 3, 7, 10, and 11.
Assessments of AEs and concomitant medications will be performed 
at each visit.
Sentinel Cohort 2 (GS-9131 180 mg plus Current Failing 
Regimen) and Randomized Cohort (GS-9131 or PTM plus 
Current Failing Regimen) 
Following Screening and Day 1 (baseline) visits, all study 
medication will be delivered by DOT on Days 1-14.
Laboratory analyses (hematology, chemistry, and urinalysis) will be 
performed at Days 1 (baseline), 3, 5, 7, 10, 14, and 15. A fasting 
metabolic profile will be performed on Day 1. Urine and serum 


GS-9131 (+BIC+TAF)
Protocol GS-US-442-4148
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Amendment 3
CONFIDENTIAL
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pregnancy test (females of childbearing potential only) will be done 
at Screening and Day 1 and a urine pregnancy test on Days 10 and 
14; positive urine pregnancy test will be confirmed with a serum 
pregnancy test. CD4 T cell count will be performed at Screening and 
Days 1 (baseline), 10, 14, and 15. A plasma sample for phenotypic 
and genotypic testing of HIV-1 resistance will be collected at 
Screening and Days 1, 10, 14, and 15. A whole blood sample for 
genotypic testing of HIV-1 resistance will be collected at Day 1. A 
complete physical examination will be performed at Screening and 
Days 1 (baseline), and 14. Symptom driven physical exam will be 
performed on Days 2 and 7. ECGs will be performed at Screening, 
Day 1and Day 15. 
On Day 14, all subjects will participate in a PK evaluation.
Samples for HIV-1 RNA will be collected at Screening and Days 1 
(baseline), 3, 7, 10, 14, and 15.
Assessments of AEs and concomitant medications will be performed 
at each visit.
Part 2:
GS-9131 + BIC + DRV + RTV Regimen (Sentinel Cohort 1)
Subjects in the Sentinel Cohort  1 who had a > 0.5 log10 decline in 
HIV-1 RNA in Part 1 will discontinue their current failing regimen 
and  begin treatment with GS-9131 + BIC + DRV + RTV once daily 
for 24 weeks. Subjects who had a ≤ 0.5 log10 decline in HIV-1 RNA 
are not eligible to continue onto Part 2 and will be discontinued from 
the study.
At their Day 1 visit for Part 2, AEs, concomitant medications, drug 
accountability, vital signs, physical examinations, HIV-1 RNA, 
estimated GFR, hematology, chemistry, CD4 cell count, and 
urinalysis will be performed.
All subjects will be required to visit the clinic on Day 1, and 
Weeks 1, 2, 4, 8, 12, 18, and 24. At each visit, AEs, concomitant 
medications, drug accountability, hematology, chemistry, HIV-1 
RNA, CD4 cell count, vital signs, and estimated GFR will be 
evaluated. A fasting metabolic profile will be performed on Day 1, 
Week 12 and 24 visits. A complete physical examination will be 
done at Day 1, Week 12 and 24 visits. A symptom directed physical 
examination will be done at all other visits. Urinalysis will be 
performed at Day 1, and Week 4, 12, and 24 visits. Urine pregnancy 
test (females of childbearing potential only) will be done on Day 1, 
and Weeks 4, 8, 12, 18, and 24; positive urine pregnancy test will be 
confirmed with a serum pregnancy test.


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment3 
GS-9131 + BIC + TAF (Sentinel Cohort 2 and Randomized 
Cohort) 
Subjects in the Sentinel Coho1t 2 or Randomized Coho1t (A-C) who 
had a > 0.5 log10 decline in HIV-I RNA in Pait 1 will discontinue 
their cunent failing regimen and begin treatment with GS-9131 
+ BIC + TAF once daily for 24 weeks. Subjects who had 
a ~ 0.5 log10 decline in HIV-I RNA ai·e not eligible to continue onto 
Pait 2 and will be discontinued from the study. Subjects in 
Randomized Coho1t D will begin treatment with GS-9131 (180 mg) 
+ BIC (75 mg)+ TAF (25 mg) once daily for 24 weeks after 
successful completion of Part 1. 
At their Day 1 visit for Pait 2, AEs, concomitant medications, dmg 
accountability, vital signs, physical examinations, HIV-I RNA, 
estimated GFR, hematology, chemistiy, CD4 cell count, and 
urinalysis will be perfo1med. 
All subjects will be required to visit the clinic on Day 1, and 
Weeks 1, 2, 4, 8, 12, 18, and 24. At each visit, AEs, concomitant 
medications, diug accountability, hematology, chemistiy, HIV-I 
RNA, CD4 cell count, vital signs, and estimated GFR will be 
evaluated. A fasting metabolic profile will be perfo1med on Day 1, 
Week 12 and 24 visits. A complete physical examination will be 
done at Day 1, Week 12 and 24 visits. A symptom directed physical 
examination will be done at all other visits. Urinalysis will be 
perfonned at Day 1, and Week 4, 12, and 24 visits. Urine pregnancy 
test (females of childbeai·ing potential only) will be done on Day 1, 
and Weeks 4, 8, 12, 18, and 24; positive urine pregnancy test will be 
confnmed with a semm pregnancy test. 
Page 12 
01 November 2018 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of 
Administration: 
CONFIDENTIAL 
Protocol-Specific Stopping Rules 
Final 
Amendment3 
By Subject: Study drng dosing for a subject will be discontinued if 
that subject experiences a Grade 3 or Grade 4 treatment-emergent 
adverse event (AE) or confomed laborato1y abno1mality judged by 
the study investigator to be possibly related to study drng, or any 
serious adverse event (SAE) considered to be possibly related to 
studydrng. 
By Sentinel Coho1t: Study diug dosing for the Sentinel Coho1is will 
be discontinued if any of the following criteria is met: 
• 
2 or more subjects experiencing Grade 3 or Grade 4 treatment-
emergent AEs judged by the study investigator to be possibly 
related to study diug, or 
• 
2 or more subjects experiencing confomed Grade 3 or Grade 4 
laborato1y abno1malities, or 
• 
2 or more subjects experiencing any SAE that is considered to be 
possibly related to study di11g. 
For the Randomized Coho1i and Pali 2: If2 or more subjects in the 
Randomized Coho1i who are subsequently assigned to treatment 
cohorts in Paii 2 experience a Grade 3 or 4 treatment-emergent AE 
leading to study di11g discontinuation or an SAE judged by the study 
investigator to be possibly related to study di11g, the IDMC will be 
convened to review all preliminaiy safety data generated in subjects 
dosed to date. 
Subjects will be followed as clinically indicated until the 
treatment-emergent AE or laborato1y abno1mality returns to baseline 
or is othe1w ise explained, whichever occms first. Grade 3 and 4 
laborato1y abno1malities that are not confnmed by repeat testing will 
be managed according to the clinic's practice; a decision to reinitiate 
dosing may be made by Gilead in consultation with the investigator 
and after a safety review. 
Paii 1 Sentinel Coho1i 1 : GS-9131 ( 60 mg) 
Paii 1 Sentinel Coho1i 2 and Randomized Coho1i: GS-9131 (up to 
180 mg) and PTM 
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01 November 2018 


GS-9131 (+BIC+TAF)
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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 14
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Part 2: 
Sentinel Cohort 1: GS-9131 (60 mg) + BIC (30 mg) + DRV 
(800 mg) + RTV (100 mg)
Sentinel Cohort 2 and Randomized Cohort: GS-9131 (doses up to 
180 mg) + BIC (75 mg) + TAF (25 mg)
Reference Therapy, 
Dose, and Mode of 
Administration:
Part 1:Current ARVs
Part 2: None
Criteria for Evaluation:
Efficacy:
The primary endpoint is:

The proportion of subjects with plasma HIV-1 RNA decreases 
from baseline exceeding 0.5 log10 (copies/mL) at Day15 in the 
Randomized Cohort. 
The secondary endpoints are:

The change from baseline in plasma log10 HIV-1 RNA 
(copies/mL) at Day 11 for Sentinel Cohort 1 and Day 15 for
Sentinel Cohort 2 and the Randomized Cohort in Part 1. 

The proportion of subjects with plasma HIV-1 
RNA < 50 copies/mL at Week 24 as defined by the US FDA 
Snapshot algorithm. The number of subjects with 
treatment-emergent NRTI, PI, or INSTI mutations at the time of 
virologic failure.
Safety:
The safety and tolerability of GS-9131 in subjects who failed an 
NRTI-containing regimen with NRTI-resistant virus through 
Day 15, assessed by clinical exams, laboratory parameters and AE 
reporting.
The safety and tolerability of switching to the regimen of 
GS-9131 + BIC + DRV + RTV or GS-9131 + BIC + TAF in 
subjects who failed an NRTI-containing regimen with 
NRTI-resistant virus through Week 24, assessed by clinical exams, 
laboratory parameters and AE reporting.


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Phaimacokinetics: 
CONFIDENTIAL 
Final 
Amendment3 
Sentinel Cohort 1 (60 mg): Intensive plasma and PBMC samples 
will be collected in all subjects on Day 10. Serial blood samples for 
plasma and peripheral blood mononuclear cell (PBMC) PK 
assessments will be collected at the following timepoints: 
Plasma collection on Day 10: Predose (< 5 minutes prior to dosing), 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post dose. 
PBMC collection on Day 10: Predose (< 5 minutes prior to dosing), 
1, 2, 6, and 24 hours post dose. 
Sentinel Cohort 2 (1 80 mg) and Randomized Coho1i: Intensive 
plasma and PBMC PK samples will be collected in all subjects on 
Day 14. Serial blood samples for plasma and peripheral blood 
mononucleai· cell (PBMC) PK assessments will be collected at the 
following timepoints: 
Plasma collection on Day 14: Predose (< 5 minutes prior to dosing), 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post dose. 
PBMC collection on Day 14: Predose (< 5 minutes prior to dosing), 
1, 2, 6, and 24 hours post dose 
The PK of GS-9131 and its metabolite, GS-9148, in plasma, will be 
evaluated. The PK of GS-9148-diphosphate (DP) in PBMCs and the 
PK of other analytes may be explored. 
Page 15 
01 November 2018 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Statistical Methods: 
CONFIDENTIAL 
Final 
Amendment3 
For Pait 1, the propo1t ion of subjects with plasma HIV-1 RNA 
decreases from baseline exceeding 0.5 log10 at Day 15 in the 
Randomized Coho1t will be compared between each active GS-9131 
treatment group and the placebo group using Fisher's exact test. 
The change from baseline in plasma log10 HIV-1 RNA ( copies/mL) 
at Day 15 will be summarized by coho1t and treatment group. 
For Pait 2, the propo1tion of subjects with plasma HIV-1 
RNA < 50 copies/mL at Week 24 will be summai·ized by treatment 
group using the US FDA-defined Snapshot Algorithm and the 
missing = failure / excluded approaches for imputing missing HIV-1 
RNA values. The 95% confidence interval (CI) of the propo1t ion of 
subjects with HIV-1 RNA < 50 copies/mL at Week 24 will be 
calculated using the Clopper-Peai·son Exact method. In addition, the 
change from Part 2 baseline (i.e., predose of an optimized regimen 
consisting GS-9131 in Part 2) in log10 HIV-1 RNA and CD4 cell 
count at Week 24 will be summai·ized by treatment group using 
descriptive statistics. The 95% CI will be calculated. 
Adverse event data including treatment-emergent AEs and SAEs 
will be summarized by system organ class (SOC) and prefen ed tenn 
(PT) using the Medical Dictiona1y for Regulato1y Activities 
(MedDRA) by treatment group in each part and cohort. 
Listings of individual subject vital signs, 12-lead ECG parameters, 
and laborato1y results will be provided. Laborato1y results and 
change from predose/baseline values for selected tests will be 
summai·ized at scheduled visits by treatment group in each pait and 
coho1t. The incidence of treatment-emergent laborato1y 
abnonnalities will be summarized by treatment group in each pa1t 
and coho1t as well. 
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01 November 2018 


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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For the sample size and power calculation for the Randomized 
Cohort in Part 1, assuming that 70% of subjects in each GS-9131 
treatment group and 8.3% in the placebo group achieve > 0.5 log10
HIV-1 RNA decrease from baseline at Day 15, a sample size of 
12 subjects per treatment group (48 in total) provides 85% power to 
detect the difference in the response rates between at least one 
GS-9131 treatment group and the placebo group with a Fisher’s 
exact test to be done at a two-sided alpha level of 0.05.  
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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Amendment 3
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
AhR
aryl hydrocarbon receptor
AIDS
acquired immune deficiency syndrome
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
Antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration 
versus time curve
BIC, B
Bictegravir
B/F/TAF
bictegravir/emtricitabine/tenofovir alafenamide
BUN
blood urea nitrogen
CBC
complete blood count
CFR
FDA code of federal regulations
CI
confidence interval
CK
creatine kinase
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CMH
Cochran-Mantel-Haenszel
Ctau
the observed drug concentration at the end of the dosing interval
COBI
cobicistat, Tybost®
CPK
creatine phosphokinase
CRO
contract (or clinical) research organization 
CSR
clinical study report
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DOT
Directly observed therapy
DNA
deoxyribonucleic acid
DP
Diphosphate
DRV
darunavir, Prezista®
DTG
dolutegravir, Tivicay
ECG
Electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
EVG
elvitegravir, E
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya®


GS-9131 (+BIC+TAF)
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FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FSH
follicle stimulating hormone
F/TAF 
emtricitabine/tenofovir alafenamide, Descovy®
FTC/TDF 
emtricitabine/tenofovir disoproxil fumarate 
GCP
Good Clinical Practice (Guidelines)
GD
gestation day
GSI, Gilead
Gilead Sciences, Inc.
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBeAB
hepatitis B virus e-antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
hERG
human Ether-à-go-go-Related Gene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP, study drug
investigational medicinal products
INSTI
integrase strand-transfer inhibitor
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LAM
lactational amenorrhea method
LDL
low density lipoprotein
LLT
lower level term
LSM
least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
Min
Inute
mtDNA
mitochondrial DNA


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NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
N(t)RTI
nucleos(t)ide reverse transcriptase inhibitor
PAH
pulmonary arterial hypertension
PBMC
peripheral blood mononuclear cell
PI
protease inhibitor
PK
Pharmacokinetic
PP
per-protocol
PT
preferred term 
PTM
placebo-to-match
PVE
Pharmacovigilance & Epidemiology
PXR
pregnane X receptor
QD
once daily
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
ritonavir, Norvir®
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide 
TAM
thymidine analogue mutations
TDF
tenofovir disoproxil fumarate, Viread
TE
treatment experienced
TFV
Tenofovir
UGT1A1
uridine 5'-diphospho-glucuronosyltransferase 
ULN
upper limit of the normal range
US
United States
USPI
United States prescribing information
WHO
World Health Organization


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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 37 million people infected worldwide 
{UNAIDS 2016}. Standard-of-care for the treatment of HIV-1 infection involves the use of a 
combination of antiretroviral (ARV) drugs to suppress viral replication to below detectable 
limits, increase cluster determinant 4 (CD4) cell counts, and delay disease progression. While 
combination ARV therapy for the treatment of HIV-1 infection has been largely successful in 
reducing the morbidity and mortality associated with HIV disease, there remains a significant 
medical need for new well-tolerated therapies that take into consideration HIV genetic 
variability, ARV resistance, and new options for regimen simplification.
A significant proportion of treatment-experienced (TE) HIV-1 infected patients eventually lose 
virologic, immunologic, or clinical benefit from their current regimens. Highly TE 
HIV-1-infected patients with resistance to multiple ARV drug classes have very few or no 
treatment options. These patient populations include: 1) individuals requiring an extensive 
number of active ARV agents to construct a fully suppressive or partially active regimen; and 
2) individuals with extensive nucleoside reverse transcriptase inhibitor (NRTI) resistance in 
resource limited regions. Tenofovir (TFV)-based ARV regimens are the first-line treatments in 
the current antiretroviral therapy (ART) global scale-up campaign {World Health Organization 
(WHO) 2016}; often TFV resistance develops in parallel with resistance to the other ARVs in 
the regimen, compromising the effectiveness of the regimen. The reported level of TFV 
resistance ranges from 20% in Europe to more than 50% in sub-Saharan Africa {TenoRes Study 
Group 2016}.
Developing safe and effective therapies for TE subjects with ARV drug resistance remains a 
priority. Patients with multiple prior regimen failures and significant drug resistance have limited 
treatment options {Department of Health and Human Services (DHHS) 2013, Lundgren 2013, 
Thompson 2010, Williams 2014}. For these individuals, newer treatments are needed to control 
viral replication, preserve the immune function, and prevent clinical progression. In all patients, 
the ideal goal of therapy remains complete and durable viral suppression.
1.2.
GS-9131
1.2.1.
General Information
GS-9131 is the prodrug of a novel adenine nucleotide analog designated GS-9148. GS-9131 
displays a favorable in vitro resistance profile that is distinct from current NRTIs. Important 
advantages of GS-9131 over currently approved nucleos(t)ide reverse transcriptase inhibitors 
(N[t]RTIs) based on in vitro and nonclinical in vivo studies include the following:

An in vitro resistance profile that is more favorable compared with approved N(t)RTIs; 
GS-9131 maintains its in vitro antiretroviral activity against HIV-1 strains with major 


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Amendment 3
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N(t)RTI resistance mutations such as M184V, K65R, L74V, and multiple thymidine analog 
mutations (TAMs); in addition, GS-9131 selects for rare mutations in reverse transcriptase 
(RT) in vitro (a combination of K70E+D123N+T165I or Q151L), and the selected viruses 
remain sensitive to many of the currently marketed N(t)RTIs

A low potential for nephrotoxicity based on the lack of renal toxicities in animal studies, and 
reduced accumulation in human renal tissue in vitro due to the weak interaction of GS-9131 
with the renal organic anion transporters relative to that of other nucleotide analogs

A low potential to induce mitochondrial-dependent toxicities based on the lack of depletion 
of mitochondrial DNA (mtDNA) in cells exposed to GS-9131 or GS-9148, which is 
consistent with the observed weak inhibition of mtDNA polymerase γ by 
GS-9148-diphosphate (DP)

Long intracellular half-life of GS-9148-diphosphate (DP) in target cells (> 24 hours) that 
supports once daily dosing of GS-9131
For further information on GS-9131, refer to the Investigator’s Brochure (IB).
1.2.2.
Nonclinical Pharmacology and Toxicology
A core battery of safety pharmacology studies have been conducted with GS-9131. (CNS, 
cardiovascular, respiratory), repeat-dose toxicity, genetic toxicology, reproductive and 
developmental toxicity, and immunotoxicity studies. GS-9131 is not genotoxic and did not have 
adverse effects on the CNS, respiratory, or cardiovascular systems.
The NOAELs and estimated margins of exposure for GS-9131 and GS-9148 in female animals, 
based on the projected steady state clinical exposures in HIV-1 subjects with the 180 mg 
GS-9131 dose, are presented in Table 1. As GS-9131 is unstable in mouse and rat plasma due to 
the high esterase levels, prodrug exposure margins in rodents are generally low and could not be 
calculated in all instances. The predominant circulating metabolite GS-9148 was monitored in all 
studies and exposure margins are provided in Table 1.


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Table 1.
Estimated Exposure Margins for GS-9131 and GS-9148 in Female 
Animals Relative to 180 mg GS-9131
Study Type
Species/
Duration
NOEL/NOAEL 
(mg/kg/day)1
Analyte 
AUC0-24 
(ng•h/mL)
Exposure 
Margin 
vs. 180 mg2
Repeat Dose
Mouse / 13 weeks
30
GS-9148
5418
1.9
Repeat Dose
Rat / 4 weeks
300
GS-9148
40544
14.2
Repeat Dose
Rat / 26 weeks
100
GS-9148
26,259
9.2
Repeat Dose
Dog / 4 weeks
10
GS-9131
1434
0.8
GS-9148
6709
2.3
Repeat Dose
Monkey / 39 weeks
30
GS-9131
959
0.5
GS-9148
4522
1.6
Fertility
Rat / 3 weeks
100
GS-9148
15,157
5.3
Embryo-fetal development
Rat / GD 6-17
300
GS-9148
57919
20.2
Rabbit / GD 7-17
20
GS-9131
1334
0.7
GS-9148
5544
1.9
Immunotoxicity (M/F)
Rat / 4 weeks
300
GS-9148
53672
18.7
NOEL = no observed effect level; NOAEL = no observed adverse effect level; ND = not determined; GD = gestation day
1
Female animals, only
2
Based on projected AUCtau exposures of 180 mg GS-9131 (1797 ng•h/mL) and AUCtau exposures of GS-9148 
(2865 ng•h/mL) after administration of 60 mg GS-9131 in Sentinel Cohort 1 of Study GS-US-180-4148, assuming dose-
linearity 
Effects on lymphoid tissues were noted in rats and dogs. In both species, females were generally 
less sensitive than males. In a 4-week dog study, lymphoid depletion in the thymus was observed
at ≥3 mg/kg/day in males and at 20 mg/kg/day in females at exposure margins in females of 
1.7- and 4.4-fold for GS-9131 and GS-9148, respectively. The increased incidence and/or 
severity in this study may have been a stress-related change. There was no evidence of lymphoid 
depletion in the spleen or lymph nodes in dogs. In rats, lymphoid depletion in the spleen was 
observed in a 4-week immunotoxicity study, but was not noted in 4-week and 26-week repeat 
dose toxicity studies, and there were no notable changes in peripheral blood immunophenotyping 
in the 4-week rat study. In the immunotoxicity study, immunosuppressive effects (decreased 
response to keyhole limpet hemocyanin [KLH] immunization) were seen in male rats 
at ≥100 mg/kg/day; similar functional changes were not seen in females at GS-9148 exposures 
margins over 18-fold.
Reversible, hematopoietic effects were observed in a 26-week rat study with slightly lower mean 
values for red blood cells (RBC), hemoglobin (Hb) and hematocrit (HCT) in 225 mg/kg/day 
males and females, corresponding to 13- and 21-fold GS-9148 margins, respectively. In dogs, 
slightly lower RBC, Hb, and HCT values were observed at 20 mg/kg/day with dose-dependent 
decreases in total leukocyte, neutrophil and lymphocyte counts evident at ≥10 mg/kg/day, and 
decreases in monocyte and eosinophil counts and mean myeloid:erythroid (M:E) ratios occurring 
primarily at 20 mg/kg/day. The lower lymphocyte and eosinophil counts correlated with thymic 


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lymphoid depletion. Clinical studies have not revealed any clinically-relevant hematology 
changes after single or multiple dosing with GS-9131. Standard hematology evaluation should be 
adequate to monitor for potential GS-9131 effects.
In 13-week mouse and 26-week rat studies, and a 39-week repeat-dose toxicology study in 
cynomolgus monkeys, mortality was noted at correlating exposure margins of 9.1- and 21-fold 
for GS-9148 in mouse and rat studies, respectively, and 0.5- and 1.6-fold for GS-9131 and 
GS-9148, respectively in the monkey study. In all three studies, no specified target organs of 
toxicity were noted at the high dose levels associated with mortality. Specifically, in the 13-week 
mouse study, the high dose group (300 mg/kg/day) was terminated early (Day 32) due to 
mortality. In the 26-week rat study, mortality was observed in 3 of 15 females (Days 49, 171, 
and 172) in the high dose group (225 mg/kg/day).  Finally, in the 39-week monkey study, one 
high dose group (30 mg/kg/day) female was found dead (Day 85). The relationship of test article 
to mortality observed in repeat-dose toxicology studies at high dose levels is unclear. 
Effects on fertility were noted female rats at 300 mg/kg/day. At the 100 mg/kg/day NOAEL, 
exposures were 5.3-fold for GS-9148 compared to projected clinical exposures at the GS-9131 
180 mg dose. In embryo-fetal development studies in pregnant rats and rabbits, there were no 
effects on embryo-fetal development.
Further information is available in the current version of the IB for GS-9131.
1.2.3.
Clinical Trials of GS-9131
Clinical trials of GS-9131 include:
GS-US-180-0101, a Phase 1 randomized, double-blind, placebo-controlled, dose-escalation 
study to evaluate the safety, tolerability, and PK of single doses of GS-9131 (10 mg fasted, 
30 mg fasted, and 30 mg fed) in healthy subjects (completed).
GS-US-180-0103, a Phase 1, randomized, open-label, multiple-dose, six-sequence, three-way 
crossover study evaluating the PK drug interaction of GS-9131 30 mg once daily (QD) and 
Truvada (emtricitabine/tenofovir disoproxil fumarate [FTC/TDF] 200 mg/300 mg fixed-dose 
combination [FDC] tablet) QD when administered together, compared to their administration 
alone (completed).
GS-US-180-4149, a Phase 1 study to evaluate the PK of GS-9131 in combination with 
cobicistat-boosted darunavir plus bictegravir, a ritonavir-boosted protease inhibitor, or tenofovir 
alafenamide (ongoing).
GS-US-180-0104, a Phase1/2 study of the safety, PK and antiviral activity of GS-9131 in 
ARV-naïve, HIV-1 infected subjects (completed).
Further information on completed Phase 1 studies is available in the current version of the IB for
GS-9131.


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1.2.3.1.
Study GS-US-180-4149
Study GS-US-180-4149 is an ongoing Phase 1, randomized, open-label, multiple-dose, 
multi-cohort, study evaluating the PK of GS-9131 in combination with DRV/COBI
(800/150 mg) plus BIC (50 mg), ATV/RTV (300/100 mg), LPV/RTV (800/200 mg), or TAF 
(25 mg).
Subjects in Cohort 1 received 10 days of GS-9131 (10 mg) in combination with DRV/COBI
(800/150 mg) plus BIC (50 mg) (Treatment A; N=24). Subjects in Cohort 2 received 10 days of 
GS-9131 (10 mg) alone (Treatment B; N=24). 
Subjects in Cohort 3 received 10 days of GS-9131 (60 mg) alone (Treatment C; N=24) or in 
combination with DRV/COBI (800/150 mg) (Treatment D; N=24).
Subjects in Cohort 4 received 10 days of GS-9131 (30 mg) alone (Treatment F; N= 11), in 
combination with ATV+RTV (300/100 mg; Treatment E; N=12), or in combination with 
LPV/RTV (800/200 mg; Treatment G; N=10).
Subjects in Cohort 5 received 14 days of either GS-9131 (60 mg) alone (Treatment H; N= 24), 
followed by 14 day of GS-9131 (60 mg) plus TAF (25 mg) (Treatment I; N=24), or TAF (25 mg) 
alone (Treatment J; N= 29), followed by 14 day of GS-9131 (60 mg) plus TAF (25 mg) 
(Treatment I; N=29).
All doses were administered in the morning under fed conditions. Blood samples were drawn on 
the last day of each treatment to characterize PK of GS-9131 and its metabolite, GS-9148, in 
plasma, and GS-9148-DP in PBMCs. 
1.2.3.1.1.
GS-9131
GS-9131 exposures were lower when GS-9131 (10, 30 or 60 mg) was coadministered with 
DRV/COBI plus BIC, or LPV/RTV (decreases in GS-9131 AUCtau ranged from 28% to 46%; 
similar changes were observed with Cmax). Minimal changes in GS-9131 exposure were observed 
upon coadministration with ATV+RTV or with TAF (Table 4).
1.2.3.1.2.
GS-9148
With respect to GS-9148, higher exposures were observed upon coadministration of GS-9131 
(10, 30 or 60 mg) with all boosted-PI regimens tested (COBI-boosted DRV plus BIC, 
ATV+RTV or LPV/RTV). GS-9148 AUCtau increased to a greater extent when GS-9131 was 
coadministered with either DRV/co plus BIC at the GS-9131 60 mg dose (AUCtau was 436% 
higher) or with LPV/RTV or ATV+RTV, respectively, at the GS-9131 30 mg dose (AUCtau was 
314% and 236% higher, respectively) compared to the increase in GS-9148 exposures observed 
at the GS-9131 10 mg dose coadministered with DRV/co plus BIC (147% increase in AUCtau). 
Changes in GS-9148 Cmax and Ctau were consistent with changes in AUCtau. Minimal changes in 
GS-9148 exposure were observed upon coadministration with TAF (Table 2).


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Table 2.
Study GS-US-180-4149 Preliminary Plasma PK Data from
Cohorts 1-5
PK parameter
Mean (%CV)
Cohort 1
DRV/COBI + BIC+GS-9131 
(10 mg; Test)
N=24
Cohort 2
GS-9131
(10 mg; Reference) 
N=24
GLSM Ratio%
(90%CI) 
(Test/Reference)
GS-9131
AUCtau (hr*ng/mL)
55.7 (20.1)a
79.2 (27.5)b
71.7 (61.9, 83.0)
Cmax (ng/mL)
54.9 (54.9)
69.9 (48.8)
77.7 (61.1, 98.7)
GS-9148
AUCtau (hr*ng/mL)
536 (16.6)
218 (19.3)
247 (226, 269)
Cmax (ng/mL)
37.9 (14.7)
16.4 (24.3)
235 (214, 258)
Ctau (ng/mL)
14.5 (19.2) (66.8)
6.90 (66.8)
227 (196, 263)
Cohort 3
DRV/COBI + BIC+GS-9131 
(60 mg; Test)
N=23
Cohort 3
GS-9131
(60 mg; Reference) N=24
GLSM Ratio% (90%CI) 
(Test/Reference)
GS-9131
AUCtau (hr*ng/mL)
419 (23.3)b
796 (31.4)
53.9 (48.2, 60.2)
Cmax (ng/mL)
353 (48.0)
645 (40.9)
53.1 (42.6, 66.0)
GS-9148
AUCtau (hr*ng/mL)
3570 (13.7)
675 (22.5)
536 (498, 577)
Cmax (ng/mL)
237 (13.7)
52.3 (21.7)
459 (423, 499)
Ctau (ng/mL)
103 (17.1)
16.8 (23.0)
615 (572, 662)
Cohort 4
LPV/RTV +GS-9131 (30 mg; 
Test)
N=10
Cohort 4
GS-9131
(30 mg; Reference) N=11
GLSM Ratio% (90%CI) 
(Test/Reference)
GS-9131
AUCtau (hr*ng/mL)
240 (44.6)c
415 (51.5)
58.3 (43.9, 77.5)
Cmax (ng/mL)
326 (61.2)
385 (80.0)
83.5 (59.2, 118)
GS-9148
AUCtau (hr*ng/mL)
1900 (22.1)
470 (33.7)
414 (349, 492)
Cmax (ng/mL)
127 (15.6)
35.1 (29.0)
370 (316, 432)
Ctau (ng/mL)
48.4 (25.4)
12.9 (35.9)
385 (318, 467)


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Cohort 4
ATV+RTV +GS-9131 (30 mg; 
Test)
N=12
Cohort 4
GS-9131
(30 mg; Reference) N=11
GLSM Ratio% (90%CI) 
(Test/Reference)
GS-9131
AUCtau (hr*ng/mL)
320 (29.2)
415 (51.5)
84.5 (72.2, 98.9)
Cmax (ng/mL)
346 (75.9)
385 (80.0)
98.0 (86.1, 111)
GS-9148
AUCtau (hr*ng/mL)
1530 (18.1)
470 (33.7)
336 (292, 387)
Cmax (ng/mL)
112 (17.6)
35.1 (29.0)
328 (288, 374)
Ctau (ng/mL)
40.4 (18.0)
12.9 (35.9)
326 (277, 383)
Cohort 5
TAF +GS-9131 (60 mg; Test)
N=24
Cohort 5
GS-9131 (60 mg; 
Reference) N=24
GLSM Ratio% (90%CI) 
(Test/Reference)
GS-9131
AUCtau (hr*ng/mL)
854 (42.5)
865 (40.3)
98.8 (92.6, 105)
Cmax (ng/mL)
701 (44.3)
636 (33.4)
107 (95.9, 119)
GS-9148
AUCtau (hr*ng/mL)
814 (19.9)
744 (19.4)
109 (107, 112)
Cmax (ng/mL)
60.3 (16.8)
55.3 (15.0)
109 (106, 112)
Ctau (ng/mL)
22.0 (21.7)
20.1 (21.7)
109 (106, 113)
Data are presented to 3 significant figures
a
N=16
b
N = 21
c
N= 9
1.2.3.1.3.
GS-9148-DP
Exposures (AUC0-24 and C24) of PBMC-associated GS-9148-DP following once-daily dosing of
GS-9131 alone (10, 30 or 60 mg) or in combination with a boosted PI regimen (DRV/COBI plus 
BIC, LPV/RTV or ATV+RTV) for 10 days, or in combination with TAF for 14 days, are 
presented in Table 3.  The PBMC-associated GS-9148-DP concentrations at the GS-9131 30 mg 
dose in this study were similar to those observed following administration of GS-9131 30 mg 
once daily for 10 days in the POC study in treatment-naïve HIV-infected subjects, in which a 
1.03 log10 median reduction in HIV-RNA was observed (Study GS-US-180-0104).


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Table 3.
Study GS-US-180-4149 Preliminary PBMC PK Data from
Cohorts 1-5
GS-9148-DP PK parameter
Mean (%CV)
Cohort 1
DRV/COBI + BIC+GS-9131 
(10 mg)
N=24
Cohort 2
GS-9131 (10 mg) N=24
AUC0-24 (uM*hr)
40.4 (33.0)
30.1 (27.1)
C24 (uM)
1.48 (37.5)
0.95 (28.2)
Cohort 3
DRV/COBI + BIC+GS-9131 
(60 mg)
N=23
Cohort 3
GS-9131 (60 mg) N=23
AUC0-24 (uM*hr)
179 (53.3)
124 (46.4)a
C24 (uM)
8.35 (64.8)
5.26 (52.3)
Cohort 4
LPV/RTV +GS-9131 (30 mg)
N=10
Cohort 4
GS-9131 (30 mg) N=11
AUC0-24 (uM*hr)
70.8 (43.0)
91.4 (27.3)
C24 (uM)
2.00 (28.7)
3.25 (32.0)
Cohort 4
ATV+RTV +GS-9131 (30 mg)
N=12
Cohort 4
GS-9131 (30 mg) N=11
AUC0-24 (uM*hr)
138 (29.7)
91.4 (27.3)
C24 (uM)
5.34 (29.7)
3.25 (32.0)
Cohort 5
TAF +GS-9131 (60 mg)
N=24
Cohort 5
GS-9131 60 mg) N=24
AUC0-24 (uM*hr)
188 (49.0)
212 (78.2)
C24 (uM)
5.83 (50.5)
6.76 (56.9)
Data are presented to 3 significant figures
a
N=23
1.2.3.1.4.
BIC and DRV/COBI
Preliminary data demonstrated that BIC (50 mg) exposure following co-administration with 
DRV/COBI (800/150 mg) and GS-9131 (10 mg) in Cohort 1 was within the range of BIC 
(75 mg) exposure previously observed in Phase 1 and 2 studies (Studies GS-US-141-1233, 
GS-US-141-1475, GS-US-141-1478, GS-US-141-1479,  GS-US-141-1480, GS-141-1485,
GS-US-141-1487, and GS-US-311-1790).  Exposures of DRV and COBI were consistent with 
historical data {PREZCOBIX 2018}. 


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1.2.3.1.5.
TAF, TFV and TFV-DP
Preliminary TAF plasma exposures were higher following coadministration with GS-9131 60 mg 
(AUCtau and Cmax were 69% and 17% higher, respectively) as compared to TAF alone, these 
TAF exposures were  within the range of TAF exposures for which safety and efficacy has been 
established {Genvoya 2018}.
Preliminary plasma exposures of TFV were lower following coadministration with GS-9131 
60 mg (AUCtau and Cmax were 51% and 57% lower, respectively) as compared to TAF alone; as 
TFV is an inactive metabolite, this change was not considered clinically meaningful.
Preliminary exposures (AUC) of TFV-DP in PBMCs were 135% higher upon coadministration 
with GS-9131 60 mg with TAF compared with TAF alone. Values were within the range of 
those observed in historical studies of approved FTC/TAF containing products 
(Studies GS-US-311-1089, GS-US-292-0112, GS-US-292-1825, GS-US-380-4017)
1.2.3.1.6.
Preliminary safety
GS-9131 was generally well tolerated at the doses evaluated.  Preliminary data indicate that AEs 
were mild to moderate in severity. There were no deaths, pregnancies, Grade 3 or 4 AEs or 
SAEs. One subject in Cohort 4 experienced study drug related Grade 2 AEs of pruritus and
dermatitis while receiving GS-9131 30 mg coadministered with Reyataz® and discontinued study 
drugs.
1.2.3.2.
Study GS-US-180-0104
Study GS-US-180-0104 was a single-center, randomized, double-blind, multiple-dose, 
placebo-controlled study evaluating the antiviral activity, safety, and PK of GS-9131 in 
ARV-naive subjects chronically infected with HIV-1. Eligible subjects were randomized in a 
2:1 ratio to receive GS-9131 30 mg or matching placebo for 10 consecutive days. Eighteen male 
subjects were randomized and treated and all subjects completed 10 days of treatment. 
Derived PK parameters of GS-9131 and GS-9148 after single dose administration of GS-9131 
were similar to values seen previously in Study GS-US-180-0101. GS-9131 was rapidly 
hydrolyzed and exhibited a short plasma t1/2, while GS-9148 exhibited a mean t1/2 of > 20 hours
{reference IB}. GS-9148 exhibited near-linear pharmacokinetics, with accumulation ratios of 
nearly one (AUC geometric mean ratio was 79.35 [90% confidence interval: 70.42, 89.41])
{reference IB}. In Study GS-US-180-0104, single and multiple doses of GS-9131 resulted in 
high concentrations of the active antiretroviral metabolite, GS-9148-DP, in PBMCs (Table 4).
PK parameters of GS-9131 and GS-9148 after 10 days multiple dose administration of GS-9131
(30 mg) are presented in Table 1.


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Table 4.
Study GS-US-180-0104 Multiple Dose PK Data
PK parametera
Mean (%CV)
GS-9131 30 mg
(N=12)
GS-9131
AUCtau (hr*ng/mL)
250 (25.7)
Cmax (ng/mL)
386 (32.2)
GS-9148
AUCtau (hr*ng/mL)
411 (23.3)
Cmax (ng/mL)
47.3 (18.4)
GS-9148-DP
AUC0-24 (uM*hr)
100 (51.0)
C24 (uM)
5.29 (49.0)
a
Values are presented to 3 significant figures.
The primary efficacy endpoint was the maximum reduction from baseline in HIV-1 RNA 
(log10 copies/mL) on measurements taken between Days 2 to 11.  HIV-1 RNA levels in the 
GS-9131 group steadily decreased over the dosing period, and the maximum reduction from 
baseline in HIV-1 RNA (log10 copies/mL) up to Day 11 (primary endpoint) was significantly 
greater in the GS-9131 group (median [IQR] -1.03 [-1.37, -0.76] copies/mL) than in the placebo 
group (median [IQR] -0.10 [-0.43, -0.05] copies/mL) (p = 0.001). Seven of twelve (58.3%) 
subjects in the GS-9131 group compared to zero of six subjects in the placebo group achieved at 
least a 1.0 log10 decrease from baseline in HIV-1 RNA from Days 2 to 11 (p = 0.038). 
Changes from baseline in CD4 counts and percentages were not significantly different between 
the treatment groups. 
Resistance analyses showed no evidence of primary drug resistance mutations at baseline.
Overall, no RT mutations associated with NRTI or GS-9131 resistance developed in subjects 
treated with GS-9131. In addition, HIV-1 showed full phenotypic susceptibility to GS-9131 from 
baseline through Day 11 for subjects in the GS-9131 group.
The safety findings demonstrated that GS-9131 was generally well tolerated. All AEs were mild 
to moderate in severity. No treatment-related AEs ≥Grade 3, SAEs, pregnancies, deaths, or AEs 
leading to study drug interruption or premature study drug discontinuation were reported. 
Four subjects (1 [8.3%] in GS-9131 group, 3 [50%] in placebo group) had treatment-emergent 
Grade 3 or 4 laboratory abnormalities; none were considered related to study drug.
1.2.3.3.
Study GS-US-442-4148
Preliminary data from Sentinel Cohort 1 in Table 5 indicate that GS-9131, GS-9148, and 
GS-9148-DP exposure in HIV-infected subjects following administration of GS-9131 60 mg is
approximately 2-fold higher than that observed in HIV-infected subjects receiving GS-9131 
30 mg (Study GS-US-180-0104; Table 4), and similar to that observed in healthy volunteers 
receiving GS-9131 60 mg (Study GS-US-180-4149; Table 2).


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Table 5.
Study GS-US-442-4148 Preliminary PK Data 
PK parametera
Mean (%CV)
GS-9131 60 mg
(N=11)
GS-9131
AUCtau (hr*ng/mL)
599 (65.9)
Cmax (ng/mL)
777 (72.6)
GS-9148
AUCtau (hr*ng/mL)
955 (51.3)
Cmax (ng/mL)
69.3 (46.9)
GS-9148-DP
AUC0-24 (uM*hr)
202 (50.0)
C24 (uM)
7.70 (68.9)
a
Values are presented to 3 significant figures.
1.2.3.3.1.1.
Clinical Results from the GS-9131 60 mg Sentinel Cohort
In Study GS-US-442-4148, clinical data from the Sentinel Cohort showed 2 of 11 subjects 
experienced a > 0.5 log decline in viral load from baseline and an additional 3 of 11 subjects 
experienced a > 0.3 log decline in viral load from baseline (Figure 1). Viruses from all 
11 subjects were phenotypically sensitive to GS-9148 at Day 1 and Day 11 and there was no 
development of new HIV resistance mutations. There were no changes in genotypic or 
phenotypic sensitivity to NRTIs, NNRTIs, or PIs observed in these subjects. One subject 
progressed to Part 2 of the study and achieved virologic suppression (< 50 copies/ml) on the 
regimen of GS-9131(60 mg)+ BIC (30 mg) + DRV (800 mg)+ RTV (100 mg).
GS-9131 60 mg was generally well tolerated with Grade 3 cellulitis reported for 1 subject and 
considered not related to study drug. No subjects had Grade 3 or 4 laboratory abnormalities 
associated with GS-9131.


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Figure 1.
Study GS-US-442-4148: Changes in Viral Load by Subject and 
Failing ARV Regimen in the Sentinel Cohort
1.3.
Bictegravir
1.3.1.
General Information
Bictegravir (BIC, previously known as GS-9883), is a potent inhibitor of HIV-1 integrase. 
Antiviral testing has shown that BIC is active against a broad panel of HIV-1 viral lab strains and 
clinical isolates. Bictegravir is fully active against a panel of mutant viruses with resistance to 
NRTIs, NNRTIs, and PIs.
1.3.2.
Nonclinical Pharmacology, Pharmacokinetics and Toxicology
The volume of distribution of BIC ranged between 0.09 and 0.22 L/kg in the preclinical species, 
which indicates that the distribution of BIC is limited to the extracellular compartment due to its 
high binding to plasma proteins. The projected half-life of BIC in humans is approximately 
20 hours based upon the estimates of clearance and volume of distribution.
The oral toxicity of BIC has been studied in transgenic mice, rats, and monkeys for treatment 
periods up to 39 weeks. In a 39-week repeat dose chronic toxicology study in monkeys, 
hepatobiliary toxicity at the high dose of 1000 mg/kg/day was the only notable adverse finding at 
0.5 
0.25 
-0.5 
-0.75 
I 
1 
GS-9131 60 mg qd 
-
EFV+ 3TC+ TDF 
-- NVP + 3TC + AZT 
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:... ... 
.. .. .... --... _ ..... .... .. _ 
______________________________ ......... ~ _ 
- - -
... -... -..:- - - - - - - - - - -
...... 
,, 
......... ,, 
I 
2 
I 
3 
Day 
I 
7 
• 
I 
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10 
11 


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BIC plasma exposures that were 16-fold higher than those observed in patients at a 50 mg BIC 
dose. The effects were partially reversible after a four week period of non-exposure (recovery).  
No toxicity was observed at the mid-dose of 200 mg/kg/day which provided a margin of 
exposure 7-fold greater than the clinical exposure. No target organs were identified following 
repeat oral administration of 1000 mg/kg/day BIC in cynomolgus monkeys for up to 13 weeks. 
No adverse findings were noted in transgenic mouse or rat repeat dose toxicology studies up to 
26 weeks dosing duration with exposure margins at the NOAELs of ≥18-fold the BIC plasma 
exposure at the clinical dose of 50 mg in the BIC/FTC/TAF FDC.
For more information on the preclinical studies of BIC, please refer to the BIC IB. 
1.3.3.
Clinical Studies of Bictegravir
To date, 23 Phase 1, 2 or 3 clinical studies have been completed or are ongoing in which 
568 healthy subjects and over 1600 HIV-infected subjects have been dosed with BIC, either as a 
single agent or as BIC/FTC/TAF. Clinical trials entailing the use of BIC include:

GS-US-141-1218, a Phase 1, double blind, randomized, placebo-controlled, first-in-human, 
single- and multiple-ascending dose study evaluating the safety, tolerability, and PK of oral 
GS-9883 (BIC) in healthy subjects and a randomized, open label, 2-cohort, 3-period, 
crossover, PK study evaluating the drug interaction potential between FTC/TAF FDC tablet 
and GS-9883 in healthy subjects (completed)

GS-US-141-1219, a Phase 1b, randomized, double-blinded, sequential cohort placebo 
controlled study of the safety, PK, and antiviral activity of GS-9883 (5 mg, 25 mg, 50 mg, 
100 mg) in HIV-1 infected subjects (completed)

GS-US-141-1233, a Phase 1, open-label, two-cohort, multiple-period, fixed sequence, 
crossover study to evaluate 1) the relative bioavailability of two GS-9883/FTC/TAF
(75/200/25 mg and 50/200/25 mg) FDC tablets versus a GS-9883 (75 mg) tablet and an
FTC/TAF (200/25 mg) FDC tablet administered simultaneously and 2) the effect of food on 
the PK of GS-9883, FTC and TAF when administered as GS-9883/FTC/TAF (75/200/25 mg 
and 50/200/25 mg) FDC (completed)

GS-US-141-1478, a Phase 1, open-label, parallel-group, adaptive single dose study to 
evaluate the PK of GS-9883 in subjects with normal and impaired hepatic function 
(completed)

GS-US-141-1479, a Phase 1, open-label, parallel-group, adaptive single dose study to 
evaluate the PK of GS-9883 in subjects with normal and impaired renal function (completed)

GS-US-141-1480, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-9883 on the QT/QTc interval in healthy subjects 
(completed)


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
GS-US-141-1481, a Phase 1 study to evaluate the PK, metabolism, and excretion of GS-9883 
in healthy subjects (completed)

GS-US-141-1485, a Phase 1 adaptive study to evaluate transporter, CYP-mediated and 
UGT1A1 drug-drug interactions between GS-9883 and probe drugs (completed)

GS-US-141-1487, a Phase 1, randomized, blinded, placebo-controlled Phase 1 study 
evaluating the effect of GS-9883 on renal function as assessed by markers of glomerular 
filtration rate (completed)

GS-US-311-1790, a Phase 1, randomized, open-label, drug interaction study evaluating the 
effect of FTC/TAF FDC tablet or GS-9883 on the PK of a representative hormonal 
contraceptive medication, norgestimate/ethinyl estradiol (completed)

GS-US-141-1475, a Phase 2, randomized, double-blinded study of the safety and efficacy of 
GS-9883 + FTC/TAF versus dolutegravir + FTC/TAF in HIV-1 infected, ART-naive adults
(ongoing)

GS-US-380-1489, a Phase 3, randomized, double-blind study to evaluate the safety and 
efficacy of GS-9883/FTC/TAF versus Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine 
(3TC) in HIV-1 infected, ART-naïve adults (ongoing)

GS-US-380-1490, a Phase 3, randomized, double-blind study to evaluate the safety and 
efficacy of GS-9883/FTC/TAF versus DTG + FTC/TAF in HIV-1 infected, ART-naïve 
adults (ongoing)

GS-US-380-1844, a Phase 3, randomized, double-blind study to evaluate the safety and 
efficacy of switching from a regimen of DTG and ABC/3TC, or an FDC of ABC/DTG/3TC 
to an FDC of GS-9883/FTC/TAF in HIV-1 infected subjects who are virologically 
suppressed (ongoing)

GS-US-380-1878, a Phase 3, randomized, open-label study to evaluate the safety and 
efficacy of switching from regimens consisting of boosted Atazanavir or DRV plus either 
FTC/TFV or ABC/3TC to GS-9883/FTC/TAF in virologically suppressed HIV-1 infected 
adults (ongoing)

GS-US-380-1961, a Phase 3, randomized, open label study to evaluate the safety and efficacy 
of switching to a FDC of GS-9883/FTC/TAF from elvitegravir (EVG)/COBI/FTC/TAF, 
EVG/COBI/FTC/TDF or atazanavir + ritonavir + FTC/TDF in virologically suppressed 
HIV-1 infected women (ongoing)

GS-US-380-1474, a Phase 2/3, open-label study of the PK, safety, and antiviral activity of 
the GS-9883/FTC/TAF FDC in HIV-1 infected virologically suppressed adolescents and 
children (ongoing)
Please refer to the BIC for further information about these studies.


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1.3.3.1.
Study GS-US-141-1219 (Phase 1b Proof of Concept)
The first HIV-1 infected human subjects were dosed in the fasted state with 10 days of BIC in 
Study GS-US-141-1219. A total of 23 subjects were randomized 4:1 to receive BIC or placebo to 
match at doses of 5 mg, 25 mg, 50 mg, and 100 mg QD for 10 days; 20 subjects received study 
treatment and completed the study. 
Mean HIV-1 RNA change on Day 11 was -2.08 log10 copies/mL in the 25 mg 
cohort, -2.06 log10 copies/mL in the 50 mg cohort, and -2.43 log10 copies/mL in the 100 mg 
cohort. Time weighted average change from baseline at Day 11 (DAVG11) was -0.92 log10
copies/mL in the 5 mg cohort, -1.33 log10 copies/mL in the 25 mg cohort, -1.37 log10 copies/mL
in the 50 mg cohort and -1.61 log10 copies/mL in the 100 mg cohort. Viral suppression (HIV-1 
RNA < 50 copies/mL) was not achieved by the end of the study (Day 17) for 1 subject (25.0%) 
in the BIC 50 mg group and 2 subjects (50%) in the BIC 100 mg group. No subject developed a 
primary INSTI-R substitution. 
Bictegravir was generally well tolerated at the doses evaluated. No deaths or pregnancies were 
reported. No Grade 3 or 4 AEs, SAEs, or AEs leading to discontinuation of study drug were 
reported in any cohort. There was no increase in the incidence of AEs with increasing doses of 
BIC. The majority of AEs were considered by the investigator to be not related to study drug.
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. No Grade 3 
treatment-emergent laboratory abnormalities were observed. One subject had a Grade 4
laboratory abnormality (elevated creatine phosphokinase, GS-9883 5 mg treatment group), which
was also reported as an AE (Grade 2 severity, not considered related to study drug). Median 
serum creatinine changes at Day 10 were: 0.05 mg/dL (5 mg), 0.04 mg/dL (25 mg), 0.06 mg/dL 
(50 mg), and 0.15 mg/dL (100 mg). These changes in serum creatinine appeared to be transient 
and returned close to baseline values on discontinuation of study drug. 
1.3.3.2.
Summary of Phase 2 Study GS-US-141-1475
Study GS-US-141-1475 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of a regimen containing BIC + FTC/TAF 
versus DTG + FTC/TAF in HIV-infected, ART-naive adult subjects. Ninety-eight eligible 
subjects were randomized in a 2:1 ratio to BIC + FTC/TAF (n=65) and DTG + FTC/TAF group
(n=33), stratified by HIV-1 RNA level (≤ 100,000 copies/mL, 100,000 copies/mL to 
400,000 copies/mL, or > 400,000 copies/mL) at screening.
At the time of the Week 24 data analysis, 2 subjects (2.0%) had prematurely discontinued from 
the study, 1 in each treatment group; both subjects were lost to follow-up. At Week 48, 
2 additional subjects in each treatment group prematurely discontinued the study. In the 
BIC + FTC/TAF group, one subject discontinued due to an AE of urticaria and one subject 
withdrew consent at Week 48. In the DTG + FTC/TAF group, 2 subjects discontinued due to 
study drug non-compliance.
Virologic success at Weeks 12, 24 and 48 were assessed using the US FDA-defined snapshot 
algorithm, defined as plasma HIV-1 RNA < 50 copies/mL. At each time point, virologic success 
was high and similar between the 2 treatment groups as follows: Week 12 BIC + FTC/TAF 


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93.8%, DTG + FTC/TAF 93.9% (stratum-adjusted difference in percentages: −1.3%; 
95% CI: −12.9% to 10.2%; p = 0.79); Week 24 BIC + FTC/TAF 95.4%, DTG + FTC/TAF 
93.9% (1.0%; 95% CI: −10.7% to 12.7%; p = 0.84); Week 48 BIC + FTC/TAF 96.9%, 
DTG + FTC/TAF 90.9% (6.4%; 95% CI: -6.4% to 18.8%; p = 0.17). Through Week 48, there 
was no virologic resistance seen in any subject treated with BIC + FTC/TAF. Following 
initiation of study drug, the increases from baseline in CD4 cell count were similar between 
treatment groups. 
Both BIC + FTC/TAF and DTG + FTC/TAF were generally well-tolerated through 48 weeks of 
treatment. The most commonly reported treatment-emergent AEs were diarrhea and headache 
(7.7% each) in the BIC + FTC/TAF group and nausea (12.1%) and diarrhea (9.1%) in the 
DTG + FTC/TAF group. Three subjects experienced SAEs, 1 of which was also a Grade 3 AE; 
none of these events were considered related to study drug by the investigator, or led to study 
drug discontinuation. There was one Grade 3AE (urticaria) that led to study drug discontinuation 
in the BIC + FTC/TAF group. There were no other Grade 3 or 4 AEs, and no deaths, 
pregnancies, or AEs leading to premature study drug discontinuation reported. The percentage of 
subjects with at least 1 treatment-emergent laboratory abnormality was similar between 
treatment groups. The majority of treatment-emergent laboratory abnormalities were Grade 1 
or 2 in severity. There were similar increases from baseline in serum creatinine in both treatment 
groups at Week 48. 
1.4.
Tenofovir Alafenamide (TAF)
Tenofovir alafenamide (TAF) is a second generation oral prodrug of tenofovir (TFV), a 
nucleotide analog that inhibits HIV-1 reverse transcription. Tenofovir is metabolized 
intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a competitive inhibitor 
of HIV-1 reverse transcriptase (RT) that terminates the elongation of the viral DNA chain.  The 
intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Tenofovir alafenamide is also part of the 
approved fixed dose combinations (FDCs) of Genvoya® (elvitegravir (EVG)/cobicistat 
(COBI)/FTC/TAF), Descovy® (FTC/TAF), Odefsey® (FTC/rilpivirine (RPV)/TAF), and 
Biktarvy (BIC/FTC/TAF) for the treatment of HIV-1 infection. Additionally, TAF (Vemlidy®) is 
approved for the treatment of chronic hepatitis B virus (HBV) infection.
Please refer to the TAF Investigator Brochure for further information.
1.5.
Darunavir (DRV, Prezista®)
Prezista® (darunavir (DRV)), is an HIV-1 protease inhibitor and is indicated for the treatment of 
HIV-1 infection in adult patients in combination with other antiretroviral agents. In patients with 
no DRV resistance associated mutations, the recommended dosage, is 800 mg DRV taken in 
combination with and 100 mg of Norvir® (ritonavir (RTV)) taken once daily with food.
The most common clinical adverse drug reactions to Prezista/ritonavir (incidence greater than or 
equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, 
nausea, rash, headache, abdominal pain and vomiting. Rare instances of severe hepatotoxicity 


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were observed, primarily in patients with pre-existing liver dysfunction.  Severe skin reactions 
accompanied by fever and/or elevations in transaminases were reported in 0.4% of subjects, and 
Stevens-Johnson syndrome occurred in less than 0.1%.
Further information regarding DRV is available in the Prezista® Package Insert. 
1.6.
Ritonavir (RTV, Norvir®)
Ritonavir is a pharmacoenhancer with CYP3A inhibitory activity that boosts DRV systemic 
exposures. In addition to the common adverse reactions noted in combination with DRV, 
potentially serious and/or life-threatening adverse events can occur due to drug-drug interactions, 
hepatotoxicity, or pancreatitis. Other serious reactions include severe skin reactions, heart block, 
lipid elevations, hyperglycemia, or body fat changes. Further information regarding RTV is 
available in the Norvir® Package Insert. 
1.7.
Rationale for This Study
The United States Department of Health and Human Services (US DHHS) Guidelines (2016) 
{Panel on Antiretroviral Guidelines for Adults and Adolescents 2016} and World Health 
Organization (WHO) Guidelines (2016) {World Health Organization (WHO) 2016} outline the
approach to treatment failure in both resource-rich and resource-limited settings, respectively. 
Both guidelines make it clear that the addition of 2-3 antiretroviral agents with anticipated full 
antiviral activity should be used {Panel on Antiretroviral Guidelines for Adults and Adolescents 
2016, World Health Organization (WHO) 2016}.
Gilead Sciences’ novel drug GS-9131, a prodrug of the novel adenine nucleotide analog 
GS-9148, is a potent inhibitor of HIV-1 in primary human peripheral blood mononuclear cells 
(PBMCs), CD4 T-lymphocytes, and macrophages. GS-9131 has exhibited a favorable resistance 
profile in in vitro studies that is distinct from that of most marketed N(t)RTIs. GS-9131 is 
anticipated to provide full activity against many NRTI mutations. In addition, GS-9131 has 
demonstrated a low potential for renal and mitochondrial toxicity, an important advantage over 
currently approved N(t)RTIs.  
Extensive phenotypic resistance profiling of GS-9131 (and GS-9148) with multiple
NRTI-resistant patient-derived HIV-1 strains and site-directed mutants resulted in a resistance
profile superior to any marketed NRTI. GS-9131 retained full activity against viruses with
M184V, K65R, or L74V mutations and viruses with 4 to 6 TAMs with or without the T69 
insertion mutation. In vitro data demonstrate a high resistance barrier based on delayed resistance 
development and either low-level resistance or high-level resistance with replication-limiting 
fitness defects. Ongoing in vitro selections with multidrug-resistant (MDR) NRTI mutants of 
HIV (3 TAMs or K65R) with GS-9131 have found no additional resistance development through 
at least 8 weeks of culture. 
The primary objective of this study is to evaluate the antiviral efficacy of GS-9131 as functional 
monotherapy in subjects who are failing their existing antiretroviral regimen containing NRTIs 
and an NNRTI. In vitro evidence supports GS-9131 activity against NRTI resistant viruses, but 
the efficacy of GS-9131 against such viruses has not yet been demonstrated in human subjects.


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Virologic response was low following administration of GS-9131 60 mg for 10 days in the 
Sentinel Cohort 1 of this study (GS-US-442-4148), which may be attributed to suboptimal 
dosing and duration. The prodrugs of NRTIs require metabolic modification to release the 
prodrug and phosphorylation to achieve the active metabolite, and a longer duration of time 
(up to 14 days) is required for NRTIs in order to quantify maximal viral load decline 
{Barditch-Crovo 2001, Squires 2003}. In order to optimize intracellular loading and processing 
in HIV-1 infected target cells, virologic response to GS-9131 in TE HIV-1 infected subjects will 
be assessed in a second Sentinel Cohort of GS-9131 180 mg once daily for14 days.  Subjects 
from this second sentinel cohort who successfully complete the functional monotherapy, defined 
as a >0.5 log10 reduction in plasma HIV-1 RNA from baseline, will initiate a regimen of 
GS-9131, BIC, and TAF for 24 weeks. Bictegravir is a potent INSTI with a high resistance 
barrier that will represent a new class of ARV for this TE population. TAF has safety advantages 
over tenofovir disoproxil fumarate and delivers higher drug levels to cells that may translate to 
improved antiviral activity against HIV-1 with NRTI resistance. BIC and TAF are approved 
components of Biktarvy (BIC/FTC/TAF), a complete regimen for the treatment of HIV-1 
infection.
1.8.
Rationale for the Dose Selection
1.8.1.
GS-9131
GS-9131 is a nucleotide reverse transcriptase inhibitor (NtRTI) prodrug, a class that includes 
tenofovir alafenamide (TAF). In the TAF study (Study GS-US-120-0104) of similar duration and 
design to Study GS-US-180-0104, decreases in HIV-1 RNA of -1.08, -1.46, and -1.73 log10
copies/mL were observed on Day 10, at TAF doses of 8 mg, 25 mg, and 40 mg QD, respectively 
{Ruane 2013}. Additionally, in subjects treated with FTC, a nucleoside reverse transcriptase 
inhibitor, decreases in HIV-1 RNA of -1.4, -1.5 and -1.7 log10 copies/mL were observed on 
Day 10 at FTC doses of 25 mg, 100 mg, and 200 mg QD, respectively {Rousseau 2003}.  These 
data suggest that the decrease in HIV-1 RNA of -1.03 log10 copies/mL observed with the 30 mg 
dose of GS-9131 evaluated in GS-US-180-0104 may not be providing the maximum reduction in 
viral load. This study will evaluate if greater viral load reduction may be observed at higher 
doses of GS-9131. 
In Sentinel Cohort 1 Part 1, GS-9131 was administered once daily at doses of 60 mg for 10 days,
in combination with the subject’s current failing background regimen. GS-9131 60 mg 
represented a dose escalation (2-fold) over the previously evaluated 30 mg dose of GS-9131. 
Upon completion of the functional monotherapy, eligible participants discontinued the failing 
background regimen and initiated a complete regimen of GS-9131 (60 mg) in combination with 
BIC (30 mg) plus DRV (800 mg) + RTV (100 mg) for 24 weeks.
As only 2 of the 11 subjects achieved a 0.5 log decline in HIV-1 RNA during the functional 
monotherapy, the second Sentinel Cohort will evaluate 14 days of treatment with GS-9131 
180 mg, representing a 3-fold dose escalation over the previously evaluated GS-9131 60 mg dose
and a longer treatment period. GS-9131 exhibits approximately dose-proportional PK over the 
dose range of 10 mg to 60 mg {Begley 2018}. Assuming dose-proportional increases through 
180 mg, projected exposures (AUC) at 180 mg of GS-9131 and GS-9148 in HIV-1 infected 


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subjects are 1797 (hr*ng/mL) and 2865 (hr*ng/mL), respectively (relative to HIV-infected 
subjects receiving 60 mg in Study GS-US-442-4148; Table 5). This dose range up to 180 mg 
allows sufficient dose separation to support evaluation of a dose/exposure-response relationship
for GS-9131 in this study.
Safety data from Study GS-US-442-4148 demonstrated multiple daily doses of GS-9131 60 mg 
were well tolerated in HIV-infected subjects. Similarly, safety data from Study GS-US-180-4149
demonstrated multiple daily doses of GS-9131 60 mg, administered alone or in combination with 
DRV/COBI or TAF for up to 14 days, were well tolerated in healthy subjects. As no clinical 
safety data are currently available for GS-9131 180 mg, safety for these doses in female subjects 
are supported by safety margins in female animals in nonclinical toxicology studies. Safety 
margins relative to female animals in the nonclinical toxicology studies have been calculated for 
both GS-9131 and GS-9148 (Table 1). Safety, tolerability and PK of GS-9131 will be 
characterized in this study.
1.8.2.
Bictegravir (BIC)
Preliminary data from Study GS-US-180-4149 demonstrate BIC (50 mg) exposures are 
~90% higher following co-administration with DRV/COBI (800/150 mg) and GS-9131 , as 
compared to those observed in HIV-infected subjects receiving BIC/FTC/TAF (50/200/25 mg) in 
Phase 3 studies (Section 1.2.3.1). In an unboosted setting, BIC (75 mg) provides exposure 
modestly higher (~30%) than that observed in subjects receiving BIC/FTC/TAF (50/200/25 mg) 
(Study GS-US-141-1233). Based on these data, a 30 mg dose of BIC, when co-administered 
with DRV+RTV and GS-9131, and a 75 mg dose of BIC, when co-administered with TAF and 
GS-9131, are expected to provide BIC exposures similar to those observed following 
administration of BIC/FTC/TAF (50/200/25 mg), where it has been safe and efficacious in 
Phase 3 studies. 
1.8.3.
Ritonavir-Boosted Darunavir (DRV + RTV)
The dose of DRV (800 mg once daily) to be used in this study is the approved, recommended 
dose of DRV (boosted with RTV 100 mg) given once daily with food for the treatment of HIV-1 
infection (Prezista United States Prescribing Information [USPI] and Norvir USPI). Ritonavir
100 mg is the approved, recommended dose of RTV as a PK enhancer.
1.8.4.
Tenofovir Alafenamide (TAF)
The dose of TAF (25 mg once daily) to be used in this study is the approved, recommended dose 
in the fixed dose combinations (FDCs) Descovy (FTC/TAF), Odefsey (FTC/RPV/TAF), and 
Biktarvy (BIC/FTC/TAF) for the treatment of HIV-1 infection. Additionally, TAF (Vemlidy®) is 
approved for the treatment of chronic hepatitis B virus (HBV) infection.


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1.9.
Risk/Benefit Assessment for the Study
All patients with HIV-1 infection, including those with drug resistant viruses, benefit from 
receiving effective ART. The risks in the study  patient population who are failing their current 
ARV regimen are considered to be low. Important risks will be appropriately managed by study 
inclusion/exclusion criteria, as well as close monitoring during the study. 
All subjects will be monitored daily during the functional monotherapy period and at frequent 
intervals in Part 2 of the study. Monitoring will include clinical evaluation, safety laboratory 
tests, and HIV-1 RNA viral load. In addition, stopping criteria will be implemented on an 
individual and cohort basis and the study will be monitored by an independent data safety 
monitoring board as well as local ethics committees. Important risks will be appropriately 
managed by study inclusion/exclusion criteria, as well as close monitoring, including clinical 
evaluation, safety laboratory assessment, individual and by-cohort stopping rules, and HIV-1 
RNA viral load monitoring during the study. 
If a median of > 0.5 log decrease in HIV-1 RNA is observed following administration of 
GS-9131 180 mg in the second Sentinel Cohort, GS-9131 doses ≤180 mg may be evaluated in 
the Randomized Cohort. 
The only significant effect identified in chronic animal studies with BIC was hepatobiliary 
toxicity in monkeys following 39 weeks of administration at a dose (1000 mg/kg/day) which 
produced plasma exposures to BIC that were 16-fold higher than those observed in patients at a 
50 mg BIC dose.  The effects were partially reversible after a 4- week period of non-exposure 
(recovery).  No toxicity was observed at the mid-dose of BIC 200 mg/kg/day, which provided a 
margin of exposure 7-fold greater than the projected clinical exposure. Potential hepatobiliary 
toxicity is appropriately managed by study inclusion/exclusion criteria, close clinical and 
laboratory monitoring, as well as specific toxicity management guidance to investigators.  As of 
06 August 2018, 2740 subjects have been exposed to B/F/TAF in clinical trials with no evidence 
of hepatotoxicities. (Refer to BIC & TAF IB).
Consistent with other members of the INSTI class, BIC has been well-tolerated in clinical studies 
to date.
Tenofovir alafenamide (TAF) is a second generation oral prodrug of tenofovir (TFV), a 
nucleotide analog that inhibits HIV-1 reverse transcription. TAF is an approved medication and 
is marketed in multiple countries as FDC (Odefsey, Descovy, Genvoya, Biktarvy).  
DRV and RTV are approved medications and are marketed in multiple countries under the 
tradenames Prezista and Norvir (Refer to the USPI). Use of DRV with RTV has been associated 
with abnormal liver function tests and hepatic toxicity and hypersensitivity reactions. The 
complete safety profiles for these drugs are available in their respective prescribing information. 
Parameters for discontinuation of the study drugs due to AEs are defined in this study protocol 
and will be closely followed.


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Thus, the combination of GS-9131 with BIC and DRV + RTV or GS-9131 with BIC and TAF in 
TE individuals failing an NRTI/NNRTI containing regimen will provide an active regimen to the 
study cohorts. This active regimen will provide an important treatment option particularly in 
settings where routine drug resistance monitoring is not routinely available. The overall 
benefit-risk assessment of this study is favorable at this time.
1.10.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate the short-term antiviral potency of a regimen containing GS-9131 at doses up to 
180 mg compared to placebo-to-match (PTM) GS-9131, each administered once daily with 
the existing failing ARV regimen, as demonstrated by the proportion of subjects with HIV-1 
RNA decreases from baseline exceeding 0.5 log10 through 14 days of therapy in HIV-1 
positive, ARV TE adult subjects with nucleos(t)ide resistant virus.
The secondary objectives of this study are:
Part 1

To evaluate the efficacy of GS-9131 functional monotherapy as determined by the change 
from baseline in log10 HIV-1 RNA at Day 11 (Sentinel Cohort 1) or Day 15 (Sentinel Cohort 
2 and Randomized Cohort)..
Part 2

To evaluate the safety and efficacy of a regimen containing GS-9131 (60 mg) 
+ bictegravir (BIC) + darunavir (DRV) + ritonavir (RTV) through 24 weeks of treatment in 
subjects from Sentinel Cohort 1 who switched from a failing regimen. 

To evaluate the safety and efficacy of a regimen containing GS-9131 + bictegravir (BIC) 
+ tenofovir alafenamide (TAF) through 24 weeks of treatment in subjects from Sentinel 
Cohort 2 and Randomized Cohort who switched from a failing regimen. 

To characterize the pharmacokinetics (PK) of GS-9131 in treatment-experienced patients.

To evaluate the number of subjects with treatment-emergent nucleos(t)ide reverse 
transcriptase inhibitor (NRTI), protease inhibitor (PI), and integrase strand-transfer inhibitor 
(INSTI) mutations at the time of virologic failure.


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The proportion of subjects with plasma HIV-1 RNA decreases from baseline exceeding 
0.5 log10 at Day 15 in the Randomized Cohort in Part 1. 
The secondary endpoints of this study are:
Part 1

The change from baseline in plasma log10 HIV-1 RNA (copies/mL) at Day 11 (Sentinel 
Cohort 1) and Day 15 (Sentinel Cohort 2 and Randomized Cohort) in Part 1. 
Part 2

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL as defined by the 
US FDA Snapshot algorithm at Week 24. 

The change from Part 2 baseline in plasma log10 HIV-1 RNA (copies/mL) at Week 24.

The change from Part 2 baseline in CD4 cell count (cells/µL) at Week 24.

Number of subjects with treatment-emergent NRTI, PI, and INSTI mutations at the time of 
virologic failure.
3.2.
Study Design
This protocol describes a partially-randomized, partially-blinded, multicenter, two-part study.
Part 1 consists of three cohorts: Two Sentinel Cohorts followed by a Randomized Cohort. 
The Sentinel Cohort 1 is an open-label cohort that will enroll 10 HIV-1 positive subjects to 
receive GS-9131 60 mg plus their current failing regimen for 10 days. Subjects who 
achieve > 0.5 log decrease at Day 11 will initiate a regimen of GS-9131 (60 mg) + BIC (30 mg)
+ DRV (800 mg) + RTV (100 mg) for 24 weeks.
The Sentinel Cohort 2 is an open-label cohort that will enroll up to 10 HIV-1 positive subjects to 
receive GS-9131 180 mg plus their current failing regimen for 14 days. Subjects who 
achieve > 0.5 log decrease at Day 15 will proceed to Part 2 in which they will initiate a regimen 
of GS-9131 + BIC (75 mg) + TAF (25 mg) for 24 weeks.
The Randomized Cohort of the study is double-blinded, randomized, and will assess the efficacy
of GS-9131 doses up to 180 mg versus placebo in up to 48 HIV-1 infected, TE subjects who are 
failing their current ARV regimen. Subjects who achieve > 0.5 log decrease at Day 15 will 
proceed to Part 2 in which they will initiate a regimen of GS-9131 + BIC (75 mg) + TAF 
(25 mg) for 24 weeks. Subjects who achieve > 0.5 log decrease at Day 15will proceed to Part 2 
in which they will initiate a regimen of GS-9131 + BIC (75 mg) + TAF (25 mg) for 24 weeks.


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Study Treatments 
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Subjects who provide written consent and meet all eligibility criteria will be allocated to one of 
the following treatment groups as follows: 
Part 1: GS-9131 Functional Monotherapy 
Pait 1 consists of 3 cohorts: 
Sentinel Cohort 1: 
Approximately 10 TE viremic HIV-I subjects will be enrolled to receive open-label 
GS-9131 60 mg in addition to their cunent failing ARV regimen. 
Sentinel Cohort 2: 
Up to 10 TE viremic HIV-I subjects will be enrolled to receive open-label GS-9131 180 mg in 
addition to their cunent failing ARV regimen. 
Randomized Cohort: 
Up to 48 subjects failing their cmTent ARV regimen will be randomized to GS-9131 (up to 
180 mg) or PTM. These drngs will be added to their failing regimen for 14 days described 
below. Doses and number of coho1ts will be determined by data from Sentinel Cohort 2: 
• 
Treatment Anns A-C: GS-9131 up to 180 mg once daily + cmTent failing ART regimen 
(n=12 per coho1t ) 
• 
Treatment Alm D: PTM GS-9131 + cmTent failing ART regimen (n=12) 
Randomization will be stratified by HIV-I RNA level(~ 100,000 copies/mL 
and > 100,000 copies/mL) at screening. 
Subjects enrolled in Pait 1 who do not successfully complete the study diug doses in Pait 1 will 
not continue onto Pait 2 of the study. 
Subjects enrolled in Pait 1 who do not show a reduction in HIV RNA > 0.5 log10 from baseline 
to Pait 2 Day 1 will have an Eai·ly Study Drng Discontinuation (ESDD) visit within 72 homs of 
laborato1y results being available. They will have study medications discontinued and will not 
continue to Pait 2. 
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Part 2: GS-9131 + BIC + TAF Regimen (Subjects in Sentinel Cohort 2 and Randomized 
Cohorts) 
All subjects who successfully complete all study drng doses in Sentinel Coho1t 2 and the 
Randomized Coholis will discontinue study drng from Pait 1 on Day 15. To continue to Pait 2, 
subjects must have a > 0.5 log10 decline in plasma HIV-I RNA from their pre-GS-9131 baseline 
in the 14 days of functional monotherapy. Since this result will not be immediately available at 
the completion of Pait 1, all subjects completing Pait 1 will continue on their failing regimen 
until results are available. Results will be available no later than 9 days after completion of 
Pait 1. Subjects who meet criteria will proceed to Day 1 of Pait 2. Any subjects in the Sentinel 
Coho1t, and Treatment Anns A, B and C who do not meet the criterion for > 0.5 log10 decline in 
plasma HIV-I RNA from their pre-GS-9131 baseline will not continue to Part 2. All subjects in 
Treatment Alm D will be eligible to continue to Pait 2. In Pait 2, subjects from the Sentinel 
Coho1t 2 and the Randomized Coho1t will stait a regimen consisting of GS-9131 (up to 180 mg) 
+ BIC (75 mg)+ TAF (25 mg) as described below. 
• 
Treatment Alms A-C: GS-9131 (up to 180 mg)+ BIC + TAF 
• 
Sentinel Coho1t 2 and Treatment Alm D: GS-9131 180 mg+ BIC + TAF 
At Week 8, subjects who have plasma HIV-I RNA < 200 copies/mL or who have an HIV-I 
RNA 200 copies/mL and a reduction in HIV-I RNA > 1 log10 from baseline at any study visit 
will continue study medications. 
Subjects who have a confnmed sub-optimal virologic response at Week 8 defined as plasma 
HIV-I RNA 200 copies/mL and reduction in HIV-I RNA :S 1 log10 from baseline at all study 
visits up to Week 12 may be discontinued from the study and further optimization of their ARV 
regimen if feasible will be done by the Investigator. Subjects meeting criteria for sub-optimal 
virologic response as fuither defined in Section 6.10.1 will be contacted for an ESDD visit and 
discontinued from the study within 72 hours of results being available. 
Subjects with protocol-defined virologic failure and evidence of treatment emergent resistance to 
any component of their regimen at any time will be discontinued from the study diug and treated 
with an ARV regimen chosen by the Investigator. For additional info1mation, please reference 
ESDD (Section 6.4.1). 
3.4. 
Duration of Treatment 
I . • 
• • 
I . 
I . 
• • 
I 
I 
• 
I • 
• . 
• 
• 
I . 
• 
• • 
I . . 
. 
I . I 
I 
'! .. I I 
II 
I II 
I . . 
. 
I II 
. . . • 
• I 
I 
I II • 
• 
I 
:11 
I • 
• 
II 
• . 
CONFIDENTIAL 
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01 November 2018 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment3 
The duration of Sentinel Coho1t 2 and Randomized Coho1ts in Pait 1 of the study is 15 days 
each. Subjects who successfully complete the 14 day functional monotherapy, defined as 
a > 0.5 log10 reduction in plasma HIV-1 RNA from baseline or who are from the PTM ann, will 
be administered GS-9131 + BIC (75 mg) + TAF (25 mg) through Week 24. Doses of GS-9131 
for subjects in the Sentinel Coho1t 2 and Placebo coho1t will be 180 mg; doses of GS-9131 and 
PTM for subjects in the Randomized Coho1ts Treatment Anns A-C will co1Tespond to the 
respective dose selected for coho1ts (A-C). All subjects will continue a regimen of GS-9131 
+ BIC (75 mg) + TAF (25 mg) at the assigned GS-9131 dose until determination of the o timal 
GS-9131 dose followin Pait 1 data review of the Randomized Coho1t. 
Figure 2. 
Study Schema - Cohort 1 
Discontinue 
Failing ARV 
Screening 
~ 30 days 
prior to 
day I 
Sentinel Cohort••\ (n=l O) 
OS-9131 (60 mg) + Ctmcnt Failing ARV 
Cont 
inue 
Curr 
ent 
Faili 
GS-9131 (60 mg) + BlC (30 mg) + DRV (800 
mg)/ COB! (150 mg) 
ng 
Day l 
Day 
Day 1 
10c 
(Part2) 
Week 
24 
a 
Randomization and dosing into the Randomized Coho1t of Pait I will begin after the Day IO safety and efficacy data from 
the IO subjects in the Sentinel Coho1t are reviewed. 
b 
Subjects on GS-9131 (including all subjects in the Sentinel Coho1t and those on Treatment Arm A, B, and C of the 
Randomized Cohort) who have a::: 0.5 loglO decline in HIV-I RNA will be discontinued from the study and will not be 
eligible to continue into Pait 2 of the study. The Sponsor will notify the site regarding subject enrolhnent criteria for Part 2 
prior to the visit." 
c 
Subjects who complete Day 10 of Pait 1 (from either the Sentinel Coho1t or Treatment Anu D of the Randomized Coho1t) 
will discontinue their GS-913 I or PTM but remain on their failing ARV regimen nntil the site is notified of the subject's 
I' 
eligibili to roceed to Part. 2. 
CONFIDENTIAL 
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01 November 2018 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Final 
Gilead Sciences, Inc. 
Amendment 3 
Figure 3. 
Study Schema - Cohort 2 
Part 1 
StnUnel Cohort 2-.•: (n• l O) 
GS.913 l ( l80ng)•Curre:at Failu:tg ARV 
RU\lgup[Md C9h0r• ""·": (u- 12) 
Treatment Ann A: GS,9131 (dioseTSD")"" Currea Faili:'13 ARV 
Continue 
Part 2 
GS-9IJI (I 10 mg) + 8!C (75 mg) + T AF (2l mg) 
OS-9131 (doseTBD') + BIC (J5 rov+ TAF(lS mv 
Current >--------------------
lludomtztd Cobo11 za•~ (a= 12) 
Failing 
Treatment Am B: OS-9 1 JI (dose TBO-) - CWTffit Falling ARV 
AR ye 
RaodomU.NI Cobor11"'": (o• U) 
Treatment Ame: os.91;1 (doseTBD') +Curmtl Failing ARV 
,Randomized co•ort 2•: (n• 12) 
TrNtae-a,Arm D GS.91ll PTM. • C\l:ino1Failioe, AJt.V 
OS,9131 (doseTBD') + BIC (J5 mv + TAF(l5 mg) 
OS-9131 (doseTBD') + BIC (75 fl!) + TAF(l5 my 
GS-9lll (ISO mi) + BIC (7l fl!) + T AF (ll mg) 
0 3)' 1 
D•l' l 
(Part 2) 
wee~ 24 
a. 
Randomiza1ion and dosing into the Randomized Cob on of Part I will begin after the Day 15 safety and efficacy data from the Sentinel 
Cobon is reviewed. 
b. Subjects on GS-9131 (including all subjecrs in the Sentinel Cobon and those on Treatmem Ann A, 8, and C oftbe Randomized Cohort) 
who have a :'i 0 . .5 log! Odecline in HIV-I IU<A will be disconrinued from rbe srudy and will nor be eligible 10 cominue imo Part 2 of 1be 
srudy. Tbe Sponsor will noril)' !lie sire regarding subje<:1 enrollmem criteria for Pan 2 p,ior 10 the visit. 
c. 
Subjects who complete Day 14 of Pan I (from either rbe Seminel Cohon or Treanneut Ann D of the Randomized Cohon) will discontinue 
their GS-9131 or PTM but remain on their failing ARV regimen umil the sire is oorified of the subject's eligibility roproceed 10 Part 2 . 
• 
e. 
lo Pan I Ran onuze Co 10n 2, Tream1ent Anns A·C ,vill be assigned up 1othree dose levels ofGS-9131 ,up 10 180mg. Tiie GS,9131 dose 
for Trearmenr Ann A-C will be detem1ined following review of the Sentinel Cobon 2. Doses ofGS-9131 for subjecrs in the randomized 
cohons A·C will correspond 10 rhe respective dose selecred in Pan 2. All subjects will continue a regimen ofGS-9131 +BIC+TAF at rhe 
assigned GS-9131 umil de1ennina1ion of rbe optimal GS-9131 dose following Pan I dara review of the randomized cohon. 
-
CONFIDENTIAL 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 68 subjects who meet eligibility criteria will be enrolled.
Replacement subjects may be enrolled for subjects who do not complete all procedures in the 
GS-913114-day functional monotherapy treatment for reasons other than discontinuation due to 
treatment related AEs.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) Non-pregnant/non-lactating females, ≥ 18 years of age at Screening
3)
Plasma HIV-1 RNA ≥ 500 copies/mL at Screening Visit
4) Currently taking a failing ARV regimen that contains  2 NRTIs and an NNRTI
5) No prior or current ARV regimens containing integrase inhibitor (INSTI) or protease 
inhibitor (PI)
6) Screening genotype must show at least the following resistance mutation profile (a local 
genotype (within 3 months of the Screening visit) is acceptable for enrollment upon review 
by the Sponsor): 
a) K65R or at least 3 TAMS ( defined as: M41L, D67N, K70R, L210W, T215F/Y or 
K219Q/E/N/R) or Q151M
b) and at least one primary resistance mutation to an NNRTI (defined as L100I, K101E/P, 
K103N/R/S, V106M/A, V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188C/H/L, 
G190A/E/Q/S, H221Y, P225H, F227C or M230L/I)
7) Adequate renal function:
Estimated glomerular filtration rate ≥70 mL/min according to the Cockcroft-Gault formula 
for creatinine clearance {Cockcroft 1976}:

Female:
(140 – age in years) (wt in kg) 0.85 CLcr (mL/min)
72 (serum creatinine in mg/dL)
(140 – age in years) (wt in kg)
0.85 CLcr (mL/sec)
72 (serum creatinine in μmol/L) 0. 6786


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8) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
9) CD4 > 100 cells/μL
10) Hepatic transaminases (AST and ALT) 2 upper limit of normal (ULN)
11) Total bilirubin 1.5 mg/dL (26 μmol/L), or normal direct bilirubin
12) Adequate hematologic function (absolute neutrophil count ≥750/mm3 (≥ 0.75 GI/L); 
platelets ≥50,000/mm3 (≥50 GI/L); hemoglobin ≥ 10 g/dL (≥100g/L))
13) Serum amylase ≤ 2 × ULN (subjects with serum amylase > 2 × ULN will remain eligible if 
serum lipase is ≤2 × ULN)
14) A negative serum pregnancy test is required for female subjects of childbearing potential (as 
defined in Appendix 7).  Female subjects of childbearing potential must agree to utilize 
protocol-recommended highly effective contraceptive methods or be non-heterosexually 
active or practice sexual abstinence (as defined in Appendix 7)
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to 
screening (refer to Appendix 6)
2) Subjects with cirrhosis, compensated or decompensated (e.g., ascites, encephalopathy, or 
variceal bleeding)
3) Have been treated with immunosuppressant therapies or chemotherapeutic agents within 
3 months of study screening, or expected to receive these agents or systemic steroids during 
the study (e.g., corticosteroids, immunoglobulins, and other immune- or cytokine-based
therapies)
4) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
5) Malignancy within 5 years of screening other than cutaneous Kaposi’s sarcoma, completely 
resected non-melanoma skin cancer (basal cell carcinoma or non-invasive cutaneous 
squamous carcinoma), or completely resected carcinoma in-situ of the cervix (CIN 3) or anus 
(AIN 3). A prior malignancy treated with curative therapy and for which there has been no 
evidence of disease for at least five years prior to screening is allowed.
6) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1


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7) Participation in any other clinical trial, including observational studies, without prior 
approval from the sponsor is prohibited while participating in this trial
8) Use of an investigational drug other than GS-9131 or BIC or TAF 
9) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with the dosing requirements
10) Known hypersensitivity to investigational medicinal products GS-9131, BIC, TAF, DRV,
RTV, their metabolites, or formulation excipient
11) Acute hepatitis in the 30 days prior to randomization
12) Subjects with chronic hepatitis B virus infection are not permitted to participate. 

For the purposes of this study, chronic HBV infection is defined as: Positive HBV 
surface antigen and negative HBV surface antibody, regardless of HBV core antibody 
status

Positive HBV core antibody and negative HBV surface antibody, regardless of HBV 
surface antigen status, at the screening visit
13) Subjects with chronic HCV infection requiring HCV therapy during the course of the study. 
Subjects with chronic HCV are eligible if the investigator does not anticipate treatment for 
HCV.
14) Active tuberculosis infection
15) Subjects receiving ongoing therapy with any of the medications listed in Section 5.4, 
including drugs not to be used with BIC, TAF, DRV and RTV.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
It is the responsibility of the investigator to ensure that the subject is eligible for the study prior 
to enrollment. Subjects will be assigned a screening number at the time of consent.
Subjects who meet criteria will first be enrolled in the Sentinel Cohorts. The Sentinel Cohort 1 is 
an open-label cohort that will enroll 10 HIV-1 positive subjects to receive GS-9131 60 mg plus 
their current failing regimen for 10 days. The Sentinel Cohort 2 is an open-label cohort that will 
enroll up to 10 HIV-1 positive subjects to receive GS-9131 180 mg plus their current failing 
regimen for 14 days. Randomization and dosing of the Randomized Cohort of Part 1 will begin 
after the Day 15 safety, efficacy, and available PK data from the Sentinel Cohort 2 are reviewed.
Once eligibility has been confirmed for the Randomized Cohort and prior to or during the Part 1 
Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web 
Response System (IWRS). Once a subject number has been assigned to a subject, it will not be 
reassigned to any other subject. The subject number assignment and randomization may be 
performed up to 3 days prior to the in-clinic Part 1 Day 1 visit provided that all screening 
procedures have been completed and subject eligibility has been confirmed. The Investigator 
must have results from genotype testing and confirmed eligibility before proceeding with subject 
randomization. 
The IWRS will assign study drug bottle numbers of blinded GS-9131 or PTM at each study visit 
for each subject. At the beginning of Part 2, IWRS will assign GS-9131 + BIC + TAF.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS system 
for that subject. Gilead recommends but does not require that the investigator contact the Gilead
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine emergency medical care for the subject. The rationale 
for unblinding must be clearly explained in source documentation and on the electronic case 
report form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in the event of any 
treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Pharmacovigilance and Epidemiology (PVE) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
5.2.1.1.
GS-9131 tablets, 30 mg
GS-9131 tablets, 30 mg, are round, film-coated white, plain-faced tablets. In addition to the 
active ingredient, the GS-9131 tablets contain the following inactive ingredients: lactose 
anhydrous, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl 
alcohol, polyethylene glycol, talc and titanium dioxide.
5.2.1.2.
Bictegravir tablets, 30 and 75 mg
Bictegravir tablets, 30 mg and 75 mg are round, film-coated yellow, plain-faced tablets. In 
addition to the active ingredient, the bictegravir tablets contain the following inactive 
ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, sodium stearyl 
fumarate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.
5.2.1.3.
Prezista® (DRV)
Information regarding the formulation of commercially available Prezista® (DRV) 800 mg
tablets can be found in the package insert from the USPI or summary of product characteristics.
5.2.1.4.
Norvir® (RTV)
Information regarding the formulation of commercially available Norvir® (RTV) 100 mg tablets 
can be found in the package insert from the USPI or summary of product characteristics.
5.2.1.5.
Tenofovir alafenamide tablets (Vemlidy, TAF)
Tenofovir alafenamide (TAF) tablets are round, film-coated yellow tablets debossed with 
“25” on one side of the tablet and “GSI” on the other side. In addition to the active ingredient, 
the tablet cores contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron 
oxide yellow.
5.2.1.6.
Placebo-to-match GS-9131 tablets 
Placebo-to-match (PTM) GS-9131 tablets 30 mg, are round, film-coated white, plain-faced 
tablets. The PTM GS-9131 tablets contain the following inactive ingredients: lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl 
alcohol, polyethylene glycol, talc and titanium dioxide. 
5.2.2.
Packaging and Labeling
GS-9131 tablets, 30 mg, and PTM are packaged in white, high density polyethylene (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.  


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Bictegravir tablets, 30 mg and 75 mg, are packaged in white HDPE bottles. Each bottle contains 
30 tablets, 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.  
Tenofovir alafenamide (TAF) 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.  
Commercially available Prezista and Norvir will be used for the study.  
GS-9131, BIC, TAF, Prezista and Norvir to be distributed to centers in participating countries 
shall be labeled to meet applicable requirements of the US FDA, EU Guideline to Good 
Manufacturing Practice - Annex 13 (Investigational Medicinal Products [IMPs]), and/or other 
local regulations.
5.2.3.
Storage and Handling
GS-9131, PTM GS-9131, BIC and TAF tablets should be stored at controlled room temperature 
of 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F), or as 
otherwise specified on the label. Storage conditions are specified on the label.  Until dispensed 
to the subjects, all bottles of study drugs should be stored in a securely locked area, accessible 
only to authorized site personnel. 
To ensure stability and proper identification, study drug(s) 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. 
Commercial Prezista and Norvir will be used for the study. Further information regarding storage 
and handling are available in the Prescribing Information.
5.3.
Dosage and Administration of GS-9131, BIC, DRV, RTV, TAF and PTM 
GS-9131 
Study drug GS-9131, BIC, DRV, RTV, TAF, and PTM GS-9131 tablets will be provided by 
Gilead.
In Sentinel Cohort 1, subjects will begin assigned GS-9131 60 mg once daily. All other ARVs in 
the current regimen will be continued. All ARVs, including GS-9131, will be administered by 
directly observed therapy (DOT) on Days 1-10. If the current regimen includes ARVs taken 
more than once daily, taken at night, or with certain meals, additional doses will be documented 


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment3 
by the subject in a dosing diaiy provided for the study. GS-9131 must be administered by DOT 
on Days 1-10. Subjects who successfully complete all study dmg doses through Day 10 and 
show a reduction in plasma HIV RNA > 0.5 log10 from their pre-GS-9131 baseline during 
functional monotherapy will discontinue their cmTent failing regimen, and staii an optimized 
regimen consisting of GS-9131 (60 mg) + BIC (30 mg) + DRV (800 mg)+ RTV (100 mg) for 
24 Weeks. 
In Sentinel Coho1i 2 and the Randomized Coho1i, Paii 1, subjects will begin assigned GS-9131 
doses up to 180 mg, or PTM once daily. All other ARVs in the cmTent regimen will be 
continued. All ARVs, including GS-9131, will be administered by directly observed therapy 
(DOT) on Days 1-14. If the cmTent regimen includes ARVs taken more than once daily, taken at 
night, or with ce1iain meals, additional doses will be documented by the subject in a dosing diaiy 
provided for the study. GS-9131 must be administered by DOT on Days 1-14. 
Subjects in Sentinel Coho1i 2 and Randomized Coho1i Treatment Alms A-C who successfully 
complete all study diug doses in Paii 1 and show a reduction in plasma HIV RNA > 0.5 log10 
from their pre-GS-9131 baseline during functional monotherapy will emoll in Paii 2, discontinue 
their cmTent failing regimen, and start an optimized regimen consisting of GS-9131 (up to 
180 mg)+ BIC (75 mg)+ TAF (25 mg). The GS-9131 dose in the combination regimen will be 
defined by the open-label or randomization dose given in Paii 1. Reduction of plasma HIV 
RNA > 0.5 log10 from baseline must be demonstrated at Day 15. Dose of GS-9131 for the 
Randomized Cohort will be dete1mined following review of Sentinel Cohort 2. The dose of 
GS-9131 for the OLE will be detennined following review of the safety, efficacy and available 
PK data of the Randomized Coho1i in Paii 1 from Paii 2. 
Subjects will be instructed to bring all study medication in the original container to each clinic 
visit for dmg accountability (unless othe1wise specified in Section 5.5). The Investigator will be 
responsible for maintaining accurate records for all study dmg bottles dispensed and tablets 
returned. The invento1y and dispensing logs must be available for inspection by the study 
monitor. Study medication supplies, including paii ially used or empty bottles, must be accounted 
for by the study monitor prior to desti11ction or retmn . 
5.4. 
Prior and Concomitant Medications For Subjects in Sentinel Cohort 2, 
Randomized Cohort and Part 2: GS-9131 + BIC + TAF 
Invih'o data suggest GS-9131 is a substi·ate of Pgp ti·anspo1iers and an inhibitor of OATPl B/1B3 
ti·anspo1i ers. Concomitant use of some medications and herbal/natm·al supplements with study 
diug may result in phaimacokinetic interactions resulting in increases or decreases in exposure of 
study mugs or these medications. 
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Representative medications listed in the following table and herbal/natural supplements are 
excluded or should be used with caution while subjects are participating in the study, this table is 
not exhaustive. During Part 1 of the study, physicians should also refer to the prescribing 
information for the current background regimen in addition to the recommendations listed in the 
table below. Subjects should discontinue disallowed concomitant medications 30 days prior to 
initiation of study drug.
In Part 2, the use of medications for the treatment of HIV, other than GS-9131 + BIC + TAF, are 
prohibited. 
Table 6.
Prior and Concomitant Medications*
Drug Class
Agents Disallowed**
Use Discouraged and To Be Used With 
Caution
Medications or oral 
supplements containing 
polyvalent cations (e.g., 
Mg, Al, Ca, Fe): 
Calcium or iron 
supplements 
Cation-containing antacids 
or laxatives 
Buffered medications
Administer Study Drug 2 hours before or 2 hours 
after taking medications or oral supplements 
containing polyvalent cations.
Alternatively, Study Drug and medications or 
oral supplements containing polyvalent cations 
can be taken together with food.
Antiarrhythmic Agent
Dofetilide
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antiretrovirals
Any antiretroviral drug that is 
not part of the study regimen
Statins
Pravastatin, pitavastatin, rosuvastatin, 
atorvastatin: Monitor for statin-related AEs
Herbal/Natural 
Supplements
St. John’s Wort
*
For Prior and Concomitant Medications relevant to subjects in Part 2: DRV/r+BIC+GS-9131, see Appendix 8. 
**
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the 
duration of the study
Should subjects have a need to initiate treatment with any excluded concomitant medication, the
Gilead Medical Monitor must be consulted prior to initiation of the new medication. In instances 
where an excluded medication is initiated prior to discussion with the Sponsor, the Investigator 
must notify Gilead as soon as he/she is aware of the use of the excluded medication.


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5.5.
Accountability of IMP
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, subject initials, and the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits returned, along with the initials of the 
person recording the information.
5.6.
Investigational Medicinal Product Return or Disposal
Study drug return and disposal will be performed as outlined in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and Appendix 3 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor
or contact research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
enrollment. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Part 1 Day 1 to determine eligibility for 
participation in the study. A single 14 day extension to the screening window may be granted 
with permission from the Medical Monitor. The following will be performed and documented at 
screening:

Obtain written informed consent

Obtain medical history, including history of HIV-1 disease-related events, complete ARV 
treatment history and all prior medications within 30 days of the Screening visit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Height

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

12-lead ECG performed supine

Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3. 

Review and document locally performed HIV resistance data including genotype and/or 
phenotype
HIV-1 genotype testing (integrase, protease, and reverse transcriptase) can be performed 
locally or centrally at the screening visit. Central lab HIV-1 genotype testing will not be 
performed for subjects that fail to meet other eligibility criteria.

Review of AEs and concomitant medications


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Subjects that meet all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for the Day 1 Visit. Subjects must continue to take their 
prior treatment regimen until they are instructed to do otherwise. Subjects will be required to 
take their prior regimen through completion of Part 1 until the initiation of the Part 2 regimen. 
From the time of obtaining informed consent through the first administration of IMP, all serious 
adverse events (SAEs), as well as any AEs related to protocol-mandated procedures, will be 
recorded on the AE eCRF.  All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history, will be captured on the 
medical history eCRF.  See Section 7 Adverse Events and Toxicity Management for additional 
details.
6.3.
Treatment Assessments
6.3.1.
Part 1 – Functional Monotherapy (Sentinel and Randomized Cohorts)
Subjects who meet criteria will first be enrolled in the Sentinel Cohort 1. The Sentinel Cohort 1
is an open-label cohort that will enroll approximately10 HIV-1 positive subjects to receive
GS-9131 60 mg plus their current failing regimen for 10 days. The Sentinel Cohort 2 is an 
open-label cohort that will enroll approximately 10 HIV-1 positive subjects to receive GS-9131 
180 mg plus their current failing regimen for 14 days. 
Randomization and dosing into the Randomized Cohort of Part 1 will begin after review of the 
Day 15 safety and efficacy, and available PK data from the Sentinel Cohort 2.
Once eligibility has been confirmed for the Randomized Cohort and prior to or during the Part 1 
Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web 
Response System (IWRS). Once a subject number has been assigned to a subject, it will not be 
reassigned to any other subject. The subject number assignment and randomization may be 
performed up to 3 days prior to the in-clinic Part 1 Day 1 visit provided that all screening 
procedures have been completed and subject eligibility has been confirmed. The Investigator 
must have results from genotype testing and confirm eligibility before proceeding with 
randomization. 

Review concomitant medications

Record any SAEs and all AEs related to protocol mandated procedures occurring after 
signing of the consent form.

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator) (Screening, Day 1, 14, and 15)

Symptom-directed physical examination (Days 2, 7, 10, and 14)

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight (Screening, Days 1, 3, 7,  10, and 14)


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
12-lead ECG performed supine (approximately 1 hour post dose) (Screening, Days 1, 10,
and 15)

Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3.

Collect subject dosing diary from all subjects (Day 15)

Administration of study drug by DOT. Study drug, as well as other ARVs, will be 
administered by DOT once daily. Any additional doses of ARVs, other than GS-9131, that 
cannot be administered at the same time will be documented by the subject in a dosing diary 
provided for the study. Study drug should be administered at approximately the same time 
each day.
6.3.2.
Part 2
All subjects must complete Part 1 prior to initiating any Part 2 Day 1 Visit procedures. Before 
proceeding into Part 2, subjects who have completed Day 14 of Part 1 will discontinue GS-9131 
or PTM but remain on their failing regimen until the site is notified of the subject’s eligibility to
proceed to Part 2. This period shall be no longer than 14 days (for Sentinel Cohort 1)/9 days 
(Sentinel Cohort 2 and Randomized Cohort), while awaiting HIV-1 RNA results and the 
authorization to proceed from Gilead.
Once notified of their eligibility into Part 2 of the study, the subject will discontinue their failing
regimen before initiating any Part 2 Day 1 study procedures. Subjects who received GS-9131
(including all subjects in the Sentinel Cohort 2 and those on Treatment Arms A-C of the 
Randomized Cohort) and had a ≤ 0.5 log10 decline in HIV-1 RNA will be discontinued from the 
study early and will have a 30 day visit following this visit.
In the event the plasma HIV-1 RNA test results performed by the central laboratory are delayed,
a subject may still proceed to Part 2 of the study if the test results from the local laboratory show
a reduction in plasma HIV-1 RNA > 0.5 log10 compared to pre-GS-9131 baseline during the 
14 days of GS-9131 functional monotherapy in Part 1 of the study. If the local laboratory test 
results do not show a reduction in plasma HIV-1 RNA > 0.5 log10 and the central laboratory test 
results are not received ≤ 9 days from completion of Day 15 of Part 1, the subject will be 
discontinued from the study and will be required to return to the clinic 30 days after the last dose 
of study drug for the 30-Day Follow-Up Visit. After a subject has terminated their participation 
in the study, long-term care for the subject will remain the responsibility of their primary treating 
physician, who will have access to the subject’s clinical information, including plasma HIV-1 
RNA viral load and HIV-1 genotype testing results.


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Part 2 Day 1 Treatment Assessments
All subjects who successfully complete all study drug doses in Part 1 and meet criteria to 
proceed to Part 2 will transition to Part 2and discontinue their current failing regimen. 
The following evaluations are to be completed on Day 1 of Part 2.  The Investigator must have 
confirmed eligibility before proceeding with the Part 2 Day 1 visit. The subject must complete all 
study procedures before being administered the study drug. Initiation of treatment with the study 
drug must take place within 24 hours after the Day 1 visit.

Review concomitant medications

Record any SAEs and all AEs related to protocol mandated procedures occurring after 
signing of the consent form

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator) 

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3

Document study drug dispensation and accountability for all study drugs dispensed
Subjects must be reminded to take study drug at the same time each day with food
6.3.3.
Part 2 (Weeks 1-24)
All study visits are to be scheduled relative to the Part 2 Day 1 visit date. Visit windows are 
± 4 days of the protocol-specified date through Week 24
The following will be performed at the Part 2 visits from Part 2 Week 1 up to Week 24:

Review concomitant medications

Record any SAEs and all AEs related to protocol mandated procedures occurring after 
signing of the consent form.

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator) (Day 1, Weeks 12 and 24)

Symptom-directed physical examination (Weeks 1, 2, 4, 8, and 18)


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment3 
• 
Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight 
• 
Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3 
• 
Collect subject dosing diaiy from all subjects (Weeks 4, 8, 12, 18, and 24) 
• 
Document study drng dispensation and accountability for all study drngs dispensed 
-
Subjects must be reminded to take study chug at the same time each day with food 
• 
Subjects who meet the criteria for virologic failure will be managed according to the 
Sub-optimal Virologic Response Section 6.10.2. and Management ofVirologic Rebound 
Section 6.10.3 
I 
I 
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I 
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Protocol GS-US-442-4 148 
Gilead Sciences, Inc. 
Post-Treatment Assessments 
Final 
Amendment3 
6.4. 
6.4.1. 
Early Study Drug Discontinuation Visit for Premature Discontinuation from 
Study 
Subjects who discontinue study diug before Week 24 will be required to complete an ESDD visit 
within 72 hours of stopping study di11g. Prior to Week 24, if a subject discontinues study dosing 
(for example, as a result of an AE), eve1y attempt should be made to keep the subject in the study 
and continue to perfonn the required study-related follow-up and procedures (see Section 6.5, 
Criteria for Discontinuation of Study Treatment). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdi·awn from the study. 
At the ESDD Visit, any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drug will be repeated weekly ( or as 
often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline (Day 1) value, or is otherwise explained. 
The following evaluations are to be completed at the ESDD Visit: 
• 
Review concomitant medications 
• 
Record any SAEs and all AEs related to protocol mandated procedures occmTing after 
signing of the consent fonn. 
• 
Complete physical examination (urogenital/anorectal exams will be perfo1med at the 
discretion of the Investigator) 
• 
Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight 
• 
Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3 
• 
Collect subject dosing diaiy from all subjects 
• 
Document study diug accountability for all study diu g dispensed 
• 
Document reason for discontinuation 
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GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
6.4.2. 
30 Day Follow-Up Visit 
Final 
Amendment3 
Subjects meeting criteria for sub-optimal virologic response in Pait 1, defined as a reduction in 
plasma HIV RNA :S 0.5 log10 from pre-GS-9131 baseline after 10 days for Sentinel Coho1t 1 and 
after 14 days for Sentinel Coho1t 2 of GS-9131 functional monotherapy, will be required to 
return to the clinic 30 days after the last dose of study diug for the 30-Day Follow-Up Visit. 
Subjects who prematurely discontinue study diug prior to Week 24 visit of the Pait 2 phase and 
refuse to continue in the study will be asked to return to the clinic 30 days after the completion of 
the ESDD Visit for the 30-Day Follow-Up Visit. 
Those subjects who prematurely discontinue study drug prior to the Week 24 visit of the 
Part 2 phase and continue in the study through at least one subsequent visit after the ESDD 
Visit will not be required to complete the 30-Day Follow-Up Visit. 
For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used. 
The following evaluations are to be completed at the 30-Day Follow-Up Visit: 
• 
Review concomitant medications 
• 
Record any SAEs and all AEs related to protocol mandated procedures occmTing after 
signing of the consent fonn. 
• 
Symptom-directed physical examination 
• 
Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight 
• 
Obtain blood and urine samples as described in Sections 6.8.1, 6.8.2, Appendix 2, and 
Appendix 3 
At the 30-Day Follow-Up Visit, any evaluations showing abno1mal results believed to be a 
reasonable possibility of a causal relationship with the study di11gs will be repeated weekly ( or as 
often as deemed prndent by the Investigator) until the abnonnality is resolved, retmns to baseline 
(Day 1) value, or is othe1wise explained. 
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Amendment 3
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6.5.
Criteria for Discontinuation of Study Treatment
Study medication will be discontinued in the following instances:

Unacceptable toxicity, as defined by the toxicity management section of the protocol, 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 subject’s best interest

Subject request to discontinue for any reason

Pregnancy during the study; refer to Appendix 7

Development of active tuberculosis infection

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Lack of efficacy

Subject noncompliance
6.5.1.
Study Stopping Criteria
By Subject: Study drug dosing for a subject will be discontinued if that subject experiences a 
Grade 3 or Grade 4 treatment-emergent adverse event (AE) or confirmed laboratory abnormality 
judged by the study investigator to be possibly related to study drug, or any serious adverse event 
(SAE) considered to be possibly related to study drug.
By Sentinel Cohort: Study drug dosing during Part 1 for the Sentinel Cohorts will be 
discontinued if any of the following criteria is met:

2 or more subjects experiencing Grade 3 or Grade 4 treatment-emergent AEs judged by the 
study investigator to be possibly related to study drug, or

2 or more subjects experiencing confirmed Grade 3 or Grade 4 laboratory abnormalities, or

2 or more subjects experiencing any SAE that is considered to be possibly related to study 
drug.
For the Randomized Cohort and Part 2: If 2 or more subjects in Part 1 of the Randomized Cohort 
who are subsequently assigned to treatment cohorts in Part 2 experience a Grade 3 or 4 treatment 
emergent AE leading to study drug discontinuation or an SAE judged by the study investigator to 
be possibly related to study drug, the IDMC will be convened to review all preliminary safety 
data generated in subjects dosed to date.


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Subjects will be followed as clinically indicated until the treatment-emergent AE or laboratory 
abnormality returns to baseline or is otherwise explained, whichever occurs first. Grade 3 and 4
laboratory abnormalities that are not confirmed by repeat testing will be managed according to 
the clinic’s practice; a decision to reinitiate dosing may be made by Gilead in consultation with 
the investigator and after a safety review.
6.6.
End of Study
The end of study will be the last patient’s last observation (or visit).
6.7.
Post Study Care
After a subject has completed/terminated their participation in the study, long-term care for the 
subject will remain the responsibility of their primary treating physician.
6.8.
Clinical Laboratory Assessments
Blood and urine samples will be collected throughout the study as outlined below, within 
Section 6, in Appendix 2, and in Appendix 3.
6.8.1.
Blood Samples

Blood samples will be collected for the following laboratory analyses (Refer to 
Appendix 2, and Appendix 3):
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled (Screening and Day 1 only). Positive urine pregnancy tests 
will be confirmed with a serum test. 
Follicle-stimulating hormone (FSH) (females who have ceased menstruating for greater 
than or equal to 12 months but do not have documentation of ovarian hormonal failure)
Female subject post-menopausal for less than two year,  if FSH 40 mIU/ mL a serum 
pregnancy test will be required (Screening only)
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, blood urea nitrogen (BUN), calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
amylase (reflex lipase testing is performed in subjects with total amylase 1.5 ULN)
Metabolic profile: Fasting (no food or drinks, except water, at least 8 hours prior to blood 
collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, and triglycerides) 
collected at Part 1 – Day 1, Part 2 – Day 1, Weeks 12 
 
.
■
If the subject has not fasted prior to the visit, the visit may proceed, but the subject 
must return within 72 hours in a fasted state to draw blood for the metabolic 
assessments 
CCI


GS-9131 (+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment3 
-
eGFR according to the Cockcroft-Gault fo1mula: 
Female: 
(140 - age in years) x (wt in kg) x 0.85 = CLcr (mL/min) 
72 x (sennn creatinine in mg/dL) 
(140 - age in years) x (wt in kg) 
x 0.85 = CLcr (mL/sec) 
72 x (sennn creatinine in umol/L) x 0. 6786 
-
Hematology profile: complete blood count (CBC) with differential and platelet count. 
-
CD4 cell count and percentage 
-
Plasma HIV-I RNA 
-
HBV blood panel: Hepatitis B vims surface antigen serology (HBsAg), Hepatitis B vims 
surface antibody (HBsAb) and Hepatitis B vims core antibody (HBcAb) 
The following tests will be conducted by the central laborato1y if the following criteria 
are met: 
If positive HBsAg, reflex testing for plasma HBV DNA, Hepatitis B vims e-antigen 
(HBeAg) (if negative, reflex Hepatitis B vims e-Antibody [HBeAb ]), and quantitative 
HBsAg. 
If positive HBcAb with negative HBsAg and negative HBsAb: reflex testing for 
plasma HBV DNA (if positive, reflex HBeAg). IfHBeAg is perfonned and found to 
be negative, reflex HBeAb 
If the subject meets the definition of HBV infection at screening, they will not be 
emolled. If the subject meets the definition of HBV infection during the study, HBV 
treatment and study continuation must be discussed with the Gilead Medical Monitor. 
-
Hepatitis C Vims (HCVAb) serology. Subjects who are HCVAb positive will have a 
HCV RNA test perfonned. 
I 
and semm storage sample for safety, or virology testing 
-
HIV-I genotype/phenotype testing for subjects with virologic failure (Screening, Days 1 
15 (Sentinel Cohort 2) 
-
Sparse PK Samples: 
Single Anytime PK Sample: collected without regard to time of dosing 
(Part 2 - Weeks 2, 8 and 24) 
Timed PK Sample: collected at predose and one within 15 minutes-4 hours post dose 
(Part 2 - Weeks 4, 12, and 18) 
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Intensive PK 
Final 
Amendment3 
Plasma samples will be collected on Day 10 for Sentinel Coho1i 1 and Day 14 for 
Sentinel Coho1i 2 and Randomized Coho1i. 
Prior to the administration of study diug, a predose ( < 5 minutes prior to dosing) will 
be collected. Subjects will then take an observed dose of study di11g at the clinic. 
Additional blood samples will be collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hour 
post dose. 
-
PBMC samples will be collected on Day 10 for Sentinel Cohort 1 and Day 14 for 
Sentinel Cohort 2 and Randomized Cohort: Predose (<5 minutes prior to dosing), 1, 2, 
6 and 24 hours post dose 
-
Subjects must be instmcted to not to take their study mugs on the morning of their visit. 
Prior to the administration of study di11g, a predose ( < 5 minutes prior to dosing) plasma 
blood sample will be collected. Subjects will then take an observed dose of study diug at 
the clinic. Additional plasma blood samples will be collected at 0.5, 1, 1.5, 2, 3, 4, 6, and 
8 hours post dose. PBMC PK samples will be collected at predose ( <5 minutes prior to 
dosing), 1, 2, and 6 hours post dose. 
6.8.2. 
Urine Samples 
• 
Urine samples will be collected for the following laboratory analyses (Refer to 
Appendix 2 and Appendix 3): 
-
Urinalysis 
-
Urine pregnancy testing (females of childbearing potential only) 
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Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
6.10. 
Virologic Failure 
Final 
Amendment3 
Virologic failure is defined as virologic rebound (Section 6.10.2) or as suboptimal virologic 
response in relation to pre-GS-9131 baseline plasma HIV-1 RNA levels at the time points 
described below. 
6.10.1. 
Suboptimal Virologic Response 
Subjects who meet the criteria listed below will be considered to have suboptimal virologic 
response (Figure 4): 
A) Functional monotherapy Sentinel Coho1i 1: Suboptimal virologic response for Sentinel 
Coho1i 1 is defined as a reduction in plasma HIV RNA::; 0.5 log10 from pre-GS-9131 
baseline after 10 days of GS-9131 functional monotherapy. This is assessed at Day 11 in 
Sentinel Coho1i 1. Subjects meeting criteria for suboptimal virologic response will be 
contacted for an ESDD visit and discontinued from the study within 72 hours of these results 
being available. 
Functional monotherapy Sentinel Coho1i 2 and Randomized Coho1is: Suboptimal virologic 
response is defined as a reduction in plasma HIV RNA ::; 0.5 log10 from pre-GS-9131 at Day 15 
during GS-9131 functional mono therapy period ( excludes placebo group). Subjects meeting 
criteria for suboptimal virologic response will be contacted for an ESDD visit and discontinued 
from the study within 72 hours of these results being available. 
B) All Subjects Pait 2: Suboptimal virologic response is defined as plasma HIV-1 RNA 
200 copies/mL AND reduction in HIV-1 RNA ::; 1 log10 from pre-GS-9131 baseline at the 
Week 8 visit with confmnation at the next scheduled or unscheduled visit. Subjects with 
suboptimal virologic response at Week 8 will have a repeat test of plasma HIV-1 
RNA 1-3 weeks later. If the repeat test shows a suboptimal virologic response defined as 
plasma HIV-1 RNA 200 copies/mL AND reduction in HIV-1 RNA ::; 1 log10 from 
pre-GS-9131 baseline, an HIV-1 genotype/phenotype will be done. If no new resistance to 
study diugs is detected from the genotype or phenotype, the subject may remain on study 
diugs and a repeat test of HIV-1 RNA should be conducted (1 to 3 weeks after the last HIV-1 
RNA test). Investigators should cai·efully evaluate the benefits and risks of remaining on 
study diug for each individual subject and document this assessment in the on-site medical 
record. If new resistance to study dmgs is detected, subjects will discontinue study diugs. For 
subjects who are off study diug but remain on study, it will be the Investigator's discretion to 
optimize their regimen and manage virologic rebound. 
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Amendment 3
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Figure 4.
Suboptimal Virologic Response Schema
a
If virologic rebound is not confirmed, the subject 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/phenotype (reverse 
transcriptase, protease, and integrase) will be analyzed.
c
Based on the results of the genotypic/ phenotypic assays, the subject will remain on study drugs or study drugs will be 
discontinued. If genotyping/ phenotyping assay fails, a new ARV regimen may be configured at the discretion of the 
Investigator.
d
If no new resistance is detected, HIV-1 RNA will be repeated (1-3 weeks later).  Investigator reviews study drug 
continuation/discontinuation options and discusses with the Medical Monitor prior to study drug discontinuation
e
A new ARV regimen may be configured, at the Investigator’s discretion, and the subject will remain in the study.
Screening 
Treatment 
Treatment 
30-Day 
Part 1 
Part2 
Follow-up 
l 
Reduction in HIV RNA:::, 0.5 log10 from pre-GS-
9131 baseline (Both Sentinel and Randomized 
Cohorts in Part 1 ( Functional Monotherapy)) 
Weeks 
! 
Submt.1i..wAl.Yit:.QlqgkJi.e~PJms.e. 
Discontinue study medications. 
Subject discontinues within 3 days 
of the HN-1 RNA results. 
', 
Part 2 Week 8 Visit: A plasma HIV-! RNA~ 200 copies/mL A.."'\1D reduction in 
HIV-! RNA:::, 1 log10 from pre-9131 baseline. 
Retest (1-3 weeks later) A plasma HN-1 RNA ~ 200 copies/mL 
A!~ reduction in HIV-! RNA:::, 1 log10 from pre-91 31 baseline.•~ 
HIV-! Genotype/Phenotype< 
If no new reverse 
transcriptase, protease or 
integrase resistance mutations 
are detected, may continue on 
study drugs<! 
If new reverse transcriptase, 
protease or integrase 
resistance mutations are 
detected to study drug, 
discontinue study drug and 
construct a new AR\ 
regimen• 


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Amendment 3
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6.10.2.
Virologic Rebound
Subjects who meet the criteria listed below will be considered to have virologic rebound:
A) At any visit, after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 
RNA ≥50 copies/mL, which is subsequently confirmed at the following scheduled or 
unscheduled visit; 
OR
B) At any visit, a 1 log10 increase in HIV-1 RNA from the nadir which is subsequently 
confirmed at the following scheduled or unscheduled visit
6.10.3.
Management of Virologic Rebound
Following the unconfirmed virologic rebound, subjects will be asked to return to the clinic for a 
scheduled or unscheduled blood draw (1 to 3 weeks after the date of the original test that resulted 
in HIV-1 RNA virologic rebound) for confirmation of virologic rebound. If virologic rebound is 
confirmed at the scheduled or unscheduled visit and the HIV-1 RNA is ≥200 copies/mL, the 
blood sample from the confirmation visit will be the primary sample used for HIV-1 genotypic 
and phenotypic testing. After a subject’s first post-baseline resistance test, additional testing will 
be conducted on a case-by-case basis. Any subject may be discontinued at Investigator’s 
discretion or per local treatment guidelines.
If no new resistance is detected from the genotype or phenotype, the subject may remain on 
study drugs and a repeat HIV-1 RNA should be conducted (1 to 3 weeks after date of test with 
HIV-1 RNA ≥ 50 copies/mL). Investigators should carefully evaluate the benefits and risks of 
remaining on study drug for each individual subject and document this assessment in the on-site 
medical record.
Subjects who are noncompliant on an ongoing basis will be considered for discontinuation per 
the Investigator’s discretion or local treatment guidelines. Investigators who opt to discontinue 
study drugs for an individual subject must discuss with the Medical Monitor prior to study drug 
discontinuation.
For subjects who are off study drug but remain on study, it will be the Investigator’s discretion to 
manage virologic rebound. 
Please refer to Figure 5 for the management of subjects who meet the criteria for virologic 
rebound.


GS-9131 (+BIC+TAF)
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Gilead Sciences, Inc. 
Amendment 3
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Figure 5.
Virologic Rebound Schema
a
If virologic rebound is not confirmed, the subject 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/phenotype (reverse 
transcriptase, protease and integrase) will be analyzed.
c
Based on the results of the genotypic/ phenotypic assays, the subject will remain on study drugs or study drugs will be 
discontinued. If genotyping/ phenotyping assay fails, a new ARV regimen may be configured at the discretion of the 
Investigator.
d
If no new resistance is detected, HIV-1 RNA will be repeated (1-3 weeks later).  Investigator reviews study drug 
continuation/discontinuation options and discusses with the Medical Monitor prior to study drug discontinuation
e
A new ARV regimen may be configured, at the Investigator’s discretion, and the subject will remain in the study.
6.10.4.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Discontinuation and 
Week 24
Subjects with HIV-1 RNA ≥ 50 copies/mL at study discontinuation or last visit will be 
considered virologic failures. Subjects with HIV-1 RNA ≥ 50 copies/mL at Week 24 will be 
asked to return for an unscheduled visit within the visit window for a retest.
Subjects with HIV-1 RNA ≥ 200 copies/mL at study drug discontinuation, last visit, or at
Week 24 will also have resistance testing conducted.
Screening 
nconfirmed 
virolo ic 
rebound: remain 
on current 
regimen • 
Treatment 
Treatment 
30-Day 
Part 1 
Part 2 
Follow-up 
Day 1 
l 
At any visit, after achieving HIV-1 RNA< 50 copies/mL, a rebound in HIV-1 RNA to 
50 copies/mL OR> l logIO in crease in HIV-1 RNA from their nadir 
l 
Return for scheduled/unscheduled HIV-1 
RNA and potential genotyp e/phenotype 
sampling (1-3 weeks later) 
l 
Confirmed viroloe:ic rebound 
and HIV-1 
Genotype and Phenotypeb,c 
' 
I l 
If no new reverse transcriptase, 
protease, or integrase resistance 
mutations a.re detected , may 
continue on study drugsd 
Remain 
on 
study 
If new reverse transcriptase, 
protease, or integrase resistance 
mutations a.re detected to study 
drug, discontinue study drugs and 
construct a new ARV regimen e 


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, 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 medicinal product, whether or not considered related to the medicinal product.
AEs may also include pre- or post-treatment complications that occur as a result of 
protocol-specified procedures, overdose, drug abuse/misuse reports, or occupational exposure.
Preexisting events that increase in severity or change in nature during or as a consequence of 
participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event 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 (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be preexisting and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject 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 subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
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 IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the IMP. For SAEs, an alternative 
causality must be provided (eg, preexisting condition, underlying disease, intercurrent illness, 
or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the IMP.
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 (e.g., 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, (e.g., venipuncture)


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7.2.2.
Assessment of Severity
AE severity should be recorded and graded according to the GSI Grading Scale for Severity of
Adverse Events and Laboratory Abnormalities (Appendix 5). For adverse events 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.
The distinction between the seriousness and the severity of an adverse event should be noted.
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For
example, a headache may be severe in intensity, but would not be classified as serious unless it
met one of the criteria for serious events.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for Collection Prior to Study Drug Initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and AEs related to protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study medication, all AEs, regardless of cause or relationship, until 
30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up 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.
7.3.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead PVE as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, 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 study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead PVE

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 


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Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead PVE contact information:
Fax: 
E-mail:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject 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 in the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
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, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
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All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an AE, 
as well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(e.g., 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 
(i.e., anemia) not the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Toxicity Grading Scale which can 
be found in Appendix 5).
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.
7.6.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 and as outlined below.
Refer to Section 6.5 for additional specific discontinuation criteria. Specific toxicity 
discontinuation criteria in Section 6.5 and Appendix 4 supersede the general toxicity guidelines
below, and in general, where a discrepancy is present, the more conservative criteria apply.  The 
Gilead Medical Monitor should be consulted prior to study drug discontinuation when medically 
feasible.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event

All Grade 3 and 4 laboratory abnormalities should be repeated immediately to confirm 
toxicity grade. Confirmation of toxicity grade is required prior to the next dose of 
investigational medicinal product for any Grade 3 and 4 laboratory abnormality that in the 
opinion of the Investigator is clinically significant and may pose a risk to the subject’s safety.

For a Grade 3 clinically significant laboratory abnormality or clinical event, IMP may be 
continued if the event is considered to be unrelated to IMP.


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
For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to IMP, IMP should be withheld until the 
toxicity returns to ≤ Grade 2.

If a laboratory abnormality recurs to ≥ Grade 3 following re-challenge with IMP and is 
considered related to IMP, then IMP should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to IMP may not require permanent discontinuation.
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to IMP, IMP should be permanently discontinued and 
the subject managed according to local practice. The subject 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.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 creatine kinase [CK] after 
strenuous exercise or triglyceride elevation that is nonfasting or that can be medically managed) 
or a clinical event considered unrelated to IMP.
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Medical Monitor, who will have a discussion with the investigator and decide the 
appropriate course of action. Whether considered treatment-related or not, all subjects 
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 Gilead Medical Monitor.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, 
pregnancy reports regardless of an associated AE, and AE in an infant following exposure from
breastfeeding.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.


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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as a complaint arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure is defined as exposure to a medicinal product as a result of one’s
professional or non-professional occupation.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism
of pregnancy reporting.
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. 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 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must
be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE 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 PVE. Gilead PVE contact information is as follows: 
Email: 
 and Fax: 
 
Refer to Appendix 7 for Pregnancy Precautions, Definition for Female of Childbearing Potential,
and Contraceptive Requirements.
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7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of the study is to evaluate the short-term antiviral potency of GS-9131 
functional monotherapy compared to PTM GS-9131, each administered once daily with the 
existing failing ARV regimen, as demonstrated by the proportion of subjects achieving HIV-1 
RNA > 0.5 log10 decreases from baseline after up to 14 days of therapy in HIV-1 positive, ARV
TE adult subjects with nucleos(t)ide resistant virus.
The secondary objectives of this study are:
Part 1

To evaluate the efficacy of GS-9131 functional monotherapy as determined by the change 
from baseline in log10 HIV-1 RNA at Day 11 for Sentinel Cohort 1 and Day 15 for Sentinel 
Cohort 2 and Randomized Cohort.
Part 2

To evaluate the safety and efficacy  of a regimen containing GS-9131 (60 mg) + BIC + DRV
+ RTV through 24 weeks of treatment in subjects from Sentinel Cohort 1 who switched from
a failing regimen as determined by achievement of HIV-1 RNA < 50 copies/mL at Week 24.

To evaluate the safety and efficacy of a regimen containing GS-9131(up to 180 mg) + BIC 
+ TAF through 24 weeks of treatment in Subjects from Sentinel Cohort 2 and Randomized 
Cohort who switched from a failing regimen as determined by achievement of HIV-1 
RNA < 50 copies/mL at Week 24.

To characterize the PK of GS-9131 following multiple doses of GS-9131 in TE patients.

To evaluate the number of subjects with treatment-emergent NRTI, PI, and INSTI mutations 
at the time of virologic failure.
8.1.2.
Primary Endpoint
The primary endpoint is the proportion of subjects with plasma HIV-1 RNA decreases from 
baseline exceeding 0.5 log10 at Day 15 in the Randomized Cohort in Part 1.
8.1.3.
Secondary Endpoints
The secondary endpoints include:

The change from baseline in plasma log10 HIV-1 RNA (copies/mL) at Day 11 for Sentinel 
Cohort 1 and Day 15 for Sentinel Cohort 2 and Randomized Cohort in Part 1.

Number of subjects with treatment-emergent NRTI, PR, and INSTI mutations at the time of 
virologic failure.


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8.1.4.
Other Endpoints of Interest

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL as defined by the 
US FDA Snapshot algorithm at Week 24 in Part 2.

The change from Part 2 baseline in plasma log10 HIV-1 RNA (copies/mL) at Week 24 in 
Part 2.

The change from Part 2 baseline in CD4 cell count (cells/µL) at Week 24 in Part 2.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
All Enrolled Analysis Set
The all enrolled analysis set includes all subjects who enroll into the study either in the sentinel 
cohorts or randomized cohort. This is the primary analysis set for by-subject listings.
8.2.1.2.
Efficacy
The primary analysis set for efficacy analysis is defined as follows:
8.2.1.2.1.
Full Analysis Set (FAS)
Two full analysis sets will be defined, one for the Randomized Cohort in Part 1 and one for 
Part 2.  The FAS for the Randomized Cohort in Part 1 will include all subjects who (1) are 
randomized to Part 1 Randomized Cohort, and (2) have received at least one dose of study 
medication in Part 1. Subjects in the Randomized Cohort in Part 1 will be grouped according to 
the treatment to which they were randomized. The FAS for Part 2 will include all subjects who 
(1) are enrolled into Part 2, and (2) have received at least one dose of study medication in Part 2.
8.2.1.2.2.
Per-Protocol (PP) Analysis Set
The Per-Protocol analysis set will only be defined for the Randomized Cohort in Part 1.  The 
Per-Protocol analysis set will include all subjects who (1) are randomized to Part 1 Randomized 
Cohort, (2) have received at least one dose of study medication in Part 1, and (3) have not 
committed any major protocol violation in the randomized cohort in Part 1, including the 
violation of key entry criteria. Subjects in the PP analysis set will be grouped according to the 
treatment they actually received.
8.2.1.3.
Safety
Two safety analysis sets will be defined, one for the Randomized Cohort in Part 1 and one for 
Part 2.  The safety analysis set for the Randomized Cohort in Part 1 will include all subjects who 
(1) are randomized to Part 1 Randomized Cohort, and (2) received at least one dose of study 
drug in Part 1. Subjects in the safety analysis set in Part 1 will be grouped according to the 
treatment they actually received. The safety analysis set for Part 2 will include all subjects 
enrolled into Part 2 who have received at least one dose of study drug in Part 2. All the data 
collected up to 30 days after subjects permanently discontinue their study regimen will be 
included in the safety summaries.


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8.2.1.4.
Pharmacokinetics
8.2.1.4.1.
Pharmacokinetic Analysis Set for Part 1
8.2.1.4.2.
The PK analysis set will include all subjects who (1) are enrolled or randomized 
into the study, (2) have received at least one dose of study medication and 
(3) have at least 1 non-missing PK concentration data for any analyte of  interest. 
The PK analysis set will be used for analyses of general 
pharmacokinetics.Pharmacokinetic Analysis Set for Part 2
8.2.1.4.3.
The PK analysis set will include all subjects who (1) are enrolled or randomized 
into the study, (2) have received at least one dose of study medication and 
(3) have at least 1 non-missing PK concentration data for any analyte of interest. 
The PK analysis set will be used for analyses of general pharmacokinetics. PBMC 
PK Analysis Set
The PBMC PK analysis set will include all subjects who (1) are enrolled or randomized into the 
study, (2) have received at least one dose of study medication and (3) have at least 1 non-missing 
PBMC PK concentration data for any analyte of interest. The PBMC analysis set will be used for 
analyses of general pharmacokinetics.
8.2.1.5.
Sentinel Cohort Analysis Set
The Sentinel Cohort analysis set will include all subjects who are enrolled into the Sentinel 
Cohorts and received at least 1 dose of study medication. Both safety and efficacy data will be 
analyzed using this analysis set for subjects enrolled in Part 1 Sentinel Cohorts.
8.3.
Data Handling Conventions
HIV-1 RNA results of “No HIV-1 RNA detected” and “< 20 cp/mL HIV-1 RNA Detected” will 
be imputed as 19 copies/mL for analysis purposes.
Natural logarithmic transformation of plasma concentrations and PK parameters will be applied 
for PK analysis.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit plus 
or minus one significant digit, respectively (e.g., if the result of a continuous laboratory test 
is < 20, a value of 19 will be assigned).
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. However, a missing pre-treatment laboratory result would be 
treated as normal (i.e., no toxicity grade) for the laboratory abnormality summary.
All available data for subjects that do not complete the study will be included in data listings.


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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized for each part and cohort (Part 1)
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 data will include race, ethnicity, and age.
Baseline characteristics will include body weight, height, body mass index, and eGFR, HIV-1 
infection, and enrollment distribution by randomization stratum (if applicable) will be 
summarized.
For the Randomized Cohort in Part 1, the Cochran–Mantel–Haenszel (CMH) test will be used to 
compare treatment arms for categorical demographic and baseline characteristics, and the 
Wilcoxon rank sum test will be used for continuous demographic and baseline characteristics.
No comparison is needed for the Sentinel Cohorts in Part 1 and Part 2.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA decreases from 
baseline exceeding 0.5 log10 copies/mL at Day 15 for Part 1, Randomized Cohort. Subjects who 
have missing HIV-1 RNA values at Day 15 will be considered as without an HIV-1 RNA 
decrease from baseline exceeding 0.5 log10 copies/mL at Day 15. The difference between each of 
the GS-9131 treatment groups and the placebo group will be compared using a Fisher’s exact test 
at a two-sided significant level of 0.05.
The null hypothesis is that there is no difference in proportion of subjects with HIV-1 RNA 
decreases exceeding 0.5 log10 at Day 15 between each of the GS-9131 treatment groups and the 
placebo group; the alternative hypothesis is that there is a difference in the proportion of subjects 
with HIV-1 RNA decreases exceeding 0.5 log10 copies/mL at Day 15 between each of the 
GS-9131 treatment groups and the placebo group.
The primary analysis of the efficacy will be based on FAS in Part 1.
8.5.2.
Secondary Analyses
For Part 1 Randomized Cohort, the change from baseline in plasma log10 HIV-1 RNA 
(copies/mL) and CD4 cell count at Day15 will be summarized and compared between each of 
GS-9131 groups and placebo group using a two-sided Wilcoxon rank sum test at a two-sided 
significant level of 0.05.
For Part 1 Sentinel Cohorts, the proportion of subjects with HIV-1 RNA decreases from baseline 
exceeding 0.5 log10 copies/mL at Days 11 (Sentinel Cohort 1) and 15 (Sentinel Cohort 2) and the 
change from baseline in plasma log10 HIV-1 RNA (copies/mL) and CD4 cell count at Days 11
(Sentinel Cohort 1) and 15 (Sentinel Cohort 2) will be summarized using the Sentinel Cohort 
analysis set.


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For Part 2, the percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 24, as 
defined by the FDA snapshot algorithm and missing = failure/excluded methods, will be 
summarized and the 95% confidence intervals using the Clopper-Pearson Exact method will also 
be presented. The change from Part 2 baseline in log10 HIV-1 RNA, CD4 cell count and 
percentage at Week 24 will be summarized using descriptive statistics. These analyses will be 
based on the FAS in Part 2. As a sensitivity analysis these analyses will be repeated by utilizing 
subjects from randomized cohort only.
8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set by part and cohort.
For each part and cohort, all safety data collected on or after the date that the study drug was first 
administered up to the date of the last dose of study drug plus 30 days, unless specified 
otherwise, will be summarized for subjects in the safety analysis set according to the study drug 
received.
Data for the pretreatment period and the period after the date of last dose of study drug plus 
30 days will be included in data listings for all enrolled subjects.
The safety analysis set for the Sentinel Cohorts is the Sentinel Cohort analysis set.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration page in CRF. Exposure data will be summarized by part, cohort, and treatment.
Duration of exposure to study drug will be expressed as the number of days for Part 1 and weeks 
for Part 2 between the first and last dose of the study drug, inclusive, regardless of temporary 
interruptions in study drug administration and summarized by treatment in each part and cohort.
Dosing information for individual subjects will be listed.
8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the MedDRA. System Organ Class (SOC), 
High-Level Group Term (HLGT), High-Level Term (HLT), Preferred Term (PT), and 
Lower-Level Term (LLT) 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 with onset date on or after the study drug start date and no later 
than 30 days after the study drug stop date; or any AE leading to study drug discontinuation.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC, HLT [if 
applicable], and PT) will be provided by part, cohort, and treatment. Additional summaries will
include summaries for AEs by grade, Investigator’s assessment of relationship to study drug, and 
effect on study drug dosing.


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AEs will be reviewed on an ongoing basis for events that might meet the definition of 
Category C events that are indicative of an AIDS-Defining Diagnoses. If further information is 
needed to assess whether the event meets the Category C definition, a Clinical Endpoint 
Summary Sheet will be sent to the Investigator to collect additional pertinent information and the 
Gilead Medical Monitor will review the possible Category C events and approve the events that 
meet the definition. Those events that do meet the Category C definition of an AIDS-Defining 
Diagnosis will be summarized. A listing of Category C, AIDS-Defining Diagnosis can be found 
in Appendix 6.
8.6.3.
Laboratory Evaluations
Selected laboratory data 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 defined in Grading of 
laboratory abnormalities provided in Appendix 5.
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 regimen plus 30 days, will be summarized by part, cohort, and treatment. If baseline 
data are missing, then any graded abnormality (i.e., at least a Grade 1) will be considered 
treatment-emergent. The maximum toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of study regimen or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.
8.6.4.
Other Safety Evaluations
Vital signs and safety ECG data will be summarized as appropriate.
8.7.
Pharmacokinetic Analysis
For the plasma PK, the concentration data of any analyte of interest (eg, GS-9131, BIC, or other 
available analytes, as appropriate) will be summarized by nominal sampling time using 
descriptive statistics for each part. Pharmacokinetic parameters will be listed and summarized 
using descriptive statistics by part. Plasma concentrations over time from intensive PK will be 
plotted in semi-logarithmic and linear formats as mean ± standard deviation, and median 
(Q1, Q3). Additional analyses may be conducted. 
For the sparse PK in Part 2, the pharmacokinetics of GS-9131, BIC, and TAF may be 
summarized in a listing, 
For subjects who have evaluable concentrations in PBMCs, the PK concentration and parameters 
of GS-9148-DP or TFV-DP will be listed and summarized using descriptive statistics.


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8.8.
Biomarker Analysis
Not Applicable.
8.9.
Sample Size
For the Randomized Cohort in Part 1, a total of 48 HIV-1 positive adults, randomized in a 
1:1:1:1 ratio to 4 arms (3 dose levels of GS-9131 up to 180 mg, and placebo) achieves 
85% power to detect a 61.7% difference in the proportion of subjects with HIV-1 RNA decreases 
from baseline exceeding 0.5 log10 between at least one of the GS-9131 treatment arms and 
placebo arm at Day 21.  For sample size and power computation, it is assumed that 70% of 
subjects in each GS-9131 arm achieved a reduction exceeding 0.5 log10 HIV-1 RNA while 
8.3% of subjects in the placebo arm achieved such a reduction (based on internal Viread Study 
907), and a Fisher’s exact test at a two-sided significance level of 0.05 was conducted.
Sample size and power calculations were made using nQuery Advisor 6.0.
8.10.
Data Monitoring Committee
An external Independent Data Monitoring Committee (IDMC) will review the progress, efficacy, 
and safety data of this study while the study is ongoing. The committee will convene after 
approximately 50% of subjects enrolled in Part 2 complete Week 12 of the study. However, 
Gilead will defer to the IDMC for any decision to convene earlier or more frequently. The IDMC 
will examine the safety results of the trial and also focus on logistical issues such as accrual, 
retention, quality of clinical and laboratory data, and implications of results of external studies. 
Blinding will be preserved for Part 1 during the conduct of the study and access to unblinded 
data will be limited to designated parties.
No formal stopping rules will be used by the IDMC for safety outcomes. Rather, a clinical 
assessment will be made to determine if the nature, frequency, and severity of adverse events 
associated with a study regimen warrant the early termination of the study in the best interest of 
the participants.
An analysis for the Week 12 IDMC meeting will be conducted after approximately 50% of 
subjects enrolled in Part 2 complete Week 12 of the study. 
Gilead does not have a prior intent to ask the IDMC to consider early termination of the study 
even if there is early evidence of favorable efficacy.
8.11.
Analysis Schedule
The Part 1 analysis will be conducted after all subjects either complete their Part 1 last scheduled 
visit or prematurely discontinue from the study drug before the last scheduled visit in Part 1. The 
Week 24 analysis will be conducted after all subjects complete Week 24 or prematurely 
discontinue from the study.  Final analysis will be conducted after all subjects complete the 
study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and GCP Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR 50, and 
21 CFR 56.
The investigator and all applicable subinvestigators will comply with 21 CFR 54, providing 
documentation of their financial interest or arrangements with Gilead, or proprietary interests in 
the investigational drug under study. This documentation must be provided prior to the 
investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to the local regulatory agency and/or ethics committee. The investigator will 
not begin any study subject activities until approval from all applicable bodies has been received 
and has been documented and provided as a letter to the investigator.
Before implementation, the investigator (or sponsor as appropriate according to local 
regulations) will submit to and receive documented approval from the local regulatory agency 
and/or ethics committee any modifications made to the protocol or any accompanying material to 
be provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.
9.1.3.
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 


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potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current approved consent form for documenting written informed 
consent. Each informed consent (or assent as applicable) will be appropriately signed and dated 
by the subject or the subject’s legally authorized representative and the person conducting the 
consent discussion, and also by an impartial witness if required by local requirements. The 
consent form will inform subjects about pharmacogenomic testing and sample retention, if 
applicable as per protocol. 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law), and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor or laboratory. Laboratory specimens must be 
labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions. NOTE: The investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. Subject 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, eCRF, the IMP, and any other study information, remain the sole and exclusive 
property of Gilead during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of the 
study or as required by law) without prior written consent from Gilead. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
9.1.5.
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 two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, ethics 
committee and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject 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 IMP, including dates of dispensing and return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including 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 until 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, United States, 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, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 


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source data verification within the EDC system. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency.
The site 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 (e.g., data entry error). Original entries as well as any changes to data fields will be stored 
in the audit trail of the system. Prior to any interim time points or database lock (as instructed by 
Gilead), the investigator will use his/her log in credentials to confirm that the forms have been 
reviewed, and that the entries accurately reflect the information in the source documents. At the 
conclusion of the trial, Gilead will provide the site with a read-only archive copy of the data 
entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to ethics committees, 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.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator (or the sponsor, as appropriate according to local 
regulations) must submit all protocol modifications to the regulatory agency and ethics 
committee, and any other bodies as required in accordance with local legislation and receive all 
documented approvals before modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 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 in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years, and 

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g., attendance at Investigator's 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 trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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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 in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor 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 appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, et al. Phase I/II trial of 
the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil 
fumarate in HIV-1 infected adults. Antimicrob Agents Chemother 2001;45 
(10):2733-9.
Begley R, Majeed SR, Cao H, West SK, vu A. Pharmacokinetics, Food Effect, and Safety of GS-
9131, a Novel N(t)RTI for Use in Treatment of Experienced HIV-Infected 
Patients. ASCPT 2018 Annual Meeting; 2018 21-24 March; Orlando, FL. 
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.
Genvoya, Gilead Science Inc. GENVOYA® (elvitegravir, cobicistat, emtricitabine, and 
tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster 
City, CA. Revised: August.  2018:
Lundgren JD, Clumeck N, Rockstroh J, Ryom L. European AIDS Clinical Society (EACS) 
Guidelines. Version 7.0 October.  2013:
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Developed by 
the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A 
Working Group of the Office of AIDS Research Advisory Council (OARAC) 
Available at: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 
Last Updated 14 July.  2016.
PREZCOBIX, Janssen Ortho LLC. PREZCOBIX (darunavir and cobicistat) tablets, for oral use. 
US Prescribing Information. Titusville, NJ. Revised: June.  2018:
Rousseau FS, Wakeford C, Mommeja-Marin H, Mxoham C, Harris J, Hulett L, et al. Prospective 
randomized trial of emtricitabine versus lamivudine short-term monotherapy in 
human immunodeficiency virus-infected patients. J Infect Dis 2003;188 
(11):1652-8.


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Ruane PJ, Dejesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral 
Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir 
Alafenamide as 10-Day Monotherapy in HIV-1-Positive Adults. J Acquir Immune 
Defic Syndr 2013;63 (4):449-55.
Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A, McKenna MT. Revised 
surveillance case definitions for HIV infection among adults, adolescents, and 
children aged <18 months and for HIV infection and AIDS among children aged 
18 months to <13 years--United States, 2008. MMWR Recomm Rep 2008;57 
(RR-10):1-12.
Squires K, Pozniak AL, Pierone G, Jr, Steinhart CR, Berger D, Bellos NC, et al. Tenofovir 
disoproxil fumarate in nucleoside-resistant HIV-1 infection. Ann Intern Med 
2003;139 (5, Part 1):313-21.
TenoRes Study Group. Global epidemiology of drug resistance after failure of WHO 
recommended first-line regimens for adult HIV-1 infection: a multicentre 
retrospective cohort study. Lancet Infect Dis 2016;16:565-75.
Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A, et al. Antiretroviral 
treatment of adult HIV infection: 2010 recommendations of the International 
AIDS Society-USA panel. JAMA 2010;304 (3):321-33.
UNAIDS. Fact Sheet 2016: Global Statistics-2015. Available at: 
http://www.unaids.org/en/resources/documents/2016/UNAIDS_FactSheet.  2016.
Williams I, Churchill D, Anderson J, Boffito M, Bower M, Cairns G, et al. British HIV 
Association guidelines for the treatment of HIV-1-positive adults with 
antiretroviral therapy 2012 (Updated November 2013. All changed text is cast in 
yellow highlight.). HIV Med 2014;15 Suppl 1:1-85.
World Health Organization (WHO). Consolidation Guidelines on HIV Prevention, Diagnosis, 
Treatment and Care for Key Populations.  2016.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table – Cohort 1
Appendix 3.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines)
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 8.
Prior and Concomitant Medications For Subjects in Sentinel Cohort 1 and Sentinel 
Cohort 1 Subjects Who Go on to Part 2: bictegravir GS-9131 + BIC + DRV + RTV


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2 Study to Evaluate the Efficacy of GS-9131 Functional Monothcrapy in 
IDV-1-Infected Adults Failing a Nucleos(t)ide Reverse Transcriptase Inhibitor-Containing 
Regimen with Nucleos(t)ide Reverse Transcriptase Inhibitor Resistant Virus 
GS-US-442-4148 Amendment 3, 01 November 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this aonroval" 
.. __________ _ 
[PPD 
[P[PD 
Date 
1 
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 
CONFIDENTIAL 
Page97 
0 I November 20 I 8 


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Appendix 2.
Study Procedures Table – Cohort 1
Study Procedures
Screeninga,b
Part 1 (Sentinel Cohort 1 Randomized)c
Days
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-
up
ESDDh
1
2
3
4
5
6
7
8
9
10
11d
Day 
1
1
2
4
8
12
18
24
Every 
12 
Weeks
Informed Consent
X
Medical History 
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Complete Physical Exam
X
X
X
X
X
X
X
Symptom-Directed 
Physical Exam
X
X
X
X
X
X
X
X
Xi
12-Lead ECG (performed 
supine)
X
X
X
X
X
X
Height
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Chemistry Profile
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Urinalysis
X
X
X
X
X
X
X
X
X
Xi
X
Metabolic Profilek
X
X
Xk
Xk
X
Estimated Glomerular 
Filtration Rate
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Serum Pregnancy Testl
X
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
X
X
X
FSH Testingv
X
Plasma, Serum, 
 
Storage Sample
X
X
X
X
X
X
X
X
X
X
X
HCV Serologym
X
X
HBV blood panel
X
X
X
X
CCI
CC
CCI
I 
-


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 99
01 November 2018
Study Procedures
Screeninga,b
Part 1 (Sentinel Cohort 1 Randomized)c
Days
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-
up
ESDDh
1
2
3
4
5
6
7
8
9
10
11d
Day 
1
1
2
4
8
12
18
24
Every 
12 
Weeks
Plasma HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4 Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/ 
Phenotypej
X
X
X
X
Timed PK Samplen
X
X
X
Single Anytime PK 
Sampleo
X
X
X
Intensive PK Samplingp
X
X
X
PBMC Samplingr
X
Randomizations
X
Collect Subject Dosing 
Diary to Subjects
X
X
X
X
X
X
X
X
In-clinic Dosingt
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensationu
X
X
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Part 1 Day 1 visit. A single 14 day extension to the screening window may be granted with permission form the Medical 
Monitor
b
Results from the screening genotype report and confirmed eligibility must be obtained before proceeding with Day 1 Visit. Local genotype at the Screening Visit is acceptable 
for enrollment upon review by the Sponsor. A single 14 day extension to the screening window may be granted with permission form the Medical Monitor if the genotype 
results are delayed. 
c
Randomization and dosing into the Randomized Cohort of Part 1 will begin after the Day 10 safety, efficacy and available PK data from the 10 subjects in the Sentinel 
Cohort are reviewed. 
CCI
CCI
CC
CC
CC
I I 


GS-9131(+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment3 
d 
Before proceeding into Part 2, subjects who have completed Day IO of Part I (from either the Sentinel or Randomized Cohorts) will discontinue GS-9131 or PTM but remain 
on their failing regimen until the site is notified of the subject's eligibility to proceed to Part. 2. This period shall be no longer than 14 days while awaiting Day IO HIV-I RNA 
results and the authorization to proceed from Gilead. Once notified of their eligibility into Pait 2 of the study, the subject w-ill discontinue their failing regimen before 
initiating any Patt 2 Day I study procedures. In the event the plasma HIV-I RNA test results pe1fotmed by the central laboratory are delayed beyond 14 days, a subject may 
still proceed to Part. 2 of the study if the test results from the local laboratory show a reduction in plasma HIV-I RNA > 0.5 log1ocompared to pre-GS-9131 baseline after IO 
days ofGS-9131 functional monotherapy in Patt I of the study. 
e 
All study visits are to be scheduled relative to the Patt 2 Da I visit date. Visit windows are± 4 da s of the rotocol s ecified date through Week 8, ± 4 days of the protocol 
r 
r 
s ecified date throu~h Week 24, 
h 
v1S1t to occur wit 1m 
1om·s o ast ose o stu y 'ltg. u 1ects wt 
subject discontinues study dtug. 
Any AE or test showing abnotmal results that is believed to have a possible or probable causal relationship with the study dmg will be repeated weekly ( or as often as deemed 
prndent by the Investigator) until the abnotmality is resolved, rettuns to baseline (Day I) value, or is otherwise explained. 
HIV-I genotype/phenotype testing for subjects with confomed virologic failure and HIV-I RNA >200 copies/mL, at early study discontinuation or Week 24. Following 
virologic rebound, subjects will be asked to rettun to the clinic (I-3 weeks later) prior to the next scheduled visit or at the next scheduled study visit for a HIV-I RNA and 
HIV-I genotype/phenotype (reverse transcriptase, protease, and integrase) blood draw. Based on the results of this testing, subjects should be managed according to the 
Virologic Rebound Schema (Section 6.10). 
k 
Collected fasted (no food or di-inks, except water, at least 8 hours prior to blood collection) only at Patt 2 - Day I, Week 12, and Week 24. Collected non-fasted at all other 
visits. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must rettun within 72 hours in a fasted state to draw blood for the assessments. 
Females of childbeat-ing potential only. Ut-ine and senllll pregnancy test will be done at Screening and Day I. If the tu-ine and senllll test is positive at screening, the subject 
will not be enrolled. A positive urine pregnancy test at any visit will be confirmed with a semm test. If the test is positive the subject will be discontinued from the study . . 
m 
Hepatitis C Vims (HCF Ab) serology. Subjects who are HCVAb positive will have a HCV RNA test performed. 
n 
Timed PK Sample: collected at predose and one within 15 minutes-4 hours post dose (Part 2 - Weeks 4, 12 and 18) 
o 
Single Anytime PK Sample: collected without regard to time of dosing (Part 2 - Weeks 2, 8 and 24) 
p 
Intensive PK samples will be collected on Patt I - Day IO. Prior to the adtninistration of study dmg, a predose (<5 minutes prior to dosing) blood sample will be collected. 
Sub ·ects will then take an observed dose of study dru at the clinic. Additional blood sam les will be collected at 0.5, I, 1.5 2 3 4 6 8 and 24 hotu· ost dose. 
r 
r 
PBMC co echon on Day IO: Pre ose <5 nunutes pnor to osmg , I, 2, 6 an 24 otu-s post ose. 
s 
Randomization may be petfonued up to 3 days prior to the in-clinic Day I visit provided that all screening procedures have been completed, and subject eligibility has been 
confomed. 
All study medication in Patt I will be delivered by directly observed therapy on Days 1-10. 
u 
Subjects must be reminded to take study dtug at the same time each day except on days with Timed PK sample and Intensive PK. 
v 
For female subject post-menopausal for less than two years, ifFSH <40 mIU/ mL a senllll pregnancy test will be required 
CONFIDENTIAL 
Page 100 
01 November 2018 


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 101
01 November 2018
Appendix 3.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Informed Consent
X
Medical History 
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
X
X
Symptom-Directed Physical 
Exam
X
X
X
X
12-Lead ECG (performed supine)
X
X
X
Height
X
Vital Signs and Weight
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
Chemistry Profile
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Metabolic Profilek
X
Estimated Glomerular Filtration 
Rate
X
X
X
X
X
X
X
Serum Pregnancy Testl
X
X
Urine Pregnancy Testl
X
X
X
X
FSH Testingv
X
Plasma, Serum, 
 Storage 
Sample
X
X
X
X
X
X
X
X
HCV Serologym
X
HBV blood panel
X
Plasma HIV-1 RNA
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
HIV-1 Genotype/ Phenotypej
X
X
X
X
Whole blood sample for 
genotypic testing
X
CCI-


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 102
01 November 2018
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Intensive PK Samplingp
X
PBMC Samplingr
X
Randomizations
X
Collect Subject Dosing Diary to 
Subjects
X
In-clinic Dosingt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Procedures
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-up
ESDDh
Day1
1
2
4
8
12
18
24
Every 12 Weeks
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Xi
X
Complete Physical Exam
X
X
X
X
Symptom-Directed Physical Exam
X
X
X
X
X
X
Xi
12-Lead ECG (performed supine)
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
X
Xi
X
Chemistry Profile
X
X
X
X
X
X
X
X
X
Xi
X
Urinalysis
X
X
X
X
X
Xi
X
Metabolic Profilek
X
Xk
Xk
X
Estimated Glomerular Filtration Rate
X
X
X
X
X
X
X
X
X
Xi
X
Serum Pregnancy Testl
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
Plasma, Serum, 
 Storage 
Sample
X
X
X
X
X
X
X
X
X
HCV Serologym
X
CCI
CCI
CCI
CC
-
--------------
11111111111111111111111111111111111111111111111111111111 
--------------
11111111111111111111111111111111111111111111111111111111 
--------------
I 


GS-9131(+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Study Procedures 
HBV lood pat el 
Plasma HIV-1 RNA 
CD4+ Cell Count 
HIV-1 Genotype/ Phenotypd 
T' e PK Sa 'I I 
s· ~le 
yt.· ue 
Sm eo 
I e s1 e 
Sa .1 pfo gP 
Collect Subject Dosing Diary to 
Subjects 
Study Dmg Dispensationu 
Drng Accountability 
Part 2 
WeeJcs•,i 
(+/- 4 days) 
Dayl 
1 
2 
4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
:it' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 
12 
18 
24 
E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
:if 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
30 Day 
Follow-uif 
l' 
2 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment3 
ESDDh 
X 
X 
X 
X 
X 
a 
Evaluations to be completed within 30 days prior to Part 1 Day 1 visit. A single 14 day extension to the screening window may be granted with pennission form the Medical 
Monitor 
b 
Results from the screening genotype report and confirmed eligibility must be obtained before proceeding with Day 1 Visit. Local genotype at the Screening Visit is acceptable 
for enrolhuent upon review by the Sponsor. A single 14 day extension to the screening window may be granted with pemiission fo1m the Medical Morutor if the genotype 
results are delayed. 
c 
Randomization and dosing into the Randoniized Cohort of Part 1 will begin after the Day 15 safety, efficacy and available PK data from the 10 subjects in the Sentinel 
Coho1t 2 are reviewed. 
d 
Before proceeding into Part 2, subjects who have completed Day 14 of Part 1 (from either the Sentinel or Randoniized Coho1ts) will discontinue GS-9131 or PTM but remain 
on their failing regimen until the site is notified of the subject's eligibility to proceed to Pait 2. This period shall be no longer than 9 days while awaiting HIV-1 RNA results 
and the authorization to proceed from Gilead. Once notified of their eligibility into Pait 2 of the study, the subject will discontinue theit· failing regituen before itiitiating any 
Pait 2 Day 1 study procedures. In the event the plasma HIV -1 RNA test results pe1fo1med by the central laboratory are delayed, beyond 9 days, a subject may still proceed to 
Patt 2 of the study if the test results from the local laborato1y show a reduction in plasma HIV-1 RNA > 0.5 log10 compared to pre-GS-9131 baseline during the 14 days of 
GS-9131 functional monotherapy in Patt 1 of the study. 
e 
All stud visits are to be scheduled relative to the Patt 2 Da 1 visit date. Visit windows are± 4 days of the protocol specified date through Week 24, 
r 
I' 
h 
ESDD v1S1t to occur wit 1m 72 1om·s o ast ose o stu y 'ltg. Su 1ects w1 
subject discontinues study dtug. 
Any AE or test showing ab1101mal results that is believed to have a possible or probable causal relationship with the study dt'l1g will be repeated weekly ( or as often as deemed 
pmdent by the Investigator) until the abno1mality is resolved, rettuns to baseline (Day 1) value, or is otherwise explained. 
CONFIDENTIAL 
Page 103 
01 November 2018 


GS-9131(+BIC+TAF) 
Protocol GS-US-442-4148 
Gilead Sciences, Inc. 
Final 
Amendment 3 
k 
m 
n 
0 
p 
r 
HIV-1 genotype/phenotype testing for subjects with confomed virologic failure and HIV-1 RNA >200 copies/nll,, at early study discontinuation or Week 24. Following 
virnlogic rebound, subjects will be asked to retmn to the clinic (1-3 weeks later) prior to the next scheduled visit or at the next scheduled study visit for a HIV-1 RNA and 
HIV-1 genotype/phenotype (reverse transcriptase, protease, and integrase) blood draw. Based on the results of this testing, subjects should be managed according to the 
Virologic Rebound Schema (Section 6.10). 
Collected fasted no food or drinks, except water, at least 8 hours prior to blood collection) only at Pait 1 - Day 1, Pait 2 - Day 1, Week 12, and Week 24, __ 
. Collected non-fasted at all other visits. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must~ 
1om·s rn a aste state to ·aw blood for the assessments. 
Females of childbearing potential only. Urine and serum pregnancy test will be done at Screening and Day land a urine pregnancy test on Days 10 and14. If the mine and 
serum test is positive at screening, the subject will not be enrolled. A positive mine pregnancy test at any visit will be confinued with a serum test. If the test is positive the 
subject will be discontinued from the study. 
Hepatitis C Virus (HCF Ab) serology. Subjects who are HCVAb positive will have a HCV RNA test performed. 
Timed PK Sample: collected at predose and one within 15 minutes-4 hours post dose (Part 2 - Weeks 4, 12 and 18) 
Single Anytime PK Sample: collected without regard to time of dosing (Part 2 - Weeks 2, 8 and 24) 
Intensive PK samples will be collected on Pait 1 - Day 10 for Sentinel Coho1t 1 and Day 14 for Sentinel Coho1t 2 and Randomized Coho1t. Prior to the administration of 
study dmg, a predose (<5 minutes prior to dosing) blood sample will be collected. Subjects will then take an observed dose of study drug at the clinic. Additional blood 
sam !es will be collected at 0.5 1 1.5 2 3 4 6 8 and 24 hour est dose. 
r 
PBMC co echon on Day 10 or Sentrne Co ort 1 an Day 14 or Sentme Co 101t 2 an Ran onuze Co 101t : Pre ose (<5 minutes prior to dosing), 1, 2, 6 and 24 hom·s post 
dose. 
s 
Randomization may be performed up to 3 days prior to the in-clinic Day 1 visit provided that all screening procedm·es have been completed, and subject eligibility has been 
confomed. 
All study medication in Pait 1 will be delivered by directly observed therapy on Days 1-14. 
u 
Subjects must be reminded to take study drug at the same time each day except on days with Timed PK sample and Intensive PK. 
v 
For female subject post-menopausal for less than two years, ifFSH <40 mIU/ nll, a semm pregnancy test will be required 
CONFIDENTIAL 
Page 104 
01 November 2018 


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 105
01 November 2018
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Grade 1 
~---Gt-·a_d_e_2_-~II ___ 
G_ra_d_e_3_-~II 
._ -----G--ra-d-e _-i ____ 
! 
! 
May continue dosing 
Repeat lab to 
at the discretion of 
confirm toxicity 
the investigator 
grade 
1 
If confinned and possibly anc or probably related to investigational 
medicinal products: 
1. 
\Vithhold in ·e,,tigational medicinal products until ~ Grade 2 
2. 
Restrut all in estigatioual medicinal prnducts at foll dose 
l 
If Grade 3 or 4 rec111rence that is coufinned and possibly or probabl) 
related to investigational medicinal products. discontinue all 
in estigationiil medicinal products dosing pennru1ently 
l 
Repeat lab to 
confinn toxicity 
grade 
l 
If C onfinnecl ru1d unrelated to 
estigational medicinal products, 
ing may continue at the discretion 
1e in ·estigator 
lllY 
dos 
oft! 
If confinued and 
possibly or probably 
related to 
in ·estigational 
medicinal products, 
discontinue 
in ·estigational 
medicinal products 
dosing pennanently ru1d 
follow at periodic 
inte1vals at least ,veekly 
until a reh1111 to 
baseline or is otherwise 
explained 
If Grade 3 or 4 rec111i-e11ce that is considered unrelated to 
investigatioual medicinal products. continue all innstigational 
medicinnl products nt the same dose at the discretion of the 
investigator 


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 106
01 November 2018
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 
Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 
Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4 Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 107
01 November 2018
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 108
01 November 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 t o <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 110
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia 
Adult and Pediatric
≥ 1 year
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


GS-9131(+BIC+TAF)
Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 111
01 November 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


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Amendment 3
CONFIDENTIAL
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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Protocol GS-US-442-4148
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes:

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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Amendment 3
CONFIDENTIAL
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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Amendment 3
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Amendment 3
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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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Amendment 3
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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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Amendment 3
CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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Final
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Amendment 3
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 
48 hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood 
(eg, agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see 
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weak-ness causing no 
or minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or 
minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of 
Existing Epilepsy the 
Grades Should Be Based 
on an Increase from 
Previous Level of Control 
to Any of These Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or minimal 
interference with usual social 
& functional activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic 
self-care functions


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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC 
Guidelines)
1. Candidiasis of bronchi, trachea, or lungs
2. Candidiasis of esophagus
3. Cervical cancer, invasive
4. Coccidioidomycosis, disseminated or extrapulmonary
5. Cryptococcosis, extrapulmonary
6. Cryptosporidiosis, chronic intestinal (1 month duration)
7. Cytomegalovirus disease (other than liver, spleen or nodes)
8. Cytomegalovirus retinitis (with loss of vision)
9. Encephalopathy, HIV-related
10. Herpes simplex: chronic ulcer(s) (1 month duration); or bronchitis, pneumonitis or 
esophagitis
11. Histoplasmosis, disseminated or extrapulmonary
12. Isosporiasis, chronic intestinal (1 month duration)
13. Kaposi’s sarcoma
14. Lymphoma, Burkitt’s (or equivalent term)
15. Lymphoma, immunoblastic (or equivalent term)
16. Lymphoma, primary, of brain
17. Mycobacterium avium complex or Myobacterium kansasii, disseminated or extrapulmonary
18. Mycobacterium tuberculosis, of any site,  pulmonary, disseminated or extrapulmonary
19. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
20. Pneumocystis jirovecii (previously known as “Pneumocystis carinii) pneumonia
21. Pneumonia, recurrent
22. Progressive multifocal leukoencephalopathy
23. Salmonella septicemia, recurrent
24. Toxoplasmosis of brain
25. Wasting syndrome attributed to HIV infection
CDC Stage-3-Defining Opportunistic Illnesses in HIV Infection - 2014 {Schneider 2008}


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Appendix 7.
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 subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with 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 of any age with amenorrhea of > 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 subject of any age.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
The data on GS-9131 in pregnant women is limited or not available.  There is no suspicion of 
human teratogenicity based on class effects or genotoxic potential.  Relevant non-clinical 
reproductive toxicity studies for human pregnancy do not indicate a strong suspicion of human 
teratogenicity/fetotoxicity. In female rats, effects on embryo-fetal viability were noted, and 
effects in humans are unknown. GS-9131 and DRV + RTV have demonstrated/suspected or have
insufficient data to exclude the possibility of a clinically relevant interactions with hormonal 
contraception that results in reduced contraception efficacy.  Therefore, contraceptive steroids 
are not recommended as a contraceptive method either solely or as a part of a contraceptive 
regimen. Please refer to the latest version of the investigator’s brochure for additional 
information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  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 on the Baseline/Day 1 visit prior to randomization.  
Pregnancy tests will be performed as defined in the protocol. A pregnancy test will be performed 
at the end of systemic exposure after the last study drug dose. In the event of a delayed menstrual 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is even true for women of childbearing potential with infrequent or irregular 
periods. Female subjects must agree to one of the following from Screening until 30 days 
following the end of relevant systemic exposure.


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
Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Instructions for 
reporting pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1.


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Appendix 8.
Prior and Concomitant Medications For Subjects in Sentinel Cohort 1 
and Sentinel Cohort 1 Subjects Who Go on to Part 2: bictegravir 
GS-9131 + BIC + DRV + RTV
Subjects receiving oral contraceptives or patch contraceptives must consider other methods of 
contraception as concentrations of ethinyl estradiol, norgestimate or norethindrone may increase 
or decrease upon coadminstration with study drug.
Concomitant use of some medications and herbal/natural supplements with study drug may result 
in pharmacokinetic interactions resulting in increases or decreases in exposure of study drugs or 
these medications.
Medications listed in the following table and herbal/natural supplements are excluded or should 
be used with caution while subjects are participating in the study. During Part 1 of the study, 
physicians should also refer to the prescribing information for the current background regimen in 
addition to the recommendations listed in the table below. Subjects should discontinue 
disallowed concomitant medications 30 days prior to initiation of study drug. 
Prior and Concomitant Medications
Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Acid Reducing Agents
Antacids
Buffered Medications
Concentration of study drug (BIC) may 
decrease with antacids. Subjects may not 
take antacids (e.g,, Tums, or Rolaids); the 
ulcer medication sucralfate (Carafate); or 
vitamin or mineral supplements that contain 
calcium, iron or zinc for a minimum of 
6 hours before and 2 hours after any dose of 
study medication.
Alpha 1-adrenoreceptor 
antagonist
Alfuzosin
Analeptic
Modafinil
Analgesics
Propoxyphene:
Concentrations may increase with study 
drug(s); clinical monitoring is 
recommended.


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Antiarrhythmic Agent
Dofetilide, Dronedarone, Amiodarone, 
Bepridil, Quinidine, Systemic 
Lidocaine
Flecainide,
Propafenone, 
Mexilitine, Disopyramide:
Concentrations may increase with study 
drug(s). Therapeutic concentration 
monitoring, if available, is recommended for 
antiarrhythmics when coadministered with 
study drug(s).
Digoxin
The lowest dose of digoxin should initially 
be prescribed. The serum digoxin 
concentrations should be monitored and 
used for titration of digoxin dose to obtain 
the desired clinical effect.
Anti-anginal
Ranolazine
Antibacterials
No dose adjustment is needed when co-
administered with study drug(s) for patients 
with normal renal function. For co-
administration of clarithromycin and study 
drug(s) in patients with renal impairment, 
the following dose adjustments should be 
considered:

For subjects with CLcr of 
30-60 mL/min, the dose of 
clarithromycin should be reduced by 
50%

For subjects with CLcr of <30 mL/min, 
the dose of clarithromycin should be 
reduced by 75%
Anticoagulants
Apixaban, Rivaroxaban: Use with study 
drug is not recommended.
Dabigatran Etexilate: Concomitant use with 
dabigatran etexilate is not recommended in 
specific renal impairment groups (depending 
on the indication). Please see the dabigatran 
prescribing information for specific 
recommendations.
Warfarin: Concentrations may be affected 
by study drug(s); frequent INR 
(International Normalized Ratio) monitoring 
is recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Clonazepam, Ethosuximide, Concentrations 
may increase with study drug(s). 
Divalproex, Lamotrigine: Concentrations 
may be affected by study drug(s).
Clinical monitoring is recommended.


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Antidepressants
SSRIs, TCAs or trazodone: When 
coadministering with study drug, careful 
dose titration of the antidepressant to the 
desired effect, including using the lowest 
feasibly initial or maintenance dose, and 
monitoring for antidepressant response are 
recommended.
Antifungals
Monitor for increased study drug adverse 
reactions with concomitant use of 
itraconazole, ketoconazole or posaconazole
Ketoconazole and Itraconazole:
When co-administration of required, the 
daily dose of ketoconazole or itraconazole 
should not exceed 200 mg with monitoring 
for increased antifungal adverse events. 
Co-administration of voriconazole is not 
recommended unless benefit/risk assessment 
justifies the use of voriconazole. 
Subjects receiving antifungals should be
monitored for adequate clinical response.
Anti-Gout
Cochicine (in subjects with renal or 
hepatic impairment), Probenecid
For subjects without renal or hepatic 
impairment:

Treatment of gout 
flares - co-administration of colchicine: 
0.6 mg (1 tablet) x 1 dose followed by 
0.3 mg (half tablet) 1 hour later. 
Treatment course to be repeated no 
earlier than 3 days.

Prophylaxis of gout 
flares - co-administration of colchine: If 
the original regimen was 0.6 mg twice a 
day, the regimen should be adjusted to 
0.3 mg once a day. If the original 
regimen was 0.6 mg once a day, the 
regimen should be adjusted to 0.3 mg 
once every other day.

Treatment of familial Mediterranean 
fever – coadministration of colchicine: 
Maximum daily dose of 0.6 mg (given 
as 0.3 mg twice a day)
Anti-malarial
Artemether/lumefantrine: Monitor for 
potential decrease of antimalarial efficacy or 
potential QT prolongation
Antihistamines
Astemizole, Terfenadine


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Anti-psychotic
Lurasidone, Pimozide, Quetiapine
Perphenazine, Risperidone, Thioridazine: A 
dose decrease in anti-psychotics that are 
metabolized by CYP3A or CYP2D6 may be 
needed when co-administered with study 
drug.
Antiretrovirals
Any antiretroviral drug that is not part 
of the study regimen
Β-blockers
Clinical monitoring is recommended for 
con-administration with beta blockers that 
are metabolized by CYP2D6 (e.g., 
metoprolol, timolol). A dose decrease may 
be needed for these drugs when co-
administered with study drug(s), and a lower 
dose of the beta blocker should be 
considered.
Calcium Channel 
Blockers
Bepridil
Clinical monitoring is recommended for 
co-administration with calcium channel 
blockers metabolized by CYP3A 
(e.g., felodipine, nifedipine, 
verapamil, diltiazem, amlodipine)
Corticosteroids: 
Inhaled/Nasal 
Concomitant use of inhaled or nasal 
fluticasone or other corticosteroids 
(e.g., budesonide) that are metabolized by 
CYP3A and study drug(s) may result in 
reduced serum cortisol concentrations.
Alternatives should be considered, 
particularly for long term use.
Corticosteroids: Systemic
All agents, including dexamethasone
Use of Prednisone as a steroid burst 
(≤1 week of use) should be monitored 
appropriately.
Co-administration with dexamethasone or 
other corticosteroids that induce CYP3A 
may result in loss of therapeutic effect of 
and development of resistance to study drug.
Co-administration of study drug with 
corticosteroids that are metabolized by 
CYP3A, particularly for long term use, may 
increase the risk for development of 
systemic corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression. Consider the potential benefit 
of treatment versus the risk of systemic 
corticosteroid effects.


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Endothelin receptor 
antagonists
Bosentan: Initiation of bosentan in subjects 
taking study drug: In subjects who have 
been receiving study drug for at least 
10 days, start bosentan at 62.5 mg once daily 
or every other day based upon individual 
tolerability.
Initiation of study drug in subjects on 
bosentan: Discontinue use of bosentan at 
least 36 hours prior to initiation of study 
drug. After at least 10 days following 
initiation of study drug, resume bosentan at 
62.5 mg once daily or every other day based 
upon individual tolerability.
Ergot Derivatives
Dihydroergotamine, Ergotamine, 
Ergonovine, Methylergonovine, 
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase 
Inhibitor
Lovastatin, Simvastatin
Atorvastatin, fluvastatin, pitavastatin, 
rosuvastatin, pravastatin: Concentrations 
may increase with study drug(s). Start with 
the lowest recommended dose and titrate 
while monitoring for safety. Do not exceed 
atorvastatin 20 mg/day.
Oral Contraceptives
Effective and alternative (non-hormonal) 
forms of contraception should be considered.
Inhaled beta agonist
Salmeterol: Coadministration with study 
drug(s) may result in increased plasma 
concentrations of salmeterol, which is 
associated with the potential for serious 
and/or life threatening reactions. 
Coadministration is not recommended.
Narcotic analgesics 
metabolized by CYP3A: 
Fentanyl, oxycodone: Careful monitoring of 
therapeutic effects and adverse reactions 
associated with CYP3A-metabolized 
narcotic analgesics (including potentially 
fatal respiratory depression) is recommended 
with co-administration with study drug. 
Tramadol: A dose decrease may be needed 
for tramadol with concomitant use.


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Narcotic analgesic for 
treatment of opioid 
dependence: 
No dose adjustment for buprenorphine or
buprenorphine/naloxone is required with 
concurrent administration of study drug(s). 
Clinical monitoring is recommended if study 
drug(s) and buprenorphine or
buprenorphine/naloxone are coadministered. 
No adjustment of methadone dosage is 
required when initiating co-administration of
study drug(s).
However, clinical monitoring is 
recommended as the dose of methadone 
during maintenance therapy may need to be 
adjusted in some patients.
Meperidine (Pethidine): Dosage increase and 
long-term use are not recommended due to 
increased levels of metabolite 
normeperidine, which has analgesic and 
CNS stimulant (e.g., seizures) activities.
PDE-5 Inhibitor
Sildenafil for treatment of PAH
Avanafil: Co-administration with avanafil is 
not recommended. 
Tadalafil:
Initiation of tadalafil in subjects taking study 
drug: In subjects receiving study drug for at 
least one week, start tadalafil at 20 mg once 
daily. Increase to 40 mg once daily based
upon individual tolerability. 
Initiation of study drug in subjects taking 
tadalafil: Avoid use of tadalafil during the 
initiation of study drug. Stop tadalafil at 
least 24 hours prior to starting study drug. At 
least one week following the initiation of 
study drug, resume tadalfil at 20 mg once 
daily. Increase to 40 mg once daily based 
upon individual tolerability.
Use of PDE-5 inhibitors for erectile 
dysfunction: Sildenafil at a single dose not 
exceeding 25 mg in 48 hours, vardenafil at a 
single dose not exceeding 2.5 mg in 
72 hours, or tadalafil at a single dose not 
exceeding 10 mg in 72 hours can be used 
with increased monitoring for 
PDE-5 inhibitor –associated adverse 
reactions.
Proton pump inhibitor:
Omeprazole
When omeprazole is co-administered with 
study drug(s), monitor patients for decrease 
efficacy of omeptrazole. Consider increasing 
the omeprazole dose in patients whose 
symptoms are not well controlled; avoid use 
of more than 40 mg per day of omeprazole.


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Drug Class
Agents Disallowed*
Agents To Be Used With Caution
Sedative/hypnotic
Orally administered Midazolam, 
Triazolam
Buspirone, Clorazepate, Diazepam, 
Estazolam, Flurazepam, Zolpidem: A lower 
dose should be considered and dose titration 
is recommended. Monitoring for increased 
and prolonged effects or adverse reactions is 
recommended.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the
Gilead Medical Monitor must be consulted prior to initiation of the new medication. In instances 
where an excluded medication is initiated prior to discussion with the Sponsor, the Investigator 
must notify Gilead as soon as he/she is aware of the use of the excluded medication.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2 Study to Evaluate the Efficacy of GS-9131 Functional 
Monotherapy in HIV-1-Infected Adults Failing a Nucleos(t)ide 
Reverse Transcriptase Inhibitor-Containing Regimen with 
Nucleos(t)ide Reverse Transcriptase Inhibitor Resistant Virus
Name of Test Drug:
GS-9131(+Bictegravir+Tenofovir Alafenamide)
Study Number:
GS-US-442-4148
Protocol Version (Date):
Amendment 3 (01 November 2018)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
03 March 2020
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power..........................................................................................................................14
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................15
2.1.
Day 15 Analysis.....................................................................................................................................15
2.2.
Data Monitoring Committee Analysis ...................................................................................................15
2.3.
Week 24 Interim Analysis......................................................................................................................15
2.4.
Final Analysis ........................................................................................................................................15
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................16
3.1.
Analysis Sets..........................................................................................................................................16
3.1.1.
All Enrolled Analysis Set.....................................................................................................16
3.1.2.
Safety Analysis Set...............................................................................................................16
3.1.3.
Pharmacokinetic Analysis Set..............................................................................................16
3.1.4.
PBMC PK Analysis Set........................................................................................................16
3.2.
Subject Grouping ...................................................................................................................................17
3.3.
Strata and Covariates..............................................................................................................................17
3.4.
Examination of Subject Subgroups........................................................................................................17
3.5.
Multiple Comparisons............................................................................................................................17
3.6.
Missing Data and Outliers......................................................................................................................17
3.6.1.
Missing Data ........................................................................................................................17
3.6.2.
Outliers.................................................................................................................................17
3.7.
Data Handling Conventions and Transformations .................................................................................17
3.8.
Analysis Windows .................................................................................................................................19
3.8.1.
Definition of Predose, Postdose, and Study Day for Part 1..................................................19
3.8.2.
Analysis Visit Windows for Part 1.......................................................................................19
3.8.3.
Selection of Data in the Event of Multiple Records on the Same Day.................................21
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment and Disposition.......................................................................................................22
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................23
4.3.
Protocol Deviations................................................................................................................................23
5.
BASELINE CHARACTERISTICS....................................................................................................................24
5.1.
Demographics and Baseline Characteristics ..........................................................................................24
5.2.
Baseline Disease Characteristics............................................................................................................24
5.3.
Medical History......................................................................................................................................24
6.
EFFICACY ANALYSES ...................................................................................................................................25
7.
SAFETY ANALYSES........................................................................................................................................26
7.1.
Adverse Events and Deaths....................................................................................................................26
7.1.1.
Adverse Event Dictionary ....................................................................................................26
7.1.2.
Adverse Event Severity........................................................................................................26


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7.1.3.
Relationship of Adverse Events to Study Drug....................................................................26
7.1.4.
Serious Adverse Events........................................................................................................26
7.1.5.
Treatment-Emergent Adverse Events...................................................................................27
7.1.6.
Summaries of Adverse Events and Death ............................................................................27
7.2.
Laboratory Evaluations ..........................................................................................................................28
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................29
7.2.2.
Graded Laboratory Values ...................................................................................................29
7.3.
Body Weight, Height, and Vital Signs...................................................................................................31
7.4.
Prior and Concomitant Medications.......................................................................................................31
7.4.1.
Antiretroviral Medications ...................................................................................................31
7.4.2.
Concomitant Non-Antiretroviral Medications......................................................................31
7.5.
Electrocardiogram Results .....................................................................................................................32
7.6.
Other Safety Measures ...........................................................................................................................32
7.7.
Changes from Protocol-Specified Safety Analyses................................................................................32
8.
PHARMACOKINETIC ANALYSES ................................................................................................................33
8.1.
Estimation of Pharmacokinetic Parameters............................................................................................33
8.2.
Pharmacokinetic Parameters ..................................................................................................................33
8.3.
Statistical Analysis Methods ..................................................................................................................34
9.
REFERENCES ...................................................................................................................................................36
10.
SOFTWARE.......................................................................................................................................................37
11.
SAP REVISION..................................................................................................................................................38
12.
APPENDICES ....................................................................................................................................................39
Appendix 1.
Study Procedures Table – Cohort 1........................................................................................40
Appendix 2.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1 ..............................43
Appendix 3.
Programming Specification....................................................................................................48
LIST OF IN-TEXT TABLES
Table 3-1.
Predose and Postdose Visits for HIV-1 RNA.........................................................................20
Table 3-2.
Predose and Postdose Visits for Laboratory Tests (Hematology, Chemistry, and 
Urinalysis), and Vital Signs....................................................................................................20
Table 3-3.
Predose and Postdose Visits for CD4 Cell Count and ECG ...................................................21
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................33
Table 8-2.
Pharmacokinetic Parameters for Each Analyte ......................................................................34


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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
BIC
Bictegravir, GS-9883, B
BLQ
below limit of quantitation
BMI
body mass index
BSA
body surface area
CD4
cluster determinant 4
CG
Cockcroft-Gault
CI
confidence interval
CRF
case report form
CSR
clinical study report 
DOB
date of birth
DOT
directly observed therapy
DP
diphosphate
DNA
Deoxyribonucleic Acid
DRV
darunavir
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
eGFR(CG)
estimated glomerular filtration rate using Cockcroft-Gault formula
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
Gilead
Gilead Sciences, Inc.
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV-1
human immunodeficiency virus (Type 1) 
HLGT
high level group term
HLT
high level term
ID
identification
IDMC
independent data monitoring committee
INR
international normalized ratio
INSTI
integrase strand-transfer inhibitor
LDL
low density lipoprotein
LLOQ
lower limit of quantitation
LLT
lowest level term


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MedDRA
Medical Dictionary for Regulatory Activities
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
PBMC
peripheral blood mononuclear cell
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term
PTM
placebo-to-match
Q
quartile
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
Ritonavir
SAE
serious adverse events
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
TAF
tenofovir alafenamide 
TAM
thymidine analogue mutations
TE
treatment-experienced
TEAE
treatment-emergent AE
TFL
tables, figures, and listings
TFV
tenofovir
ULN
upper limit of normal
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
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
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 2 
by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) of the final analysis for Study 
GS-US-442-4148, which will be performed when all subjects have completed or prematurely 
discontinued from the study. This SAP is based on the study protocol amendment 3 dated 
01 November 2018 and the electronic case report form (eCRF). The SAP will be finalized before 
data finalization. Any changes made after the finalization of the SAP will be documented in the 
clinical study report (CSR).
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the short-term antiviral potency of GS-9131 functional monotherapy compared 
to placebo-to-match (PTM) GS-9131, each administered once daily with the existing failing 
antiretroviral (ARV) regimen, as demonstrated by the proportion of subjects achieving
human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) > 0.5 log10 decreases 
from baseline through up to 14 days of therapy.
The secondary objectives of this study are as follows:
Part 1

To evaluate the efficacy of GS-9131 functional monotherapy as determined by the change 
from baseline in log10 HIV-1 RNA at Day 11 (Sentinel Cohort 1) or Day 15 (Sentinel 
Cohort 2 and Randomized Cohort).
Part 2

To evaluate the safety and efficacy of a regimen containing GS-9131 + bictegravir (BIC) + 
darunavir (DRV) + ritonavir (RTV) through 24 weeks of treatment in subjects from Sentinel 
Cohort 1 switched from a failing regimen.

To evaluate the safety and efficacy of a regimen containing GS-9131 + BIC + tenofovir 
alafenamide (TAF) through 24 weeks of treatment in subjects from Sentinel Cohort 2 and 
Randomized Cohort who switched from a failing regimen.

To characterize the pharmacokinetics (PK) of GS-9131 in treatment-experienced (TE)
patients.

To evaluate the number of subjects with treatment-emergent Nucleos(t)ide Reverse 
Transcriptase Inhibitor (NRTI), Protease Inhibitor (PI), and Integrase Strand-transfer 
Inhibitors (INSTI) mutations at the time of virologic failure.


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1.2.
Study Design
Part 1: GS-9131 Functional Monotherapy 
The study will consist of 3 cohorts - 2 Sentinel Cohorts and 1 Randomized Cohort.
Sentinel Cohort 1 will enroll 10 TE viremic HIV-1 subjects to receive open-label GS-9131 
60 mg for 10 days in addition to their current failing ARV regimen.
Sentinel Cohort 2 will enroll up to 10 TE viremic HIV-1 subjects to receive open-label 
GS-9131 180 mg for 14 days in addition to their current failing ARV regimen.
Sentinel cohort subjects who meet criteria for Part 2, will transition to Part 2 and not participate 
in the randomized portion of this study.
Randomized Cohort: The Sentinel Cohorts will be followed by a Randomized Cohort that is a 
double-blind comparison of the addition of GS-9131 (up to 180 mg), or PTM to the current 
failing ARV regimen in viremic HIV-1 positive adults. Randomization and dosing into the 
Randomized Cohort will begin after review of the clinical data in the second Sentinel Cohort.
In the Randomized Cohort, up to 48 subjects failing their current ARV regimen will be 
randomized 1:1:1:1 to GS-9131 (up to 3 active dose levels, up to 180 mg), or PTM. The 
GS-9131 dose for Treatment Arms A-C will be determined following review of the safety, 
activity and available PK data from Sentinel Cohort 2.
GS-9131 will be added to their failing regimen for 14 days as follows:
Treatment Arms A-C: GS-9131 once daily + current failing antiretroviral therapy (ART) 
regimen (n 12 per Treatment Arm)
Treatment Arm D: PTM + current failing ART regimen (n 12)
Randomization will be stratified by HIV-1 RNA level (≤ 100,000 copies/mL and 
> 100,000 copies/mL) at screening.
Study medication will be administered by directly observed therapy (DOT).
Part 2: GS-9131 + BIC + DRV + RTV or GS-9131 + BIC + TAF Combination Therapy
GS-9131(60 mg) + BIC (30 mg) + DRV (800 mg) + RTV (100 mg) (Sentinel Cohort 1)
Subjects who successfully complete all study doses in Sentinel Cohort 1 and show a reduction in 
plasma HIV RNA > 0.5 log10 from their pre-GS-9131 baseline following functional monotherapy
will discontinue their current failing regimen and start an optimized regimen consisting of 
GS-9131 (60 mg) + BIC + DRV + RTV for at least 24 weeks.


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GS-9131(up to 180 mg) + BIC (75 mg) + TAF (25 mg) (Sentinel Cohort 2 and Randomized 
Cohort) 
Subjects who successfully complete all study doses in Sentinel Cohort 2 and Randomized 
Cohort (A-C), and show a reduction in plasma HIV-1 RNA> 0.5 log10 from their pre-GS-9131 
baseline during functional monotherapy will discontinue their current failing regimen and start 
an optimized regimen consisting of GS-9131 + BIC + TAF for at least 24 weeks. All Subjects 
randomized to the placebo arm (Cohort D) will discontinue their current failing regimen and start 
a regimen consisting of GS-9131(180 mg) + BIC + TAF for at least 24 weeks. 
The GS-9131 dose for the open label extension will be detennined following review of Week 12 
efficacy and safety data from Part 2. 
Key Eligibilitv Criteria 
HIV-1 infected subjects who meet the following criteria: 
• 
Non-pregnant/non-lactating females,~ 18 years of age at Screening. Females of childbearing 
potential (as defined in Protocol Appendix 7) must have a negative serum pregnancy test at 
Screening and Day 1. 
• 
Subjects of childbearing potential who engage in heterosexual intercourse must agree to use 
protocol-specified method(s) of contraception as defined in Protocol Appendix 7. 
• 
Estimated glomerular filtration rate (eGFR) (Cockcroft-Gault [CG] equation)~ 70 mUmin. 
• 
Currently taking a failing ARV regimen that contains 2 NRTls and an NNRTI. 
• 
HIV-1 RNA 
500 copies/mL at Screening. 
• 
CD4 > 100 cells/µL at Screening. 
• 
Have a screening genotype showing at least the following resistance mutation profile (a local 
genotype at the Screening visit is acceptable for enrollment upon review by the Sponsor): 
K65Ror 
at least 3 thymidine analogue mutations (TAMs); TAMs are defined as: M41L, D67N, 
K70R, L210W, T215F/Y, or K219Q/E/N/R in reverse transcriptase (RT) or 
Q151M 
and at least one primary resistance mutation to an NNRTI 
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No prior or current ARV regimens containing INSTI or PI. 
Version 1.0 
Final 
• 
No evidence of chronic viral hepatitis B or C infection. Note: Subjects with positive hepatitis 
C virus (HCV) antibody and without detectable HCV RNA are pennitted to enroll. 
• 
No evidence of active AIDS-related opportunistic infection, including tuberculosis. 
Studv Periods / Phases 
Part 1: 10 days for Sentinel Cohort 1, and 14 days for Sentinel Cohort 2 and Randomized Cohort. 
Part 2: At least 24 weeks. 
Schedule of Assessments 
At Screening, laboratory analyses (hematology, chemistry, urinalysis, and serum pregnancy test 
[for females of childbearing potential]), HIV-1 RNA, cluster detenninant 4 (CD4) cell com1t, 
vital signs, electrocardiogram (ECG), complete physical examination, and eGFR will be 
perfonned. HIV-1 protease, reverse transcriptase genotype/phenotype, and hepatitis B virus 
(HBV) and HCV serologies will be analyzed. 
Part 1: 
Sentinel Cohort 1 (GS-9131 60 mg plus Current Failing Regimen) 
Following Screening and Day 1 (baseline) visits, subjects will be required to visit the clinic daily 
on Days 2-11. All study medication will be delivered by DOT on Days 1-10. 
Laboratory analyses (hematology, chemistry, and urinalysis) will be perfonned at Day 1 
(baseline), Day 7, and Day 11. A fasting metabolic profile will be perfonned on Day 1. Urine 
and serum pregnancy test (females of childbearing potential only) will be done at Screening and 
Day 1 and a urine pregnancy test on Day 11; positive urine pregnancy test on Day 11 will be 
confinned with a serum pregnancy test. CD4 T cell count will be perfonned at Screening, Day 1 
(baseline), and Day 11. A plasma sample for phenotypic and genotypic testing of HIV-1 
resistance will be collected at Screening, Day 1, and Day 11. A complete physical exa1nination 
will be perfonned at Screening, Day 1 (baseline), and Day 11. Symptom driven physical exam 
will be perfonned on Day 2 and Day 7. ECGs will be perfonned at Screening, Day 1, and 
Day 11. 
On Day 10, all subjects will participate in a PK evaluation. 
Samples for HIV-1 RNA will be collected at Screening, Day 1 (baseline), and Days 2, 3, 7, 10, 
and 11. 
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Assessments of adverse events (AEs) and concomitant medications will be performed at each 
visit.
Sentinel Cohort 2 (GS-9131 180 mg plus Current Failing Regimen) and Randomized 
Cohort (GS-9131 or PTM plus Current Failing Regimen)
Following Screening and Day 1 (baseline) visits, all study medication will be delivered by DOT 
on Days 1-14.
Laboratory analyses (hematology, chemistry, and urinalysis) will be performed at Days 1 
(baseline), 3, 5, 7, 10, 14, and 15. A fasting metabolic profile will be performed on Day 1. Urine 
and serum pregnancy test (females of childbearing potential only) will be done at Screening and 
Day 1 and a urine pregnancy test on Days 10 and 14; positive urine pregnancy test will be 
confirmed with a serum pregnancy test. CD4 T cell count will be performed at Screening and 
Days 1 (baseline), 10, 14, and 15. A plasma sample for phenotypic and genotypic testing of 
HIV-1 resistance will be collected at Screening and Days 1, 10, 14, and 15. A whole blood 
sample for genotypic testing of HIV-1 resistance will be collected at Day 1. A complete physical 
examination will be performed at Screening and Days 1 (baseline), and 14. Symptom driven 
physical exam will be performed on Days 2 and 7. ECGs will be performed at Screening, Day 1 
and Day 15.
On Day 14, all subjects will participate in a PK evaluation.
Samples for HIV-1 RNA will be collected at Screening and Days 1 (baseline), 3, 7, 10, 14, and 
15.
Assessments of AEs and concomitant medications will be performed at each visit.
Part 2:
GS-9131 + BIC + DRV + RTV Regimen (Sentinel Cohort 1)
Subjects in Sentinel Cohort 1 who had a > 0.5 log10 decline in HIV-1 RNA will discontinue their 
current failing regimen and begin treatment with GS-9131 + BIC + DRV + RTV once daily for
24 weeks. Subjects in Sentinel Cohort 1 who had a ≤ 0.5 log10 decline in HIV-1 RNA are not 
eligible to continue onto Part 2 and will be discontinued from the study.
At their Day 1 visit for Part 2, AEs, concomitant medications, drug accountability, vital signs, 
physical examinations, HIV-1 RNA, estimated GFR, hematology, chemistry, CD4 cell count, 
and urinalysis will be performed.
All subjects will be required to visit the clinic on Day 1, and Weeks 1, 2, 4, 8, 12, 18, and 24. At 
each visit, AEs, concomitant medications, drug accountability, hematology, chemistry, HIV-1 
RNA, CD4 cell count, vital signs, and estimated GFR will be evaluated. A fasting metabolic 
profile will be performed on Day 1, Week 12 and 24 visits. A complete physical examination 
will be done at Day 1, Week 12 and 24 visits. A symptom directed physical examination will be 
done at all other visits. Urinalysis will be performed at Day 1, and Week 4, 12, and 24 visits. 


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Urine pregnancy test (females of childbearing potential only) will be done on Day 1, and Weeks 
4, 8, 12, 18, and 24; positive urine pregnancy test will be confirmed with a serum pregnancy test. 
GS-9131 + BIC + TAF (Sentinel Cohort 2 and Randomized Cohort) 
Subjects in the Sentinel Cohort 2 or Randomized Cohort (A-C) who had a> 0.5 log1 o decline in 
HIV-1 RNA in Part 1 will discontinue their current failing regimen and begin treatment with 
GS-9131 + BIC + TAF once daily for 24 weeks. Subjects who had a :S 0.5 log1odecline in HIV-1 
RNA are not eligible to continue onto Part 2 and will be discontinued from the study. Subjects in 
Randomized Cohort D will begin treatment with GS-9131(180 mg) + BIC (75 mg) + 
TAF (25 mg) once daily for 24 weeks after successful completion of Part 1. 
At their Day 1 visit for Part 2, AEs, concomitant medications, drug accountability, vital signs, 
physical examinations, HIV-1 RNA, estimated GFR, hematology, chemistry, CD4 cell count, 
and urinalysis will be perfonned. 
All subjects will be required to visit the clinic on Day 1, and Weeks 1, 2, 4, 8, 12, 18, and 24. At 
each visit, AEs, concomitant medications, drug accountability, hematology, chemistry, HIV-1 
RNA, CD4 cell com1t, vital signs, and estimated GFR will be evaluated. A fasting metabolic 
profile will be perfonned on Day 1, Week 12 and 24 visits. A complete physical examination 
will be done at Day 1, Week 12 and 24 visits. A symptom directed physical examination will be 
done at all other visits. Urinalysis will be perfonned at Day 1, and Week 4, 12, and 24 visits. 
Urine pregnancy test (females of childbearing potential only) will be done on Day 1, and 
Weeks 4, 8, 12, 18, and 24; positive urine pregnancy test will be confinned with a sermn 
pregnancy test. 
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Sentinel Cohort 1 (60 mg): Intensive plasma and PBMC samples will be collected in all 
subjects on Day 10. Serial blood samples for plasma and peripheral blood mononuclear cell 
(PBMC) PK assessments will be collected at the following timepoints: 
Plasma collection on Day 10: Predose ( < 5 minutes prior to dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 
24 hours post dose. 
PBMC collection on Day 10: Predose (< 5 minutes prior to dosing), 1, 2, 6, and 24 hours post 
dose. 
Sentinel Cohort 2 080 mg) and Randomized Cohort: Intensive plasma and PBMC PK 
samples will be collected in all subjects on Day 14. Serial blood samples for plasma and PBMC 
PK assessments will be collected at the following timepoints: 
Plasma collection on Day 14: Predose ( < 5 minutes prior to dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 
24 hours post dose. 
PBMC collection on Day 14: Predose (< 5 minutes prior to dosing), 1, 2, 6, and 24 hours post 
dose. 
The PK of GS-9131 and its metabolite, GS-9148, in plasma, will be evaluated. The PK of 
GS-9148-diphosphate (DP) in PBMCs and the PK of other analytes may be explored. 
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Randomization
In the Randomized cohort, up to 48 subjects failing their current ARV regimen will be 
randomized 1:1:1:1 to GS-9131 (up to three active dose levels, up to 180 mg), or PTM.
1.3.
Sample Size and Power
For the sample size and power calculation for the randomized cohort in Part 1, assuming that 
70% of subjects in each GS-9131 treatment group and 8.3% in the placebo group achieve 
> 0.5 log10 HIV-1 RNA decrease from baseline at Day 15, a sample size of 12 subjects per 
treatment group (48 in total) provides 85% power to detect the difference in the response rates 
between at least one GS-9131 treatment group and placebo group with a Fisher’s exact test to be 
done at a two-sided alpha level of 0.05.
Sample size and power calculations were made using the statistical software package nQuery 
Advisor (Version 6.0).


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Day 15 Analysis
The Day 15 analysis will be conducted after all subjects in Part 1 (including the sentinel cohorts
and the randomized cohort) either complete their 15-day treatment on GS-9131 or PTM in Part 1 
or prematurely discontinued the study drug in Part 1.
2.2.
Data Monitoring Committee Analysis
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will 
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination of the study, the continuation of the study, 
or the continuation of the study with modifications.
The Week 12 DMC analysis will be conducted after approximately 50% of subjects enrolled in 
Part 2 complete their Week 12 visit of the study. The purpose of this interim analysis is to 
provide the DMC with a statistical report for review. More details are documented in the DMC 
charter.
Gilead does not have a prior intent to ask the DMC to review Week 24 result or consider early 
termination of the study even if there is early evidence of favorable efficacy.
2.3.
Week 24 Interim Analysis
The Week 24 interim analysis will be conducted after all subjects either complete their Week 24
visit or prematurely discontinue from the study drug.
2.4.
Final Analysis
The final statistical analysis will be conducted after all subjects either complete the study or 
prematurely discontinue from the study.
The study was discontinued according to the pre-defined criteria: Study GS-US-442-4148 will be 
stopped if 50% or more of the subjects enrolled in the Sentinel Cohort 2 fail to achieve 
> 0.5 log10 reduction in plasma HIV RNA from baseline after 14 days of GS-9131 functional 
monotherapy. Therefore, no interim analyses have been performed. This SAP describes the final 
analysis.
All data collected in Part 1 up to the first dose date of Part 2 (if available) will be included in the 
tables, figures and listings. Data collected in Part 2 will only be include in listings (unless 
specified otherwise), considering the small sample size in Part 2 (4 subjects).


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set unless 
otherwise specified, and sorted by subject ID number, visit date, and time (if applicable). Data 
collected on log forms, such as AEs, will be presented in chronological order within subject. The 
treatment group to which subjects are enrolled will be used in the listings.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before data 
finalization. The analysis set will be identified and included as a subtitle of each table, figure, 
and listing. A summary of the number and percentage of subjects in each analysis set will be 
provided by cohort.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening. This is the primary analysis set for by-subject listings.
3.1.2.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study medication. Both 
safety and efficacy data will be analyzed using this analysis set for subjects enrolled in Part 1 
Sentinel Cohorts.
3.1.3.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all subjects who (1) are enrolled into the study, (2) have received 
at least 1 dose of active drug, and (3) have at least 1 nonmissing plasma PK concentration data 
for any analyte of interest reported by the PK lab. The PK analysis set will be used for general 
PK analyses.
3.1.4.
PBMC PK Analysis Set
The PBMC PK Analysis Set will include all subjects who (1) are enrolled into the study, 
(2) have received at least 1 dose of active drug, and (3) have at least 1 nonmissing PBMC PK 
concentration data for GS-9148-DP. The PBMC PK Analysis Set will be used for PBMC PK 
analyses of GS-9148-DP.


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3.2.
Subject Grouping
Subjects will be grouped according to the actual treatment they received.
3.3.
Strata and Covariates
There is no stratification for analysis.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for this analysis.
3.5.
Multiple Comparisons
No multiplicity adjustments will be applied.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be done to evaluate the impact of outliers on efficacy or safety 
outcomes, unless specified otherwise. All data will be included in the analyses.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presented in listings. If age on first dose date of study drug is not available for a subject, then 
age derived based on date of birth and the Day 1 visit date will be used instead. If an enrolled 
subject was not dosed with any study drug, the enrollment date will be used instead of the Day 1 
visit date. For screen failures, the date the first informed consent was signed will be used for the 
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Laboratory data (Non-PK) data that are continuous in nature but are less than the lower limit of 
quantitation (LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
Logarithm (base 10) transformation will be applied to HIV-1 RNA data for efficacy analysis. 
HIV-1 RNA results of ‘No HIV-1 RNA detected’ and “<20 cp/mL HIV-1 RNA Detected” will 
be imputed as 19 copies/mL for analysis purpose.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters in 
intensive PK samples. Concentration values that are below limit of quantitation (BLQ) will be 
presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at 
predose time points and one-half the value of the LOQ at postdose time points for summary 
purposes.
The following conventions will be used for the presentation of summary and order statistics for 
intensive PK concentrations:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
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3.8.
Analysis Windows
3.8.1.
Definition of Predose, Postdose, and Study Day for Part 1
Predose value is defined as the last available off-treatment value collected prior to the first dose 
of GS-9131 in Part 1 Sentinel cohorts.
Postdose value is defined as any value collected after the first dose of GS-9131 up to the date of 
the last dose of GS-9131 in Part 1 plus 30 days, and before the first dose date of Part 2 if 
applicable.
Study Day will be calculated from the first dosing date of GS-9131 in Part 1 Sentinel cohorts as 
follows:

For postdose study days: Assessment Date First Dosing Date + 1

For days prior to the first dose: Assessment Date First Dosing Date
Study day 1 is the day of first dose of GS-9131 administration in Part 1 Sentinel cohorts.
3.8.2.
Analysis Visit Windows for Part 1
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point and in 
general will not be included in summaries. However, the following exceptions will be made:

An unscheduled visit prior to the first dose of study drug may be included in the calculation 
of predose value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who discontinue from the study, early termination (ET) data will be summarized 
as a separate visit, labeled as “Early Termination Visit”.
Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) will be 
excluded from the summaries, but will be included in the listings.
The nominal visits for HIV-1 RNA, laboratory tests and vital signs, CD4 cell count and ECG are 
summarized in Table 3-1, Table 3-2, and Table 3-3 respectively.


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Table 3-1.
Predose and Postdose Visits for HIV-1 RNA
Cohort
Visit Label
Sentinel Cohort 1
Predose
Treatment Day 2
Treatment Day 3
Treatment Day 7
Treatment Day 10
Treatment Day 11
Sentinel Cohort 2
Predose
Treatment Day 3
Treatment Day 7
Treatment Day 10
Treatment Day 14
Treatment Day 15
Table 3-2.
Predose and Postdose Visits for Laboratory Tests (Hematology, 
Chemistry, and Urinalysis), and Vital Signs
Cohort
Visit Label
Sentinel Cohort 1
Predose
Treatment Day 7
Treatment Day 11
Sentinel Cohort 2
Predose
Treatment Day 3
Treatment Day 5
Treatment Day 7
Treatment Day 10
Treatment Day 14
Treatment Day 15
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Table 3-3.
Predose and Postdose Visits for CD4 Cell Count and ECG
Cohort
Visit Label
Sentinel Cohort 1
Predose
Treatment Day 11
Sentinel Cohort 2
Predose
Treatment Day 10
Treatment Day 14
Treatment Day 15
Note: ECG for Sentinel Cohort 2 will not be summarized on Day 14, since they were not collected on these days.
3.8.3.
Selection of Data in the Event of Multiple Records on the Same Day
Depending on the statistical analysis method, single values may be required for each day. For 
example, change from predose by visit usually requires a single value.
If multiple valid, nonmissing observations exist on a day, records will be chosen based on the 
following rules if a single value is needed:

For predose and postdose HIV-1 RNA, the latest (considering both collection date and time) 
record(s) on the scheduled visit will be selected. If both “HIV RNA Taqman 2.0” and “HIV 
RNA Repeat” (ie, the HIV-1 RNA result obtained from an additional aliquot of the original 
sample) are available with the same collection time, the results from the “HIV RNA Repeat” 
will be selected for analysis purposes; otherwise, if there are multiple “HIV RNA Taqman 
2.0” records with the same collection time, the geometric mean will be taken for analysis 
purposes.

For predose of other assessments, the last available non-missing record on or prior to the date 
and time of the first dose of study drug will be selected, unless specified differently. If there 
are multiple records with the same time or no time recorded on the same day, the predose 
value will be the average (arithmetic or geometric mean, as appropriate) of the measurements 
for continuous data, or the measurement with the lowest severity (eg, normal will be selected 
over abnormal for safety ECG findings) for categorical data.

For postdose of other assessments, if there is more than 1 record on the selected day, the 
average will be taken for continuous data and the worse severity will be taken for categorical 
data, unless otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by cohort for each country or investigator 
within a country and overall. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column.
A summary of subject disposition will be provided by cohort. This summary will include the 
number of subjects screened, screen failure subjects who were not enrolled, subjects who met all 
eligibility criteria and were not enrolled, subjects enrolled, and subjects in the Safety Analysis 
Set.
In addition, the number and percentage of the subjects in the following categories will be 
summarized:

Completed study drug in Part 1 Sentinel cohorts

Did not complete study drug with reason for premature discontinuation of study drug in 
Part 1

Entered into Part 2

Completed study drug in Part 2

Did not complete study drug with reason for premature discontinuation of study drug in 
Part 2

Completed the study

Did not complete the study with reason for premature discontinuation of study
For the Safety Analysis Set category, the denominator for the percentage calculation will be the 
total number of subjects enrolled for each column. For all other categories, the denominator for 
the percentage calculation will be the total number of subjects in the Safety Analysis Set for each 
column.
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
Recommended sentence to add for all randomized studies:
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation


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No inferential statistics will be generated. A data listing of reasons for premature study 
drug/study discontinuation will be provided.
4.2.
Extent of Study Drug Exposure and Adherence
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page in the eCRF. Exposure data will be listed.
4.3.
Protocol Deviations
A by-subject listing will be provided for those subjects who did not meet at least 1 eligibility 
(inclusion or exclusion) criterion. The listing will present the eligibility criterion (or criteria if 
more than 1 violation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. Any deviations identified will be evaluated to determine if it justifies excluding the 
subject from any analysis sets.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized by 
cohort using descriptive statistics for continuous variables and using number and percentage of 
subjects for categorical variables. The summary of demographic data will be provided for the 
Safety Analysis Set.
A by-subject demographic listing will be provided by subject ID number in ascending order.
5.2.
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized:

HIV-1 RNA (copies/mL)

CD4+ cell count (/μL)

Mode of infection (HIV risk factors)

HIV disease status

eGFRCG (mL/min)
A by-subject listing of baseline disease characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only.
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order. The listing will include relevant medical condition or procedure reported term, 
onset date, ongoing status, and resolution date (if applicable).


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6.
EFFICACY ANALYSES
Since the study was prematurely discontinued, there was no efficacy data from the randomized 
cohort. The efficacy analysis will only include the efficacy data from the sentinel cohorts.
Predose and change from Predose in log10 HIV-1 RNA, CD4 cell count, and CD4% will be 
summarized by visit and cohort for Part 1.
All efficacy data including HIV-1 RNA, CD4 cell count, and CD4 % from the entire study
including Part 2 will be listed.


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7.
SAFETY ANALYSES
Safety data from the Sentinel Cohorts of the study in Part 1 will be summarized for the subjects 
in the Safety Analysis Set. All safety data collected up to 30 days after the Part 1 Sentinel 
Cohorts last dose date and before the Part 2 first dose date (if applicable) will be summarized by 
cohort, unless specified otherwise. All safety data from both Parts of the study will be included 
in data listings.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. System organ 
class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and 
lowest-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe) or Grade 4 (life threatening) according to toxicity criteria specified in the protocol. The 
severity grade of events for which the investigator did not record severity will be left as 
“missing” data listings.
7.1.3.
Relationship of Adverse Events to Study Drug
Study drug related AEs are those for which the investigator selected “Related” on the AE CRF to 
the question of “Related to Study Treatment.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definition of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
and Epidemiology Department before database finalization.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of the study drug.

Any AEs leading to premature discontinuation of study drug.
The TEAE definitions will be applied to Part 1 only. AEs onset date will be compared with the 
Part 1 first dose date and last dose date and premature discontinuation of study drug refers to 
study drug discontinuation during Part 1. An AE meeting the TEAE criteria will be considered as 
a TEAE in Part 1. All AE data including Part 2 will be listed.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, the month and year (or year alone if month is not recorded) of onset determine 
whether an AE is treatment emergent. The event is considered treatment emergent if both of the 
following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the date of first dose of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to the minimum of (1) 30 days after the date of the Part 1 last dose of study 
drug and (2) Part 2 first dose date if applicable.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date marked as ongoing or on or after the date of the Part 1 first dose of study drug, will be 
considered to be treatment emergent. In addition, an AE with the onset date missing and 
incomplete stop date with the same or later month and year (or year alone if month is not 
recorded) as the first dosing date of study drug will be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Death
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by cohort in Part 1. All 
treatment-emergent deaths observed in the study will also be included in this summary. The 
number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and cohort as follows:

TEAEs


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
Grade 2, 3, or 4 TEAEs

Grade 3 or 4 TEAEs

Treatment-emergent study drug-related AEs

Grade 2, 3, or 4 treatment-emergent study drug-related AEs

Grade 3 or 4 treatment-emergent study drug-related AEs

Treatment-emergent SAEs

Treatment-emergent study drug-related SAEs

TEAEs leading to premature discontinuation from study drug
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study.
In addition to the above summary tables, all TEAEs, Grade 3 or 4 TEAEs, treatment-emergent 
study drug-related AEs, Grade 2, 3, or 4 treatment-emergent study drug-related AEs, and 
treatment-emergent SAEs will be summarized by PT only, in descending order of total 
frequency.
In addition, data listings for all AEs regardless of Part will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Study-Drug-Related SAEs

Deaths report

AEs leading to premature discontinuation of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during Part 1 of the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set. The analysis will be based on values reported in conventional units. When 
values are below the LOQ, they will be listed as such, and the imputed value will be used for the 
purpose of calculating summary statistics as specified in Section 3.7.


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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately for all data 
collected from both Parts of the study. Values falling outside of the reference range and/or 
having a severity grade of 1 or higher on the Gilead Grading Scale for Severity of Adverse 
Events and Laboratory Abnormalities will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by Cohort (different dose of GS-9131) for each laboratory 
test specified in the study protocol as follows:

Predose values

Values at each postdose time point

Change from predose at each postdose timepoint
Predose and postdose values will be defined as described in Section 3.8.1. Change from predose 
to a postdose visit will be defined as the visit value minus the predose value. Laboratory test 
results collected at unscheduled visits will be included for the predose and postdose maximum 
and minimum value selection. The mean, median, Q1, Q3, minimum, and maximum values will 
be displayed to the reported number of digits; SD values will be displayed to the reported 
number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all 
values that do not meet the criteria for an abnormality of at least Grade 1. For laboratory tests 
with criteria for both increased and decreased levels, analyses for each direction (ie, increased, 
decreased) will be presented separately.
If there is any laboratory toxicity grading scale overlapping with the normal reference ranges 
(eg, grade 1 scale overlaps with normal reference ranges), laboratory values that are within the 
normal range will be grade 0, except for lipid tests.
For triglycerides, LDL, and cholesterol, protocol-specified toxicity grading scale is for fasting 
test values, so nonfasting lipid results (or lipid results without a known fasting status) will not be 
graded or summarized by toxicity grades.


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7.2.2.1.
Treatment Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from predose at any posedose time point, up to 30 days after Part 1 last dose date
or before Part 2 first dose date (if applicable), whichever occurs earlier. If the relevant predose
laboratory value is missing, any abnormality of at least Grade 1 observed within the time frame 
specified above will be considered treatment-emergent.
Fasting glucose and nonfasting glucose (including glucose results without a known fasting 
status) are graded based on different grading scales as specified in the protocol.
Treatment-emergent laboratory abnormalities will be summarized for fasting glucose. Maximum 
postdose grade, instead of treatment-emergent grade, for nonfasting glucose (including glucose
results without a known fasting status) will be summarized, as nonfasting glucose was not 
assessed at predose visit for most of the subjects; therefore, an abnormality is treatment-emergent 
or not cannot be determined for these subjects.
Both urine RBC based on microscopic examination, labeled as Hematuria (Quantitative), and 
urine blood based on dipstick, labeled as Hematuria (Dipstick), are assessed routinely and 
assigned a toxicity grade in this study. Urine RBC based on microscopic examination will be 
presented in laboratory toxicity summary tables and listings while urine blood based on dipstick 
will be presented in the listings only.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at predose and each scheduled postdose time point.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and cohort; subjects will be categorized according to 
the most severe postdose abnormality grade for a given lab test:

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 and 4 laboratory abnormalities

Treatment-emergent Grade 2, 3, and 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
any nonmissing postdose values up to the minimum of (1) 30 days after Part 1 last dose date, and 
(2) Part 2 first dose date (if applicable).
A by-subject listing of all treatment-emergent laboratory abnormalities and treatment-emergent 
Grade 3 or 4 laboratory abnormalities will be provided by subject ID number and visit in 
chronological order. This listing will include all test results that were collected throughout the 
study (including Part 2) for the lab test of interest, with all applicable severity grade displayed.


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7.3.
Body Weight, Height, and Vital Signs
Descriptive statistics will be provided by Cohort for vital signs and body weight as follows:

Predose values

Values at each postdose time point

Change from predose at each postdose time point
Predose and postdose values will be defined as described in Section 3.8.1. Change from predose 
to a postdose visit will be defined as the postdose value minus the predose value. Body weight 
and vital signs measured at unscheduled visits will be included for the predose value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs for the entire study (including Part 2) will be provided by 
subject ID number and visit in chronological order. In the same listing, a by-subject listing of 
body weight, height, and BMI will be provided.
7.4.
Prior and Concomitant Medications
7.4.1.
Antiretroviral Medications
Any nonstudy ARV medications used prior to, during, or after the study (if collected) are all 
recorded on the ARV eCRF. All ARV medications recorded on the ARV eCRF will be coded 
using the Gilead-modified World Health Organization (WHO) Drug Dictionary for ARV 
medication. The WHO preferred name and drug code will be attached to the clinical database. 
All ARV medications recorded on the ARV eCRF will be listed. No inferential statistics will be 
provided.
7.4.2.
Concomitant Non-Antiretroviral Medications
Concomitant non-ARV medications (ie, medications other than study drug that are taken while 
receiving study drug) will be coded using the WHO Drug Dictionary. The WHO preferred name 
and drug code will be attached to the clinical database. Use of concomitant medications from 
Part 1 first dose date to Part 1 last dose date and before Part 2 first dose date, whichever occurs 
earlier, will be summarized (number and percentage of subjects) by Cohort and preferred name.
Multiple drug use (by preferred name) will be counted only once per subject. The summary will 
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If the start or stop date of non-ARV medications is incomplete, the month and year (or year 
alone, if month is not recorded) of the start or stop date will be used to determine whether the 
non-ARVs are concomitant or not. The medication is concomitant if the month and year of the 
start or stop (or year of the start or stop, if month is not recorded) of the medication does not 
meet either of the following criteria:

The month and year of start of the medication is after Part 1 last dose date

The month and year of stop of the medication is before Part 1 first dose date
If the start and stop date of non-ARV medications are complete, the start date is not after Part 1
last dose date and the stop date is not before Part 1 first dose date, or the non-ARV medications 
are marked as ongoing and start date is on or before Part 1 last dose date, the non-ARV 
medications are concomitant for Part 1 of the study.
Summaries of non-ARV concomitant medications will be provided for the Safety Analysis Set. 
Subjects with any non-ARV concomitant medications during the study (including Part 2) will be 
listed. No inferential statistics will be provided.
7.5.
Electrocardiogram Results
A shift table of the investigators’ assessment of ECG results at each visit compared with predose
values will be presented by Cohort using the following categories: normal; abnormal, not 
clinically significant; abnormal, clinically significant; or missing. The number and percentage of 
subjects in each cross-classification group of the shift table will be presented. Subjects with a 
missing value at predose or postdose will not be included in the denominator for percentage 
calculation. No inferential statistics will be provided.
A by-subject listing for ECG assessment results for the entire study including Part 2 will be 
provided by subject ID number and visits in chronological order.
7.6.
Other Safety Measures
A by-subject listing of subject pregnancies during the study will be provided by subject ID 
number. No additional safety measures are specified in the protocol.
Although not necessarily related to safety, a by-subject listing of all comments received during 
the study on the comments form will be provided by subject ID number, and form for which the 
comment applies.
7.7.
Changes from Protocol-Specified Safety Analyses
Due to the early discontinuation of the study, the safety analyses (tables) will be performed for 
Sentinel Cohorts in Part 1 only. All safety data including Part 2 will be listed.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Estimation of Pharmacokinetic Parameters
Pharmacokinetic parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of zero 
to prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will 
be treated as missing data in WinNonlin. The nominal time point for a key event or dosing 
interval (τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCinf, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of the drug. The appropriateness of calculating these 
parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK 
scientist.
8.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be generated for all subjects for whom parameters can be 
derived. The analyte(s) presented in Table 8-1 will be evaluated if data are available.
Table 8-1.
Study Treatments and Associated Analytes
Treatment
Analyte(s)
Part 1 Sentinel Cohort 1
GS-9131 (60 mg) tablet + Failing Regimen
GS-9131, GS-9148, GS-9148-DP
Part 1 Sentinel Cohort 2
GS-9131 (180 mg) tablet + Failing Regimen
GS-9131, GS-9148, GS-9148-DP
Part 2 (rollover from 
Sentinel Cohort 1)
GS-9131 (60 mg) tablet + BIC + DRV + RTV
GS-9131, GS-9148, BIC
Part 2 (rollover from 
Sentinel Cohort 2)
GS-9131 (180 mg) tablet + BIC + TAF
GS-9131, GS-9148, BIC, TAF, 
TFV-DP
The PK parameters of each analyte presented in Table 8-2 will be calculated, as appropriate, and 
summarized by treatment groups. The PK parameters to be estimated in this study are listed and 
defined in the Pharmacokinetic Abbreviations section.


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Table 8-2.
Pharmacokinetic Parameters for Each Analyte
Analyte
Parameters
GS-9131, BIC, 
TAF
AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F, and t1/2
GS-9148
AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau
GS-9148-DP, 
TFV-DP
AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau
8.3.
Statistical Analysis Methods
Individual subject concentration data and individual subject PK parameters for GS-9131 and its 
metabolite (GS-9148), and GS-9148-DP, TAF, its metabolite TFV-DP, and BIC, as appropriate,
will be listed and summarized using descriptive statistics by treatment group. Summary statistics 
(numbers of subjects, mean, SD, coefficient of variation [%CV], median, minimum, maximum, 
Q1, and Q3) will be presented for both individual subject concentration data by time point and 
individual subject PK parameters by treatment group. Moreover, the geometric mean, 95% 
confidence interval (CI), and the mean and SD of the natural log-transformed values will be 
presented for individual subject PK parameter data.
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
zero at predose and one-half of the LOQ for postdose time points.
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by treatment group:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics

Individual subject PBMC PK parameters and summary statistics
The following figures will be provided for each analyte by treatment group:

Individual subject concentration data versus time (on linear and semilogarithmic scales)

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)


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Individual, mean, and median postdose concentration values that are ≤LOQ will not be 
displayed in the figures and remaining points connected.
The following listings will be provided:

PK sampling details by subject, including procedures, differences in scheduled and actual 
draw times, and sample age

Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient

Listing of study drug administration record for PK dosing
There are no statistical comparisons for the PK analysis.


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9.
REFERENCES
No references in this document.


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10.
SOFTWARE
SASVersion 9.4 (SAS Institute Inc., Cary, NC, USA) is to be used for all programming of 
tables, listings, and figures.
nQuery Advisor® Version 6.0 (Statistical Solutions, Cork, Ireland) is to be used for sample size 
and power calculation.
Phoenix WinNonlin® Version 6.4 (Certara USA Inc., Princeton, NJ, USA) is to be used for all 
PK analyses.


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table – Cohort 1
Appendix 2.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1
Appendix 3.
Programming Specification


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Appendix 1.
Study Procedures Table – Cohort 1
Study Procedures
Screeninga,b
Part 1 (Sentinel Cohort 1 Randomized)c
Days
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-
up
ESDDh
1
2
3
4
5
6
7
8
9
10
11d
Day 1
1
2
4
8
12
18
24
Every 
12 
Weeks
Informed Consent
X
Medical History 
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Complete Physical Exam
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam
X
X
X
X
X
X
X
X
Xi
12 Lead ECG (performed 
supine)
X
X
X
X
X
X
Height
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Chemistry Profile
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Urinalysis
X
X
X
X
X
X
X
X
X
Xi
X
Metabolic Profilek
X
X
Xk
Xk
X
Estimated Glomerular 
Filtration Rate
X
X
X
X
X
X
X
X
X
X
X
Xi
X
Serum Pregnancy Testl
X
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
X
X
X
FSH Testingv
X
Plasma, Serum, 
 
Storage Sample
X
X
X
X
X
X
X
X
X
X
X
HCV Serologym
X
X
HBV blood panel
X
X
X
X
Plasma HIV 1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI 
-


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Study Procedures
Screeninga,b
Part 1 (Sentinel Cohort 1 Randomized)c
Days
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-
up
ESDDh
1
2
3
4
5
6
7
8
9
10
11d
Day 1
1
2
4
8
12
18
24
Every 
12 
Weeks
CD4 Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV 1 Genotype/ 
Phenotypej
X
X
X
X
Timed PK Samplen
X
X
X
Single Anytime PK 
Sampleo
X
X
X
Intensive PK Samplingp
X
X
X
PBMC Samplingr
X
Randomizations
X
Collect Subject Dosing 
Diary to Subjects
X
X
X
X
X
X
X
X
In clinic Dosingt
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensationu
X
X
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Part 1 Day 1 visit. A single 14 day extension to the screening window may be granted with permission form the Medical 
Monitor
b
Results from the screening genotype report and confirmed eligibility must be obtained before proceeding with Day 1 Visit. Local genotype at the Screening Visit is acceptable 
for enrollment upon review by the Sponsor. A single 14 day extension to the screening window may be granted with permission form the Medical Monitor if the genotype 
results are delayed. 
c
Randomization and dosing into the Randomized Cohort of Part 1 will begin after the Day 10 safety, efficacy and available PK data from the 10 subjects in the Sentinel Cohort 
are reviewed. 
CCI
CCI
CC
CC
CC
I I 


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Before proceeding into Part 2, subjects who have completed Day 10 of Part I (from either the Sentinel or Randomized Cohorts) will discontinue GS 9 13 1 or PTM but remain 
on their failing regimen until the site is notified of the subject's eligibility to proceed to Part 2. This period shall be no longer than 14 days while awaiting Day IO HIV I RNA 
results and the authorization to proceed from Gilead. Once notified of their eligibility into Part 2 of the study, the subject will discontinue their failing regimen before 
initiating any Part 2 Day I study procedures. In the event the plasma HIV I RNA test results perfornied by the central laboratory are delayed beyond 14 days, a subject may 
still proceed to Part 2 of the study if the test results from the local laboratory show a reduction in plasma HIV I RNA > 0.5 log10 compared to pre GS 9 131 baseline after 
IO days of GS 9 13 1 functional monotherapy in Part I of the study. 
e 
All study visits are to be scheduled relative to the Part 2 Da I visit date. Visit windows are ± 4 da s of the rotocol specified date through Week 8, ± 4 days of the protocol 
r 
I 
s ecified date throu h Week 24, 
h 
v1s1t to occur wit m 
ours o ast ose o stu y mg. u ~ects w1 
subject discontinues study drng. 
Any AE or test showing abnorn1al results that is believed to have a possible or probable causal relationship with the study drng will be repeated weekly (or as often as deemed 
prndent by the Investigator) until the abnorn1ality is resolved, returns to baseline (Day I) value, or is otherwise explained. 
HIV I genotype/phenotype testing for subjects with confirnied virologic failure and HIV I RNA >200 copies/mL, at early study discontinuation or Week 24. Following 
virologic rebound, subjects will be asked to return to the clinic ( I 3 weeks later) prior to the next scheduled visit or at the next scheduled study visit for a HIV I RNA and 
HIV I genotype/phenotype (reverse transcriptase, protease, and integrase) blood draw. Based on the results of this testing, subjects should be managed according to the 
Virologic Rebound Schema. 
k 
Collected fasted (no food or drinks, except water, at least 8 hours prior to blood collection) only at Part 2 
Day I, Week 12, and Week 24. Collected non fasted at all other 
visits. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state to draw blood for the assessments. 
Females of childbearing potential only. Urine and semm pregnancy test will be done at Screening and Day I. If the urine and semm test is positive at screening, the subject 
will not be enrolled. A positive urine pregnancy test at any visit will be confirn1ed with a semm test. If the test is positive the subject will be discontinued from the study. 
m 
Hepatitis C Vims (HCFAb) serology. Subjects who are HCVAb positive will have a HCV RNA test perfornied. 
n 
T imed PK Sample: collected at predose and one within 15 minutes 4 hours post dose (Part 2 Weeks 4, 12 and 18) 
o 
Single Anytime PK Sample: collected without regard to time of dosing (Part 2 Weeks 2, 8 and 24) 
p 
Intensive PK samples will be collected on Part I 
Day I 0. Prior to the administration of study drng, a predose ( <5 minutes prior to dosing) blood sample will be collected. 
Sub· ects will then take an observed dose of study dru at the clinic. Additional blood sam les will be collected at 0.5 I 1.5 2 3 4 6 8 and 24 hour ost dose. 
I' 
r 
PBMC collection on Day 10: Predose (<5 minutes pnor to dosing), I, 2, 6 and 24 hours post dose. 
s 
Randomization may be perforn1ed up to 3 days prior to the in clinic Day I visit provided that all screening procedures have been completed, and subject eligibility has been 
confirn1ed. 
All study medication in Part I will be delivered by directly observed therapy on Days I 10. 
u 
Subjects must be reminded to take study drng at the same time each day except on days with T imed PK sample and Intensive PK. 
v 
For female subject post menopausal for less than two years, if FSH <40 mIU/ mL a semm pregnancy test will be re.quired 
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Appendix 2.
Study Procedures Table – Sentinel Cohort 2/Randomized Cohort Part 1
Study Procedures/Sentinel 
Cohort 2/Randomized Cohort 
Part 1
Screeninga,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Informed Consent
X
Medical History 
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
X
X
X
Symptom-Directed Physical 
Exam
X
X
X
12-Lead ECG (performed supine)
X
X
X
X
Height
X
Vital Signs and Weight
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
Chemistry Profile
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Metabolic Profilek
X
Estimated Glomerular Filtration 
Rate
X
X
X
X
X
X
X
Serum Pregnancy Testl
X
X
Urine Pregnancy Testl
X
X
X
X
FSH Testingv
X
Plasma, Serum, 
 Storage 
Sample
X
X
X
X
X
X
X
X
HCV Serologym
X
HBV blood panel
X
Plasma HIV-1 RNA
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
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Study Procedures/Sentinel 
Cohort 2/Randomized Cohort 
Part 1
Screeninga,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
HIV-1 Genotype/ Phenotypej
X
X
X
X
X
Whole blood sample for 
genotypic testing
X
Intensive PK Samplingp
X
PBMC Samplingr
X
Randomizations
X
Collect Subject Dosing Diary to 
Subjects
X
In-clinic Dosingt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Procedures
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-up
ESDDh
Day1
1
2
4
8
12
18
24
Every 12 Weeks
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Xi
X
Complete Physical Exam
X
X
X
X
Symptom-Directed Physical 
Exam
X
X
X
X
X
X
Xi
12-Lead ECG (performed supine)
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
Hematology Profile
X
X
X
X
X
X
X
X
X
Xi
X
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Study Procedures
Part 2 
Weekse,j
(+/- 4 days)
30 Day 
Follow-up
ESDDh
Day1
1
2
4
8
12
18
24
Every 12 Weeks
Chemistry Profile
X
X
X
X
X
X
X
X
X
Xi
X
Urinalysis
X
X
X
X
X
Xi
X
Metabolic Profilek
X
Xk
Xk
X
Estimated Glomerular Filtration 
Rate
X
X
X
X
X
X
X
X
X
Xi
X
Serum Pregnancy Testl
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
Plasma, Serum, 
 Storage 
Sample
X
X
X
X
X
X
X
X
X
HCV Serologym
X
HBV blood panel
X
X
X
Plasma HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/ Phenotypej
X
Timed PK Samplen
X
X
X
Single Anytime PK Sampleo
X
X
X
Intensive PK Sampling & PBMC 
Samplingp
X
X
Collect Subject Dosing Diary to 
Subjects
X
X
X
X
X
X
X
Study Drug Dispensationu
X
X
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Part 1 Day 1 visit. A single 14 day extension to the screening window may be granted with permission form the Medical 
Monitor
b
Results from the screening genotype report and confirmed eligibility must be obtained before proceeding with Day 1 Visit. Local genotype at the Screening Visit is acceptable 
for enrollment upon review by the Sponsor. A single 14 day extension to the screening window may be granted with permission form the Medical Monitor if the genotype 
results are delayed. 
CCI
CCI
CC
CC
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c 
Randomization and dosing into the Randomized Cohort of Part I will begin after the Day 15 safety, efficacy and available PK data from the IO subjects in the Sentinel 
Cohort 2 are reviewed. 
d 
Before proceeding into Part 2, subjects who have completed Day 14 of Part I (from either the Sentinel or Randomized Cohorts) will discontinue GS 9 13 1 or PTM but remain 
on their failing regimen until the site is notified of the subject's eligibility to proceed to Part 2. This period shall be no longer than 9 days while awaiting HIV I RNA results 
and the authorization to proceed from Gilead. Once notified of their eligibility into Part 2 of the study, the subject will discontinue their failing regimen before initiating any 
Part 2 Day I study procedures. In the event the plasma HIV I RNA test results perforn1ed by the central laboratory are delayed, beyond 9 days, a subject may still proceed to 
Part 2 of the study if the test results from the local laboratory show a reduction in plasma HIV I RNA > 0.5 log10 compared to pre GS 9 13 1 baseline during the 14 days of 
GS 9 13 1 functional monotherapy in Part I of the study. 
e 
All stud visits are to be scheduled relative to the Part 2 Da I visit date. Visit windows are ± 4 days of the protocol specified date through Week 24, 
r 
I 
h 
ESDD VISlt to occur within 72 hours of last dose of study drng. Subjects will be asked to continue attending the scheduled study v1S1ts through the Week 24 visit even as the 
subject discontinues study drng. 
Any AE or test showing abnorn1al results that is believed to have a possible or probable causal relationship with the study drng will be repeated weekly (or as often as deemed 
prndent by the Investigator) until the abnorn1ality is resolved, returns to baseline (Day I) value, or is otherwise explained. 
HIV I genotype/phenotype testing for subjects with confirn1ed virologic failure and HIV I RNA >200 copies/mL, at early study discontinuation or Week 24. Following 
virologic rebound, subjects will be asked to return to the clinic ( I 3 weeks later) prior to the next scheduled visit or at the next scheduled study visit for a HIV I RNA and 
HIV I genotype/phenotype (reverse transcriptase, protease, and integrase) blood draw. Based on the results of this testing, subjects should be managed according to the 
Virologic Rebound Schema (Protocol Section 6. I 0). 
k 
Collected fasted (no food or drinks, except water, at least 8 hours prior to blood collection) only at Part I 
Day I, Part 2 
Day I, Week 12, and Week 24,_ 
. Collected non fasted at all other visits. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return 
within 72 hours m a fasted state to draw blood for the assessments. 
Females of childbearing potential only. Urine and semm pregnancy test will be done at Screening and Day I and a urine pregnancy test on Days IO and 14. If the urine and 
semm test is positive at screening, the subject will not be enrolled. A positive urine pregnancy test at any visit will be confirn1ed with a semm test. If the test is positive the 
subject will be discontinued from the study. 
m 
Hepatitis C Vims (HCFAb) serology. Subjects who are HCVAb positive will have a HCV RNA test perforn1ed. 
n 
T imed PK Sample: collected at predose and one within 15 minutes 4 hours post dose (Part 2 
Weeks 4, 12 and 18) 
o 
Single Anytime PK Sample: collected without regard to time of dosing (Part 2 
Weeks 2, 8 and 24) 
p 
Intensive PK samples will be collected on Part I 
Day 10 for Sentinel Cohort I and Day 14 for Sentinel Cohort 2 and Randomized Cohort. Prior to the administration of 
study drng, a predose (<5 minutes prior to dosing) blood sample will be collected. Subjects will then take an observed dose of study drug at the clinic. Additional blood 
samples will be collected at 0.5, I, 1.5, 2, 3, 4, 6, 8, and 24 hour post dose. 
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r 
PBMC collection on Day 10 tor Sentmel Cohort I and Day 14 for Sentinel Cohort 2 and Randomized Cohort: Predose (<5 minutes prior to dosing), I, 2, 6 and 24 hours post 
dose. 
s 
Randomization may be perfom1ed up to 3 days prior to the in clinic Day I visit provided that all screening procedures have been completed, and subject eligibility has been 
confim1ed. 
All study medication in Part I will be delivered by directly observed therapy on Days I 14. 
u 
Subjects must be reminded to take study dmg at the same time each day except on days with Timed PK sample and Intensive PK. 
v 
For female subject post menopausal for less than two years, if FSH <40 m!U/ mL a semm pregnancy test will be re.quired 
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Appendix 3.
Programming Specification
1. AGE calculated as follows:
a.
AGE (years) is calculated from the number of days between the date of birth (DOB) and 
Day 1 (Sentinel Cohorts first dose date),
b. Use the SAS INTCK function to determine the number of “1st-of-month days” 
(eg, January 1st, February 1st, March 1st) between DOB and Day 1 (inclusive),
c.
Divide the result in (b) by 12,
d. AGE  the integer of the result in (c),
e.
If the DOB and Sentinel Cohorts first dose date have the month in common and the 
birthday is later in the month than the date of Sentinel Cohorts first dose date, then 
subtract one from the AGE result above.
2. All screened subjects refer to all subjects who are screened (ie, with nonmissing screening 
date) and have a screening number. For summaries, the same subject is counted only once. 
DOB and other demographic information such as sex, race, ethnicity, country, and initials 
will be used to identify unique screened subjects.
3. Screen failure subjects are the subjects who are screened and answered “No” for any 
inclusion criteria or “Yes” for any exclusion criteria regardless of which version of protocol 
the subject was consent to.
4. In disposition table, the reasons for premature discontinuation are displayed in the order as 
they appear on the eCRF.
5. Body mass index and Body Surface Area (BSA)
BMI and BSA will be calculated only at Part 1 sentinel cohorts predose as follows:
■
BMI
 (weight [kg])/ (height [meters]
2)
■
BSA (m2)  SQRT( [Height(cm) x Weight(kg) ]/ 3600 )
Predose height and weight in the Sentinel cohorts Part 1 of the study will be used for this 
calculation.
6. Toxicity Grades:
1) For toxicity grade summaries, include all postdose graded results up to 30 days after the 
Part 1 Sentinel cohorts last dose of study drug, and before Part 2 first dose date 
(if applicable), not just those used in by-visit summaries.


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2) For glucose grading, as specified in SAP Section 7.2.2.1, the treatment-emergent flag 
cannot be determined for nonfasting glucose (including glucose results without a known 
fasting status). As a result, these records will be excluded from the “Maximum 
Treatment-emergent Toxicity Grade” summary in the “Treatment-emergent Laboratory 
Abnormalities” or “Treatment-emergent Grade 3 or 4 Laboratory Abnormalities” 
summary tables. In addition, fasting glucose and non-fasting glucose will be listed as two 
separate laboratory tests in the “Laboratory Abnormalities” and “Grade 3 or 4 Laboratory 
Abnormalities” listings. Only a maximum postbaseline toxicity flag will be displayed and 
the treatment-emergent flag will not be displayed for nonfasting glucose as the 
treatment-emergent flag cannot be determined for nonfasting glucose.
7. Graded Laboratory Abnormalities Summary
The following labels will be used for treatment-emergent laboratory abnormalities and 
treatment-emergent Grade 3 or 4 laboratory abnormalities summary tables and listings: 
Battery
Lab Test Label 
Used in l-labtox Listing
Toxicity 
Direction
Lab Test Label Used in t-labtox Table
Hematology
Hemoglobin
Decrease
Hemoglobin (Decreased)
Neutrophils
Decrease
Neutrophils (Decreased)
Platelets
Decrease
Platelets (Decreased)
WBC
Decrease
WBC (Decreased)
Chemistry
Albumin 
Decrease
Albumin (Decreased)
Alkaline Phosphatase
Increase
Alkaline Phosphatase (Increased)
ALT
Increase
ALT (Increased)
Amylase
Increase
Amylase (Increased)
AST
Increase
AST (Increased)
Bicarbonate
Decrease
Bicarbonate (Decreased)
Corrected Calcium
Increase
Corrected Calcium (Hypercalcemia)
Corrected Calcium
Decrease
Corrected Calcium (Hypocalcemia)
Creatine Kinase (CK)
Increase
Creatine Kinase (Increased)
Creatinine
Increase
Creatinine (Increased)
GGT
Increase
GGT (Increased)
Lipase
Increase
Lipase (Increased)
Magnesium
Decrease
Magnesium (Hypomagnesemia)
Phosphate
Decrease
Phosphate (Hypophosphatemia)
Serum Glucose (Fasting)
Increase
Serum Glucose (Fasting, Hyperglycemia)
Serum Glucose (Fasting) 
Decrease
Serum Glucose (Fasting, Hypoglycemia)


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Battery
Lab Test Label 
Used in l-labtox Listing
Toxicity 
Direction
Lab Test Label Used in t-labtox Table
Serum Glucose 
(Nonfasting)
Increase
Serum Glucose (Nonfasting, Hyperglycemia)
Serum Glucose 
(Nonfasting)
Decrease
Serum Glucose (Nonfasting, Hypoglycemia)
Serum Potassium
Increase
Serum Potassium (Hyperkalemia)
Serum Potassium
Decrease
Serum Potassium (Hypokalemia)
Serum Sodium
Increase
Serum Sodium (Hypernatremia)
Serum Sodium
Decrease
Serum Sodium (Hyponatremia)
Total Bilirubin
Increase
Total Bilirubin (Hyperbilirubinemia)
Total Cholesterol (Fasting)
Increase
Total Cholesterol (Fasting, Hypercholesterolemia)
Triglycerides (Fasting) 
Increase
Triglycerides (Fasting, Increased)
LDL (Fasting)
Increase
LDL (Fasting, Increased)
Urea Nitrogen (BUN)
Increase
Urea Nitrogen (Increased)
Uric Acid
Increase
Uric Acid (Hyperuricemia)
Uric Acid
Decrease
Uric Acid (Hypouricemia)
Prothrombin Intl. 
Normalized Ratio (INR)
Increase
N/A
Prothrombin Time (PT)
Increase
N/A
Urinalysis
Urine Blood
Increase
N/A
Urine Glucose
Increase
Urine Glucose (Glycosuria)
Urine Protein
Increase
Urine Protein (Proteinuria)
Urine RBC
Increase
Urine RBC (Hematuria, Quantitative)
Note: Prothrombin Intl. Normalized Ratio (INR) and Prothrombin Time (PT) were graded based on the protocol defined toxicity 
grade scale. The results and toxicity grade will be listed in listing, but not be summarized in lab toxicity summary table.
8. Clarification for “Pharmacokinetic Blood Sampling Time Record” listing
A new variable “Sample age” will be added in this listing, defined as the duration in day 
between sample collection date and assay date, ie, sample age  assay date sample 
collection date + 1.
SAMTIME (hours)  sample collection time (xx:xx) - last dose time before sample 
collection (xx:xx).


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9. Non-study drug ARV medications (ie, ARV medications other than study drug that are taken 
while receiving study drug) will be flagged in “Antiviral Medication” listing. Please note that 
for ARVs recorded on the “Prior ARV” eCRF will NOT be considered as ARVs taken during 
study. All Prior ARVs with missing end date will be queried to confirm the ARVs were 
stopped before the Part 1 Sentinel cohort dose date.
10. HBV DNA results of “<20 IU/mL HBV DNA detected” or “No HBV DNA detected” will be 
imputed as 19 IU/mL for analysis purpose. HCV RNA results of “<15 IU/mL HCV RNA 
detected” or “No HCV RNA detected” will be imputed as 14 IU/mL for analysis purpose.
11. PK parameters at the individual subject level should be displayed with the following reported
number of decimal places:
LambdaZ, r2, r2 adj, and CORRXY: 3 decimal places
t1/2, Tlast, Tmax, BEGHOUR, and ENDHOUR: 2 decimal places
AUCtau, AUC0 last, AUCinf, %otAUCexp, Vz/F, CL/F, CLss/F, Cmax, Clast and Ctau: 1 
decimal place
NPOINTS: 0 decimal place
PK concentration data will be reported with 1 decimal place.


SAP_GS-US-442-4148_Final
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 03-Mar-2020
16:13:09
Biostatistics eSigned
03-Mar-2020
17:06:00
PPD
PPD--