Clinical trial NCT02600819
Conditions: HIV-1 Infection
Keywords: End stage renal disease Hemodialysis Open-label HIV-1 Infection
Sponsor: Gilead Sciences
Start date: 2015-12-14; Completion date: 2019-10-15
Enrollment: 55 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) in human immunodeficiency virus (HIV-1) infected adults with end-stage renal disease (ESRD) on chronic hemodialysis (HD).

Detailed description:

Arms: arm 1: Participants will switch their current antiretroviral regimen to E/C/F/TAF and receive treatment for 96 weeks. After Week 96, participants in the United States (US) who wish to participate in the open-label (OL) rollover extension will continue to take E/C/F/TAF FDC until the End of E/C/F/TAF Visit. arm 2: At Week 96 or the End of E/C/F/TAF Visit (whichever occurs last), participants will be given the option to receive open-label bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for at least 48 weeks.
Interventions: intervention 1: E/C/F/TAF intervention 2: B/F/TAF
Intervention descriptions: intervention 1: 150/150/200/10 mg FDC tablets administered orally once daily intervention 2: 50/200/25 mg FDC tablets administered orally once daily

Protocol documents:
Prot_009.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Efficacy of E/C/F/TAF Fixed Dose 
Combination (FDC) in HIV-1 Infected Subjects on Chronic 
Hemodialysis
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002713-30
NCT02600819
Indication:
HIV-1 Infection
Protocol ID:
GS-US-292-1825
Clinical Program 
Manager:
Name:
Telephone:
Fax:
Gilead Medical Monitor:
Name:
Telephone:
Fax:
Protocol Version/Date:
Original:
08 July 2015
Amendment 1:
13 October 2015
Amendment 2:
28 November 2016
Amendment 2.1 (US Only):
01 May 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
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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....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................15
1.2.3.
Nonclinical Pharmacokinetics..............................................................................................16
1.2.4.
Nonclinical Toxicology........................................................................................................17
1.2.5.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF) ...................................................................................................18
1.3.
Bictegravir (GS-9883, B, BIC) ..............................................................................................................22
1.3.1.
General Information .............................................................................................................22
1.3.2.
Preclinical Pharmacology and Toxicology...........................................................................22
1.3.3.
Clinical Trials of Bictegravir................................................................................................24
1.4.
Rationale for This Study ........................................................................................................................38
1.4.1.
Rationale for Dose Selection................................................................................................39
1.5.
Risk/Benefit Assessment for the Study..................................................................................................42
1.6.
Compliance ............................................................................................................................................43
2.
OBJECTIVES.....................................................................................................................................................44
3.
STUDY DESIGN................................................................................................................................................45
3.1.
Study Design..........................................................................................................................................45
3.2.
Study Treatments ...................................................................................................................................45
3.3.
Duration of Treatment............................................................................................................................46
3.4.
End of Study...........................................................................................................................................46
3.5.
Post Study Care......................................................................................................................................46
3.6.
Source Data............................................................................................................................................46
3.7.
........................................................................................46
4.
SUBJECT POPULATION..................................................................................................................................47
4.1.
Number of Subjects and Subject Selection ............................................................................................47
4.2.
Inclusion Criteria....................................................................................................................................47
4.3.
Exclusion Criteria...................................................................................................................................49
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.2.
Description and Handling of Study Drug...............................................................................................51
5.2.1.
Formulation..........................................................................................................................51
5.2.2.
Packaging and Labeling .......................................................................................................52
5.2.3.
Storage and Handling...........................................................................................................52
5.3.
Dosage and Administration of E/C/F/TAF ............................................................................................53
5.4.
Prior and Concomitant Medications.......................................................................................................53
5.5.
Accountability for Investigational Medicinal Product (IMP).................................................................58
5.5.1.
Study Drug Return or Disposal ............................................................................................59
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6.
STUDY PROCEDURES ....................................................................................................................................60
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................60
6.2.
Pretreatment Assessments......................................................................................................................60
6.2.1.
Screening Visit .....................................................................................................................60
6.2.2.
Day 1 Assessments...............................................................................................................62
6.3.
Treatment Assessments (Weeks 2-96) ...................................................................................................63
6.4.
Treatment Assessments (Post Week 96 until the Open-Label Rollover Extension) ..............................66
6.4.1.
Post Week 96 Assessments to End of E/C/F/TAF visit........................................................66
6.4.2.
End of E/C/F/TAF Visit .......................................................................................................67
6.4.3.
Open-Label Rollover Extension...........................................................................................68
6.5.
Post-treatment Assessments ...................................................................................................................70
6.5.1.
30-Day Follow-up Assessments...........................................................................................70
6.5.2.
Early Study Drug Discontinuation Assessments (ESDD)....................................................71
6.5.3.
Criteria for Discontinuation of Study Treatment..................................................................73
6.6.
Other Evaluations...................................................................................................................................73
6.6.1.
.........................................................................................73
6.6.2.
Blood Storage.......................................................................................................................74
6.7.
Virologic Failure....................................................................................................................................74
6.7.1.
Management of Virologic Failure ........................................................................................74
6.7.2.
Subjects with ≥ 400 copies/mL of HIV-1 in the Absence of VR .........................................75
6.7.3.
Management of Virologic Rebound (Open-Label B/F/TAF Rollover 
Extension) ............................................................................................................................77
6.7.4.
Subjects with ≥ 200 copies/mL of HIV-1 in the Absence of VR .........................................77
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................79
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................79
7.1.1.
Adverse Events.....................................................................................................................79
7.1.2.
Serious Adverse Events........................................................................................................79
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................80
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................80
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................80
7.2.2.
Assessment of Severity ........................................................................................................81
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................81
7.3.1.
Adverse Events.....................................................................................................................81
7.3.2.
Serious Adverse Events........................................................................................................81
7.4.
Gilead Reporting Requirements.............................................................................................................83
7.5.
Special Situations Reports......................................................................................................................83
7.5.1.
Definitions of Special Situations..........................................................................................83
7.5.2.
Instructions for Reporting Special Situations.......................................................................84
7.6.
Toxicity Management ............................................................................................................................85
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................85
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................86
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................86
8.
STATISTICAL CONSIDERATIONS................................................................................................................87
8.1.
Analysis Objectives and Endpoints........................................................................................................87
8.1.1.
Analysis Objectives..............................................................................................................87
8.1.2.
Primary Endpoint .................................................................................................................87
8.1.3.
Secondary Endpoints............................................................................................................87
8.2.
Analysis Conventions.............................................................................................................................88
8.2.1.
Analysis Sets ........................................................................................................................88
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8.3.
Demographic Data and Baseline Characteristics ...................................................................................88
8.4.
Primary and Secondary Analysis ...........................................................................................................89
8.4.1.
Primary Analysis..................................................................................................................89
8.4.2.
Secondary Analyses .............................................................................................................89
8.5.
Safety Analysis.......................................................................................................................................89
8.5.1.
Extent of Exposure...............................................................................................................89
8.5.2.
Adverse Events.....................................................................................................................89
8.5.3.
Laboratory Evaluations ........................................................................................................90
8.5.4.
Other Safety Evaluations......................................................................................................90
8.6.
Pharmacokinetic Analysis......................................................................................................................90
8.7.
Sample Size............................................................................................................................................90
8.8.
Data Monitoring Committee ..................................................................................................................91
9.
RESPONSIBILITIES..........................................................................................................................................92
9.1.
Investigator Responsibilities ..................................................................................................................92
9.1.1.
Good Clinical Practice..........................................................................................................92
9.1.2.
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................92
9.1.3.
Informed Consent.................................................................................................................92
9.1.4.
Confidentiality......................................................................................................................93
9.1.5.
Study Files and Retention of Records ..................................................................................93
9.1.6.
Case Report Forms...............................................................................................................94
9.1.7.
Study Drug Accountability and Return ................................................................................95
9.1.8.
Inspections............................................................................................................................95
9.1.9.
Protocol Compliance............................................................................................................95
9.2.
Sponsor Responsibilities ........................................................................................................................96
9.2.1.
Protocol Modifications.........................................................................................................96
9.2.2.
Study Report and Publications .............................................................................................96
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................96
9.3.1.
Payment Reporting...............................................................................................................96
9.3.2.
Access to Information for Monitoring..................................................................................97
9.3.3.
Access to Information for Auditing or Inspections ..............................................................97
9.3.4.
Study Discontinuation..........................................................................................................97
10.
REFERENCES ...................................................................................................................................................98
11.
APPENDICES ..................................................................................................................................................101
Appendix 1.
Investigator Signature Page..................................................................................................102
Appendix 2.
Study Procedures Table (E/C/F/TAF Phase)........................................................................103
Appendix 3.
Study Procedures Table (Open Label Rollover Extension)..................................................106
Appendix 4.
..................................................................................................108
Appendix 5.
Management of Clinical and Laboratory Adverse Events....................................................109
Appendix 6.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............110
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................132
Appendix 8.
Definitions of HIV-1 Related Disease (CDC Guidelines) {Selik 2014}..............................135
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LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-292-1825: Steady-State TAF, TFV, FTC, EVG, and COBI Plasma PK 
Parameters (PK Substudy Analysis Set).................................................................................21
Table 1-2.
GS-US-141-1218: Bictegravir Mean (%CV) PK Parameters Following Single Doses 
of bictegravir in Healthy Subjects (Bictegravir PK Analysis Set; Part A: Single 
Dosing)...................................................................................................................................28
Table 1-3.
GS-US-141-1218: Bictegravir Plasma Pharmacokinetic Parameters by bictegravir 
Dose Following Multiple-Dose Administration of bictegravir (Analysis Set: 
Bictegravir PK Part B: Multiple-Dose) ..................................................................................29
Table 1-4.
GS-US-141-1218: Statistical Comparison of Bictegravir Pharmacokinetic Parameters 
Following Single-Dose Administration of Bictegravir in the Fasted and Fed States 
(Bictegravir PK Analysis Set).................................................................................................30
Table 1-5.
Trough Bictegravir Plasma Concentrations at Steady State Following Bictegravir 
Administration Under Fasting Conditions and Corresponding Protein-Adjusted IQ95
Values (Bictegravir PK Analysis Set) ....................................................................................31
Table 1-6.
GS-US-141-1475: Virologic Outcome at Week 48 Using the US FDA-Defined 
Snapshot Algorithm and HIV-1 RNA < 50 copies/mL (FAS) ...............................................34
Table 1-7.
Comparison of Plasma TFV Exposures After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis Versus TDF-Containing Regimens in 
Patients with Normal Renal Function.....................................................................................41
Table 4-1.
Disallowed Agents (E/C/F/TAF Phase)..................................................................................50
Table 4-2.
Disallowed Agents (Open-Label B/F/TAF Rollover Extension)............................................50
Table 5-1.
Prior and Concomitant Medications (E/C/F/TAF) .................................................................54
Table 5-2.
Prior and Concomitant Medications (Open-Label B/F/TAF Rollover Extension) .................58
LIST OF IN-TEXT FIGURES
Figure 1-1.
GS-US-141-1219: Mean and 95% CIs of Change from Baseline in HIV-1 RNA 
(log10 copies/mL) (PP Analysis Set).......................................................................................31
Figure 1-2.
Predicted Steady-State TFV PK Profile After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis..............................................................................40
Figure 3-1.
Study Schema.........................................................................................................................45
Figure 6-1.
Schema for Management of Virologic Failure (E/C/F/TAF) .................................................76
Figure 6-2.
Virologic Rebound Schema (Open-Label B/F/TAF Rollover Extension)..............................78


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy of E/C/F/TAF 
Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002713-30
NCT02600819
Study Centers Planned:
Approximately 25 study sites in North America and Europe
Objectives:
The primary objective of this study is as follows:

To evaluate the safety and tolerability of the 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
(EVG/COBI/FTC/TAF; E/C/F/TAF) fixed-dose combination 
(FDC) in HIV-1 infected adults with end stage renal disease 
(ESRD) on chronic hemodialysis (HD) at Week 48
The secondary objectives of this study are as follows: 

To evaluate the safety and tolerability of the 
EVG/COBI/FTC/TAF; E/C/F/TAF FDC) in HIV-1 infected 
adults with ESRD on chronic HD at Week 96

To evaluate the proportion of subjects receiving E/C/F/TAF FDC 
achieving virologic response (HIV-1 RNA < 50 copies/mL, as 
defined by the FDA Snapshot analysis) at Weeks 24, 48, and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, 
TAF and TFV in HIV-1 infected patients with ESRD on
chronic HD

To evaluate the safety and tolerability of 
bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) FDC 
in HIV-1 infected adults with ESRD on chronic HD in the open 
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Study Design:
Open-label, multicenter, single-arm study to assess the safety, 
tolerability, pharmacokinetics, and efficacy of E/C/F/TAF FDC 
dosed once daily in HIV-infected adult subjects with ESRD on 
chronic HD. 
All subjects will switch from their current antiretroviral (ARV) 
regimen to E/C/F/TAF on Day 1. The treatment duration will be at 
least 96 weeks.
After Week 96, subjects in the US will continue to take their study 
drug and attend visits every 12 weeks until the End of E/C/F/TAF 
visit. At Week 96 or the End of E/C/F/TAF Visit, subjects will 
discontinue E/C/F/TAF FDC and be given the option to receive OL 
B/F/TAF FDC. All subjects participating in the OL rollover 
extension of B/F/TAF FDC will return for study visits at Week 4 OL, 
Week 12 OL, and every 12 weeks thereafter for at least 48 weeks.
Subjects who do not wish to participate in the B/F/TAF OL rollover 
extension phase will discontinue study drug at Week 96.
Number of Subjects 
Planned:
Approximately 50 subjects with ESRD on chronic HD will be 
enrolled.
Target Population:
HIV-1 infected adults (≥18 years) with ESRD on chronic HD for 
≥6 months prior to screening, and HIV-1 RNA < 50 copies/mL on a 
stable antiretroviral (ARV) regimen for ≥ 6 consecutive months 
prior to screening.
Duration of 
Treatment:
Subjects will be treated for at least 96 weeks. After Week 96, all 
subjects participating in the OL rollover extension phase will receive 
B/F/TAF FDC for at least 48 weeks.
Diagnosis and Main 
Eligibility Criteria:
HIV-1-infected adults who meet the following criteria:

No documented history of HIV-1 resistance to EVG, FTC, 3TC 
or TFV

Currently receiving a stable antiretroviral regimen for 
≥6 consecutive months prior to screening 

Plasma HIV-1 RNA < 50 copies/mL for at least 6 months 
preceding the screening visit

CD4+ T cell count of ≥ 200 cells/μL

ESRD with eGFR < 15 mL/min by Cockcroft-Gault, on chronic
HD for ≥ 6 months prior to screening

Hepatitis C (HCV) infection allowed 

Hepatitis B (HBV) infection not allowed


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Study Procedures/
Frequency:
Following Screening, eligible subjects will be required to return for 
study visits at Day 1, Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 
96. 
All subjects participating in the OL B/F/TAF rollover extension will 
be required to return for visits at Week 4 OL, Week 12 OL, Week 24 
OL, Week 36 OL, and Week 48 OL.
For all subjects, HBV and HCV serologies will be analyzed at 
Screening. Adverse events, concomitant medications, complete or 
symptom-directed physical examinations, laboratory analyses 
(hematology and chemistry), fasting lipids and glucose, 
HIV-1 RNA, CD4+ T cell count and estimated GFR will be 
performed at the Screening, Day 1, and all subsequent study visits.
Pre-dose blood draw for plasma and PBMC samples will be 
collected from all subjects at Week 4 or Week 12, which must be the 
day of hemodialysis. 
 
Test Product, Dose, and 
Mode of 
Administration:
FDC of elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 
200 mg / tenofovir alafenamide 10 mg administered orally once 
daily with food until the next hemodialysis. On the day of 
hemodialysis, study drug should be administered after completion of 
hemodialysis. 
FDC of bictegravir 50 mg/ emtricitabine 200 mg/ tenofovir 
alafenamide 25 mg (B/F/TAF) administered orally, once daily 
without regard to food until the next hemodialysis. On the day of 
hemodialysis, study drug should be administered after completion of 
hemodialysis. 
Reference Therapy, 
Dose, and Mode of 
Administration:
N/A
Criteria for Evaluation:
Safety:
Safety evaluations will include reporting of adverse events, clinical 
laboratory tests, physical examinations, and vital signs. An
Independent Data Monitoring Committee (IDMC) will be convened 
after the first 25 subjects enrolled in the study complete Week 12 of 
the study. 
Efficacy:
Virologic response will be determined using the percentages of
subjects with HIV-1 RNA < 50 copies/mL at Weeks 24, 48, and 96
(FDA snapshot analysis).
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Pharmacokinetics:
At Week 4 or Week 12, on the day of hemodialysis, pre-dose (within 
30 minutes prior to study drug administration) blood draws for 
plasma and PBMC samples will be collected from all subjects. Study 
drug administration will be observed. Plasma concentrations of 
EVG, COBI, FTC, TAF and TFV and intracellular concentrations of 
TFV-DP may be explored.
 
 
 
 
B/F/TAF OL rollover extension phase
On the day of hemodialysis at Week 4 OL, Week 24 OL and 
Week 48 OL study visits, a sparse timed blood sample will be 
collected within 10 minutes prior to hemodialysis initiation from all 
subjects. Pre-dose (within 30 minutes prior to study drug 
administration) blood draws for plasma samples will also be 
collected at these visits. Study drug administration will be observed. 
Plasma concentrations of BIC may be determined. Plasma 
concentrations of other analytes may also be explored.
Health Related 
Questionnaires:
SF-36, VAS (visual analogues scale), HIV-TSQ (HIV Treatment
Satisfaction Questionnaire) and Health Utilization Questionnaire 
will be administered per the information provided in the study 
procedures section of this protocol.
Statistical Methods:
The primary endpoint will be the incidence of treatment-emergent 
Grade 3 or higher adverse events up to Week 48 in subjects 
receiving E/C/F/TAF.
The proportions of subjects receiving E/C/F/TAF with virologic 
response (HIV-1 RNA < 50 copies/mL, as defined by the FDA 
snapshot analysis) and the associated 95% confidence intervals at 
Weeks 24, 48, and 96, respectively will be constructed.
 
 
 
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A sample size of approximately 50 subjects is based on practical 
consideration and is considered to be sufficient to evaluate the 
primary objective of this study. The Grade 3 or higher AE rate in 
Study GS-US-292-0112 subjects that had mild to moderate renal 
impairment was 8.8% at Week 48 analysis for the E/C/F/TAF arm. 
Therefore, with 50 subjects, and an assumed rate of Grade 3 or 
higher AEs being 10%, this study would provide 95% confidence for 
the primary endpoint to be (1.7%, 18.3%) assuming normal 
approximation to binomial proportions. 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C 
degrees Celsius
°F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time 
curve
B
Bictegravir, GS-9883
B/F/TAF
bictegravir 50 mg/ emtricitabine 200 mg/ tenofovir alafenamide 25 mg fixed-dose 
combination, Biktarvy®
bsAP
serum bone specific alkaline phosphatase
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CG
Cockcroft-Gault
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Cmin
minimum plasma concentration
CNS
central nervous system
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
PVE
Pharmacovigilance and Epidemiology
ECG
Electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
E/C/F/TAF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir alafenamide (TAF) 10 mg fixed-dose combination, Genvoya®
E/C/F/TDF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg / 
tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination, Stribild®
ESRD
End stage renal disease
FAS
full analysis set


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FDA
(United States) Food and Drug Administration
FDC
fixed-dose combination
FS
failure to suppress
FTC
Emtricitabine, F
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GS-7340 
tenofovir alafenamide, TAF, L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester
HAART
highly active antiretroviral therapy
HBsAg
hepatitis B virus surface antigen serology
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus serology
HD
Hemodialysis
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-TSQ
HIV Treatment Satisfaction Questionnaire
HIV-TSQs
HIV Treatment Satisfaction Questionnaire Status
HIV-TSQc
HIV Treatment Satisfaction Questionnaire Change
HMG-CoA
5-hydroxy-3-methylglutaryl-coenzyme A
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
DMC
Data Monitoring Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IRB
institutional review board
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MH
Mantel-Haenszel
Min
minute
mmHg
millimeters mercury
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OC
osteocalcin
P1NP
procollagen Type 1 N-terminal propeptide


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PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term 
PTH
parathyroid hormone
QD
once daily 
RNA
ribonucleic acid
SAE
serious adverse event
SVR
suboptimal virologic response
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
ULN
upper limit of the normal range
US
United States
VR
virologic rebound


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 infection is a life-threatening and serious disease of major 
public health significance, with approximately 34 million people infected with HIV worldwide 
{World Health Organization (WHO) 2011}. The goals of highly active antiretroviral therapy 
(HAART) for HIV-1 infection are to delay disease progression and prolong survival by 
achieving maximal and durable suppression of HIV-1 replication. Prompt antiretroviral therapy 
(ART) initiation after diagnosis is based on growing evidence that untreated HIV infection or 
uncontrolled viremia is associated with development of non- acquired immune deficiency 
syndrome (AIDS)-defining diseases, including cardiovascular disease (CVD), kidney disease, 
liver disease, neurologic complications, and malignancies. The success of ART has shifted 
clinical attention towards regimens that optimize long-term adherence, tolerability and safety. 
Adherence to ART is required to prevent development of drug resistance and subsequent loss of 
virologic suppression, and adherence to ART is improved by reducing pill burden and dosing 
frequency {Chesney 2000, Stone 2002}. Once-daily, single tablet regimens are associated with 
high adherence, better clinical outcomes, including fewer hospitalizations, improved patient 
satisfaction, and excellent virologic outcomes {Arribas 2004, Felizarta 2004, Maggiolo 2001, 
Parienti 2009, Sax 2010}.
Despite current therapy that effectively suppresses viremia, HIV disease remains a serious 
condition due to non-AIDS associated comorbidities. As treatment guidelines recommend early 
treatment of HIV-1 infection, there is a need for regimens offering enhanced product safety and 
tolerability, effectiveness, and convenience for long-term treatment.
Though antiretroviral drugs have led to dramatic improvements in survival and disease 
progression, complications such as kidney, liver, and cardiac disease have become increasingly 
important causes of morbidity and mortality for HIV patients taking effective therapy 
{Center for Disease Control and Prevention 2007, Linley 2007, Selik 2002}. Recent data has 
shown that even with treatment, HIV patients experience more age-related co-morbidities, such 
as renal and bone disease, which manifest earlier than their age-matched HIV-uninfected peers 
{Guaraldi 2011}. Moreover, the prevalence and incidence of chronic kidney disease (CKD) and
end stage renal disease (ESRD) in the US are expected to rise as the prevalence of HIV infection 
continues to rise {Schwartz 2005}. Worldwide, prevalence may be even greater; 
one cross-sectional study in the East African Republic of Burundi reported 46% of HIV-positive 
adults fulfilled criteria for CKD {Cailhol 2011}.
Patients with HIV are at risk for acute and chronic kidney disease from a wide spectrum of 
etiologies, including HIV-associated nephropathy, immune complex kidney disease, thrombotic 
microangiopathy, and kidney disease associated with comorbidities such as diabetes, hypertension, 
hepatitis B and hepatitis C coinfections, as well as medications associated with nephrotoxicity. 
Clearly, new therapies that improve on the current standard of care are needed, so that life-long 
antiviral therapy is more effective, more tolerable, and safer for patients. Since the majority of 
currently available nucleos(t)ide backbones are prescribed as fixed-dose combinations, 
HIV-positive patients with chronic kidney disease have particularly limited therapeutic options.


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The availability of a single tablet regimen composed of potent agents with improved tolerability 
and long-term safety, that does not require dose adjustment at eGFR < 50 mL/min, would 
represent an important therapeutic innovation in this special patient population, providing more 
convenient dosing and potentially improving patient adherence.
Tenofovir alafenamide (TAF) has a unique metabolism that provides enhanced lymphatic 
delivery of tenofovir, resulting in higher intracellular levels of the active phosphorylated 
metabolite, tenofovir-diphosphate (TFV-DP), and lower circulating levels of TFV {Birkus 2007, 
Birkus 2008, Lee 2005}. The distinct metabolism of TAF offers an improved clinical profile 
compared with TDF, which is associated with nephrotoxicity and decreased bone mineral density 
{Department of Health and Human Services (DHHS) 2012, Gilead Sciences Inc 2012}. 
Compared with TDF, TAF is characterized by lower systemic exposures and higher intracellular 
levels of TFV. Additionally, TFV exposures achieved with TAF in subjects with severe renal 
impairment are comparable to those with normal renal functions receiving TDF 300 mg, 
indicating that TAF can be administered to HIV-1 infected patients with renal impairment 
without dose modification. 
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is an prodrug of TFV, 
a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolized intracellularly 
to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 reverse transcriptase (RT) 
that terminates the elongation of the viral deoxyribonucleic acid (DNA) chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids. 
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
Tenofovir alafenamide is metabolized to TFV, a nucleotide analog (ie, a nucleoside 
monophosphate analog) which is not dependent on an intracellular nucleoside kinase activity for 
the first step in the conversion to the active metabolite, TFV-DP. The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{Kalayjian 2003} and nucleotide diphosphate kinase, which are highly active and ubiquitous. 
AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most 
efficiently by AK2.


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The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T cells, natural killer (NK) 
cells, B-cells and macrophages/monocytes. TAF is metabolized inside host cells to the active 
metabolite TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell 
populations.
1.2.2.2.
Safety Pharmacology
Single doses of TAF did not induce pharmacologic effects on the central nervous system of the 
rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the cardiovascular system of the 
dog (100 mg/kg).
1.2.3.
Nonclinical Pharmacokinetics
All nonclinical PK experiments were performed using TAF monofumarate (GS-7340-02), and all 
study data described in this section reflect the dosage of the monofumarate. For reference, 
100 mg of TAF monofumarate is equivalent to 80 mg of the GS-7340 free base (TAF).
Key results from nonclinical absorption, distribution, metabolism, and excretion studies of TAF 
are as follows: 

Following oral administration in dogs and monkeys, TAF demonstrated rapid absorption, 
with peak plasma concentrations between 0.25 and 0.5 hours. Thereafter, TAF plasma 
concentrations declined rapidly with a terminal half-life of less than 1 hour. 
Tenofovir alafenamide exposure (Cmax and AUC values) was nonlinear with dose and greater 
than expected with increasing dose. Repeat-dose studies in rats and monkeys showed no 
change in pharmacokinetics over time. 

Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. 

Following oral administration of [14C]-radiolabeled TAF to dogs, a mean total recovery of 
radioactivity at 24 hours of 63% was demonstrated. Radioactivity was detected in all tissues 
except brain with the majority present in the contents of the gastrointestinal tract, liver, 
kidney, and large intestine. Tissue concentrations were the highest in kidney, peripheral 
blood mononuclear cells (PBMCs), liver, large intestine, and bile. Additional studies in dogs, 
TFV concentrations in PBMCs following oral administration of TAF were approximately 
50-fold greater than observed in plasma, with an estimated t½ of greater than 24 hours. 

The major route of elimination of TAF-related radioactivity was via feces, with 
approximately 35% of the dose recovered in feces through 48 hours postdose. The primary 
route of elimination of TFV is renal excretion of unchanged drug based on IV studies of 
TFV. 


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
Tenofovir alafenamide has been found to be a substrate for intestinal efflux transport and in 
nonclinical studies its intestinal absorption was increased by the transport inhibitor 
cyclosporin A. 

No significant inhibition of human drug metabolizing cytochrome P450 (CYP) enzymes, 
uridine diphosphate glucuronyltransferase (UGT) 1A1 or transporters including 
P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide 
(OATP)1B1 and OATP1B3 was observed with TAF in vitro. 

Tenofovir alafenamide did not activate human pregnane X receptor (hPXR) or aryl 
hydrocarbon receptor (AhR).

Tenofovir alafenamide was not a substrate for drug-metabolizing CYP enzymes except for 
CYP3A4, which metabolized the compound slowly. 
1.2.4.
Nonclinical Toxicology
Key results from nonclinical toxicology studies of TAF are as follows:

Based on TFV exposure, the no observed adverse effect levels (NOAELs) in the 6-month rat, 
9-month dog, and 1-month monkey studies provide 14-, 4-, and 22-fold safety margins, 
respectively, for a human dose of 25 mg/day.

In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment with TAF 
100 mg/kg/day; however, effects were not seen at lower doses. Tenofovir alafenamide also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above.

In chronic studies in dogs after 9 months of treatment at doses up to TAF 18/12 mg/kg/day 
(the high dose was reduced from 18 to 12 mg/kg/day due to the occurrence of death, severe 
clinical signs and reduced body weight), the primary target organs were kidney 
(slight to moderate renal tubular degeneration and karyomegaly) and bone 
(decreased bone mineral density [BMD] in metaphyseal cancellous bone). 

Tenofovir alafenamide had no discernable electrocardiograph effect at the low dose of 
2 mg/kg/day. There was some evidence at 6 and 18/12 mg/kg/day for an effect to slightly 
prolong PR intervals. 

After 9 months of treatment, some dogs administered the highest dose of TAF 
(18/12 mg/kg/day) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given 
lower doses and it has not occurred in other animal studies. 


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
There were no clear treatment-related effects observed in monkeys following 28 days of 
TAF treatment at 3 and 30 mg/kg/day, including no changes in mitochondrial function and 
mitochondrial DNA (mtDNA) content in the liver, kidney, and skeletal muscle, and 
characterization of lymphocyte populations.

Tenofovir alafenamide was not genotoxic in either in vitro or in vivo assays. 
Tenofovir alafenamide had no adverse effects on male or female fertility parameters in rats. 
There was no effect on fetal viability or fetal development in pregnant rats administered 
doses of TAF up to 250 mg/kg/day or in pregnant rabbits administered TAF up to 
100 mg/kg/day; the highest doses were maternally toxic.
1.2.5.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF)
Emtricitabine and TAF have been combined with the integrase inhibitor EVG and its 
pharmacoenhancer COBI in the E/C/F/TAF FDC, which has been designed to be a complete 
treatment regimen for HIV-1 infection and is being evaluated in a broad clinical development 
program. The details of the key clinical studies are provided below:

GS-US-292-0102, a randomized, double-blinded controlled Phase 2 study in which 
E/C/F/TAF is compared to Stribild® (STB), as initial treatment of HIV-infection in 
ART-naive patients. This is a single-variable clinical comparison of the 2 tenofovir prodrugs, 
TAF and TDF 

GS-US-292-0104 and GS-US-292-0111, Phase 3 randomized, double-blinded studies of the 
safety and efficacy of E/C/F/TAF versus E/C/F/TDF in HIV-1 infected, antiretroviral 
treatment-naive adults. The interim Week 48 key conclusions from pooled data are as 
follows: 1) E/C/F/TAF once daily was noninferior to STB once daily when administered
for 48 weeks to HIV-infected, ART-naive adults, as assessed using the US Food and Drug
Administration (FDA)-defined snapshot algorithm with HIV-1 RNA < 50 copies/mL 
(E/C/F/TAF 92.4%; STB 90.4%; difference in percentages: 2.0%, 95% CI: −0.7% to 4.7%), 
2) administration of E/C/F/TAF resulted in > 90% lower plasma TFV and higher intracellular 
TFV-DP relative to STB, 3) E/C/F/TAF showed an improved renal and bone safety profile 
with significantly less decline in hip and spine BMD, less increase in serum creatinine and 
reduction in estimated glomerular filtration rate (eGFR), 4) Increases from baseline in fasting 
total cholesterol fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides 
were noted in the E/C/F/TAF group. At Week 96 86.6% in the TAF arm and 85.2% in the 
TDF arm maintained HIV-RNA <50 c/ML.


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
GS-US-292-0112, a Phase 3 open-label safety study of E/C/F/TAF in HIV-1 positive patients 
with mild to moderate renal impairment; Week 48 results demonstrated that patients who 
switched to E/C/F/TAF had no change in eGFR, and had significant improvements in 
measures of renal function including proteinuria, albuminuria, retinol binding protein and 
beta-2-microglobulin. These subjects also had improvements in measures of bone mineral 
density. Importantly, because FTC was given without dose adjustment to patients with 
eGFR 30-50 mL/min, these patients had comparable safety profile to patients with 
eGFR 50-69 mL/min, with no increased rate of potential FTC related drug reactions, 
supporting the safety of FTC at higher exposures. In addition, 92% of study participants 
maintained virologic suppression (HIV-1 RNA < 50 copies/ml) at Week 48 after switching to 
E/C/F/TAF. The virologic suppression rate was 88% at Week 96.

GS-US-292-0109, a Phase 3 study designed to evaluate the safety, efficacy, and tolerability 
of switching to E/C/F/TAF in individuals who are virologically suppressed on regimens 
containing TDF. The interim Week 48 key conclusions from this study are as follows: 
1) switching to E/C/F/TAF was noninferior to maintaining FTC/TDF+3rd Agent 
(STB, efavirenz/emtricitabine/tenofovir DF (ATR), atazanavir (ATV)/boosted+Truvada®) as 
assessed using the FDA snapshot algorithm (Week 48 FAS) with HIV-1 RNA cutoff at 
50 copies/mL (E/C/F/TAF 95.6%; FTC/TDF+3rd Agent 92.9%; difference in percentages: 
2.7%, 95.01% CI: −0.3% to 5.6%), 2) An improved renal and bone safety profile was 
observed in subjects who switched to E/C/F/TAF, 3) there were no differences in ocular 
findings between treatment groups and no reported cases of uveitis.

GS-US-292-1825: Interim Week 48 data, 
Efficacy Results
The percentages of subjects in the FAS with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48, as 
determined using the US FDA-defined snapshot algorithm, were 87.3% (95% CI: 75.5% to 
94.7%) and 81.8% (95% CI: 69.1% to 90.9%), respectively. The percentages of subjects with 
HIV-1 RNA ≥ 50 copies/mL at Week 24 and Week 48 were 1.8% and 3.6%, respectively. The 
remaining subjects (10.9% at Week 24 and 14.5% at Week 48) had no virologic data in the 
corresponding window. All 6 subjects lacking virologic data in the Week 24 window and 
7 of the 8 subjects lacking virologic data in the Week 48 window had prematurely discontinued 
study drug, with their last HIV-1 RNA value < 50 copies/mL. 
The percentage of subjects in the FAS with HIV-1 RNA < 20 copies/mL at Week 48, as 
determined using the US FDA-defined snapshot algorithm, was 81.8% (95% CI: 69.1% to 
90.9%). The percentage of subjects with HIV-1 RNA ≥ 20 copies/mL at Week 48 was 3.6%. 
There was no virologic data in the Week 48 window for the remaining 8 (14.5%) subjects, 
7 of whom had prematurely discontinued study drug with their last available HIV-1 RNA 
< 20 copies/mL.


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At Week 48 there were no clinically significant differences between subgroups (age, sex, race, 
region, and study drug adherence rate) in the percentages of subjects with HIV-1 RNA 
< 50 copies/mL, determined using the US FDA-defined snapshot algorithm. Percentages of 
subjects with HIV-1 RNA < 50 copies/mL in each subgroup were generally similar to that 
observed in the overall study population.
When assessed using M = F and M = E imputation methods for missing data, the percentages of 
subjects with HIV-1 RNA < 50 copies/mL at Week 48 were 83.6% (95% CI: 71.2% to 92.2%) 
and 97.9% (95% CI: 88.7% to 99.9%), respectively. The percentage of subjects with HIV-1 
RNA < 20 copies/mL at Week 48 was 83.6% (M = F) and 97.9% (M = E). 
CD4 cell counts and CD4% remained stable through Week 48. The mean (SD) baseline CD4 cell 
count was 545 (239.2) cells/μL; the mean (SD) change from baseline at Week 48 was 
−16 (192.1) cells/μL. The mean (SD) baseline CD4% was 31.5% (9.41%); the mean (SD) change 
from baseline at Week 48 was 1.7% (4.10%).
Safety Results
In relation to the primary study endpoint, the incidence of treatment-emergent Grade 3 or higher 
AEs up to Week 48, Grade 3 or 4 AEs were reported for 32.7% of subjects (18 of 55).
Overall through the data cut date, 92.7% of subjects (51 of 55) had at least 1 AE, most common 
among which were nausea (21.8%, 12 subjects), hyperkalemia (14.5%, 8 subjects), and 
pneumonia (12.7%, 7 subjects). Most AEs were Grade 1 or 2 in severity; Grade 3 or 4 AEs were 
reported for 36.4% of subjects (20 subjects). Serious AEs (SAEs) were reported for 52.7% of 
subjects (29 subjects), among which the most common were pneumonia (12.7%, 7 subjects), 
fluid overload, hyperkalemia, and osteomyelitis (each 7.3%, 4 subjects). Adverse events 
considered related to study drug were reported for 10.9% of subjects (6 subjects), among which 
only nausea (7.3%, 4 subjects) occurred in more than 1 subject. No SAE was considered related 
to study drug.
Adverse events leading to premature study drug discontinuation were reported for 5.5% of 
subjects (3 subjects). In 2 subjects, the AE was serious (generalized edema considered not related 
to study drug in one and a scheduled renal transplant in the other); in the third, allergic pruritus 
was reported as an AE considered related to study drug. No AE leading to premature study drug 
discontinuation occurred in more than 1 subject. One treatment-emergent death was reported, 
due to heart failure and anasarca; the AEs leading to death were considered not related to study 
drug. No pregnancy was reported through the data-cut date.
Adverse events potentially associated with FTC (ie, among those listed in the Emtriva 
prescribing information as having an incidence of ≥ 10%) were reported for 45.5% of subjects 
(25 subjects), the most common among which were nausea (21.8%, 12 subjects), cough (10.9%,
6 subjects), and diarrhea (9.1%, 5 subjects). Adverse events in this category considered related to 
study drug were reported for 9.1% of subjects (5 subjects), while none led to premature 
discontinuation of study drug.


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There were no clinically relevant changes from baseline in median values for hematology or 
clinical chemistry parameters. As characteristic for patients with ESRD, median values greater 
than reference values were observed post baseline for amylase, blood urea nitrogen, parathyroid 
hormone, creatinine, and phosphate; otherwise, median values were generally within the relevant 
reference range.
Most subjects had at least 1 graded laboratory abnormality (96.4%, 53 subjects). Grade 1 or 2 
laboratory abnormalities were reported for 52.7% of subjects (29 subjects) and Grade 3 or 4 
laboratory abnormalities were reported for 43.6% of subjects (24 subjects).
No subject met Hy’s Law criteria.
There were no clinically relevant changes from baseline in median fasting values for total 
cholesterol, direct low-density lipoprotein cholesterol, high-density lipoprotein (HDL) 
cholesterol, total cholesterol:HDL cholesterol ratio, triglycerides, or glucose in serum at 
Weeks 24 and 48.
There were no clinically relevant changes from baseline in median values for vital signs or body 
weight. Three subjects, 1 with a normal ECG at baseline and 2 with abnormal (not clinically 
significant) ECGs at baseline had clinically significant abnormal ECGs at Week 48, each of
which was reported as a nonserious AE not considered related to study drug.
PK Results
The primary plasma PK parameters (AUC, Cmax, and Ctau) of TAF, TFV (the major metabolite 
of TAF), FTC, EVG, and COBI calculated from the dedicated intensive PK substudy performed 
in a subset of 12 virologically suppressed, HIV-1 infected subjects with ESRD on chronic 
hemodialysis treated with GEN are shown in the table below.
Table 1-1.
GS-US-292-1825: Steady-State TAF, TFV, FTC, EVG, and COBI 
Plasma PK Parameters (PK Substudy Analysis Set)
Analyte
AUCa
Mean (%CV)
Cmax
Mean (%CV)
Ctau
Mean (%CV)
N
ng•h/mL
N
ng/mL
N
ng/mL
TAF
12
231.9 (53.2)
12
246.3 (75.4)

Not applicable
TFV (major metabolite of TAF)
10
8715.0 (39.4)
12
442.8 (40.9)
10
264.8 (73.2)
FTC
11
62929.9 (48.0)
12
4875.0 (40.6)
10
1277.3 (59.2)
EVG
10
14284.8 (54.5)
12
1258.5 (54.8)
10
174.4 (59.8)
COBI
11
10179.5 (59.0)
12
1370.4 (67.1)
10
28.9 (117.9)
For each subject in the PK Substudy Analysis set, intensive PK sampling was conducted at Week 2 or Week 4.
a
AUCtau for all analytes except TAF, for which AUClast is shown.


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Exposures of TAF, EVG, and COBI were consistent with the range of historical data obtained 
following the administration of GEN (and Stribild® [EVG/COBI/FTC/TDF] in the case of EVG 
and COBI) to HIV-1 infected subjects with normal renal function. As expected, given the 
predominantly renal elimination of FTC and TFV, exposures of these analytes were higher in 
subjects on hemodialysis compared with historical data obtained following the administration of 
GEN to HIV-1 infected subjects with normal renal function or with mild to moderate renal 
impairment.
Conclusions
The conclusions from this Week 48 interim analysis are as follows: 
1) Genvoya was well tolerated by virologically suppressed, HIV-1 infected adult subjects with 
ESRD on chronic hemodialysis. Common AEs were generally consistent with those expected 
in the study population. 
2) Virologic suppression (HIV-1 RNA < 50 copies/mL) was maintained, and CD4 cell counts 
remained stable, through 48 weeks in virologically suppressed, HIV-1 infected adult subjects 
with ESRD on chronic hemodialysis who switched to GEN. 
3) Exposures of TFV and FTC in virologically suppressed, HIV-1 infected subjects with ESRD 
on chronic hemodialysis receiving GEN were higher compared with historical data obtained 
following the administration of GEN to HIV-1 infected subjects with normal renal function 
or mild to moderate renal impairment. Exposures of TAF, EVG, and COBI were consistent 
with historical data from subjects with normal renal function.
1.3.
Bictegravir (GS-9883, B, BIC)
1.3.1.
General Information
Bictegravir, a potent inhibitor of HIV-1 integrase is being evaluated for the treatment of HIV 
infection. Antiviral testing has shown that bictegravir 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. Integrase mutant viruses that are resistant to the 
INSTIs RAL and EVG remain largely sensitive to bictegravir.
1.3.2.
Preclinical Pharmacology and Toxicology
A core battery of safety pharmacology studies have been conducted with bictegravir. These 
include assessments of cytotoxicity, off-target receptor and ion-channel binding, effects on 
human Ether-à-go-go-Related Gene (hERG) potassium current and papillary muscle action 
potential, and in vivo studies in rats and dogs that evaluated effects of bictegravir on all major 
organ systems. The volume of distribution of bictegravir ranged between 0.09 and 0.22 L/kg in 
the preclinical species, which indicates that the distribution of bictegravir is limited to the 
extracellular compartment due to its high binding to plasma proteins. The projected half-life of 
bictegravir in humans is approximately 20 hours based upon the estimates of clearance and 
volume of distribution.


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1.3.2.1.
Pharmacology
Bictegravir has IC50 values ranging from 1.5 to 2.4 nM, similar to the inhibitory effect of DTG 
and EVG. Bictegravir is highly potent against HIV replication in MT4 cells with an EC50 (50% 
effective inhibitory concentration) value of 1.9 nM and a protein adjusted EC95 value of 361 nM. 
Bictegravir does not show significant cytotoxicity against dividing and non-dividing human 
PBMCs, primary human hepatocytes and various non-target human cell lines.
Bictegravir is mainly metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT1A1) 
and CYP3A. Bictegravir does not inhibit major human CYP isoforms or UGT1A1 at 
concentrations up to 25 M. Consequently, bictegravir is unlikely to be a clinically relevant 
inhibitor of these enzymes, and is not expected to inhibit the metabolic clearance of drugs 
metabolized by these enzymes. Bictegravir only modestly inhibits renal transporter OCT2 
(IC50 = 0.42 M). As a result, bictegravir is not expected to significantly interfere with the key 
transporter responsible for creatinine tubular elimination at the clinically projected Cmax. 
Additionally, the risk that bictegravir will affect the OCT2-mediated excretion of 
co-administered drugs is considered to be low.
Bictegravir does not activate AhR and only weakly activates PXR at concentrations up to 50 μM 
(less than 5% and 40% of activation, respectively, compared to positive control compound). 
Therefore, bictegravir is not expected to act as an inducer through PXR- or AhR-mediated 
pathways at the doses and exposure levels projected in clinical use.
1.3.2.2.
Toxicology
Single oral doses of bictegravir up to 1000 mg/kg were well-tolerated in rats (AD-141-2286). 
The increase in exposure was limited (< 2-fold) between 100 and 300 mg/kg and similar 
exposure was observed between 300 and 1000 mg/kg suggesting saturation of absorption at 
300 mg/kg (AUC0-24 2205 gh/mL and 1931 gh/mL, respectively). In monkeys, single oral 
doses of bictegravir up to 1000 mg/kg were well-tolerated (AD-141-2284). The increase in 
exposure was limited (< 2-fold) between 300 to 1000 mg/kg (AUC0-24 803 μgh/mL and 
1078 μg h/mL, respectively).
In 2-week (TX-141-2029) and 26-week (TX-141-2031) oral toxicity studies in rats at doses up to 
300 mg/kg/day, bictegravir was well-tolerated with no bictegravir-related effects on clinical 
observations, body weight, food consumption, ophthalmic examinations, and anatomic 
pathology. The high dose of 300 mg/kg/day was considered the maximum feasible dose based 
upon saturation of absorption. The no observed effect level (NOEL) in the 26-week study was 
considered to be the high dose of 300 mg/kg/day. At the NOEL, bictegravir exposures in the rat 
were considered to be approximately 12-/31-fold higher (males/females) than the projected 
steady state human exposure of bictegravir following administration of B/F/TAF (50/200/25 mg) 
QD under fed conditions.
In a 39-week study in monkeys (TX-141-2032), following administration of 1000 mg/kg/day 
(high dose) of bictegravir for 39 weeks, pathology data indicated minimal to marked bile duct 
hyperplasia and minimal or moderate hepatocyte hypertrophy in both sexes, and minimal 


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regenerative hyperplasia and minimal or slight neutrophil infiltrate in males. The macroscopic 
finding of rough surface on the liver in one male administered 1000 mg/kg/day correlated with 
moderate hepatocyte hypertrophy and marked bile duct hyperplasia. After a 4-week recovery 
period, bictegravir-related microscopic liver findings included marked bile duct hyperplasia, 
slight hepatocyte hypertrophy, minimal regenerative hyperplasia, and slight lymphocyte infiltrate 
in one male and slight bile duct hyperplasia in one female administered 1000 mg/kg/day, while 
the other two animals in the high dose group had no hepatobiliary findings. Minimally to mildly 
increased ALT activities (≤3.5-fold versus baseline values), likely associated with liver findings, 
exhibited reversibility. There were no other adverse findings in the study, including clinical 
observations, or effects on body weight, body weight change, food consumption, ECGs, 
hematology, coagulation, clinical chemistry, urinalysis, and ophthalmoscopy. 
No bictegravir-related effects were observed in the mid-dose group (200 mg/kg/day) which was 
considered the no-observed-effect-level (NOEL). The estimated margin of exposure at the NOEL 
was approximately 5.1-fold based on expected human exposure with the once daily dosing of the 
B/F/TAF (50/200/25 mg) tablet. 
A standard battery of in vitro and in vivo studies was performed to assess the genotoxic potential 
of bictegravir. There was no evidence of mutagenic or clastogenic activity in an in vitro bacterial 
reverse mutation assay (Study TX-141-2026), a chromosomal aberration assay in human 
lymphocytes (Study TX-141-2027), or in a rat micronucleus test (Study TX-141-2029).
1.3.3.
Clinical Trials of Bictegravir
Clinical trials entailing the use of bictegravir 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 in healthy subjects and a randomized, open-label, 2-cohort, 3-period, crossover, PK 
study evaluating the drug interaction potential between F/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 in HIV-1 
infected subjects (5 mg, 25 mg, 50 mg, 100 mg) (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/Emtricitabine/
Tenofovir Alafenamide (75/200/25 mg and 50/200/25 mg) Fixed-Dose Combination Tablets 
Versus a GS-9883 (75 mg) Tablet and a Emtricitabine/Tenofovir Alafenamide (200/25 mg) 
Fixed-Dose Combination Tablet Administered Simultaneously and 2) the Effect of Food on 
the Pharmacokinetics of GS-9883, Emtricitabine and Tenofovir Alafenamide When 
Administered as GS-9883/Emtricitabine/Tenofovir Alafenamide (75/200/25 mg and 
50/200/25 mg) Fixed-Dose Combination Tablets (completed)


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
GS-US-141-1478, a Phase 1, Open Label, Parallel Group, Adaptive, Single-Dose Study to 
Evaluate the Pharmacokinetics 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)

GS-US-141-1481, a Phase 1 study to evaluate the pharmacokinetics, 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 1Randomized, Open Label, Drug Interaction Study Evaluating the 
Effect of F/TAF FDC Tablet or GS-9883 on the Pharmacokinetics of a Representative 
Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol (completed)

GS-US-380-1761, a Phase 1 Study to Evaluate Pharmacokinetic Drug-Drug Interaction 
Potential between GS-9883/Emtricitabine/Tenofovir Alafenamide Fumarate 
(GS-9883/F/TAF) and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) 
Tablets (completed)

GS-US-380-1991, a Phase I Single and Multiple Dose Study Evaluating the 
Pharmacokinetics, Safety, and Tolerability of GS-9883/Emtricitabine/Tenofovir Alafenamide 
Fumarate (GS-9883/FTC/TAF) in Healthy Japanese and Caucasian Subjects (completed)

GS-US-380-1999, a Phase 1 Multiple Dose Study to Evaluate the Pharmacokinetic 
Drug-Drug Interaction Potential between GS-9883/Emtricitabine/Tenofovir Alafenamide 
Fumarate and Sofosbuvir/Velpatasvir/GS-9857 in Healthy Subjects (completed)

GS-US-380-3908, a Phase 1, Blinded, Placebo-controlled, Two-period Crossover Drug 
Interaction Study to Assess the Effect of GS-9883/F/TAF on Metformin Pharmacokinetics in 
Healthy Subjects (completed)

GS-US-380-3909, a Phase 1, Open Label, Multiple-Cohort, Multiple-Period, 
Fixed-Sequence, Drug Interaction Study to Evaluate the Effect of Antacid and Mineral 
Supplements on GS-9883 Pharmacokinetics (completed)


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
GS-US-141-1475, a Phase 2 Randomized, Double-Blinded Study of the Safety and Efficacy 
of GS-9883 + Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + 
Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected, Antiretroviral Treatment-Naive 
Adults (ongoing)

GS-US-380-1489, a Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of GS-9883/Emtricitabine/Tenofovir Alafenamide Versus 
Abacavir/Dolutegravir/Lamivudine in HIV-1 Infected, Antiretroviral Treatment-Naïve 
Adults (ongoing)

GS-US-380-1490, a Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of GS-9883/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir +
Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected, Antiretroviral Treatment-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 Dolutegravir and ABC/3TC, or a Fixed Dose 
Combination (FDC) of ABC/DTG/3TC to a FDC of GS-9883/F/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 Darunavir plus 
either Emtricitabine/Tenofovir or Abacavir/Lamivudine to GS-9883/Emtricitabine/Tenofovir 
Alafenamide 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 Fixed Dose Combination (FDC) of GS-9883/Emtricitabine/
Tenofovir Alafenamide (GS-9883/F/TAF) from Elvitegravir/Cobicistat/Emtricitabine/
Tenofovir Alafenamide (E/C/F/TAF), Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Disoproxil Fumarate (E/C/F/TDF) or Atazanavir + Ritonavir + Emtricitabine/Tenofovir 
Disoproxil Fumarate (ATV+RTV+FTC/TDF) in Virologically Suppressed HIV-1 Infected 
Women (ongoing)

GS-US-380-1474, A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and 
Antiviral Activity of the GS-9883/Emtricitabine/Tenofovir Alafenamide (GS-9883/F/TAF) 
Fixed Dose Combination (FDC) in HIV-1 Infected Virologically Suppressed Adolescents 
and Children (ongoing)

GS-US-380-4030, A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of Switching from a Regimen of Dolutegravir and Either Emtricitabine/Tenofovir 
Alafenamide or Emtricitabine/Tenofovir Disoproxil Fumarate to a Fixed Dose Combination 
of Bictegravir/ Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected Subjects who are 
Virologically Suppressed Adults (ongoing)


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
GS-US-380-4449: A Phase 3b, Multicenter, Open-Label Study to Evaluate Switching froman 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combination 
Regimen or a Tenofovir Disoproxil Fumarate Containing Regimen to Fixed-Dose 
Combination of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Elderly, 
Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 65 Years (ongoing)

GS-US-380-4458: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of Fixed Dose Combination of Bictegravir/Emtricitabine/Tenofovir Alafenamide 
versus Dolutegravir + Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment Naïve, 
HIV-1 and Hepatitis B Co-Infected Adults (ongoing)
Please refer to the B/F/TAF Investigators’ Brochure for further information about these studies.
1.3.3.1.
Phase 1 Safety and Pharmacokinetics
Study GS-US-141-1218 was a four part, first-in-human study. Parts A and B were randomized, 
double-blind, placebo-controlled, single and multiple ascending dose studies of bictegravir in 
healthy male and female subjects. Part C was an open label, fixed sequence food effect study 
evaluating the effect of food on the PK of bictegravir. Part D was a randomized, open-label, 
2-cohort, 3-period, crossover PK study evaluating the drug interaction potential between F/TAF 
FDC tablet and bictegravir in healthy subjects.
There was no difference in the overall incidence or type of AEs when bictegravir was 
administered in the fasted and fed states. There was no difference in the overall incidence of AEs 
when bictegravir or F/TAF was each administered alone or in combination.
No deaths or pregnancies were reported. No Grade 3 or 4 AEs or SAEs, were reported in any 
cohort.
Changes in serum creatinine were observed in this study, presumably via inhibition of the renal 
transporter OCT2. In the MAD cohorts (fasted), serum creatinine change at Day 14 ranged from 
0.05 mg/dL for the 5 mg cohort to 0.18 mg/dL for the 300 mg/dL cohort. In Part D (DDI), 
conducted in the fed state (regular meal), subjects received 100 mg bictegravir monotherapy for 
7 days and 100 mg bictegravir with F/TAF for 7 days, the mean serum creatinine change at 
Day 7 was 0.14 mg/dL following bictegravir and 0.17 mg/dL following bictegravir + F/TAF. All 
changes returned to baseline after discontinuation of bictegravir.
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. Grade 3 laboratory 
abnormalities included 10 subjects with Grade 3 urine dipstick tests for blood. All of these 
subjects were female, none of the labs were considered by the Investigator to be clinically 
significant, and all were associated with menstruation. No other Grade 3 or 4 laboratory 
abnormalities were observed.
Based on results in study GS-US-141-1218, pharmacokinetic profile of bictegravir was 
characterized by rapid absorption with time to peak plasma concentrations (median Tmax of 
cohorts) ranging between 1 and 4 hours following administration under fasted conditions. 


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bictegravir exposures were appropriately dose proportional following single dose 25-100 mg 
dose administration, with decreasing dose proportional at higher doses. The half-life of 
bictegravir was approximately 18 hours, with no changes observed across studied dose range as 
evidenced by parallel terminal phase slopes. A high-fat meal increased AUCinf and Cmax
(geometric mean, 84% and 101%, respectively) following 100 mg single dose administration. 
Steady state was achieved after 4-6 days of once daily dosing of bictegravir with average 
accumulation ratios for AUC24hr of 1.6.
Table 1-2.
GS-US-141-1218: Bictegravir Mean (%CV) PK Parameters Following 
Single Doses of bictegravir in Healthy Subjects (Bictegravir PK 
Analysis Set; Part A: Single Dosing)
Bictegravir 
PK Parameter
Mean (%CV)
5mg
(N=6)
25 mg
(N=6)
50 mg
(N=6)
100 mg
(N=6)
300 mg
(N=6)
600 mg
(N=6)
Cmax (ng/mL)
691.2
(22.1)
1618.3
(26.7)
3965.0
(40.1)
6998.3
(36.1)
14605.0 
(27.1)
20050.0
(7.5)
Tmax (hr)
1.25 
(1.00-1.50)
2.00
(1.00-3.00)
3.00
(1.50-4.00)
2.25
(1.50-3.00)
3.50
(2.00-6.00)
3.5
(2.00-4.00)
AUCinf (ng hr/mL)
13059.7
(25.1)
35718.2 
(21.3)
78399.5 
(29.7)
163028.2 
(24.3)
355917.3 
(32.9)
454446.8 
(19.9)
T1/2 (hr)
18.51
(16.81-19.99)
18.08
(16.63-19.64)
16.72
(15.77-17.11)
18.90
(17.96-20.05)
18.14
(17.86-20.53)
17.89
(16.38-19.52)
T1/2 and Tmax: Median (Q1, Q3)
Table 1-3 presents bictegravir plasma PK parameters following administration of bictegravir 
(5, 25, 50, 100, and 300 mg) once daily for 7 days. Following administration of either bictegravir 
(5, 25, 50, 100, or 300 mg) once daily for 7 days, the PK absorption profile observed on 
Days 1 and 7 was similar to that observed in Part A (SAD). The median Tmax values ranged from 
1.5 to 2.5 hours on Day 1 and 1.5 to 4.0 hours on Day 7. Linearity was observed comparing 
bictegravir AUC and Cmax on Days 1 and 7 over the dose range of 25 to 50 mg. Steady state 
levels of bictegravir were achieved between Study Days 4 to 6 of dosing and maintained through 
Day 14. Accumulation is approximately 1.6-fold, which is consistent with the observed half-life 
of bictegravir (approximately 18 hours).


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Table 1-3.
GS-US-141-1218: Bictegravir Plasma Pharmacokinetic Parameters by 
bictegravir Dose Following Multiple-Dose Administration of 
bictegravir (Analysis Set: Bictegravir PK Part B: Multiple-Dose)
Bictegravir PK Parameter 
Mean (%CV)a
Multiple-Dose Bictegravir
5 mg
(N = 6)
25 mg
(N = 6)
50 mg
(N = 6)
100 mg
(N = 6)
300 mg
(N = 6)
Day 1
AUC0-24 (hr*ng/mL)
9033.6
(8.2)
27,775.1
(28.3)
58,371.4
(18.9)
79,773.8
(18.9)
180,714.3
(17.6)
Cmax (ng/mL)
709.7
(9.5)
2220.0
(35.6)
4648.3
(18.7)
6248.3
(26.8)
13,716.7
(19.1)
Tmax (hr)
1.50
(1.50, 1.50)
1.75
(1.00, 3.00)
1.50
(1.00, 2.00)
2.50
(2.00, 3.00)
2.50
(2.00, 4.00)
Day 7
AUCtau (hr*ng/mL)
14,392.0
(16.7)
50,008.2
(26.6)
89,710.1
(22.7)
126,785.8 
(23.7)
277,200.2 
(16.7)
Cmax (ng/mL)
982.5
(7.9)
3455.0
(24.1)
6538.3
(17.6)
9396.7
(20.8)
19,900.0 
(21.2)
Ctau (ng/mL)
400.83
(26.9)
1322.00
(27.8)
2241.67
(28.2)
3145.00 
(26.1)
6758.33 
(21.6)
Tmax (hr)
1.50
(1.00, 2.00)
3.00
(2.00, 3.00)
1.75
(1.50, 2.00)
1.75
(1.50, 3.00)
4.00
(2.00, 4.00)
Accumulation Ratio of AUC (%)
160.5
(19.0)
182.2
(17.1)
154.0
(15.9)
158.5
(12.1)
157.5
(22.6)
a
Data are presented as mean (%CV), except for Tmax, and t½, which are presented as median (Q1, Q3)
Table 1-4 presents the GLSM ratios and associated 90% CIs for the test (fed) versus reference 
(fasted) treatments for the primary plasma PK parameters of bictegravir. Administration of a 
single dose of bictegravir 100 mg with food (high-calorie/high-fat breakfast) increased the 
GLSM values of Cmax and AUCinf 101% (90% CI of GLSM ratio 165.93% to 242.74%) and 84% 
(90% CI of GLSM ratio 152.05% to 222.59%), respectively. There were no apparent changes in 
clearance and T1/2 following administration with food, indicating that food enhanced the 
bioavailability of bictegravir by improving its solubility and/or absorption.


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Table 1-4.
GS-US-141-1218: Statistical Comparison of Bictegravir 
Pharmacokinetic Parameters Following Single-Dose Administration of 
Bictegravir in the Fasted and Fed States (Bictegravir PK Analysis Set)
Bictegravir PK Parameter 
Mean (%CV)
% GLSM Ratio 
(90% CI)
Test
Bictegravir 100 mg Fed
(n=8)
Reference
Bictegravir 100 mg Fasted
(n=8)
AUCinf (hr*ng/mL)
214,146.3 (15.9)
117,777.1 (23.3)
183.97 (152.05, 222.59)
AUClast (hr*ng/mL)
209,259.9 (15.1)
115,681.7 (24.0)
183.58 (151.91, 221.86)
Cmax (ng/mL)
11,268.8 (15.1)
5885.0 (34.9)
200.69 (165.93, 242.74)
CI = confidence interval; GLSM = geometric least squares mean
1.3.3.2.
Phase 1b Proof of Concept
The first HIV-1 positive human subjects were dosed in the fasted state with 10 days of 
bictegravir in study (GS-US-141-1219). Four cohorts of 5 subjects each were randomized 4:1 to 
receive bictegravir or placebo to match at doses of 5 mg, 25 mg, 50 mg, and 100 mg once daily 
for 10 days. 
Bictegravir was generally well tolerated at the doses evaluated. A total of 9 of 20 subjects had an 
AE in this study. The most frequently reported AEs across all subjects were diarrhea (2 subjects), 
and headache (3 subjects). No other AE was reported in more than 1 subject. There was no 
increase in the incidence of AEs with increasing doses of bictegravir. 
The majority of AEs were considered by the investigator to be not related to study drug. A total 
of 2 subjects experienced mild diarrhea that was considered related to study drug (1 in the 5 mg 
cohort, 1 in the 100 mg cohort).   
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. 
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. No Grade 3 
treatment emergent laboratory abnormalities were observed. 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. One Grade 4 new onset laboratory abnormality 
was seen in 1 subject who received 5 mg bictegravir. This was a Grade 4 CPK seen on Day 17, 
7 days following his last dose of study medication. The subject was asymptomatic. The 
Investigator felt that this was unrelated to study medication and was due to resumption of crystal 
methamphetamine use by the subject. An adverse event of elevated CK was reported unrelated to 
study medication. 


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Amendment 2.1 (US Only) 
Based on PK infonnation collected in study GS-US-141-1219, which was in line with PK 
observed in study GS-US-141-1218, the median IQ for each dose were calculated and aTe 
presented in Table 1-5 below. 
Table 1-5. 
Trough Bictegravir Plasma Concentrations at Steady State Following 
Bictegravir Administration Under Fasting Conditions and 
Corresponding Protein-Adjusted IQ95 Values (Bictegravir PK 
Analysis Set) 
Bictegravir dose 
n 
Median (range) C 1au,ss (ng/mL) 
Median (range) pai Q9/ 
5 mg 
4 
206.5 (146.0 to 342.0) 
1.3 (0.9 to 2.1) 
25mg 
4 
797.5 (714.0 to 1900.0) 
4.9(4.4to 11.7) 
50 mg 
4 
2170.0 (852.0 to 3020.0) 
13.4 (5.3 to 18.6) 
100mg 
4 
4190.0 (3730.0 to 5970.0) 
25.9 (23.0 to 36.9) 
a 
TI1e protein adjusted IQ95 (paiQ95) value is estimated based on steady-state Ctau values and the in vitro paiC95 value for 
wild-type HIV-1 (162 ng/ml). 
The mean and 95% Cis of change from baseline in HIV -1 RNA (log10 copies/mL) are presented 
in Figure 1-1. 
Figure 1-1. 
G$-9883 5 mg 
Gs-9883 25 mg 
Gs-9883 50 mg 
GS-9883100 mg 
GS-US-141-1219: Mean and 95% Cis of Change from Baseline in 
HIV-1 RNA (log10 copies/mL) (PP Analysis Set) 
• 
= GS-9883 5 mg 
0 = GS-9883 25 mg 
/::, = GS-9883 50 mg 
0 = GS-9883100 mg 
<> =Placebo 
BL 
2 
3 
3 
3 
3 
4 
3 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
7 
8 
3 
3 
3 
3 
4 
4 
4 
4 
4 
3 
4 
4 
4 
4 
4 
9 
10 
Day 
3 
3 
4 
4 
4 
4 
4 
4 
4 
4 
11 
3 
4 
4 
4 
4 
14 
3 
4 
4 
4 
4 
17 
3 
3 
4 
4 
4 
NOTE: Baseline value was the last available value c.olle.cted prior to the time of the first dose of study drug. 
2 
-1 
-2 
-3 
-4 
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Mean viral load change on Day 11 was -2.08 log10 in the 25 mg cohort, -2.06 log10 in the 50 mg 
cohort, and -2.43 log10 in the 100 mg cohort. Time weighted average change from baseline at 
Day 11 (DAVG11) was -0.92 log10 in the 5 mg cohort, -1.33 log10 in the 25 mg cohort, 
−1.37 log10 in the 50 mg cohort and -1.61 log10 in the 100 mg cohort. Viral suppression (HIV-1 
RNA < 50 copies/mL) was ever achieved by the end of the study (Day 17) by 1 subject (25.0%) 
in the bictegravir 50 mg group and 2 subjects (50%) in the bictegravir 100 mg group.
1.3.3.3.
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 B+F/TAF versus 
dolutegravir (DTG)+F/TAF in HIV-infected, ART-naive adult subjects.
Eligible subjects were randomized in a 2:1 ratio to one of the following treatment groups, 
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:

Treatment Group 1: Bictegravir 75 mg + F/TAF (200/25 mg) + placebo-to-match DTG 
50 mg once daily

Treatment Group 2: DTG 50 mg + F/TAF (200/25 mg) + placebo-to-match bictegravir 75 mg 
once daily
Week 48 interim data are summarized below. 
Subject Disposition and Baseline Characteristics
A total of 98 subjects were randomized and treated in the study: 65 subjects in the B+F/TAF 
group and 33 subjects in the DTG+F/TAF group. At the time of the Week 48 data analysis, 
5 subjects (5.1%) had prematurely discontinued study drug, 3 in the B+F/TAF group and 2 in the 
DTG+F/TAF group. The reasons for study drug discontinuation were as follows (one subject 
each): AE, withdrawal of consent, and lost to follow-up in the B+F/TAF group, and 
noncompliance with study drug and lost to follow up in the DTG+F/TAF group.
Demographic and baseline characteristics were similar between the 2 treatment groups. Key 
baseline disease characteristics (ie, viral load, CD4+ cell count, and estimated glomerular 
filtration rate [eGFR]CG) were similar between the 2 treatment groups.
Median (Q1, Q3) baseline HIV-1 RNA was 4.45 (3.96, 4.79) log10 copies/mL, with 82.7% 
having ≤ 100,000 copies/mL at baseline. Five subjects (5.1%) had > 400,000 copies/mL at 
baseline; of these, 4 subjects were randomized to B+F/TAF and 1 subject was randomized to 
DTG+F/TAF. 
Median (Q1, Q3) baseline CD4+ cell count was 444 (316, 595) cells/μL, with 41.8% of subjects 
having ≥ 500 cells/μL at baseline. Median (Q1, Q3) baseline eGFRCG was 
125.3 (105.7, 147.0) mL/min.


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Efficacy Results
The primary efficacy endpoint was the proportion of subjects with HIV-1 RNA 50 copies/mL 
at Week 24 as determined by the United States (US) Food and Drug Administration 
(FDA)-defined snapshot algorithm. The percentages of subjects with HIV-1 RNA 
< 50 copies/mL at Week 24 were high in both groups, as follows: BIC+F/TAF 96.9%;
DTG+F/TAF 93.9%; difference in percentages: 2.9%, 95% CI: −8.5% to 14.2%. Because the 
lower bound of the 95% CI for the difference in response rate (B+F/TAF – DTG+F/TAF) was 
greater than the prespecified −12% margin, B+F/TAF was determined to be noninferior to 
DTG+F/TAF.
The percentages of subjects with HIV-1 RNA < 50 copies/mL at Week 48 were similar between 
the 2 treatment groups when assessed using the US FDA-defined snapshot algorithm based on 
the full analysis set (FAS) (Table 1-6), as follows: B+F/TAF 96.9%; DTG+F/TAF 90.9%; 
difference in percentages: 6.4%, 95% CI: −6.0% to 18.8%.
As expected for an INSTI-containing regimen, HIV-1 RNA levels decreased rapidly in the 
first 4 weeks following initiation of study drug in both treatment groups. After Week 4, HIV-1 
RNA values were stable and similar between the 2 treatment groups through Week 48; mean 
(SD) decreases from baseline at Week 48 using the FAS were as follows: B+F/TAF 
−3.09 (0.752) log10copies/mL; DTG+F/TAF −3.11 (0.852) log10copies/mL; difference in 
least-squares mean (LSM): −0.06 log10copies/mL, 95% CI: −0.32 to 0.20 log10 copies/mL.
The mean (SD) increases from baseline in CD4+ cell counts were similar between the 
2 treatment groups through Week 48 using the FAS, as follows: B+F/TAF 258 (221.7) cells/μL; 
DTG+F/TAF 192 (242.0) cells/μL; difference in LSM: 72 cells/μL, 95% CI: −30 to 174 cells/μL.


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Table 1-6.
GS-US-141-1475: Virologic Outcome at Week 48 Using the US 
FDA-Defined Snapshot Algorithm and HIV-1 RNA < 50 copies/mL 
(FAS)
B+F/TAF
(N = 65)
DTG+F/TAF
(N = 33)
B+F/TAF vs DTG+F/TAF
p-valuea
Difference in 
Percentages 
(95% CI)b
HIV-1 RNA < 50 copies/mL
63 (96.9%)
30 (90.9%)
0.17
6.4% 
(−6.0% to 18.8%)
HIV-1 RNA ≥ 50 copies/mL
1 (1.5%)
2 (6.1%)
HIV-1 RNA ≥ 50 copies/mL in Week 48 
window
0
1 (3.0%)
Discontinued study drug due to lack of efficacy
0
0
Discontinued study drug due to other reasons 
and last available HIV-1 RNA ≥50 copies/mLc
1 (1.5%)
1 (3.0%)
No virologic data in Week 48 window
1 (1.5%)
1 (3.0%)
Discontinued study drug due to AE/death
1 (1.5%)
0
Discontinued study drug due to other reasons 
and last available HIV-1 RNA < 50 copies/mLc
0
1 (3.0%)
Missing data during window but on study drug
0
0
Week 48 window was between Day 295 and 378 (inclusive).
a
p-value for the superiority test comparing the percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment 
groups was from the Cochran-Mantel-Haenszel test stratified by baseline HIV-1 RNA stratum (≤100,000 vs 
> 100,000 copies/mL).
b
Difference in percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment groups and its 95% CI were 
calculated based on the baseline HIV-1 RNA stratum-adjusted Mantel-Haenszel proportion.
c
Discontinuation due to other reasons included subjects who prematurely discontinued study drug due to investigator’s 
discretion, withdrew consent, lost to follow-up, noncompliance with study drug, protocol violation, pregnancy, and study 
termination by sponsor.
Interim Virology Resistance Data
Through Week 48, no emergent drug resistance was detected in the B+F/TAF group.
Safety Results
Adverse Events
Adverse events were reported in 84.6% (55 of 65 subjects) in the B+F/TAF group and 66.7% 
(22 of 33 subjects) in the DTG+F/TAF group. The most commonly reported AEs by treatment 
group were as follows:

B+F/TAF group—diarrhea (12.3%, 8 of 65 subjects); and headache, nausea, and upper 
respiratory tract infection (each 7.7%, 5 subjects)

DTG+F/TAF group—diarrhea and nausea (each 12.1%, 4 of 33 subjects); and arthralgia, 
fatigue, flatulence, furuncle, gastroenteritis, costochondritis, hemorrhoids, and pruritus 
(each 6.1%, 2 subjects)


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The majority of AEs were Grade 1 in severity, with similar incidence of Grade 2, 3, or 4 AEs 
between the 2 treatment groups. Grade 3 AEs were uncommon, with all Grade 3 AEs reported in 
the B+F/TAF group (6.2%, 4 subjects); only 1 Grade 3 AE was considered related to study drug 
by the investigator (urticaria in a B+F/TAF subject). No individual Grade 3 AE was reported for 
> 1 subject. No Grade 4 AEs were reported.
Serious AEs were uncommon, with all reported SAEs occurring in the B+F/TAF group 
(4.6%, 3 subjects). No SAE was considered related to study drug by the investigator. The SAEs 
reported were appendicitis, psychotic disorder/suicidal ideation, and diabetic ketoacidosis.
The incidence of AEs considered related to study drug by the investigator was similar between 
the 2 treatment groups (B+F/TAF 20.0%, 13 subjects; DTG+F/TAF 21.2%, 7 subjects). Nearly 
all study drug-related AEs were Grade 1 in severity, with similar incidence of Grade 2, 3, or 4 
study drug-related AEs between the 2 treatment groups (B+F/TAF 3.1%, 2 subjects; 
DTG+F/TAF 3.0%, 1 subject). The only Grade 3 study drug-related AE reported (urticaria in a 
B+F/TAF subject) was also the only AE leading to premature study drug discontinuation; the 
event began on Day 130 and led to discontinuation of study drug on Day 162.
No deaths or pregnancies were reported in either treatment group.
Clinical Laboratory Evaluations
Most subjects in both treatment groups had at least 1 laboratory abnormality (B+F/TAF 84.4%, 
54 of 64 subjects; DTG+F/TAF 87.5%, 28 of 32 subjects). Most of the reported laboratory 
abnormalities were Grade 1 or 2 in severity. The incidence of Grade 3 or 4 laboratory 
abnormalities was similar between the 2 treatment groups (B+F/TAF 25.0%, 16 subjects; 
DTG+F/TAF 21.9%, 7 subjects). 
Graded laboratory abnormalities in ALT and aspartate aminotransferase (AST) were reported 
more frequently and with greater severity in the B+F/TAF group than in the DTG+F/TAF group. 
Graded ALT abnormalities were reported in 23.4% (15 of 64 subjects) in the B+F/TAF group 
and 9.4% (3 of 32 subjects) in the DTG+F/TAF group, and graded AST abnormalities were 
reported in 20.3% (13 of 64 subjects) in the B+F/TAF group and 9.4% (3 of 32 subjects) in the 
DTG+F/TAF group. Grade 3 ALT elevations occurred in 1 subject in the B+F/TAF group and 
none in the DTG+F/TAF group. Grade 3 AST elevations were seen in 3 subjects in the B+F/TAF 
group (one of whom also had a Grade 3 ALT elevation) and none in the DTG+F/TAF group. Of 
the 3 subjects who had Grade 3 transaminase elevations, 2 were associated with simultaneous 
Grade 4 CK elevations, were transient, and resolved rapidly without any associated AEs. 
One participant had both Grade 3 AST and ALT persistent elevations that were attributed to 
ongoing alcohol use. No Grade 4 transaminase elevations were observed in either treatment 
group.
Grade 3 or 4 CK elevations were seen in 9.4% (6 of 64 subjects) in the B+F/TAF group and in 
3.1% (1 of 32 subjects) in the DTG+F/TAF group. All of the Grade 3 or 4 CK elevations 
occurred in young men (age range, 24 to 31 years), were transient, and resolved without 
treatment interruption, and none of these laboratory abnormalities were associated with AEs.


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There were similar increases from baseline in median (Q1, Q3) serum creatinine in both treatment 
groups at Week 48: B+F/TAF 0.08 (0.02, 0.15) mg/dL; DTG+F/TAF 0.12 (0.02, 0.20) mg/dL. 
There were decreases in median (Q1, Q3) eGFRCG at Week 48, which were smaller in the 
B+F/TAF than in the DTG+F/TAF group: B+F/TAF −7.0 (−18.7, 1.6) mL/min; DTG+F/TAF 
−11.3 (−24.5, −0.8) mL/min.
There were no clinically significant changes from baseline or differences between treatment 
groups in the median values for hematology, chemistry, or metabolic parameters. 
Conclusions
Key conclusions from Study GS-US-141-1475 at Week 48 include the following:

The percentages of subjects with HIV-1 RNA < 50 copies/mL at Week 48 were similar 
between the 2 treatment groups when assessed using the US FDA-defined snapshot algorithm 
based on the FAS, as follows: B+F/TAF 96.9%; DTG+F/TAF 90.9%; difference in 
percentages: 6.4%, 95% CI: −6.0% to 18.8%. There was a similar increase in the mean (SD) 
CD4+ cell count between the 2 treatment groups: B+F/TAF 258 (221.7) cells/μL; 
DTG+F/TAF 192 (242.0) cells/μL; difference in LSM: 72 cells/μL, 95% CI: 
−30 to 174 cells/μL.

No resistance to any INSTIs, NRTIs, NNRTIs, or PIs was detected through Week 48 in the 
B+F/TAF group.

Both B+F/TAF and DTG+F/TAF were generally well tolerated through 48 weeks of 
treatment. 
The most commonly reported AEs were diarrhea (12.3%, 8 of 65 subjects); and 
headache, nausea, and upper respiratory tract infection (each 7.7%, 5 subjects) in the 
B+F/TAF group, and diarrhea and nausea (each 12.1%, 4 of 33 subjects); and arthralgia, 
fatigue, flatulence, furuncle, gastroenteritis, costochondritis, hemorrhoids, and pruritus 
(each 6.1%, 2 subjects) in the DTG+F/TAF group. 
One subject discontinued study drug due to AE: Grade 3 urticaria beginning on Day 130 
in a B+F/TAF subject. There were SAEs in 3 subjects, none of which were considered 
related to study drug by the investigator, or led to study drug discontinuation. 
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. Graded laboratory abnormalities in ALT and 
AST were reported more frequently and with greater severity in the B+F/TAF group than 
in the DTG+F/TAF group. 
There were similar increases from baseline in serum creatinine in both treatment groups at 
Week 48. The decrease from baseline in eGFRCG was smaller in the B+F/TAF group than in the 
DTG+F/TAF group.


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1.3.3.4.
Summary of Phase 3 Studies
GS-US-380-1489
Results from a blinded phase 3 study were reported that compared B/F/TAF FDC to 
co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC, Triumeq®) 
{Gallant 2017}. HIV-infected, treatment-naïve, HLA-B*5701-negative, HBV-uninfected adults 
with estimated glomerular filtration rate (eGFR) ≥50 mL/min were randomized 1:1 to receive 
blinded treatment with fixed-dose combination B/F/TAF (50/200/25 mg) or ABC/DTG/3TC 
(600/50/300 mg) with matching placebos once daily. The primary endpoint was proportion of 
participants with HIV-1 RNA (VL) < 50 c/mL at W48 (FDA snapshot). Noninferiority was 
assessed through 95.002% confidence intervals (CI) (12% margin). Secondary endpoints were 
safety (adverse events [AEs] and laboratory abnormalities) and pre-defined analyses of changes 
from baseline in bone mineral density (BMD) and measures of renal function, including eGFR 
and proteinuria. Six hundred and twenty nine participants were randomized and treated 
(314 B/F/TAF, 315 ABC/DTG/3TC): 10% women, 36% Black, 16% VL >100,000 c/mL, 11% 
CD4 < 200 cells/mL. Median baseline characteristics: age 32 yrs, CD4 count 444 cells/μL, and 
VL 4.47 log10 c/mL. At W48, B/F/TAF was noninferior to ABC/DTG/3TC, with 92.4% on 
B/F/TAF and 93.0% on ABC/DTG/3TC achieving HIV-1 RNA < 50 c/mL (difference -0.6%; 
95.002%CI -4.8% to 3.6%, p=0.78). No resistance mutations emerged in either group. 
Comparing B/F/TAF to ABC/DTG/3TC throughout, the most common AEs were diarrhea (13%, 
13%), headache (11%, 14%), and nausea (10%, 23%). Few participants (0 vs 4 [1%]) had any 
AEs leading to premature study drug discontinuation. At W48, mean % changes from baseline in 
BMD were -0.83% vs. -0.60% (p=0.39) [lumbar spine] and -0.78% vs. -1.02% (p=0.23) [total 
hip]. No differences between treatments were noted in changes from baseline for eGFR and 
proteinuria at W48. At W48, B/F/TAF achieved virologic suppression in 92.4% of 
treatment-naïve adults and was noninferior to ABC/DTG/3TC, with no emergent resistance. 
B/F/TAF was safe and well tolerated with less nausea than ABC/DTG/3TC. Bone and renal 
safety profiles were similar between groups.
GS-US-380-1490
A second phase 3 study compared bictegravir and DTG, each with F/TAF, utilizing a single-pill 
co-formulation of B/F/TAF {Sax 2017}. Treatment-naïve, HIV-infected adults with estimated 
glomerular filtration rate (eGFR) ≥30 mL/min were randomized 1:1 to receive blinded treatment 
with fixed dose combination B/F/TAF (50/200/25 mg) or DTG (50 mg) + F/TAF (200/25 mg) 
with matching placebos once daily through W48. Chronic hepatitis B and/or C infection was 
allowed. The primary endpoint was the proportion of participants with HIV-1 RNA 
< 50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% 
confidence intervals (CI) using a margin of 12%. Secondary endpoints were safety measures 
(adverse events [AEs] and laboratory results). There were 645 participants randomized and 
treated (320 B/F/TAF, 325 DTG + F/TAF): 12% women, 31% Black, 19% viral load (VL) 
>100,000 c/mL, 12% CD4 < 200 cells/μL, median age 34 yrs, CD4 count 440 cells/μL, and VL 
4.44 log10 c/mL. At W48, B/F/TAF was noninferior to DTG + F/TAF, with 89.4% on B/F/TAF 
and 92.9% on DTG + F/TAF achieving HIV-1 RNA < 50 c/mL (difference -3.5%; 95.002%CI 
−7.9% to 1.0%, p=0.12). Six subjects discontinued treatment for the following reasons: patient 
decision-3, protocol violation due to incarceration-1, lost to follow-up-1 and investigator 


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discretion-1. Both the Missing=Excluded (M=E) and Missing=Failure (M=F) sensitivity analyses 
were pre-specified M=E analysis (B/F/TAF vs DTG + F/TAF, % treatment difference (95% CI); 
p-value): 99.0% (288/291) vs. 99.3% (304/306), -0.4% (-2.3, 1.6); p=0.63 and M=F analysis 
(B/F/TAF vs DTG + F/TAF, % treatment difference (95% CI); p-value): 90.0% (288/320) vs. 
93.5% (304/325), -3.4% (-7.7, 0.9); p=0.12. Missing values represent a potential source of bias 
in a clinical trial. Therefore, the study protocol pre-specified the M=E analysis as one imputation 
method for missing data. The M=E population analysis excludes subjects in the full analysis set 
who do not have HIV-1 RNA data at the efficacy analysis time point. Of note, the M=E analysis 
set includes subjects with HIV-1 RNA data at the efficacy analysis time point, even if the subject 
has discontinued study antiretroviral medications but remained “in the study” on non-study 
antiretroviral medications (for the treatment of HIV). The study protocol pre-specified the M=F 
analysis as a 2nd imputation method for missing data The M=F population considers subjects in 
the full analysis set who do not have HIV-1 RNA data at the efficacy analysis time point as 
having HIV-1 RNA ≥ 50 copies/mL. Of note, the M=F analysis set includes subjects with HIV-1 
RNA data at the efficacy analysis time point, even if the subjects has discontinued study 
antiretroviral medications but remained “in the study” on non-study antiretroviral medications 
(for the treatment of HIV). At W48, proportion of participants with HIV-1 RNA ≥50 c/mL was 
< 1% in each arm. No study subject in either treatment arm developed resistance to any of the 
study drugs. The most common AEs were headache (13% B/F/TAF, 12% DTG + F/TAF) and 
diarrhea (12% for both). Few participants (5 [2%], 1 [< 1%]) had AEs leading to premature study 
discontinuation. Lipid changes were not significantly different between study arms. No renal 
discontinuations and no cases of proximal renal tubulopathy were reported. After 48 weeks, 
B/F/TAF achieved virologic suppression in 89.4% of treatment-naïve adults and was noninferior 
to DTG + F/TAF. B/F/TAF was safe and well tolerated.
1.4.
Rationale for This Study
Because of the increasing average age of HIV-infected patients, the high prevalence of chronic 
kidney disease, and the increasing prevalence of co-morbid conditions that require medical 
management, medical regimens in ESRD patients are complex and can impact a patient’s overall 
risk of morbidity and mortality. The availability of a single-tablet regimen composed of potent 
agents with improved tolerability and long-term safety that does not require dose adjustment at 
eGFR < 15 mL/min, would represent an important therapeutic innovation for HIV infected
patients with ESRD. EVG, COBI, TAF, and BIC are not renally eliminated, while the metabolite 
of TAF (TFV) and FTC are renally eliminated. 
The E/C/F/TAF FDC was recently shown to be safe and efficacious in HIV-infected patients 
with mild to moderate chronic kidney disease (CKD; eGFR 30-69 mL/min) in study 
GS-US-292-0112 through 48 weeks. The long-term safety of E/C/F/TAF remains to be 
established in subjects at more advanced stages of renal impairment, including those with ESRD 
on hemodialysis. The present study will provide the pharmacokinetic data describing TFV and 
FTC exposures in these patients when administered as the E/C/F/TAF FDC, dosed once daily, as 
well as safety and efficacy data in this special population through 96 weeks. 
B/F/TAF has demonstrated efficacy and safety in Phase 2 and Phase 3 studies in HIV-infected 
patients. It is approved in the U.S. for the treatment of HIV-infected individuals who have an 
eGFR ≥30 mL/min.


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1.4.1.
Rationale for Dose Selection
The E/C/F/TAF FDC containing EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg),
has been approved for use once daily for the treatment of human immunodeficiency virus type 1 
(HIV-1) infection in adults and pediatric patients 12 years of age and older without any known 
resistance to the individual components and with an eGFR ≥ 30 mL/min. This FDC contains the 
equivalent doses of EVG and COBI in the marketed product, Stribild®. The FTC (200 mg) in the 
E/C/F/TAF FDC represents the marketed dose in several approved FDC products: 
emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, and 
emtricitabine/rilpivirine/tenofovir DF for the treatment of HIV-1 infection.
EVG, COBI, and TAF are not renally eliminated, while the metabolite of TAF (TFV) and FTC, 
are renally eliminated. 
B/F/TAF
The dose of B/F/TAF 50/200/25 mg FDC is the approved dose of B/F/TAF once daily for the 
treatment of HIV-1 infection in adults (Biktarvy USPI).
BIC is not renally eliminated and the F/TAF 200/25 mg dose in B/F/TAF is expected to provide
exposures of FTC, TAF, and TFV that are similar to those in the E/C/F/TAF FDC, that was 
shown to be safe and efficacious in the hemodialysis population (please refer to Section 1.2.4 of 
this protocol here). As such, the B/F/TAF 50/200/25 mg dose is appropriate for evaluation in 
subjects with ESRD on hemodialysis.
TAF and TFV
The Phase 3 study GS-US-292-0112 demonstrated that patients with moderate renal impairment 
(baseline eGFR 30-50 mL/min) who switched to E/C/F/TAF had no change in eGFR, and had 
significant improvements in measures of renal function including proteinuria, albuminuria, 
retinol binding protein and beta-2-microglobulin. These subjects also had improvements in 
measures of bone mineral density. TAF PK in subjects with screening eGFR 30-69 mL/min was 
consistent with data following administration of E/C/F/TAF in non-renally-impaired 
HIV-infected subjects in Phase 2 and Phase 3 studies. 
Data from GS-US-120-0108 demonstrated that in HIV uninfected subjects with an eGFR of 
15-29 mL/min, plasma TAF exposures increased < 2-fold. Study GS-US-292-1825 will evaluate 
TAF (as well as TFV and FTC) PK in the setting of daily administration of E/C/F/TAF FDC in 
treatment-experienced subjects with eGFR < 15 mL/min on chronic hemodialysis.
To support TAF dosing in ESRD patients, simulation for TFV exposures was conducted using an 
established population pharmacokinetic model for TFV following administration of E/C/F/TAF 
and with information from previously conducted Gilead Study (GS-01-919) where TDF was 
administered in ESRD subjects (Figure 1-2).


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Figure 1-2.
Predicted Steady-State TFV PK Profile After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis
Figure 1-2 shows the simulated TFV PK profile following E/C/F/TAF once-daily for two weeks in subjects with ESRD on 
chronic hemodialysis three-times per week. IPRED represents the model predicted plasma concentration of TFV. The double 
blue arrows represent a four-hour hemodialysis session.
In subjects with ESRD on chronic hemodialysis three-times per week, systemic TFV exposures 
are expected to be higher following administration of E/C/F/TAF, relative to E/C/F/TAF in 
subjects with eGFR > 30 mL/min, due to the renal elimination pathway for TFV. In subjects with 
ESRD on chronic hemodialysis, E/C/F/TAF administered once daily is predicted to result in a 
mean (% CV) TFV exposure of 3610 (21.6) h•ng/mL. Given the extensive safety data available 
for TDF, TFV exposures following administration of E/C/F/TAF in ESRD subjects on chronic 
hemodialysis are expected to be in the range of those following TDF-containing regimens in 
patients with normal renal function (Table 1-7) and, as such, would not require TAF dose 
modification. 


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Table 1-7.
Comparison of Plasma TFV Exposures After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis Versus 
TDF-Containing Regimens in Patients with Normal Renal Function
TFV AUC (Mean [%CV])
E/C/F/TAF regimen
3610 (21.6)
TDF-Containing Regimens in Normal Renal Function
Atazanavir+Ritonavira
3940 (30)
Darunavir+Ritonavirb
4630 (16)
Fosamprenavir+Ritonavirc
2930 (1780, 4280)
Lopinavir+Ritonavird
3500 (27)
Saquinavir+Ritonavire
3110 (24)
Rilpivirinef
3590 (22)
Emtricitabine+TDFg
2870 (25)
Efavirenz/Emtricitabine/TDFh,i
2270 (19)
Elvitegravir/Cobicistat/Emtricitabine/TDFh
3940 (20)
a
Study GS-US-216-0114
b
{Hoetelmans 2007}
c
mean (90% CI) {Luber 2010}
d
Studies 00-909 and 01-943
e
Study GS-US-104-0236
f
{Hoetelmans 2005}
g
Studies GS-US-236-0101 and GS-US-236-0110
h
Studies GS-US-236-0120 
i
Study GS-US-334-0131
FTC
The FTC dose (200 mg) in the E/C/F/TAF FDC represents the marketed dose as part of the 
approved products FTC (Emtriva®), FTC/TDF (Truvada®), efavirenz/FTC/TDF (Atripla®), 
FTC/rilpivirine/TDF (Complera® or Eviplera®), and E/C/F/TDF (Stribild®) for the treatment of 
HIV-1 infection. Emtricitabine is principally eliminated by the kidney and higher exposures are 
observed in patients with moderate to severe renal impairment. For eGFR of 30-49 mL/min, 
Emtriva prescribing information recommends dose interval adjustment of the 200 mg oral 
capsule to q48h. However, available clinical experience suggests the plasma FTC may not 
require dose adjustment in the setting of renal impairment. In study GS-US-292-0112, FTC was 
given without dose adjustment to patients with eGFR 30-50 mL/min, and these patients had 
comparable safety profile to patients with eGFR 50-69 mL/min, with no increased rate of 
potential FTC related drug reactions, supporting the safety of FTC at higher exposures. 
In Study FTC-107, an open-label, parallel-group study of single-dose emtricitabine 200 mg in 
HIV uninfected subjects with varying degrees of renal impairment, 6 subjects with moderate 
renal impairment (30-49 mL/min), 5 subjects with severe renal impairment (< 30 mL/min) and 
6 subjects on dialysis were treated. Of note, subjects with baseline eGFR of 30-49 mL/min had 


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only twice the mean FTC systemic exposure (mean (%CV) AUCinf: 25.08 hr•μg/mL (23)) 
compared to subjects with eGFR > 80 mL/min (mean (%CV) AUCinf: 11.78 (25) hr•μg/mL. 
Subjects on dialysis had an AUCinf of 53.22 hr•μg/mL (19). In all cohorts, the overall incidence 
of adverse events was low and there was no apparent relationship between the incidence of AEs 
and the degree of renal impairment. 
In Study GS-US-104-0235, the safety and tolerability of FTC+TDF (200/300 mg) in 
treatment-naïve and treatment-experienced HIV infected subjects with various degrees of renal 
impairment were assessed. One subject in this study assigned to the mild impairment group was 
later found to have moderate impairment (eGFR ≥30 and < 50 mL/min) and one subject 
assigned to moderate impairment was found to have severe impairment (eGFR < 30 mL/min) 
after 40 days of treatment. Based on PK analyses of these subjects, the subject with moderate 
renal impairment was continued on FTC 200 mg daily because FTC exposures remained within 
the predicted range for subjects without renal impairment and the subject with severe renal 
impairment continued to receive FTC 200 mg every 48 hours based upon appropriate FTC 
systemic exposures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.
Risk/Benefit Assessment for the Study
Potential risks of a patient’s study involvement include switching to an unfamiliar regimen with 
potential loss of virologic control and/or new adverse events, the inconvenience of more frequent 
clinic visits and laboratory blood draws and the associated pain and discomfort of phlebotomy. 
Strategies to mitigate these risks include close monitoring of viral load, CD4+ T cell count and 
other lab values as well as monitoring of adverse events. Parameters for discontinuation of the 
study drug due to adverse events or lack of efficacy will be well-defined and closely followed. In 
addition, an independent data monitoring committee will be convened at Week 12 to evaluate 
safety data and determine whether the risks/benefits warrant continuation of the study. 
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Potential benefits may include the patient receiving a FDC antiretroviral regimen that is more 
convenient leading to improved adherence, with potentially fewer adverse events than the current 
regimen, E/C/F/TAF and B/F/TAF may provide an alternative treatment for a patient population 
with fewer therapeutic options than the general HIV-1-infected population. 
Considering the above, the benefit-risk balance for this study is considered positive.
1.6.
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 safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with
ESRD on chronic HD at Week 48
The secondary objectives of this study are:

To evaluate the safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with 
ESRD on chronic HD at Week 96

To evaluate the proportion of subjects receiving E/C/F/TAF FDC achieving virologic 
response (defined as HIV-1 RNA < 50 copies/mL, as defined by the FDA Snapshot analysis) 
at Weeks 24, 48, and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in 
HIV-1 infected patients with ESRD on chronic HD

To evaluate the safety and tolerability of bictegravir/emtricitabine/tenofovir alafenamide
(B/F/TAF) FDC in HIV-1 infected adults with ESRD on chronic HD in the open label 
extension phase


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3. 
STUDY DESIGN 
3.1. 
Study Design 
Final 
Amendment 2.1 (US Only) 
This is an open-label, multicenter, single-rum study to assess the safety, tolerability, 
phatmacokinetics, and efficacy ofEIC/FITAF FDC in HIV-1 infected adult subjects with ESRD 
on chronic HD. 
Approximately 50 subjects with ESRD on chronic HD will be emolled. All subjects will switch 
from their cunent antiretroviral regimen to EICIFITAF on Day 1. The total treatment dmation 
will be at least 96 weeks. After at least 96 weeks, subjects will be given the option to roll into an 
OL extension ofB/F/TAF FDC for at least 48 weeks. 
Figure 3-L 
Screening 
::::_ 30 days 
prior to 
Baseline 
Study Schema 
Day 1 
Week48 
(Primary Endpoint) 
96 Weeks of Treatment 
on E/C/F/TAF 
(n = approximately 50)
3 
Week96 
30-Day Follow-
up orOL 
extension b,c,d 
a 
Following the Day 1 Visit, subjects will rettu11 for stttdy visits at Weeks 2, 4, 8, 12, 24, 36,48, 60, 72, 84, and 96. 
b 
After Week 96, subjects in the US will continue to take d1eir srudy drug and attend visits every 12 weeks tmtil ilie End of 
E/C/FffAF Visit. At Week 96 or the End ofE/C/FffAF Visit, subjects will discontinue E/C/FffAF FDC and be given ilie 
option to receive OL B/FffAF FDC. All subjects participating in ilie OL rollover extension ofB/FffAF FDC will rettun for 
stttdy visits at Week 4 OL, Week 12 OL, and every 12 weeks thereafter for at least 48 weeks. 
c 
Subjects who discontinue srudy drug administration before ilieir Week 96 Visit \viii complete an ESDD Visit. These subjects 
may remain on ilie stttdy off study drug up to the Week 96 Visit. Subjects patticipating in the OL rollover extension of 
B/FffAF FDC who discontinue study dmg prematttrely will complete an ESDD Visit. 
d 
Subjects who complete ilie stttdy through the Week 96 Visit and do not continue on ilie OL rollover extension ofB/FffAF 
FDC will be required to rettm1 to the clinic after the Week 96 visit for a 30 Day Follow-Up Visit. 
3.2. 
Study Treatments 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg I cobicistat 150 mg I emtricitabine 200 mg I tenofovir alafenamide 10 mg 
(EICIFITAF), on Day 1. 
After Week 96, subjects in the US who wish to participate in the OL rollover extension will 
continue to take their study dmg and attend visits evety 12 weeks 1mtil the End ofEIC/F/TAF 
Visit. At Week 96 or the End ofEIC/F/TAF Visit (whichever occms last), subjects will discontinue 
EICIFITAF FDC and be given the option to receive OL B/F/TAF FDC for at least 48 weeks. 
CONFIDENTIAL 
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Ol May20l8 


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Study drug will be administered orally once daily with food at approximately the same time 
every day. On the day of hemodialysis, study drug administration should occur after completion 
of hemodialysis. 
3.3.
Duration of Treatment
The study will consist of a 30-day screening period (within 30 days before Day 1 visit), followed 
by a 96 week treatment period. After Day 1, subjects will return for study visits at Weeks 2, 4, 8, 
12, 24, 36, 48, 60, 72, 84, and 96. 
After Week 96, all subjects participating in the OL rollover extension will receive B/F/TAF FDC 
for at least 48 weeks. At the Week 96 or End of E/C/F/TAF Visit (whichever occurs last), 
subjects will return for study visits at Week 4 OL, Week 12 OL, Week 24 OL, Week 36 OL, and 
Week 48 OL.
3.4.
End of Study
End of the study will occur when the last subject enrolled in the study has completed their last 
observation (or visit).
3.5.
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. 
3.6.
Source Data
Sponsor will provide source document worksheets for all study visits.
3.7.
 
 
 
 
 
 
 
 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects who meet the eligibility criteria will be enrolled. 
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 screening procedures
2) Age ≥ 18 years
3) Currently receiving a stable antiretroviral regimen for ≥ 6 consecutive months prior to 
screening 
4) Documented plasma HIV-1 RNA concentrations < 50 copies/mL for at least 6 months 
preceding the screening visit (measured at least twice using the same assay) and have 
HIV-1 RNA < 50 copies/mL at screening
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
≥50 copies/mL and < 400 copies/mL) is acceptable, only if HIV-1 RNA is 
< 50 copies/mL immediately before and after the blip. 
b) To determine virologic suppression in the preceding 6 months prior to screening, the 
lower limit of quantification (LLOQ) by the local HIV-1 RNA assay may be used, only if 
its LLOQ is greater than 50 copies/mL (e.g. LLOQ of 75 copies/mL)
5) No documented history of HIV-1 resistance to EVG, FTC, 3TC or TFV and no history of 
switching off EVG, FTC, 3TC or TFV due to concern for resistance
6) CD4+ T cell count of ≥200 cells/μL
7) ESRD with eGFR < 15 mL/min by Cockcroft-Gault formula for creatinine clearance 
{Cockcroft 1976}
Male:
(140 – age in years) × (wt in kg) Clcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 Clcr (mL/min)
72 × (serum creatinine in mg/dL)
8) On chronic HD for ≥ 6 months prior to screening


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9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Chronic Hepatitis C (HCV) infection allowed if liver function is stable for ≥6 months prior to 
screening: ALT ≤ 10 × ULN, AST ≤ 10 × ULN, total bilirubin ≤ 2.5, or normal direct 
bilirubin (subjects with documented Gilbert’s Syndrome or hyperbilirubinemia due to 
atazanavir therapy may have total bilirubin up to 5 × ULN), INR ≤ 1.5 and albumin ≥3 g/dL; 
no evidence of cirrhosis or hepatocellular carcinoma by imaging in the last 12 months
11) Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; 
platelets ≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
12) Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤ 5 × ULN)
13) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant confirmed by a negative serum pregnancy test (unless permanently sterile 
or greater than two years post-menopausal)
b) Of non-child bearing potential (i.e. women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for ≥ 12 months) of previously occurring menses
Female subjects who have stopped menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure must have a serum follicle stimulating 
hormone (FSH) level at screening within the post-menopausal range based on the 
Central Laboratory Reference range. 
c) Of childbearing potential and agrees to utilize the protocol specified method of 
contraception or be non-heterosexually active or practice abstinence from screening 
throughout the duration of the study treatment and for 30 days following study drug 
discontinuation (as defined in Appendix 7)
d) Female subjects who utilize hormonal contraception as one of the birth control methods 
must have used the same method for at least three months prior to the study dosing. 
14) Male subjects must agree to use protocol specified method(s) of contraception from 
screening throughout the duration of study treatment and for 30 days following 
discontinuation of study drugs (Appendix 7).
15) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days 
after the last study drug dose.
16) Lactating females must agree to discontinue nursing before the study drug is administered.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Hepatitis B surface antigen (HBsAg) positive
2) Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
3) Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening
4) Treatment with radiation, cytotoxic chemotherapeutic agents, or any immunomodulator 
within 30 days of screening
5) Any other clinical history, condition, or test result that, in the opinion of the Investigator, 
would make the subject unsuitable for the study or unable to comply with dosing 
requirements
6) Administration of other investigational agents (unless approved by Gilead Sciences). 
Participation in any other clinical trial, including observational trials, without prior approval 
from the sponsor is prohibited while participating in this trial.
7) History or presence of allergy or intolerance to the study drugs or their components
8) A new AIDS-defining condition (excluding CD4+ T cell count and percentage criteria) 
diagnosed within the 30 days prior to screening, with the exception of 
oropharyngeal candidiasis (see Appendix 8)
9) Have an implanted defibrillator or pacemaker
10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
carcinoma
12) Received solid organ or bone marrow transplant
13) Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures
14) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1
15) Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use]), immunosuppressant, or 
immunomodulating agents
16) Subjects receiving ongoing therapy with any of the following medications in the Table 4-1
below, including drugs not to be used with EVG, COBI, FTC, TAF, and BIC


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Table 4-1.
Disallowed Agents (E/C/F/TAF Phase)
Drug Class
Agents Disalloweda
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Calcium Channel Blockers
Bepridil
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Direct Oral Anticoagulants (DOACs)
Apixaban, Rivaroxaban
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
Inhaled Beta Agonist
Salmeterol
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a
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. 
Table 4-2.
Disallowed Agents (Open-Label B/F/TAF Rollover Extension)
Drug Class
Agents Disallowed*
Antiarrhythmic Agent
Dofetilide
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antiretrovirals
Any antiretroviral drug that is not part of the study regimen
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
*
Administration of any of the above medications must be discontinued at least 30 days prior to the End of E/C/F/TAF Visit 
and for the remainder of the study.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label, single arm study. All eligible subjects will receive open-label E/C/F/TAF.
Enrollment and Day 1 Visit cannot occur until subject eligibility has been confirmed.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment. Once eligibility is confirmed, each subject will be assigned a unique subject 
number using 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 may be performed up to 3 days prior to the in-clinic Day 1 Visit, provided that all 
other screening procedures have been completed and subject eligibility has been confirmed. 
Eligibility must be confirmed and all Day 1 tests and procedures must be completed prior 
to the administration of the first dose of study drug.
IWRS will assign study drug bottle numbers at each study visit. Initiation of study drug must 
take place on the day of Day 1 Visit.
Post-Week 96
At the End of E/C/F/TAF Visit, the IWRS will assign open-label B/F/TAF FDC.
5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
5.2.1.1.
Elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 
200mg / tenofovir alafenamide (TAF) 10mg fixed-dose combination
(E/C/F/TAF, Genvoya)
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets and are debossed with “GSI” on
one side of the tablet and “510” on the other side of the tablet. E/C/F/TAF tablets contain 150 mg
of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of TAF fumarate).
The E/C/F/TAF tablet core contains silicon dioxide, croscarmellose sodium, hydroxypropyl
cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine aluminum 
lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.2.1.2.
Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF, Biktarvy) 
50/200/25mg fixed-dose combination
B/F/TAF tablets are capsule-shaped, film-coated purplish-brown, debossed with "GSI" on one 
side of the tablet and "9883" on the other side of the tablet. Each tablet core contains 50 mg of 
bictegravir, 200 mg of emtricitabine, and 25 mg of TAF. In addition to the active ingredients, the 


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B/F/TAF tablets contain croscarmellose sodium, magnesium stearate, and microcrystalline 
cellulose. The tablet cores are film-coated with iron oxide red, iron oxide black, polyethylene 
glycol, polyvinyl alcohol, talc, and titanium dioxide.
5.2.2.
Packaging and Labeling
5.2.2.1.
Elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 
200 mg / tenofovir alafenamide (TAF) 10 mg fixed-dose combination
(E/C/F/TAF, Genvoya)
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle
contains 30 tablets, silica gel desiccant and polyester packaging material. Each bottle is enclosed
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
Study drug to be distributed to centers in the US and other participating countries shall be labeled 
to meet applicable requirements of the United States Food and Drug Administration (FDA), 
EU Guideline to Good Manufacturing Practice −Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.2.2.
Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF, Biktarvy) 
50/200/25 mg fixed-dose combination
B/F/TAF tablets 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.
Study drug(s) to be distributed to centers in the US shall be labeled to meet applicable 
requirements of the US FDA, EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products), and/or other local regulations. 
5.2.3.
Storage and Handling
Study drugs 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). Storage conditions are specified on the 
label. Until dispensed to the subjects, all bottles of study drug should be stored in a securely
locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure through inhalation when handling.


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5.3.
Dosage and Administration of E/C/F/TAF
E/C/F/TAF FDC and B/F/TAF FDC tablets will be provided by Gilead Sciences.
E/C/F/TAF FDC tablets containing 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 
10 mg of TAF will be provided to all eligible subjects at Day 1. Study drug will be administered
orally at approximately the same time each day with food. 
B/F/TAF FDC tablets containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of 
TAF will be provided to all subjects who participate in the OL rollover extension of B/F/TAF 
FDC at the End of E/C/F/TAF Visit. Study drug will be administered orally at approximately the 
same time each day with food.
On the day of hemodialysis, study drug administration should occur after completion of 
hemodialysis. 
Subjects will be instructed to bring all study drug in the original container at each clinic visit for 
drug accountability (unless otherwise specified in the study procedures sections of this protocol). 
The Investigator will be responsible for maintaining accurate records for all study drug bottles 
dispensed and tablets returned. The inventory and dispensing logs must be available for 
inspection by the study monitor. Study drug supplies, including partially used or empty bottles, 
must be accounted for by the study monitor prior to destruction or return.
5.4.
Prior and Concomitant Medications

For subjects receiving hormonal contraceptives, investigators and/or the subject’s healthcare 
providers should consider additional methods of contraception, as concentrations of ethinyl 
estradiol may decrease and progestin level may increase on co-administration with study drug. 

The use of medications for the treatment of HIV, other than study drug, is prohibited.

For subjects receiving concomitant medications that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious adverse 
events, investigators and/or the subject’s healthcare providers should consider alternative 
concomitant medications.

During the study, subjects may not receive any of the following concomitant medications:
Competitors of renal excretion (e.g., probenecid; high-dose non-steroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin and pentamidine)

Medications listed in the following tables and use of herbal/natural supplements are excluded 
or should be used with caution while subjects are participating in the study. Any concomitant 
medication requiring adjustment or discontinuation due to renal impairment or a change in 
renal function on study should be managed per that drug’s prescribing information.


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Table 5-1.
Prior and Concomitant Medications (E/C/F/TAF)
Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Concentration of study drug may decrease with 
antacids. Subjects may not take antacids 
(eg, Tums, Mylanta); the ulcer medication 
sucralfate (Carafate); or vitamin or mineral 
supplements that contain calcium, iron or zinc for a 
minimum of 2 hours before and 2 hours after any 
dose of study drug.
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: Concentrations may 
increase with study drug(s); clinical monitoring is
recommended.
Antiarrhythmics
Amiodarone, Flecainide Quinidine, Propafenone, 
Systemic Lidocaine, Mexiletine, Disopyramide: 
Concentrations may increase with study drug(s) 
resulting in a potential for cardiac arrhythmias; 
clinical and ECG monitoring is recommended.
Calcium Channel Blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, Verapamil, 
Diltiazem, Amlodipine: Concentrations may 
increase with study drug(s). Clinical and ECG 
monitoring of subjects is recommended
Digoxin
Digoxin: Concomitant use may result in increased 
levels; use with caution and with appropriate 
monitoring of serum digoxin levels. Digoxin 
therapy should be initiated at the lower dose, and 
the dose should be titrated to clinical response.
Direct Oral Anticoagulants
(DOACs)
Apixaban, Rivaroxaban
DOACs are primarily metabolized by CYP3A4 
and/or transported by P-gp. Coadministration with 
GENVOYA may result in increased plasma 
concentrations of the DOAC, which may lead to an 
increased bleeding risk.
Dabigatran, Edoxaban, Betrixaban: Clinical 
monitoring and/or dose adjustment is recommended 
when a DOAC transported by P-gp, including 
dabigatran, edoxaban, or betrixaban is 
coadministered with GENVOYA. Refer to the 
prescribing information of the coadministered 
DOAC.
Antibacterials
Clarithromycin and Telithromycin: Concentrations 
may be altered with study drug(s); consider an 
alternative.
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR (International
Normalized Ratio) monitoring is recommended.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics: Concentrations may increase or decrease 
with study drug(s). Concentration monitoring is 
recommended to ensure adequate clinical response.
Trazodone: Concomitant use with 
CYP3A inhibitors results in increased 
concentrations and adverse events; dose reduction 
should be considered.
Antifungals
Ketoconazole and Itraconazole: Concomitant use 
with study drug may result in an increase in 
concentrations. Daily dose of ketoconazole and 
itraconazole should be restricted to 200 mg. 
Subjects receiving ketoconazole or itraconazole 
should be monitored for adequate clinical response.
Voriconazole: Concomitant use with study drug 
may result in an increase in concentrations. 
Clinical monitoring may be needed.
Antigout
Colchicine: Concentrations may increase with 
study drug(s). Dose reductions of colchicine may be 
required. Should not be coadministered in patients 
with renal or hepatic impairment.
Treatment of Gout Flare:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg 
(half tablet) 1 hour later. Treatment course may be 
repeated no earlier than 3 days.
Prophylaxis of Gout Flares:
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:
Maximum daily dose of 0.6 mg 
(may be given as 0.3 mg twice a day).
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol: Clinical and ECG monitoring 
of subjects is recommended. A dose decrease 
may be needed.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Corticosteroids (all routes 
excluding cutaneous):
dexamethasone (oral)
Systemic dexamethasone, a CYP3A inducer, may 
significantly decrease elvitegravir and cobicistat 
plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative corticosteroids should be considered.
Use of Prednisone as a steroid burst (≤1 week of 
use) should be monitored appropriately.
Betamethasone, Budesonide, Fluticasone, 
Mometasone, Triamcinolone: Coadministration 
with corticosteroids that are sensitive to CYP3A 
inhibition can increase the risk for Cushing’s 
syndrome and adrenal suppression, which have 
been reported during postmarketing use of 
cobicistat-containing products. Consider the risk of 
systemic corticosteroid effects if GENVOYA is 
coadministered with corticosteroids that are 
sensitive to CYP3A inhibition.
Alternative corticosteroids should be considered, 
particularly for long-term use.
Endothelin receptor 
antagonists
Bosentan: coadministration may lead to decreased 
elvitegravir exposures and loss of therapeutic effect 
and development of resistance. Alternative 
endothelin receptor antagonists may be considered.
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin
Atorvastatin: Concentrations may increase with 
study drug(s). Start with the lowest dose; gradual 
increase in dose may be tailored to clinical 
response. Careful monitoring for signs and 
symptoms of muscle weakness or myopathy, 
including rhabdomyolysis.
Hormonal Contraceptives
Drospirenone: Plasma concentrations of 
drospirenone may be increased when 
coadministered with cobicistat-containing products. 
Clinical monitoring is recommended due to the 
potential for hyperkalemia.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s).
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: A dose 
decrease may be needed.
Opiates
Methadone: Methadone exposures are unaffected 
upon coadministration with elvitegravir and 
cobicistat. No dose adjustment of methadone is 
required upon coadministration with study drug(s).
Meperidine (Pethidine): Dosage increase and 
long-term use are not recommended due to 
increased levels of metabolite normeperidine, 
which has analgesic and CNS stimulant 
(eg, seizures) activities.
Buprenorphine: Concentrations of buprenorphine 
and norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and 
cobicistat, with no effect on opioid 
pharmacodynimcs. The concentration changes are 
not considered clinically relevant and no dose 
adjustment of buprenorphine/naloxone is required 
upon coadministration with study drug(s).
Phosphodiesterase-5 
Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil: Caution should be exercised, including 
consideration of dose reduction, when 
coadministered for treatment of pulmonary arterial 
hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil: It is recommended 
that a single dose of Sildenafil no more than 25 mg 
in 48 hours, Vardenafil no more than 2.5 mg in 
72 hours, or Tadalafil no more than 10 mg in 
72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem: A dose decrease may be 
needed for these drugs. Clinical monitoring 
is recommended.


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Table 5-2.
Prior and Concomitant Medications (Open-Label B/F/TAF Rollover 
Extension)
Drug Class
Agents Disallowed*
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Buffered medications
Antacids containing Al/Mg or Calcium: B/F/TAF
can be taken under fasting conditions 2 hours before 
antacids containing Al/Mg or calcium. Routine 
administration of B/F/TAF simultaneously with, or 
2 hours after, antacids containing Al/Mg or calcium 
is not recommended.
Supplements containing Calcium or Iron:
B/F/TAF and supplements containing calcium or 
iron can be taken together with food. Routine 
administration of B/F/TAF under fasting conditions 
simultaneously with, or 2 hours after, supplements 
containing calcium or iron are not recommended.
Antiarrhythmic Agent
Dofetilide
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
Antiretrovirals
Any antiretroviral drug that 
is not part of the study 
regimen
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
Oral Hypoglycemic Agent
Refer to the prescribing information of metformin 
for assessing the benefit and risk of concomitant use 
of B/F/TAF and metformin.

Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the Gilead Sciences 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 Sciences as soon as he/she is aware of 
the use of the disallowed medication.
5.5.
Accountability for Investigational Medicinal Product (IMP)
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. Accountability records (Study Drug Inventory Log) will be provided to each study site in 
order to:

Record the date received and the quantity of study drug bottles.

Record the date, subject number, subject initials, the study drug bottle number dispensed.

Record the date, quantity of used and unused study drug returned by the subject, along with 
the initials of the person recording the information.


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The Investigator [or designee (e.g., study center pharmacist) will acknowledge receipt of the 
study drugs from Gilead Sciences (or designee) after reviewing the shipment’s content and 
condition. The Investigator (or designee) will be responsible for maintaining an accurate 
inventory of the dates and quantities of all study drugs received, dispensed, and returned. 
Subjects should be instructed to return all unused study drug to the site at their study visits. 
Each dose of the study drug administered at the study center will be administered by qualified 
study center personnel. All doses of study drug administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Study Drug Inventory Logs provided by 
Gilead Sciences (or on equivalent documentation maintained by the study center), which 
indicates the date and quantity of all doses of study drug dispensed to individual subjects. 
The requirements of all applicable drug dispensing laws will apply to all doses of study drugs 
dispensed by the Investigator (or designee). 
The study drug inventory log must be available for inspection by the study monitor. Study drug
supplies, including partially used or empty bottles, must be accounted for by the study monitor 
prior to destruction or return.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions to the sites regarding the return of used and unused 
study drug. If return is not possible, the study monitor will evaluate each study center’s study 
drug disposal procedures and provide appropriate instruction for destruction of unused study 
drug. 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 study 
drug bottles in accordance with that site’s approved SOP. A copy of the site’s approved SOP will 
be obtained for central files.
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead. The study monitor will review study drug inventory and 
associated records at periodic intervals.


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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 described in the text that follows. 
The investigator must document any deviation from protocol procedures in the subject’s source 
documents and electronic Case Report Forms (eCRFs). In addition, the Sponsor and the 
Contract Research Organization (CRO) should be promptly notified of any protocol deviations. 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment. Please refer to Section 5.1 for details about enrollment and 
treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Day 1 Visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events, substance use, 
family history of cardiovascular disease (i.e. myocardial infarction, stroke, peripheral 
vascular/arterial disease, and/or angina) and prior medications within 30 days of the 
Screening Visit

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) and weight

12-lead ECG performed supine

Height

Blood sample collection for the following laboratory analyses: 
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
FSH test is required for female subjects who have stopped menstruating for > 12 months 
but do not have documentation of ovarian hormonal failure.


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Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and parathyroid hormone (PTH)
■
Sample should be drawn prior to hemodialysis 
○
Timing of draw and timing of hemodialysis should be recorded
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ T cell count
Plasma HIV-1 RNA (Taqman v2.0)
Hepatitis B virus surface antigen serology (HBsAg)
Hepatitis C virus (HCVAb) serology. If the antibody test result is positive, HCV RNA
test will be performed to confirm HCV viremia.

HIV-TSQs (HIV Treatment Satisfaction Questionnaire Status) should be completed by the 
subject. Subject is to read the questionnaire by him/herself and write/mark answers directly 
onto the questionnaire.

Review of AEs and concomitant medications (adverse events related to protocol mandated 
procedures occurring after signing of the consent form)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for Day 1 assessments. 
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF). All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF. See Section 7
Adverse Events and Toxicity Management for additional details.


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6.2.2.
Day 1 Assessments
The following evaluations are to be completed after confirmation of eligibility, and before the 
study drug is dispensed to the subject. Initiation of treatment with the study drug must take place 
within 24 hours after the Day 1 Visit.

Obtain subject number and study drug bottle assignment from IWRS. The subject number 
assignment and enrollment may be performed up to 3 days prior to the in-clinic Day 1 Visit 
provided that all screening procedures have been completed and subject eligibility has been 
confirmed.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, phosphorus, magnesium, potassium, sodium, uric acid, amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN) and PTH
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Metabolic assessments: 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). 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
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Whole blood storage sample collection for virology analyses
Plasma storage sample for virology, safety and/or PK testing


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Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, VAS and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation. Study drug will be dispensed in an open-label fashion. Subjects 
must initiate dosing of study drug on the day of the Day 1 Visit. 

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. On the days of hemodialysis, subjects should be instructed to take study 
drug after completion of hemodialysis. Subjects should also be counseled regarding the 
importance of adherence and taking their study drugs at approximately the same time each 
day.
6.3.
Treatment Assessments (Weeks 2-96)
All study visits are to be scheduled relative to the Day 1 Visit date. Study visits are to be 
completed within ± 2 days of the protocol-specific visit date through Week 12 and completed 
within ± 6 days of the protocol-specific visit date through Week 36. The visit window at 
Week 48 will be ± 6 weeks of the protocol-specific visit date, and this clinical visit window 
coincides with the Week 48 statistical analysis window for HIV-1 RNA. Unless notified by the 
Sponsor, Week 48 visit should be completed within ± 6 days of the protocol-specific visit date. 
Following the Week 48 Visit, study visits are to be completed within ± 6 days of the 
protocol-specific visit date through Week 84. The visit window at Week 96 will be ± 6 weeks of 
the protocol-specific visit date. Unless notified by the Sponsor, Week 96 visit should be 
completed within ± 6 days of the protocol-specific visit date.
The following evaluations are to be completed at the end of Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 
84, and 96, unless otherwise specified. 
Note: Regularly scheduled evaluations will be made on all subjects whether or not they continue 
to receive study drug. 

Pre-dose (within 30 minutes prior to study drug administration) whole blood samples
collection for plasma and PBMC samples (Week 4 or Week 12 only). 
Note: Week 4 or Week 12 Visit should occur on the day of hemodialysis for this sample 
collection. Study drug administration should occur after completion of hemodialysis and 
should be observed on-site. 
PBMC sample processing will be performed by the central laboratory and plasma sample 
processing will be performed on-site. Details of the blood sampling procedures and 
sample management will be documented in the central laboratory manual. 


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
 
 
 
 
 

 
 

Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24, 48, and 96 only) (urogenital/anorectal exams 
will be performed at the discretion of the Investigator)

Symptom-directed physical examination as needed (Weeks 2, 4, 8, 12, 36, 60, 72, and 84)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

12-lead ECG performed supine (Weeks 48 and 96)

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase
> 1.5 × ULN) and PTH
Note: At Weeks 24, 48, 72, and 96, analyses of glucose will be done as part of the fasting 
metabolic assessments and not as part of the chemistry profile.
■
Chemistry profile will include PT/INR only at Week 24 and Week 48
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Metabolic assessments: 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). 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 (Weeks 24, 48, 72, and 96 only)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
CCI
CCI


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Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.7.1).
CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
■
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 

Subject completed questionnaires:
SF-36 completed at Weeks 24, 48, 72, and 96 only
HIV-TSQs completed at Weeks 4, 24, 48, 72, and 96. HIV-TSQc (HIV Treatment 
Satisfaction Questionnaire Change) completed at Weeks 24, 48, 72, and 96.
VAS completed at all visits
The questionnaires should be completed by the subject. Subject is to read the questionnaire 
by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation (except at Week 2). Document study drug dispensation and 
accountability. 
At Day 1, study drug will be dispensed for 30 days. At the Week 2 Visit, study drug will 
not be dispensed. 
Note: At the Week 2 Visit, provide the scheduled Week 4 Visit date to the subject. Week 4 
Visit should occur on day of hemodialysis. Instruct the subject to take study drug at Week 4 
on-site (after completion of hemodialysis).

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. 

Subjects should also be counseled regarding the importance of adherence and taking their 
study drugs at approximately the same time each day.


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6.4.
Treatment Assessments (Post Week 96 until the Open-Label Rollover 
Extension)
6.4.1.
Post Week 96 Assessments to End of E/C/F/TAF visit
After the Week 96 visit, subjects will continue to take their study drug and attend visits every 
12 weeks until the End of E/C/F/TAF visit. Study visits are to be completed within ± 6 days of 
the protocol-specified visit date unless otherwise specified.
Note: Regularly scheduled evaluations will be made on all subjects whether or not they continue 
to receive study drug. 

Review of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH
Metabolic assessments: 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). 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 (Every 24 weeks)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.7.1).
CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing


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Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
■
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 

Study drug dispensation. Document study drug dispensation and accountability. 

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. On the days of hemodialysis, subjects should be instructed to take study 
drug after completion of hemodialysis. 
6.4.2.
End of E/C/F/TAF Visit
At Week 96 or the End of E/C/F/TAF Visit, subjects will discontinue E/C/F/TAF FDC and have 
the option to receive OL B/F/TAF FDC. 
Subjects who complete the study through the End of E/C/F/TAF Visit and do not continue on the 
open label B/F/TAF FDC extension phase will be required to return to the clinic after the End of 
E/C/F/TAF visit for a 30-Day Follow-Up Visit. 
Subjects who have discontinued drug study prior to the Week 96 or End of E/C/F/TAF Visit will 
not be eligible for the open-label rollover extension; these subjects will be asked to continue 
attending the scheduled study visits through the Week 96 Visit.
The following will be performed at the End of E/C/F/TAF Visit:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

12 Lead ECG (performed supine)

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH
Note: At the End of E/C/F/TAF Visit, analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry profile. 
■
This sample should be drawn prior to hemodialysis. 
○
The timing of draw and timing of hemodialysis should be recorded.


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Metabolic assessments: 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). 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 
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.7.1).
CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
■
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 

SF-36 and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Study drug dispensation. Document study drug dispensation and accountability. 

Subjects who wish to continue in the Open-Label Rollover extension study will receive open 
label B/F/TAF FDC.
6.4.3.
Open-Label Rollover Extension
For purposes of study visit identification during the open-label rollover extension, study visits 
will be identified by the number of weeks that have elapsed between the Week 96 or End of 
E/C/F/TAF Visit (whichever occurs later) and the corresponding open-label study visit, and 
labeled with “OL” (eg. Week 4 OL, Week 12 OL, Week 24 OL, etc.)
All subjects participating in the B/F/TAF OL extension phase will return for study visits at 
Week 4 OL, Week 12 OL and every 12 weeks thereafter for at least 48 weeks.


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The Week 4 OL Visit should be completed within ±2 days of the protocol-specified visit date. 
All other study visits are to be completed within ± 6 days of the protocol-specified visit date, 
unless otherwise specified.
The following will be performed at the Open-Label Extension Visits:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination as needed (Complete physical exam performed at 
Week 48 OL)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

12 Lead ECG (performed supine) (Week 48 OL only)

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. 
Note: At Week 24 OL, and Week 48 OL analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry profile. 
■
This sample should be drawn prior to hemodialysis. 
○
The timing of draw and timing of hemodialysis should be recorded.
Metabolic assessments: 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). 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 (Every 24 Weeks)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.7.1).


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CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
■
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 
At Week 4 OL, Week 24 OL and Week 48 OL study visits, on the day of hemodialysis, a 
sparse timed blood sample will be collected within 10 minutes before hemodialysis 
initiates from all subjects. Pre-dose (within 30 minutes prior to study drug administration) 
blood draws for plasma samples will also be collected at these visits. Study drug 
administration will be observed. Plasma concentrations of BIC may be determined. 
Plasma concentrations of other analytes may also be explored.

SF-36 and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.
(Week 4 OL, Week 24 OL, and Week 48 OL only)

Study drug dispensation. Document study drug dispensation and accountability. 
6.5.
Post-treatment Assessments
6.5.1.
30-Day Follow-up Assessments
Those subjects who prematurely discontinue study drug and continue in the study through at 
least one subsequent visit after the Early Study Drug Discontinuation Visit will not be required 
to complete the 30-Day Follow-Up Visit.
Subjects who prematurely discontinue study drug and refuse to continue in the study through the 
End of E/C/F/TAF Visit will be asked to return to the clinic 30 days after the completion of the 
ESDD Visit for the 30-Day Follow-Up Visit.
Subjects who complete the study through the End of E/C/F/TAF Visit and do not continue on the 
B/F/TAF OL rollover extension will be required to return to the clinic after the End of 
E/C/F/TAF visit for a 30 Day Follow-Up Visit. 
Subjects who prematurely discontinue study drug during the Open-Label rollover extension will 
be asked to return to the clinic 30 days after the completion of the ESDD Visit for the 30-day 
Follow-Up Visit. The subject will not continue attending the scheduled study visits.


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Subjects who complete the Open-Label rollover extension will be asked to return to the clinic 
30 days after the completion of study drug for 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 of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, 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) and PTH.
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Serum pregnancy test (females of childbearing potential only)
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
At the 30 Day Follow Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with the study drug will be repeated weekly (or as 
often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.5.2.
Early Study Drug Discontinuation Assessments (ESDD)
Subjects who have discontinued study drug prior to the Week 96 or End of E/C/F/TAF Visit will 
not be eligible for the open-label rollover extension study; these subjects will be asked to return 
to the clinic within 72 hours of stopping the study drug for the Early Study Drug Discontinuation 
Visit. The subject will be asked to continue attending the scheduled study visits through Week 96
Visit (if applicable).


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Every attempt should be made to keep the subject in the study through Week 96 Visit and 
continue to perform the required study-related follow-up and procedures (see Section 6.5.3, 
Criteria for Discontinuation of Study Treatment). If this is not possible or acceptable to the
subject or investigator, the subject may be withdrawn from the study.
If the subject discontinues study drug during the Open-Label rollover extension, the subject will 
be asked to return to the clinic within 72 hours of stopping the study drug for the Early Study 
Drug Discontinuation Visit.
At the Early Study Drug Discontinuation Visit, any evaluations showing abnormal results 
indicating that there is a possible or probable causal relationship with the study drug, 
should be repeated weekly (or as often as deemed prudent by the Investigator) until the 
abnormality is resolved, returns to baseline, or is otherwise explained.
The following evaluations are to be completed at the Early Study Drug Discontinuation Visit

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, 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)
and PTH
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.7.1).
CD4+ T cell count


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Plasma sample for virology testing or pharmacokinetic testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, HIV-TSQc and VAS questionnaires should be completed by the subject. Subject is to 
read the questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Drug accountability
6.5.3.
Criteria for Discontinuation of Study Treatment
Study drug 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.

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Lack of efficacy

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 7

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.6.
Other Evaluations
6.6.1.
 
 
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6.6.2.
Blood Storage
From subjects who provide additional consent, a portion of the blood drawn at all visits 
(except the Screening Visit and Unscheduled Visits) will be frozen and stored. These stored 
blood samples may be used by the Sponsor or its research partners for future testing to learn 
more about how the study drug has worked against HIV-1 or clinical laboratory testing to 
provide additional safety data. No human genetic testing will be performed without expressed 
consent of study subjects. At the conclusion of this study, these samples may be retained in 
storage by Gilead Sciences, Inc. for a period up to 15 years.
6.7.
Virologic Failure
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure.
Subjects will be considered to have virologic rebound if they have confirmed HIV-1 RNA 
≥50 copies/mL (two consecutive tests) at a scheduled or unscheduled visit.
6.7.1.
Management of Virologic Failure

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-4 weeks after the date of the original test with HIV-1 RNA 
≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented. Assessments should include:
Adherence
Concomitant medication
Comorbidities (for example: active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed, and the HIV-1 RNA is < 400 copies/mL, subjects may 
remain on their current regimen at the discretion of the Investigator. Subject will return for a 
repeat within 2-4 weeks. 
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
If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 400 copies/mL, the blood samples from the confirmation visit will be used for 
HIV-1 genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and HIV-1 RNA should be repeated (2-4 weeks from the date of confirmed 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 
subject’s source documents. Investigators who opt to discontinue study drugs for an 
individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.7.2.
Subjects with ≥400 copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at Week 24, Week 48, Week 96, any visit prior to the End of E/C/F/TAF Visit
or at the last visit while receiving study drugs (or within 72 hours of discontinuation of study 
treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.


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Figure 6-1. 
Schema for Management of Virologic Failure (E/CIF/TAF) 
Screening 
Treatment Period 
30-Day Follow-up 
D ay1 
I 
At any visit, a rebound in HIV-1 RNA 
50 copies/mL 
I 
Unconfu·med 
Return for scheduled/unscheduled HIV-1 
vit·ologic rebound: 
.... 
RNA and potential genotype/phenotype 
remain on cmTent 
(2-4 weeks later) 
regimen• 
' 
Confit•med virologic rebound and 
HIV-1 RNA 
400 copies/mL b 
,, 
Remain on study 
I 
HIV-1 genotype/phenotype' I 
' 
' 
If no reverse transcriptase t•esistance 
If reverse 
detected, continue on studl drugs. 
or integt·ase resistance detected, 
Repeat HIV-1 RNA ,d 
disc.ontinue study drugs and 
constntct a new ARV regimen• 
a 
If virologic rehotmd is not conftrmed, the subje-ct will remain on their cturent regin1en. 
b 
If virologic rehotmd is confmued, and the HIV-1 RNA is< 400 copies/mL, subjects may remain on their ctm·ent regimen at 
the discretion of the Investigator. Subje.ct will rettu11 for a repeat within 2-4 weeks. If virologic rebotuld is conftnued, and 
HlV -1 RNA is :::: 400 copies/mL, the HlV -1 genotype and phenotype (reverse transcriptase, protease, and, if applicable, 
integrase resistance) will be analyzed. 
c 
Base·d on the results of the genotype/phenotype assays, the subject will remain on stt1dy dmgs or study dmgs will be 
discontinued. If genotyping/phenotyping assay fails, a new AR V regin1enmay be conftgm·ed at the discretion of the 
hlVestie:ator. 
d 
If no r.;istance detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews stt1dy drug 
continuation/discontinuation options and discuss with Medical Monitor prior to stt1dy dmg discontinuation. 
e 
A new AR V regimen will be configtu·ed, at the Investigator's discretion, and the subject will remain in the study. 
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6.7.3.
Management of Virologic Rebound (Open-Label B/F/TAF Rollover 
Extension)

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-3 weeks after the date of the original test with HIV-1 RNA 
≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented. Assessments should include:
Adherence
Concomitant medication
Comorbidities (for example: active substance abuse, depression, other intercurrent 
illnesses)

If virologic rebound is confirmed, and the HIV-1 RNA is < 200 copies/mL, subjects may 
remain on their current regimen at the discretion of the Investigator. Subject will return for a 
repeat within 2-3 weeks. 

If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 200 copies/mL, the blood samples from the confirmation visit will be used for HIV-1 
genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and HIV-1 RNA should be repeated (2-3 weeks from the date of confirmed 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 
subject’s source documents. Investigators who opt to discontinue study drugs for an 
individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.7.4.
Subjects with ≥200 copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 200 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at the last visit while receiving study drugs (or within 72 hours of 
discontinuation of study treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.


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Figure 6-2. 
Virologic Rebound Schema (Open-Label BIF/TAF Rollover 
Extension) 
Week 96 or End of 
Open-Label Treatment Period 
30-Day 
E/CIF/TAF Visit 
Follow-up 
Day 1 
l 
At any visit, after achieving HIV-1 
<50 copies/mL, a rebound in HIV-1 RNA to 
copies/mL OR> 11oglo inct·ease in HIV -1 RNA from their nadir 
l 
Unconfirmed 
Yit·ologic 
rebound: remain 
on current 
regimen a 
Retum for scheduled/unscheduled HIV-1 
Rl'JA and potential genotype/phenotype 
sampling (2-3 weeks latH) 
If no J'eYerse tJ·anscriptase or 
integrase resistance detected, 
continue on study drugs d 
l 
Confmned virologic. rebound 
andHIV-1 
Genotype and Phenotype b, < 
Remain 
on 
study 
If J'eYet·se transc.t-ipt.ase ot· integt·ase 
resistance detected, discontinue 
study drugs and construct a new 
ARV •·egimen • 
a 
If virologic rebotmd is not confmned, the subject will remain on their ctment regimen. 
b 
If virologic rebotmd is c.onfumed and the HIV -1 RNA is :0:: 200 copieslmL, the HIV -1 genotype and phenotype (reverse 
transcriptase, protease and integrase) will be analyzed. 
c 
Based on the results of the genotypic and phenotypic assays, the subject will remain on study drugs or study drugs will be 
disc.ontinued. If genotyping or phenotyping assays fail, a new ARV regimen may be configured at the discretion of the 
Investigator. 
d 
If no resistanc.e is detected, HIV-1 RNA will be repeated (2-3 weeks later). Investigator reviews study drug 
continuation/discontinuation options and discuss with the Medical Monitor prior to study drug discontinuation 
e 
A new ARV regimen will be configured, at the Investigator's discretion, and the subject will remain in the study. 
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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 adverse event (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, lack of efficacy, 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.

Pre-existing 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 7.5)

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 pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (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

Persistent or significant disability/incapacity


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
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.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.6.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to 
study drug using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event 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 adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 6) 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.
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 drug, the following types of events should 
be reported on the case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences 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 Pharmacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported. 
All SAEs should be followed up until resolution if possible. If by the last day on study (including 
the off-study drug follow-up period) the SAE has not resolved, then the SAE will be followed up 
until the investigator and/or Gilead Sciences determine that the subject's condition is stable. 
However, Gilead Sciences may request that certain SAEs be followed until resolution.
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 study drug, 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. 
Serious Adverse Event Paper Reporting Process

Serious Adverse Event Paper Reporting Process (only to be used if EDC System is not
available)
All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of:
Gilead Sciences PVE:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
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 the SAE was reported via paper, it 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.


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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the 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 investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with the study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE. 
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.
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 


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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 complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug 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 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 7.3.2. 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: 
Gilead Sciences PVE:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
Refer to Appendix 7 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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7.5.2.2.
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 drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does 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 the CRF/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.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 5 as outlined below.

All clinically significant Grades 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of study drug for any Grade 3 and 4 laboratory abnormality that in the opinion 
of the Investigator is clinically significant and may pose a risk to the subject’s safety.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(refer to Appendix 6).

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the Investigator.


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7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued and the 
subject managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug 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 study drug, study drug 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.
Study Drug may be continued without dose interruption for a clinically non-significant 
Grade 3-4 laboratory abnormality (e.g., CK elevation after strenuous exercise, or triglyceride 
elevation that is non-fasting or that can be medically managed) or a Grade 3-4 clinical event 
considered unrelated to study drug.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the safety and tolerability of the elvitegravir/cobicistat/emtricitabine/
tenofovir alafenamide (EVG/COBI/FTC/TAF; E/C/F/TAF) fixed-dose combination (FDC) in 
HIV-1 infected adults with end stage renal disease (ESRD) on chronic hemodialysis (HD) at 
Week 48
The secondary objectives of this study are:

To evaluate the safety and tolerability of the EVG/COBI/FTC/TAF; E/C/F/TAF FDC in 
HIV-1 infected adults with ESRD on chronic HD at Week 96

To evaluate the proportion of subjects receiving E/C/F/TAF FDC with virologic response 
(HIV-1 RNA < 50 copies/mL, as defined by the FDA Snapshot analysis) at Weeks 24, 48
and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in HIV-1 
infected patients with ESRD on chronic HD

To evaluate the safety and tolerability of B/F/TAF in HIV-1 infected patients with ESRD on
chronic HD
8.1.2.
Primary Endpoint
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events up 
to Week 48 in subjects receiving E/C/F/TAF.
8.1.3.
Secondary Endpoints

Incidence of treatment-emergent grade 3 or higher adverse events up to Week 96 in subjects 
receiving E/C/F/TAF

Proportion of subjects receiving E/C/F/TAF with HIV-1 RNA < 50 copies/mL at 
Weeks 24, 48, and 96 as defined by the FDA snapshot algorithm

The pharmacokinetics parameters of EVG, COBI, FTC, TAF and TFV, 
 
.
Similar safety and tolerability measures will be used to characterize the safety and tolerability of 
B/F/TAF in HIV-1 infected patients with ESRD on chronic HD. 
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
Full Analysis Set (FAS): The Full Analysis Set will include all the subjects who were enrolled
and received at least one dose of study drug. The FAS will exclude subjects with major protocol 
violations. The FAS analysis set is the primary analysis set for the efficacy analyses.
There will be 2 FAS: the E/C/F/TAF FAS which includes subjects who received at least one dose 
of E/C/F/TAF study drug, and the B/F/TAF FAS which includes subjects who received at least 
one dose of B/F/TAF study drug.
8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses is defined as all subjects that received at least 
one dose of study drug.
There will be 2 safety analysis sets: the E/C/F/TAF safety analysis set which includes subjects 
who received at least one dose of E/C/F/TAF study drug, and the B/F/TAF safety analysis set 
which includes subjects who received at least one dose of B/F/TAF study drug.
All data collected during treatment will be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) analysis set will include all subjects for whom concentration data of 
any one analyte (e.g., BIC, TAF, EVG, COBI, TFV and/or FTC) of interest are available.
There may be 2 PK analysis sets: the E/C/F/TAF PK analysis set which includes subjects who 
received at least one dose of E/C/F/TAF study drug, and the B/F/TAF PK analysis set which 
includes subjects who received at least one dose of B/F/TAF study drug.
 
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index and HIV-1
infection.
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8.4.
Primary and Secondary Analysis
8.4.1.
Primary Analysis
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events up 
to Week 48 in subjects receiving E/C/F/TAF. Treatment-emergent adverse events are defined in 
Section 8.5.2.
8.4.2.
Secondary Analyses
The proportion of subjects receiving E/C/F/TAF who achieve HIV-1 RNA < 50 copies/mL at 
Weeks 24, 48, and 96 will be computed using the FDA snapshot algorithm.
 
 
.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis sets.
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be summarized. Data for pre-treatment period and the 
period post the date of last dose plus 30 days will be included in data listings.
8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized. 
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of each study drug, inclusive, regardless of temporary interruptions in study drug
administration, and summarized. Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (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.
Treatment-emergent adverse events are adverse events that meet one of the following criteria:

Adverse events with onset dates on or after the first dose date of study drug, and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation
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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
HLT [if applicable], and PT) will be provided. Additional summaries will include summaries for 
adverse events by grade, Investigator’s assessment of relationship to study drug, and effect on 
study drug dosing.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 6).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
drug plus 30 days, will be summarized. 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 drug or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.
8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the safety analysis sets. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
The concentration data of any analyte (e.g., BIC, TAF, EVG, COBI, TFV and/or FTC) of interest, 
as applicable, will be listed. 
 
8.7.
Sample Size
A sample size of approximately 50 subjects is based on practical considerations and is 
considered to be sufficient to evaluate the primary objective of this study. The Grade 3 or higher 
AE rate in Study GS-US-292-0112 in subjects that had mild to moderate renal impairment was 
8.8% at Week 48 analysis for the E/C/F/TAF arm. Therefore, with 50 subjects, and an assumed 
rate of Grade 3 or higher AEs being 10%, this study would provide 95% confidence for the 
primary endpoint to be (1.7%, 18.3%) assuming normal approximation to binomial proportions. 
 
. 
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8.8.
Data Monitoring Committee
An external multidisciplinary independent data monitoring committee (IDMC) will review the 
progress of the study and perform interim reviews of safety, efficacy, and PK data and provide 
recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study drug warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications. The committee will convene after the first 25 subjects enrolled complete Week 12
of the study. The IDMC’s specific activities will be defined by a mutually agreed charter, which 
will define the IDMC’s membership, conduct and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with 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 Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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 an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC approved consent form for documenting written 


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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 IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, IRB or IEC, 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 
investigator brochure, this protocol, eCRF, the study drug, 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,
IRB or IEC 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 study drug, including dates of dispensing and 
return;

Record of all adverse events 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 (i.e. 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 will be completed by an authorized study staff member 
whose training for this function is completed in EDC. 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 source data verification within 


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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 coordinator 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.
Study Drug Accountability and Return
The study monitor will provide instructions for return of used and unused study drug. If return is 
not possible, the study monitor will evaluate each study center’s study drug disposal procedures 
and provide appropriate instruction for destruction of unused study drug supplies. If the site has 
an appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead, 
the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead.
The study monitor will review study drug inventory 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, IRBs or IECs, or 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 must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB [or] IEC approval before 
modifications can be implemented.
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

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
Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P. Adherence, treatment 
satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) 
antiretroviral therapy (AT), in a large prospective observational cohort (CUVA 
Study).  [Poster WePeB5780]. . XV International AIDS Conference; 2004 July 
11-16; Bangkok, Thailand. 
Birkus G, Kutty N, He G-X, Mulato A, Lee W, McDermott M, et al. Activation of GS-7340 and 
Other Tenofovir Phosphonoamidate Prodrugs by Human Proteases. Antiviral Res 
2007;74:A57.
Birkus G, Kutty N, He GX, Mulato A, Lee W, McDermott M, et al. Activation of 9-[(R)-2-[[(S)-
[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-
methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate 
prodrugs by human proteases. Mol Pharmacol 2008;74 (1):92-100.
Cailhol J, Nkurunziza B, Izzedine H, Nindagiye E, Munyana L, Baramperanye E, et al. 
Prevalence of chronic kidney disease among people living with HIV/AIDS in 
Burundi: a cross-sectional study. BMC nephrology 2011;12:40.
Center for Disease Control and Prevention. HIV/AIDS Surveillance Report. Rev ed. Atlanta: 
U.S. Department of Health and Human Services, Centers for Disease Control and 
Prevention. Also available at: 
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.  2007.
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and 
adults. MMWR 1992;41 (RR-17):1-19.
Centers for Disease Control and Prevention. 1994 Revised Classification System for Human 
Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. 
MMWR 1994;43 (RR-12):1-28.
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30 
(Suppl 2):S-171-S6.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Department of Health and Human Services (DHHS). HHS Panel on Antiretroviral Guidelines for 
Adults and Adolescents Recommends a Fixed-Dose Combination Product of 
Elvitegravir/Cobicistat/Tenofovir/Emtricitabine as an Alternative Regimen in 
Antiretroviral Treatment-Naive Individuals with HIV-1 Infection.  2012:1-2. 


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Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L. Adherence and efficacy with a 
once-daily efavirenz-based regimen: 48-week results from the Daily 
Antiretroviral Therapy II (DART II) Study [Poster 5842]. . XV International 
AIDS Conference; 2004 July 11-16; Bangkok, Thailand. 
Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. A Phase 3 Randomized 
Controlled Clinical Trial of Bictegravir in a Fixed Dose Combination, B/F/TAF, 
vs DTG/ABC/3TC in Treatment-Naïve Adults at Week 48 [Presentation W48]. 
9th IAS Conference on HIV Science; 2017 23–26 July; Paris, France. 
Gilead Sciences Inc. VIREAD® (tenofovir disoproxil fumarate) Tablets and Powder for oral use. 
US Prescribing Information. Foster City, CA. Revised August 2012:
Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related 
comorbidities among HIV-infected persons compared with the general 
population. Clin Infect Dis 2011;53 (11):1120-6.
Hoetelmans R, Kestens D, Stevens M, Peeters M, Williams P, Bastiaanse L, et al. 
Pharmacokinetic interaction between the novel non-nucleoside reverse 
transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate 
(TDF) in healthy volunteers [poster]. 6th International Workshop on Clinical 
Pharmacology of HIV Therapy; 2005 April 28-30; Québec City, Canada. Poster 
No. 2.11. 
Hoetelmans RM, Marien K, De Pauw M, Hill A, Peeters M, Sekar V, et al. Pharmacokinetic 
interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in 
healthy volunteers. Br J Clin Pharmacol 2007;64 (5):655-61.
Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. Age-related 
immune dysfunction in health and in human immunodeficiency virus (HIV) 
disease: association of age and HIV infection with naive CD8+ cell depletion, 
reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect 
Dis 2003;187 (12):1924-33.
Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective intracellular 
activation of a novel prodrug of the human immunodeficiency virus reverse 
transcriptase inhibitor tenofovir leads to preferential distribution and 
accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005;49 
(5):1898-906.
Linley L, Hall H, An Q, Wheeler W. HIV/AIDS diagnoses among persons fifty years and older 
in 33 states, 2001-2005 [Abstract B08-1]. Presented at: 2007 National HIV 
Prevention Conference; 2007 December 2-5; Atlanta, GA. 


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Luber AD, Condoluci DV, Slowinski PD, Andrews M, Olson K, Peloquin CA, et al. Steady-state 
amprenavir and tenofovir pharmacokinetics after coadministration of unboosted 
or ritonavir-boosted fosamprenavir with tenofovir disoproxil fumarate in healthy 
volunteers. HIV Med 2010;11 (3):193-9.
Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A. Once-a-day treatment for HIV 
infection: Final 48-week results. [Abstract 320]. 8th Conference on Retroviruses 
and Opportunistic Infections; 2001 February 4-8; Chicago, IL. 
Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-daily 
antiretroviral regimens: a meta-analysis. Clin Infect Dis 2009;48 (4):484-8.
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral Treatment Regimens 
and Correlation with Risk of Hospitalization Among Commercially Insured HIV 
Patients in the United States [Poster O113]. 10th International Congress on Drug 
Therapy in HIV Infection; 2010 November 7-11; Glasgow, UK. 
Sax PE, Pozniak A, Arribas J, Koenig E, DeJesus E, Stellbrink HJ, et al. Phase 3 Randomized, 
Controlled, Clinical Trial of Bictegravir Coformulated With FTC/TAF in a Fixed-
Dose Combination vs Dolutegravir + FTC/TAF in Treatment-Naïve HIV-1-
Positive Adults: Week 48 Results [Poster TUPDB0201LB]. 9th IAS Conference 
on HIV Science; 2017 23–26 July; Paris, France. 
Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active 
antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am 
Soc Nephrol 2005;16 (8):2412-20.
Selik RM, Byers RH, Jr., Dworkin MS. Trends in diseases reported on U.S. death certificates 
that mentioned HIV infection, 1987-1999. J Acquir Immune Defic Syndr 2002;29 
(4):378-87.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to 
HAART [abstract]. . 40th Annual Meeting of the Infectious Disease Society of 
America; 2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
World Health Organization (WHO). World Health Organization, UNAIDS, UNICEF. Global 
HIV/AIDS Response: Epidemic update and health sector progress towards 
universal access. Progress Report 2011.  2011.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table (E/C/F/TAF Phase)
Appendix 3.
Study Procedures Table (Open Label Rollover Extension)
Appendix 4.
Appendix 5.
Management of Clinical and Laboratory Adverse Events
Appendix 6.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 8.
Definitions of HIV-1 Related Disease (CDC Guidelines) {Selik 2014}
CCI


PPD
PPD
EIC/FffAF 
Protocol GS-US-292-1825 
Final 
Gilead Sciences, Inc. 
Amendment 2.1 (US Only) 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Efficacy of E/C/F/T AFFixed Dose Combination (FDC) in HIV -1 Infected Subjects on 
Chronic Hemodialysis 
GS-US-292-1825, Amendment 2.1 (US Only), 01 May 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
INVESTIGATOR STATEMENT 
1 have read the protocol, including ail appendices, and r agree that it contains all necessary 
details for me and my staff to conduct this study as described. I wil1 conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. (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 
Page 102 
OJ May2018 


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Appendix 2.
Study Procedures Table (E/C/F/TAF Phase)
Study Procedure
Screena
Day 
1b
Week 2 to Week 96c
Post 
Week 96
End of 
E/C/F/TAF
Visit
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Written Informed Consent
X
Medical History 
X
Complete Physical 
Examinationf
X
X
X
X
X
X
Symptom-directed Physical 
Examinationg
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Height
X
12-Lead ECG
X
X
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
Xj
Xj
Xj
Xj
Xw
X
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/Phenotypem
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum and Plasma Storage 
Sampleso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologyp
X


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Study Procedure
Screena
Day 
1b
Week 2 to Week 96c
Post 
Week 96
End of 
E/C/F/TAF
Visit
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36q
X
X
X
X
X
X
X
HIV-TSQq
X
X
X
X
X
X
X
X
X
VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Utilization Assessmentr
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Dispensation and 
Accountability
X
Xs
X
X
X
X
X
X
X
X
X
X
X
Xx
Xs
Pre-dose Whole Blood Sample 
Collectiont
X
X
Whole Blood Storage Samplev
X
a
Evaluations to be completed within 30 days prior to Day 1.
b
Subjects will be dispensed study drug on the Day 1 Visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 Visit.
c
All study visits are to be scheduled relative to the Day 1 Visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol 
specified date through Week 48, except Week 48. Weeks 48 Visit window is ± 6 weeks of the protocol specified date. Week 48 Visit should be completed within ± 6 day 
window, unless otherwise specified by the Sponsor. Following the Week 48 Visit, study visits are to be completed within ± 6 days of the protocol specified date through 
Week 84. The visit window at Week 96 will be ± 6 weeks of the protocol-specific visit date. Unless notified by the Sponsor, Week 96 Visit should be completed within 
± 6 days of the protocol-specific visit date.
d
Required for those subjects who complete Week 96 Visit or those subjects who prematurely discontinue study drug and do not continue in the study through at least 
one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation Visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Week 96, if the subject discontinues study drug prior to completion of Week 96 Visit.
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom-directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. At Day 1, Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry 
profile. PT/INR will be included in the chemistry profile at Screening, Weeks 24 and 48 only. This sample should be drawn prior to hemodialysis. The timing of draw and 
timing of hemodialysis should be recorded.
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j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of fasting metabolic 
assessments and not as part of the chemistry profile. 
k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian 
hormonal failure.
l
If the HIV-1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening 
and baseline results). See Section 6.7.1.
m
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV-1 RNA value ≥ 400 copies/mL. Subjects should be 
managed according to the Virologic Rebound Schema (Section 6.7.1). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the 
criteria described in this section.
n
CBC with differential and platelet count
o
For subjects who provide consent −serum and plasma storage samples for possible future testing will be collected.
p
See Section 4.2 to confirm subject eligibility prior to enrollment.
q
SF-36 is to be completed by subjects at Day 1, Week 24, Week 48, Week 72, and Week 96 Visits. HIV-TSQs should be completed by the subjects at Screening, Day 1, 
Week 4, Week 24, Week 48, Week 72, Week 96 and ESDD Visits. HIV-TSQc should be completed by the subjects at Week 24, Week 48, Week 72, Week 96 and ESDD 
Visits. 
r
Subjects will be asked about their health utilization at Day 1 Visit and every visit thereafter, including the ESDD and Unscheduled Visits.
s
Drug accountability only; study drug will not be dispensed at these visits.
t
At Week 4 or Week 12, pre-dose whole blood sample will be collected for subjects enrolled in the study. Sample collection should occur within 30 minutes prior to the study 
drug administration which should be observed on-site. PBMC processing will be completed by the central laboratory. 
u
At or between Week 2 or Week 4 study visits on a day prior to the day of hemodialysis and when the subject has administered three doses of E/C/F/TAF between two 
hemodialysis sessions.
 
v
Whole blood storage sample collected at baseline visit for virology assessments.
w
Every 24 Weeks
x
Open label study drug, B/F/TAF FDC will be dispensed to subjects participating in the Open-Label Rollover extension for at least 48 weeks.
CCI


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Appendix 3.
Study Procedures Table (Open Label Rollover Extension)
Study Procedure
End of E/C/F/TAF 
Visit
End of Weeka, c
30-Day Follow-upd
ESDDe
Week 4 OL
Week 12 OL
Week 24 OL
Week 36 OL
Week 48 OL
Complete Physical Examinationf
X
X
Symptom-directed Physical 
Examinationg
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
Xh
X
12-Lead ECG
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
X
X
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
HIV-1 Genotype/Phenotypem
X
X
X
X
X
X
X
PK Samplingp
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
Serum and Plasma Storage 
Sampleso
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
SF-36 
X
X
X
X
X
HIV-TSQ
X
X
X
X
X
Drug Dispensation and 
Accountability
X
X
X
X
X
X
Xb
a
Open label study drug, B/F/TAF FDC will be dispensed to subjects participating in the Open-Label Rollover extension for at least 48 weeks.
b
Drug accountability only; study drug will not be dispensed at these visits
c
All study visits are to be scheduled based upon the Week 96 Visit or End of E/C/F/TAF Visit date (whichever occurs later). The Week 4 OL Visit should be completed within 
±2 days of the protocol-specified visit date. All other Study visits are to be completed within ± 6 days of the protocol-specified visit date, unless otherwise specified by the 
Sponsor.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 107
01 May 2018
d
Required for those subjects who complete End of E/C/F/TAF Visit or those subjects who prematurely discontinue study drug during the Open-Label extension phase. For the 
purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation Visit to occur within 72 hours of last dose of study drug. 
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom-directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. At End of E/C/F/TAF Visit, Week 24 OL, and Week 48 OL analyses of glucose will be done as part of the fasting metabolic assessments and not as 
part of the chemistry profile. This sample should be drawn prior to hemodialysis. The timing of draw and timing of hemodialysis should be recorded.
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At End of E/C/F/TAF Visit, Week 24 OL, and Week 48 OL analyses of glucose will be 
done as part of fasting metabolic assessments and not as part of the chemistry profile. 
k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian 
hormonal failure.
l
If the HIV-1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-3 weeks after the date of the original test (except for screening 
and baseline results). See Section 6.7.3.
m
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV-1 RNA value ≥ 200 copies/mL. Subjects should be managed 
according to the Virologic Rebound Schema (Section 6.7.3). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the criteria described in 
this section.
n
CBC with differential and platelet count
o
For subjects who provide consent − serum and plasma storage samples for possible future testing will be collected.
p
At Week 4 OL, Week 24 OL and Week 48 OL study visits, on the day of hemodialysis, a sparse timed blood sample will be collected within 10 minutes before hemodialysis 
initiates from all subjects. Pre-dose (within 30 minutes prior to study drug administration) blood draws for plasma samples will also be collected at these visits. Study drug 
administration will be observed. Plasma concentrations of BIC may be determined. Plasma concentrations of other analytes may also be explored.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 108
01 May 2018
CCI


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 109
01 May 2018
Appendix 5.
Management of Clinical and Laboratory Adverse Events
1 
L_ _____ 
l\Iay 
lab to 
dosing at rhe 
confirm toiicity 
discretion ofrhe 
grade-
1 
If confinned and possibly and/or probably 
to 
inwstigational medicinal produm: 
1. Withhold inwsrigational medicinal products 
Grade 2 
2. Res ran all inwstigational medicinal 
ar full dose 
1 
lf Grade 3 or 4 t·ecwTence that is coufinned and possibly or 
probably related to inwstigational medicinal products, 
discontinue all inwstigational medicinal products dosing 
to 
confirm toxicity 
grade 
1 
1 
lf confirmed and unrelated to 
inwstigarional medicinal products, 
dosing may continue at the 
discretion of the in,·esrigator 
If confirmed and 
possiblr or probably 
-. relatedto 
inYestigarionaJ 
medicinal products, 
cliscontinue 
iuYesrigarionaJ 
medicinal products 
dosing permanently 
and follow at petiodic 
interYals at least 
weeklY until a retw·n 
to ba;eliue or is 
otherwise explained 
If Grade 3 or 4 recwnnce that is considerE"Cl uw·elared to 
inYe-srigatioual medidnaJ proclucr.s, continue all iuYesrigational 
medicinal products at the 
dose at the discretion of the 
in,·esrigatoJ· 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 110
01 May 2018
Appendix 6.
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 111
01 May 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.  


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 112
01 May 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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 113
01 May 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 114
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 115
01 May 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 116
01 May 2018
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-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 117
01 May 2018
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 118
01 May 2018
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


E/C/F/TAF
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Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 119
01 May 2018
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 120
01 May 2018
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)


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 121
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 122
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 123
01 May 2018
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)


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 124
01 May 2018
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 


E/C/F/TAF
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Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 125
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 126
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 127
01 May 2018
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 128
01 May 2018
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]


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 129
01 May 2018
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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Gilead Sciences, Inc.
Amendment 2.1 (US Only)
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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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Protocol GS-US-292-1825
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Amendment 2.1 (US Only)
CONFIDENTIAL
Page 131
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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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 132
01 May 2018
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.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of study drugs on 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. Data from clinical pharmacokinetic interaction studies of study drug 
have demonstrated that there is no reduction in the clinical efficacy of hormonal contraception or 
that the effect on hormonal contraception is insignificant. 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 
prior to study enrollment. A serum pregnancy test will be performed at all study visits and the 
end of relevant system exposure. In the event of a delayed menstrual period (over one month 
between menstruations), a serum 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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
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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)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods (the hormonal contraceptive should contain at least 30 mcg of ethinyl 
estradiol)
■
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 134
01 May 2018
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential. 
4) 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.
5) 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 30days 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. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.5.2.1.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2.1 (US Only)
CONFIDENTIAL
Page 135
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Appendix 8.
Definitions of HIV-1 Related Disease (CDC Guidelines) {Selik 2014}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†


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Amendment 2.1 (US Only)
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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV§
*
Only among children aged < 6 years
†
Only among adults, adolescents, and children aged ≥ 6 years
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy 
and HIV wasting syndrome, are described in the following references {Centers for Disease Control and 
Prevention 1992, Centers for Disease Control and Prevention 1994}.

Prot_007.pdf: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy ofE/C/F/TAF 
Fixed Dose Combination (FDC) in HIV -1 Infected Subjects on 
Chronic Hemodialysis 
Sponsor: 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
IND Number: 
111,007 
EudraCT Number: 
2015-002713-30 
Clinical Trials.gov Identifier: Not Available 
Indication: 
HIV -1 Infection 
Protocol ID: 
GS-US-292-1825 
Clinical Program Manager: 
Name: 
Telephone: 
Fax: 
Gilead Medical Monitor: 
Name: 
Telephone: 
Fax: 
Protocol Version/Date: 
Original: 
Amendment 1: 
PPD 
PPD 
PPD 
Devi SenGupta, MD 
PPD 
PPD 
08 July2015 
13 October 2015 
CONFIDENTIALITY STATEMENT 
I 
The infmmation contained in this document, patiicularly unpublished data, is the propetiy 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 infmmation 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 infmmation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessruy to obtain infmmed consent fi:om those 
persons to whom the dmg may be administered. 


EICIFITAF 
Protocol GS-US-292-1825 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
TABLE OF CONTENTS .... 
LIST OF IN-TEXT TABLES 
LIST OF IN-TEXT FIGURES 
PROTOCOL SYNOPSIS 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS. 
1. 
INTRODUCTION ..................... ................ .......... . 
1.1. 
1.2. 
1.3. 
1.4. 
1.5. 
Background ................................................ . 
Tenofovir Alafenamide (TAF, GS-7340) 
1.2.1. 
General Information ...................................... . 
1.2.2. 
Preclinical Pharmacology and Toxicology 
1.2.3. 
Nonclinical Pharmacokinetics ....................... . 
1.2.4. 
Nonclinical Toxicology .................................................................... . 
1. 2. 5. 
Clinical Trials of ElvitegraviriCobicistat/Em tricitabine!T enofovir 
Alafenamide (EICIF IT AF) ................................................................ . 
Rationale for This Study ............................. . 
1.3.1. 
Rationale for Dose Selection 
Risk/Benefit Assessment for the Study 
Compliance ................................................. . 
2. 
OBJECTIVES 
3. 
4. 
STUDY DESIGN ............ . 
3. 1. 
Study Design ....... ........ . 
3.2. 
Study Treatments ................. . 
3.3. 
Duration of Treatment 
3.4. 
End of Study ........ ................ . 
3. 5. 
Post Study Care 
3.6. 
Source Data ......... ........ . 
3.7. 
PPD 
L---------------------------~ 
SUBJECT POPULATION ............... ................ ................ . 
4.1. 
4.2. 
4.3. 
Number of Subjects and Subject Selection 
Inclusion Criteria .. . . 
Exclusion Criteria .. . 
5. 
INVESTIGATIONAL :MEDICINAL PRODUCTS 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
Emollment ............ ................ ................ ..... . 
Description and Handling ofEICIFITAF FDC Tablets 
5. 2. 1. 
Formulation ........ ........ . 
5.2.2. 
Packaging and Labeling ..... ........ . 
5.2.3. 
Storage and Handling ......... ..... . 
Dosage and Administration of EICIF IT AF 
Prior and Concomitant Medications 
Accountability for EICIF IT AF 
5.5.1. 
Study Drug Return or Disposal 
6. 
STUDY PROCEDURES .. ................ ................ ..... . 
6.1. 
6.2. 
Subject Emollment and Treatment Assignment. 
Pretreatment Assessments .... ................ ............. . 
CONFIDENTIAL 
Page 2 
Final 
Amendment 1 
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. ... 22 
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. ... 25 
.. .. 25 
. ... 26 
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. ..... .. 30 
...... .. 30 
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. ..... .. 31 
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. ..... .. 38 
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. ..... .. 38 
13 October 2015 


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Gilead Sciences, Inc.
Amendment 1
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6.2.1.
Screening Visit .....................................................................................................................38
6.2.2.
Day 1 Assessments...............................................................................................................40
6.3.
Treatment Assessments (Weeks 2-48) ...................................................................................................41
6.4.
Post-treatment Assessments ...................................................................................................................44
6.4.1.
30-Day Follow-up Assessments...........................................................................................44
6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)....................................................45
6.4.3.
Criteria for Discontinuation of Study Treatment..................................................................46
6.5.
Other Evaluations...................................................................................................................................46
6.5.1.
Pharmacokinetic (PK) Sub-study .........................................................................................46
6.5.2.
Blood Storage.......................................................................................................................47
6.6.
Virologic Failure....................................................................................................................................47
6.6.1.
Management of Virologic Failure ........................................................................................47
6.6.2.
Subjects with ≥ 400 copies/mL of HIV-1 in the Absence of VR .........................................48
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................50
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events....................................50
7.1.1.
Adverse Events.....................................................................................................................50
7.1.2.
Serious Adverse Events........................................................................................................50
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................51
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................51
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................51
7.2.2.
Assessment of Severity ........................................................................................................52
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................52
7.3.1.
Adverse Events.....................................................................................................................52
7.3.2.
Serious Adverse Events........................................................................................................52
7.4.
Gilead Reporting Requirements.............................................................................................................54
7.5.
Special Situations Reports......................................................................................................................54
7.5.1.
Definitions of Special Situations..........................................................................................54
7.5.2.
Instructions for Reporting Special Situations.......................................................................55
7.6.
Toxicity Management ............................................................................................................................56
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................56
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................56
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................58
8.1.
Analysis Objectives and Endpoints........................................................................................................58
8.1.1.
Analysis Objectives..............................................................................................................58
8.1.2.
Primary Endpoint .................................................................................................................58
8.1.3.
Secondary Endpoints............................................................................................................58
8.2.
Analysis Conventions.............................................................................................................................58
8.2.1.
Analysis Sets ........................................................................................................................58
8.3.
Demographic Data and Baseline Characteristics ...................................................................................59
8.4.
Primary and Secondary Analysis ...........................................................................................................59
8.4.1.
Primary Analysis..................................................................................................................59
8.4.2.
Secondary Analyses .............................................................................................................59
8.5.
Safety Analysis.......................................................................................................................................59
8.5.1.
Extent of Exposure...............................................................................................................60
8.5.2.
Adverse Events.....................................................................................................................60
8.5.3.
Laboratory Evaluations ........................................................................................................60
8.5.4.
Other Safety Evaluations......................................................................................................61
8.6.
Pharmacokinetic Analysis......................................................................................................................61
8.7.
Sample Size............................................................................................................................................61


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Amendment 1
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8.8.
Data Monitoring Committee ..................................................................................................................61
9.
RESPONSIBILITIES..........................................................................................................................................62
9.1.
Investigator Responsibilities ..................................................................................................................62
9.1.1.
Good Clinical Practice..........................................................................................................62
9.1.2.
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................62
9.1.3.
Informed Consent.................................................................................................................63
9.1.4.
Confidentiality......................................................................................................................63
9.1.5.
Study Files and Retention of Records ..................................................................................63
9.1.6.
Case Report Forms...............................................................................................................65
9.1.7.
Study Drug Accountability and Return ................................................................................65
9.1.8.
Inspections............................................................................................................................65
9.1.9.
Protocol Compliance............................................................................................................65
9.2.
Sponsor Responsibilities ........................................................................................................................66
9.2.1.
Protocol Modifications.........................................................................................................66
9.2.2.
Study Report and Publications .............................................................................................66
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................66
9.3.1.
Payment Reporting...............................................................................................................66
9.3.2.
Access to Information for Monitoring..................................................................................67
9.3.3.
Access to Information for Auditing or Inspections ..............................................................67
9.3.4.
Study Discontinuation..........................................................................................................67
10.
REFERENCES ...................................................................................................................................................68
11.
APPENDICES ....................................................................................................................................................71
Appendix 1.
Investigator Signature Page....................................................................................................72
Appendix 2.
Study Procedures Table..........................................................................................................73
Appendix 3.
Pharmacokinetic Sub-study....................................................................................................76
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................77
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............78
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................100
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}.....................................103
LIST OF IN-TEXT TABLES
Table 1-1.
Comparison of Plasma TFV Exposures After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis Versus TDF-Containing Regimens in 
Patients with Normal Renal Function.....................................................................................20
Table 4-1.
Disallowed Agents .................................................................................................................29
Table 5-1.
Prior and Concomitant Medications.......................................................................................33
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted Steady-State TFV PK Profile After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis..............................................................................19
Figure 3-1.
Study Schema.........................................................................................................................24
Figure 6-1.
Schema for Management of Virologic Failure .......................................................................49


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 5
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy of E/C/F/TAF 
Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002713-30
Not available 
Study Centers Planned:
Approximately 50 study sites in North America and Europe
Objectives:
The primary objective of this study is as follows:

To evaluate the safety and tolerability of the 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
(EVG/COBI/FTC/TAF; E/C/F/TAF) fixed dose combination 
(FDC) in HIV-1 infected adults with end stage renal disease 
(ESRD) on chronic hemodialysis (HD) at Week 48
The secondary objectives of this study are as follows: 

To evaluate the proportion of subjects achieving virologic 
response (defined as HIV-1 RNA < 50 copies/mL, 
Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, 
FTC, TAF and TFV in HIV-1 infected patients with ESRD 
on HD
Study Design:
Open-label, multicenter, single-arm study to assess the safety, 
tolerability, pharmacokinetics, and efficacy of E/C/F/TAF FDC
dosed once daily in HIV-infected adult subjects with ESRD on 
chronic HD. 
All subjects will switch from their current antiretroviral (ARV) 
regimen to E/C/F/TAF on Day 1. The treatment duration will be 
48 weeks.
Number of Subjects 
Planned:
Approximately 50 subjects with ESRD on chronic HD will be 
enrolled.


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Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 6
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Target Population:
HIV-1 infected adults (≥18 years) with ESRD on chronic HD for 
≥6 months prior to screening, and HIV-1 RNA < 50 copies/mL on 
a stable antiretroviral (ARV) regimen for ≥ 6 consecutive months 
prior to screening.
Duration of Treatment:
Subjects will be treated for 48 weeks.
Diagnosis and Main 
Eligibility Criteria:
HIV-1-infected adults who meet the following criteria:

No documented history of HIV-1 resistance to EVG, FTC, 3TC 
or TFV

Currently receiving a stable antiretroviral regimen for 
≥6 consecutive months prior to screening 

Plasma HIV-1 RNA < 50 copies/mL for at least 6 months 
preceding the screening visit

CD4+ T cell count of ≥ 200 cells/μL

ESRD with eGFR < 15 mL/min by Cockcroft-Gault, on 
chronic HD for ≥ 6 months prior to screening

Hepatitis C (HCV) infection allowed 

Hepatitis B (HBV) infection not allowed
Study Procedures/
Frequency:
Following Screening, eligible subjects will be required to return for 
study visits at Day 1, Weeks 2, 4, 8, 12, 24, 36 and 48. After the 
Week 48 visit, subjects will stop study drug and complete a 30-Day 
Follow-up visit to complete their participation in the study.
For all subjects, HBV and HCV serologies will be analyzed at 
Screening. Adverse events, concomitant medications, complete or 
symptom-directed physical examinations, laboratory analyses 
(hematology and chemistry), fasting lipids and glucose, 
HIV-1 RNA, CD4+ T cell count and estimated GFR will be 
performed at the Screening, Day 1, and all subsequent study visits.
Pre-dose blood draw for plasma and PBMC samples will be 
collected from all subjects at Week 4 or Week 12, which must be 
the day of hemodialysis. 
All subjects who provide consent will be eligible to participate in 
the pharmacokinetic sub-study (target n = 15).
Test Product, Dose, and 
Mode of Administration:
FDC of elvitegravir 150 mg / cobicistat 150 mg /
emtricitabine 200 mg / tenofovir alafenamide 10 mg administered
orally once daily with food until the next hemodialysis. On the 
day of hemodialysis, study drug should be administered should 
occur after completion of hemodialysis. 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 7
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Reference Therapy, 
Dose, and Mode of 
Administration:
N/A
Criteria for Evaluation:
Safety:
Safety evaluations will include reporting of adverse events, clinical 
laboratory tests, physical examinations, and vital signs. 
An Independent Data Monitoring Committee (IDMC) will be 
convened after the first 25 subjects enrolled in the study complete 
Week 12 of the study. 
Efficacy:
Virologic response will be determined using the percentages of
subjects with HIV-1 RNA < 50 copies/mL at Week 24 and 48
(snapshot analysis).
Pharmacokinetics:
At Week 4 or Week 12, on the day of hemodialysis, pre-dose 
(within 30 minutes prior to study drug administration) blood draws
for plasma and PBMC samples will be collected from all subjects. 
Study drug administration will be observed. Plasma concentrations 
of EVG, COBI, FTC, TAF and TFV and intracellular 
concentrations of TFV-DP may be explored.
Pharmacokinetic (PK) Sub-study
All subjects who provide consent will be eligible to participate in 
the PK sub-study (target n = 15). For the PK sub-study, intense 
blood sampling will be conducted at or between Week 2 or Week 4
study visits, on a day prior to the day of hemodialysis and when the 
subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. The PK of EVG, COBI, FTC, TAF and 
TFV will be evaluated. Study drug administration will be observed 
in-clinic at the sub-study visit. 
Health Related 
Questionnaires:
SF-36, VAS (visual analogues scale), HIV-TSQ (HIV Treatment
Satisfaction Questionnaire) and Health Utilization Questionnaire 
will be administered per the information provided in the study 
procedures section of this protocol.
Statistical Methods:
The primary endpoint will be the incidence of treatment-emergent 
Grade 3 or higher adverse events at Week 48.
The proportions of subjects with virologic response (HIV-1 RNA 
< 50 copies/mL, snapshot analysis) and the associated 
95% confidence intervals at Weeks 24 and 48, respectively will be 
constructed.


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Concentrations and PK parameters of EVG, COBI, FTC, TAF and 
TFV for the sub-study, and intracellular PBMC concentrations of 
TFV-DP will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV),
median, minimum, and maximum].
A sample size of approximately 50 subjects is based on practical 
consideration and is considered to be sufficient to evaluate the 
primary objective of this study. The grade 3 or higher AE rate in 
Study GS-US-292-0112 in subjects that had mild to moderate renal 
impairment was 8.8% at Week 48 for the E/C/F/TAF arm. 
Therefore, with 50 subjects, and an assumed rate of Grade 3 or 
higher AEs being 10%, this study would provide 95% confidence 
for the primary endpoint to be (1.7%, 18.3%) assuming normal 
approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating 
the PK parameters in the sub-study for practical reasons. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time curve
bsAP
serum bone specific alkaline phosphatase
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration 
of drug
Cmin
minimum plasma concentration
CNS
central nervous system
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
E/C/F/TAF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir alafenamide (TAF) 10 mg fixed dose combination
ESRD
End stage renal disease
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FS
failure to suppress
FTC
emtricitabine
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase


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GSI
Gilead Sciences, Inc.
GS-7340 
tenofovir alafenamide, TAF, L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester
HAART
highly active antiretroviral therapy
HBsAg
hepatitis B virus surface antigen serology
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus serology
HD
hemodialysis
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-TSQ
HIV Treatment Satisfaction Questionnaire
HIV-TSQs
HIV Treatment Satisfaction Questionnaire Status
HIV-TSQc
HIV Treatment Satisfaction Questionnaire Change
HMG-CoA
5-hydroxy-3-methylglutaryl-coenzyme A
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
DMC
Data Monitoring Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IRB
institutional review board
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MH
Mantel-Haenszel
Min
minute
mmHg
millimeters mercury
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OC
osteocalcin
P1NP
procollagen Type 1 N-terminal propeptide
PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term 
PTH
parathyroid hormone
QD
once daily 


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RNA
ribonucleic acid
SAE
serious adverse event
SVR
suboptimal virologic response
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
ULN
upper limit of the normal range
US
United States
VR
virologic rebound


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 infection is a life-threatening and serious disease of major 
public health significance, with approximately 34 million people infected with HIV worldwide 
{19661}. The goals of highly active antiretroviral therapy (HAART) for HIV-1 infection are to 
delay disease progression and prolong survival by achieving maximal and durable suppression of 
HIV-1 replication. Prompt antiretroviral therapy (ART) initiation after diagnosis is based on 
growing evidence that untreated HIV infection or uncontrolled viremia is associated with 
development of non- acquired immune deficiency syndrome (AIDS)-defining diseases, including 
cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and 
malignancies. The success of ART has shifted clinical attention towards regimens that optimize 
long-term adherence, tolerability and safety. Adherence to ART is required to prevent 
development of drug resistance and subsequent loss of virologic suppression, and adherence to 
ART is improved by reducing pill burden and dosing frequency {4266}, {4256}. Once-daily, 
single tablet regimens are associated with high adherence, better clinical outcomes, including 
fewer hospitalizations, improved patient satisfaction, and excellent virologic outcomes {7034}, 
{7035}, {7036}, {16557}, {16560}.
Despite current therapy that effectively suppresses viremia, HIV disease remains a serious 
condition due to non-AIDS associated comorbidities. As treatment guidelines recommend early 
treatment of HIV-1 infection, there is a need for regimens offering enhanced product safety and 
tolerability, effectiveness, and convenience for long-term treatment.
Though antiretroviral drugs have led to dramatic improvements in survival and disease 
progression, complications such as kidney, liver, and cardiac disease have become increasingly 
important causes of morbidity and mortality for HIV patients taking effective therapy {19947}, 
{19948}, {22552}. Recent data has shown that even with treatment, HIV patients experience more 
age-related co-morbidities, such as renal and bone disease, which manifest earlier than their 
age-matched HIV-uninfected peers {19946}. Moreover, the prevalence and incidence of chronic 
kidney disease (CKD) and end stage renal disease (ESRD) in the US are expected to rise as the 
prevalence of HIV infection continues to rise {22553}. Worldwide, prevalence may be even
greater; one cross-sectional study in the East African Republic of Burundi reported 
46% of HIV-positive adults fulfilled criteria for CKD {22551}.
Patients with HIV are at risk for acute and chronic kidney disease from a wide spectrum of 
etiologies, including HIV-associated nephropathy, immune complex kidney disease, thrombotic 
microangiopathy, and kidney disease associated with comorbidities such as diabetes, 
hypertension, hepatitis B and hepatitis C coinfections, as well as medications associated with 
nephrotoxicity. Clearly, new therapies that improve on the current standard of care are needed, 
so that life-long antiviral therapy is more effective, more tolerable, and safer for patients. 
Since the majority of currently available nucleos(t)ide backbones are prescribed as fixed dose 
combinations, HIV-positive patients with chronic kidney disease have particularly limited 
therapeutic options.


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The availability of a single tablet regimen composed of potent agents with improved tolerability 
and long-term safety, that does not require dose adjustment at eGFR < 50 mL/min, would 
represent an important therapeutic innovation in this special patient population, providing more 
convenient dosing and potentially improving patient adherence.
Tenofovir alafenamide (TAF) has a unique metabolism that provides enhanced lymphatic 
delivery of tenofovir, resulting in higher intracellular levels of the active phosphorylated 
metabolite, tenofovir-diphosphate (TFV-DP), and lower circulating levels of TFV {7415}, 
{13119}, {22029}. The distinct metabolism of TAF offers an improved clinical profile compared 
with TDF, which is associated with nephrotoxicity and decreased bone mineral density {21762}, 
{22031}. Compared with TDF, TAF is characterized by lower systemic exposures and higher 
intracellular levels of TFV. Additionally, TFV exposures achieved with TAF in subjects with 
severe renal impairment are comparable to those with normal renal functions receiving 
TDF 300 mg, indicating that TAF can be administered to HIV-1 infected patients with renal 
impairment without dose modification. 
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is an prodrug of TFV, 
a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolized intracellularly 
to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 reverse transcriptase (RT) 
that terminates the elongation of the viral deoxyribonucleic acid (DNA) chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids. 
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
Tenofovir alafenamide is metabolized to TFV, a nucleotide analog (ie, a nucleoside 
monophosphate analog) which is not dependent on an intracellular nucleoside kinase activity 
for the first step in the conversion to the active metabolite, TFV-DP. The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{4887} and nucleotide diphosphate kinase, which are highly active and ubiquitous. AK exists as 
multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most efficiently by 
AK2.


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The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T cells, natural killer (NK) 
cells, B-cells and macrophages/monocytes. TAF is metabolized inside host cells to the active 
metabolite TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all 
cell populations.
1.2.2.2.
Safety Pharmacology
Single doses of TAF did not induce pharmacologic effects on the central nervous system of the 
rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the cardiovascular system of the 
dog (100 mg/kg).
1.2.3.
Nonclinical Pharmacokinetics
All nonclinical PK experiments were performed using TAF monofumarate (GS-7340-02), and all 
study data described in this section reflect the dosage of the monofumarate. For reference, 
100 mg of TAF monofumarate is equivalent to 80 mg of the GS-7340 free base (TAF).
Key results from nonclinical absorption, distribution, metabolism, and excretion studies of TAF 
are as follows: 

Following oral administration in dogs and monkeys, TAF demonstrated rapid absorption, 
with peak plasma concentrations between 0.25 and 0.5 hours. Thereafter, TAF plasma 
concentrations declined rapidly with a terminal half-life of less than 1 hour. 
Tenofovir alafenamide exposure (Cmax and AUC values) was nonlinear with dose and greater 
than expected with increasing dose. Repeat-dose studies in rats and monkeys showed no 
change in pharmacokinetics over time. 

Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. 

Following oral administration of [14C]-radiolabeled TAF to dogs, a mean total recovery of 
radioactivity at 24 hours of 63% was demonstrated. Radioactivity was detected in all tissues 
except brain with the majority present in the contents of the gastrointestinal tract, liver, 
kidney, and large intestine. Tissue concentrations were the highest in kidney, peripheral 
blood mononuclear cells (PBMCs), liver, large intestine, and bile. Additional studies in dogs, 
TFV concentrations in PBMCs following oral administration of TAF were approximately 
50-fold greater than observed in plasma, with an estimated t½ of greater than 24 hours. 

The major route of elimination of TAF-related radioactivity was via feces, with 
approximately 35% of the dose recovered in feces through 48 hours postdose. The primary 
route of elimination of TFV is renal excretion of unchanged drug based on IV studies of 
TFV. 


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
Tenofovir alafenamide has been found to be a substrate for intestinal efflux transport and in 
nonclinical studies its intestinal absorption was increased by the transport inhibitor 
cyclosporin A. 

No significant inhibition of human drug metabolizing cytochrome P450 (CYP) enzymes, 
uridine diphosphate glucuronyltransferase (UGT) 1A1 or transporters including 
P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide 
(OATP)1B1 and OATP1B3 was observed with TAF in vitro. 

Tenofovir alafenamide did not activate human pregnane X receptor (hPXR) or 
aryl hydrocarbon receptor (AhR).

Tenofovir alafenamide was not a substrate for drug-metabolizing CYP enzymes except for 
CYP3A4, which metabolized the compound slowly. 
1.2.4.
Nonclinical Toxicology
Key results from nonclinical toxicology studies of TAF are as follows:

Based on TFV exposure, the no observed adverse effect levels (NOAELs) in the 6-month rat, 
9-month dog, and 1-month monkey studies provide 14-, 4-, and 22-fold safety margins, 
respectively, for a human dose of 25 mg/day.

In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment with TAF 
100 mg/kg/day; however, effects were not seen at lower doses. Tenofovir alafenamide also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above.

In chronic studies in dogs after 9 months of treatment at doses up to TAF 18/12 mg/kg/day 
(the high dose was reduced from 18 to 12 mg/kg/day due to the occurrence of death, severe 
clinical signs and reduced body weight), the primary target organs were kidney 
(slight to moderate renal tubular degeneration and karyomegaly) and bone 
(decreased bone mineral density [BMD] in metaphyseal cancellous bone). 

Tenofovir alafenamide had no discernable electrocardiograph effect at the low dose of 
2 mg/kg/day. There was some evidence at 6 and 18/12 mg/kg/day for an effect to slightly 
prolong PR intervals. 

After 9 months of treatment, some dogs administered the highest dose of TAF 
(18/12 mg/kg/day) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given 
lower doses and it has not occurred in other animal studies. 


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
There were no clear treatment-related effects observed in monkeys following 28 days of 
TAF treatment at 3 and 30 mg/kg/day, including no changes in mitochondrial function and 
mitochondrial DNA (mtDNA) content in the liver, kidney, and skeletal muscle, and 
characterization of lymphocyte populations.

Tenofovir alafenamide was not genotoxic in either in vitro or in vivo assays. 
Tenofovir alafenamide had no adverse effects on male or female fertility parameters in rats. 
There was no effect on fetal viability or fetal development in pregnant rats administered 
doses of TAF up to 250 mg/kg/day or in pregnant rabbits administered TAF up to 
100 mg/kg/day; the highest doses were maternally toxic.
1.2.5.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
(E/C/F/TAF)
Emtricitabine and TAF have been combined with the integrase inhibitor EVG and its 
pharmacoenhancer COBI in the E/C/F/TAF FDC, which has been designed to be a complete 
treatment regimen for HIV-1 infection and is being evaluated in a broad clinical development 
program. The details of the key clinical studies are provided below:

GS-US-292-0102, a randomized, double-blinded controlled Phase 2 study in which 
E/C/F/TAF is compared to Stribild® (STB), as initial treatment of HIV-infection in 
ART-naive patients. This is a single-variable clinical comparison of the 2 tenofovir prodrugs, 
TAF and TDF 

GS-US-292-0104 and GS-US-292-0111, Phase 3 randomized, double-blinded studies of the 
safety and efficacy of E/C/F/TAF versus E/C/F/TDF in HIV-1 infected, antiretroviral 
treatment-naive adults. The interim Week 48 key conclusions from pooled data are as 
follows: 1) E/C/F/TAF once daily was noninferior to STB once daily when administered
for 48 weeks to HIV-infected, ART-naive adults, as assessed using the US
Food and Drug Administration (FDA)-defined snapshot algorithm with HIV-1 RNA
< 50 copies/mL (E/C/F/TAF 92.4%; STB 90.4%; difference in percentages: 2.0%, 
95% CI: −0.7% to 4.7%), 2) administration of E/C/F/TAF resulted in > 90% lower plasma 
TFV and higher intracellular TFV-DP relative to STB, 3) E/C/F/TAF showed an improved 
renal and bone safety profile with significantly less decline in hip and spine BMD, less 
increase in serum creatinine and reduction in estimated glomerular filtration rate (eGFR), 
4) Increases from baseline in fasting total cholesterol fasting low density lipoprotein (LDL) 
cholesterol, and fasting triglycerides were noted in the E/C/F/TAF group;


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
GS-US-292-0112, a Phase 3 open-label safety study of E/C/F/TAF in HIV-1 positive patients 
with mild to moderate renal impairment; Week 48 results demonstrated that patients who 
switched to E/C/F/TAF had no change in eGFR, and had significant improvements in 
measures of renal function including proteinuria, albuminuria, retinol binding protein and 
beta-2-microglobulin. These subjects also had improvements in measures of bone mineral 
density. Importantly, because FTC was given without dose adjustment to patients with 
eGFR 30-50 mL/min, these patients had comparable safety profile to patients with 
eGFR 50-69 mL/min, with no increased rate of potential FTC related drug reactions, 
supporting the safety of FTC at higher exposures. In addition, 92% of study participants 
maintained virologic suppression (HIV-1 RNA < 50 copies/ml) at Week 48 after switching to 
E/C/F/TAF.

GS-US-292-0109, a Phase 3 study designed to evaluate the safety, efficacy, and tolerability 
of switching to E/C/F/TAF in individuals who are virologically suppressed on regimens 
containing TDF. The interim Week 48 key conclusions from this study are as follows: 
1) switching to E/C/F/TAF was noninferior to maintaining FTC/TDF+3rd Agent 
(STB, efavirenz/emtricitabine/tenofovir DF (ATR), atazanavir (ATV)/boosted+Truvada®) as 
assessed using the FDA snapshot algorithm (Week 48 FAS) with HIV-1 RNA cutoff at 
50 copies/mL (E/C/F/TAF 95.6%; FTC/TDF+3rd Agent 92.9%; difference in percentages: 
2.7%, 95.01% CI: −0.3% to 5.6%), 2) An improved renal and bone safety profile was 
observed in subjects who switched to E/C/F/TAF, 3) there were no differences in ocular 
findings between treatment groups and no reported cases of uveitis.
1.3.
Rationale for This Study
Because of the increasing average age of HIV-infected patients, the high prevalence of chronic 
kidney disease, and the increasing prevalence of co-morbid conditions that require medical 
management, medical regimens in ESRD patients are complex and can impact a patient’s overall 
risk of morbidity and mortality. The availability of a single-tablet regimen composed of potent 
agents with improved tolerability and long-term safety that does not require dose adjustment at 
eGFR < 15 mL/min, would represent an important therapeutic innovation for HIV infected
patients with ESRD. EVG, COBI, and TAF are not renally eliminated, while the metabolite of 
TAF (TFV) and FTC, are renally eliminated. 
The E/C/F/TAF FDC was recently shown to be safe and efficacious in HIV-infected patients 
with mild to moderate chronic kidney disease (CKD; eGFR 30-69 mL/min) in study 
GS-US-292-0112 through 48 weeks. The long-term safety of E/C/F/TAF remains to be 
established in subjects at more advanced stages of renal impairment, including those with ESRD 
on hemodialysis. The present study will provide the pharmacokinetic data describing TFV and 
FTC exposures in these patients when administered as the E/C/F/TAF FDC, dosed once daily, as 
well as safety and efficacy data in this special population through 48 weeks. 


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1.3.1.
Rationale for Dose Selection
The E/C/F/TDF FDC containing EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg),
is currently under review for use once daily for the treatment of human immunodeficiency virus 
type 1 (HIV-1) infection in adults and pediatric patients 12 years of age and older without any 
known resistance to the individual components and with an eGFR ≥ 30 mL/min. This FDC 
contains the equivalent doses of EVG and COBI in the marketed product, Stribild®. The FTC 
(200 mg) in the E/C/F/TAF FDC represents the marketed dose in several approved FDC 
products: emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, and 
emtricitabine/rilpivirine/tenofovir DF for the treatment of HIV-1 infection.
EVG, COBI, and TAF are not renally eliminated, while the metabolite of TAF (TFV) and FTC, 
are renally eliminated. 
TAF and TFV
The Phase 3 study GS-US-292-0112 demonstrated that patients with moderate renal impairment 
(baseline eGFR 30-50 mL/min) who switched to E/C/F/TAF had no change in eGFR, and had 
significant improvements in measures of renal function including proteinuria, albuminuria, 
retinol binding protein and beta-2-microglobulin. These subjects also had improvements in 
measures of bone mineral density. TAF PK in subjects with screening eGFR 30-69 mL/min was 
consistent with data following administration of E/C/F/TAF in nonrenally-impaired 
HIV-infected subjects in Phase 2 and Phase 3 studies. 
Data from GS-US-120-0108 demonstrated that in HIV uninfected subjects with an eGFR of 
15-29 mL/min, plasma TAF exposures increased < 2-fold. Study GS-US-292-1825 will evaluate 
TAF (as well as TFV and FTC) PK in the setting of daily administration of E/C/F/TAF STR in 
treatment-experienced subjects with eGFR < 15 mL/min on chronic hemodialysis.
To support TAF dosing in ESRD patients, simulation for TFV exposures was conducted using an 
established population pharmacokinetic model for TFV following administration of E/C/F/TAF 
and with information from previously conducted Gilead Study (GS-01-919) where TDF was 
administered in ESRD subjects (Figure 1-1).


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Figure 1-1.
Predicted Steady-State TFV PK Profile After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis
Figure 1-1 shows the simulated TFV PK profile following E/C/F/TAF once-daily for two weeks in subjects with ESRD on 
chronic hemodialysis three-times per week. IPRED represents the model predicted plasma concentration of TFV. The double 
blue arrows represent a four-hour hemodialysis session.
In subjects with ESRD on chronic hemodialysis three-times per week, systemic TFV exposures 
are expected to be higher following administration of E/C/F/TAF, relative to E/C/F/TAF in 
subjects with eGFR > 30 mL/min, due to the renal elimination pathway for TFV. In subjects with 
ESRD on chronic hemodialysis, E/C/F/TAF administered once daily is predicted to result in a 
mean (% CV) TFV exposure of 3610 (21.6) h•ng/mL. Given the extensive safety data available 
for TDF, TFV exposures follow administration of E/C/F/TAF in ESRD subjects on chronic 
hemodialysis are expected to be in the range of those following TDF-containing regimens in 
patients with normal renal function (Table 1-1) and, as such, would not require TAF dose 
modification. 


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Table 1-1.
Comparison of Plasma TFV Exposures After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis Versus 
TDF-Containing Regimens in Patients with Normal Renal Function
TFV AUC (Mean [%CV])
E/C/F/TAF regimen
3610 (21.6)
TDF-Containing Regimens in Normal Renal Function
Atazanavir+Ritonavira
3940 (30)
Darunavir+Ritonavirb
4630 (16)
Fosamprenavir+Ritonavirc
2930 (1780, 4280)
Lopinavir+Ritonavird
3500 (27)
Saquinavir+Ritonavire
3110 (24)
Rilpivirinef
3590 (22)
Emtricitabine+TDFg
2870 (25)
Efavirenz/Emtricitabine/TDFh,i
2270 (19)
Elvitegravir/Cobicistat/Emtricitabine/TDFh
3940 (20)
a
Study GS-US-216-0114
b
{11428}
c
mean (90% CI); {15426}
d
Studies 00-909 and 01-943
e
Study GS-US-104-0236
f
{8510}
g
Studies GS-US-236-0101 and GS-US-236-0110
h
Studies GS-US-236-0120
i
Study GS-US-334-0131
FTC
The FTC dose (200 mg) in the E/C/F/TAF FDC represents the marketed dose as part of the 
approved products FTC (Emtriva®), FTC/TDF (Truvada®), efavirenz/FTC/TDF (Atripla®), 
FTC/rilpivirine/TDF (Complera® or Eviplera®), and E/C/F/TDF (Stribild®) for the treatment of 
HIV-1 infection. Emtricitabine is principally eliminated by the kidney and higher exposures are 
observed in patients with moderate to severe renal impairment. For eGFR of 30-49 mL/min, 
Emtriva prescribing information recommends dose interval adjustment of the 200 mg oral 
capsule to q48h. However, available clinical experience suggests the plasma FTC may not 
require dose adjustment in the setting of renal impairment. In study GS-US-292-0112, FTC was 
given without dose adjustment to patients with eGFR 30-50 mL/min, and these patients had 
comparable safety profile to patients with eGFR 50-69 mL/min, with no increased rate of 
potential FTC related drug reactions, supporting the safety of FTC at higher exposures. 
In Study FTC-107, an open-label, parallel-group study of single-dose emtricitabine 200 mg in 
HIV uninfected subjects with varying degrees of renal impairment, 6 subjects with moderate 
renal impairment (30-49 mL/min), 5 subjects with severe renal impairment (< 30 mL/min) and 
6 subjects on dialysis were treated. Of note, subjects with baseline eGFR of 30-49 mL/min had 


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only twice the mean FTC systemic exposure (mean (%CV) AUCinf: 25.08 hr•μg/mL (23)) 
compared to subjects with eGFR > 80 mL/min (mean (%CV) AUCinf: 11.78 (25) hr•μg/mL. 
Subjects on dialysis had an AUCinf of 53.22 hr•μg/mL (19). In all cohorts, the overall incidence 
of adverse events was low and there was no apparent relationship between the incidence of AEs 
and the degree of renal impairment. 
In study GS-US-104-0235, the safety and tolerability of FTC+TDF (200/300 mg) in 
treatment-naïve and treatment-experienced HIV infected subjects with various degrees of renal 
impairment were assessed. One subject in this study assigned to the mild impairment group was 
later found to have moderate impairment (eGFR ≥30 and < 50 mL/min) and one subject 
assigned to moderate impairment was found to have severe impairment (eGFR < 30 mL/min) 
after 40 days of treatment. Based on PK analyses of these subjects, the subject with moderate 
renal impairment was continued on FTC 200 mg daily because FTC exposures remained within 
the predicted range for subjects without renal impairment and the subject with severe renal 
impairment continued to receive FTC 200 mg every 48 hours based upon appropriate FTC 
systemic exposures. 
Consistent with the renal impairment Study FTC-107 described above, results from the PK 
sub-study of GS-US-292-0112 (n = 30) showed that FTC exposure was slightly higher in 
subjects with mild to moderate renal impairment as compared with historical data on FTC in 
subjects with normal renal function (mean [%CV] FTC AUCtau 20968.6 [25.5] ng•h/mL versus 
11,714.1 [16.6] ng•h/mL in Phase 2 Study GS-US-292-0102 of non-renally-impaired 
HIV-infected subjects), as expected due to the renal elimination of FTC. Further population PK 
analysis on all subjects treated in Study GS-US-292-0112 with available FTC data (n = 241), 
confirmed the findings from the PK sub-study, showing slightly higher FTC exposures in 
subjects with baseline eGFRCG < 50 mL/min, as compared with subjects with baseline 
eGFRCG ≥50 mL/min. Importantly, these observed differences in FTC exposure by 
renal impairment subgroup did not result in a different safety profile. The incidence of adverse 
events that occurred in ≥ 5% of subjects and of treatment-related adverse events that occurred in 
≥1% of subjects was similar between groups after 48 weeks of treatment. Adverse reactions 
from the Emtriva SmPC were also specifically evaluated. Despite higher FTC exposure in this 
study, incidence of these events was similar in subjects with eGFRCG < 50 mL/min and in 
subjects with eGFRCG ≥50 mL/min. The current study will evaluate FTC exposures and safety, 
and an IDMC will be convened to monitor safety data.
1.4.
Risk/Benefit Assessment for the Study
Potential risks of a patient’s study involvement include switching to an unfamiliar regimen with 
potential loss of virologic control and/or new adverse events, the inconvenience of more frequent 
clinic visits and laboratory blood draws and the associated pain and discomfort of phlebotomy. 
Strategies to mitigate these risks include close monitoring of viral load, CD4+ T cell count and 
other lab values as well as monitoring of adverse events. Parameters for discontinuation of the 
study drug due to adverse events or lack of efficacy will be well-defined and closely followed. 
In addition, an independent data monitoring committee will be convened at Week 12 to evaluate 
safety data and determine whether the risks/benefits warrant continuation of the study. 


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Potential benefits may include the patient receiving a FDC antiretroviral regimen that is more 
convenient leading to improved adherence, with potentially fewer adverse events than the current 
regimen, E/C/F/TAF may provide an alternative treatment for a patient population with fewer 
therapeutic options than the general HIV-1-infected population. 
Considering the above, the benefit-risk balance for this study is considered positive.
1.5.
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 safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with
ESRD on chronic HD at Week 48
The secondary objectives of this study are:

To evaluate the proportion of subjects achieving virologic response (defined as HIV-1 RNA
< 50 copies/mL, Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in 
HIV-1 infected patients with ESRD on HD


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3. 
STUDY DESIGN 
3.1. 
Study Design 
Final 
Amendment 1 
This is an open-label, multicenter, single-rum study to assess the safety, tolerability, 
phrumacokinetics, and efficacy ofEICIFITAF FDC in HIV-1 infected adult subjects with 
ESRD on chronic HD. 
Approximately 50 subjects with ESRD on chronic HD will be emolled. All subjects will switch 
from their cunent antiretroviral regimen to EICIFITAF on Day 1. The total treatment dmation 
will be 48 weeks. After Week 48 visit, all subjects will stop study dmg and complete a 30-Day 
Follow-up visit. 
Figure 3-1. 
Screening 
Study Schema 
Day 1 
Week48 
(Prima1y Endpoint) 
~ 30 days 
prior to 
Baseline 
48 Weeks of Treatment on EICIFITAF 
(n = approximately soy 
30-Day 
Follow-upb, c 
a 
Following the Day 1 visit, subjects will retmn for study visits at Weeks 2, 4, 8, 12, 24, 36 and 48. 
b 
After 48 weeks, subjects will stop study dmg and complete a 30-Day Follow-up visit to end their patticipation in the study. 
c 
Subjects who discontinue study dmg administration before their Week 48 visit, will complete and ESDD visit. 
These subjects may remain on the study off study dmg up to the Week 48 visit. Upon completion of Week 48 visit, subjects 
may be required to re.t1u11 to d1e clinic for a 30-Day Follow-up visit to complete their patticipation in d1e study. 
3.2. 
Study Treatments 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg I cobicistat 150 mg I emtricitabine 200 mg I tenofovir alafenamide 10 mg 
(EICIFITAF), on Day 1. 
Study dmg will be administered orally once daily with food at approximately the same time 
every day. On the day of hemodialysis, study dmg administration should occm after completion 
of hemodialysis. 
CONFIDENTIAL 
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13 October 2015 


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3.3. 
Duration of Treatment 
Final 
Amendment 1 
The study will consist of a 30-day screening period (within 30 days before Day 1 visit), followed 
by a 48 weeks treatment period. After Day 1, subjects will retum for study visits at 
Weeks 2, 4, 8, 12, 24, 36 and 48. 
After Week 48, subjects will stop study dmg and complete a 30-Day Follow-up visit. 
3.4. 
End of Study 
End of the study will occur when the last subject emolled in the study has completed Week 48 
visit followed by a 30-Day Follow-up visit. 
3.5. 
Post Study Care 
After a subject has completed/te1minated their participation in the study, long-tenn care for the 
subject will remain the responsibility of their primmy treating physician. 
3.6. 
Source Data 
Sponsor will provide somce document worksheets for all study visits. 
3.7. 
~PD 
PD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects who meet the eligibility criteria will be enrolled. 
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 screening procedures
2) Age ≥ 18 years
3) Currently receiving a stable antiretroviral regimen for ≥ 6 consecutive months prior to 
screening 
4) Documented plasma HIV-1 RNA concentrations < 50 copies/mL for at least 6 months 
preceding the screening visit (measured at least twice using the same assay) and have 
HIV-1 RNA < 50 copies/mL at screening
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
≥50 copies/mL and < 400 copies/mL) is acceptable, only if HIV-1 RNA is 
< 50 copies/mL immediately before and after the blip. 
b) To determine virologic suppression in the preceding 6 months prior to screening, the 
lower limit of quantification (LLOQ) by the local HIV-1 RNA assay may be used, only if 
its LLOQ is greater than 50 copies/mL (e.g. LLOQ of 75 copies/mL)
5) No documented history of HIV-1 resistance to EVG, FTC, 3TC or TFV and no history of 
switching off EVG, FTC, 3TC or TFV due to concern for resistance
6) CD4+ T cell count of ≥200 cells/μL
7) ESRD with eGFR < 15 mL/min by Cockcroft-Gault formula for creatinine clearance {2202}
Male:
(140 – age in years) × (wt in kg) Clcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 Clcr (mL/min)
72 × (serum creatinine in mg/dL)
8) On chronic HD for ≥ 6 months prior to screening


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9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Chronic Hepatitis C (HCV) infection allowed if liver function is stable for ≥ 6 months prior to 
screening: ALT ≤ 10 × ULN, AST ≤ 10 × ULN, total bilirubin ≤ 2.5, or normal direct 
bilirubin (subjects with documented Gilbert’s Syndrome or hyperbilirubinemia due to 
atazanavir therapy may have total bilirubin up to 5 × ULN), INR ≤ 1.5 and albumin ≥3 g/dL; 
no evidence of cirrhosis or hepatocellular carcinoma by imaging in the last 12 months
11) Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; 
platelets ≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
12) Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤ 5 × ULN)
13) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant confirmed by a negative serum pregnancy test (unless permanently sterile 
or greater than two years post-menopausal)
b) Of non-child bearing potential (i.e. women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for ≥ 12 months) of previously occurring menses
Female subjects who have stopped menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure must have a serum follicle stimulating 
hormone (FSH) level at screening within the post-menopausal range based on the 
Central Laboratory Reference range. 
c) Of childbearing potential and agrees to utilize the protocol specified method of 
contraception or be non-heterosexually active or practice abstinence from screening 
throughout the duration of the study treatment and for 30 days following study drug 
discontinuation (as defined in Appendix 6)
d) Female subjects who utilize hormonal contraception as one of the birth control methods 
must have used the same method for at least three months prior to the study dosing. 
14) Male subjects must agree to use protocol specified method(s) of contraception from 
screening throughout the duration of study treatment and for 30 days following 
discontinuation of study drugs (Appendix 6).
15) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days 
after the last study drug dose.
16) Lactating females must agree to discontinue nursing before the study drug is administered.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Hepatitis B surface antigen (HBsAg) positive
2) Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
3) Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening
4) Treatment with radiation, cytotoxic chemotherapeutic agents, or any immunomodulator 
within 30 days of screening
5) Any other clinical history, condition, or test result that, in the opinion of the Investigator, 
would make the subject unsuitable for the study or unable to comply with dosing 
requirements
6) Administration of other investigational agents (unless approved by Gilead Sciences). 
Participation in any other clinical trial, including observational trials, without prior approval 
from the sponsor is prohibited while participating in this trial.
7) History or presence of allergy or intolerance to the study drugs or their components
8) A new AIDS-defining condition (excluding CD4+ T cell count and percentage criteria) 
diagnosed within the 30 days prior to screening, with the exception of 
oropharyngeal candidiasis (see Appendix 7)
9) Have an implanted defibrillator or pacemaker
10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
carcinoma
12) Received solid organ or bone marrow transplant
13) Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures
14) 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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15) Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use]), immunosuppressant, or 
immunomodulating agents
16) Subjects receiving ongoing therapy with any of the following medications in the Table 4-1
below, including drugs not to be used with EVG, COBI, FTC, TAF
Table 4-1.
Disallowed Agents
Drug Class
Agents Disallowed*
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Calcium Channel Blockers
Bepridil
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
Inhaled Beta Agonist
Salmeterol
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
*
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. 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label, single arm study. All eligible subjects will receive open-label E/C/F/TAF.
Enrollment and Day 1 visit cannot occur until subject eligibility has been confirmed.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment. Once eligibility is confirmed, each subject will be assigned a unique subject 
number using 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 may be performed up to 3 days prior to the in-clinic Day 1 visit, provided that all 
other screening procedures have been completed and subject eligibility has been confirmed. 
Eligibility must be confirmed and all Day 1 tests and procedures must be completed prior 
to the administration of the first dose of study drug.
IWRS will assign study drug bottle numbers at each study visit. Initiation of study drug must 
take place on the day of Day 1 visit. 
5.2.
Description and Handling of E/C/F/TAF FDC Tablets
5.2.1.
Formulation
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets and are debossed with “GSI” on
one side of the tablet and “510” on the other side of the tablet. E/C/F/TAF tablets contain 150 mg
of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of TAF fumarate).
The E/C/F/TAF tablet core contains silicon dioxide, croscarmellose sodium, hydroxypropyl
cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine aluminum 
lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.2.2.
Packaging and Labeling
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle
contains 30 tablets, silica gel desiccant and polyester packaging material. Each bottle is enclosed
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
Study drug to be distributed to centers in the US and other participating countries shall be labeled 
to meet applicable requirements of the United States Food and Drug Administration (FDA), 
EU Guideline to Good Manufacturing Practice −Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.


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5.2.3.
Storage and Handling
E/C/F/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). Storage conditions are specified on 
the label. Until dispensed to the subjects, all bottles of study drug should be stored in a securely
locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration of E/C/F/TAF
E/C/F/TAF FDC tablets will be provided by Gilead Sciences.
E/C/F/TAF FDC tablets containing 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 
10 mg of TAF will be provided to all eligible subjects at Day 1. Study drug will be administered
orally at approximately the same time each day with food. 
On the day of hemodialysis study drug administration should occur after completion of 
completion of hemodialysis. 
Subjects will be instructed to bring all study drug in the original container at each clinic visit for 
drug accountability (unless otherwise specified in the study procedures sections of this protocol). 
The Investigator will be responsible for maintaining accurate records for all study drug bottles 
dispensed and tablets returned. The inventory and dispensing logs must be available for 
inspection by the study monitor. Study drug supplies, including partially used or empty bottles, 
must be accounted for by the study monitor prior to destruction or return.
5.4.
Prior and Concomitant Medications

For subjects receiving hormonal contraceptives, investigators and/or the subject’s healthcare 
providers should consider additional methods of contraception, as concentrations of ethinyl 
estradiol may decrease and progestin level may increase on co-administration with study 
drug. 

The use of medications for the treatment of HIV, other than study drug, is prohibited.

For subjects receiving concomitant medications that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious adverse 
events, investigators and/or the subject’s healthcare providers should consider alternative 
concomitant medications.


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
During the study, subjects may not receive any of the following concomitant medications:
Competitors of renal excretion (e.g., probenecid; high-dose non-steroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin and pentamidine)

Medications listed in the following table and use of herbal/natural supplements are excluded 
or should be used with caution while subjects are participating in the study. Any concomitant 
medication requiring adjustment or discontinuation due to renal impairment or a change in 
renal function on study should be managed per that drug’s prescribing information.


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Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Concentration of study drug may decrease with 
antacids. Subjects may not take antacids 
(eg, Tums, Mylanta); the ulcer medication sucralfate
(Carafate); or vitamin or mineral supplements that 
contain calcium, iron or zinc for a minimum of 2 hours 
before and 2 hours after any dose of study drug.
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antiarrhythmics
Amiodarone, Flecainide Quinidine, Propafenone, 
Systemic Lidocaine, Mexiletine, Disopyramide: 
Concentrations may increase with study drug(s) 
resulting in a potential for cardiac arrhythmias; 
clinical and ECG monitoring is recommended.
Calcium Channel Blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, Verapamil, 
Diltiazem, Amlodipine: 
Concentrations may increase with study drug(s). 
Clinical and ECG monitoring of subjects is 
recommended
Digoxin
Digoxin:
Concomitant use may result in increased levels; use 
with caution and with appropriate monitoring of 
serum digoxin levels. Digoxin therapy should be 
initiated at the lower dose, and the dose should be 
titrated to clinical response.
Antibacterials
Clarithromycin and Telithromycin: 
Concentrations may be altered with study drug(s); 
consider an alternative.
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR 
(International Normalized Ratio) monitoring 
is recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics:
Concentrations may increase or decrease with study 
drug(s). Concentration monitoring is recommended 
to ensure adequate clinical response.
Trazodone:
Concomitant use with CYP3A inhibitors results in 
increased concentrations and adverse events; dose 
reduction should be considered.
Antifungals
Ketoconazole and Itraconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Daily dose of 
ketoconazole and itraconazole should be restricted 
to 200 mg. Subjects receiving ketoconazole or 
itraconazole should be monitored for adequate 
clinical response.
Voriconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Clinical monitoring may 
be needed.
Antigout
Colchicine:
Concentrations may increase with study drug(s). 
Dose reductions of colchicine may be required. 
Should not be coadministered in patients with 
renal or hepatic impairment.
Treatment of Gout Flare:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg 
(half tablet) 1 hour later. Treatment course may be 
repeated no earlier than 3 days.
Prophylaxis of Gout Flares:
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:
Maximum daily dose of 0.6 mg 
(may be given as 0.3 mg twice a day).
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
Corticosteroids: Inhaled/Nasal
Concomitant use of inhaled fluticasone and study 
drug(s) may increase plasma concentrations of 
fluticasone. Use is not recommended unless the 
potential benefit to the subject outweighs the risks 
of corticosteroid side effects. Alternatives should be 
considered, particularly for long-term use.
Corticosteroids: Systemic
Systemic dexamethasone, a CYP3A inducer, may 
significantly decrease elvitegravir and cobicistat 
plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative corticosteroids should be considered.
Use of Prednisone as a steroid burst (≤1 week of use)
should be monitored appropriately.
Endothelin receptor antagonists
Bosentan:
coadministration may lead to decreased elvitegravir 
exposures and loss of therapeutic effect and 
development of resistance. Alternative endothelin 
receptor antagonists may be considered.
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Atorvastatin:
Concentrations may increase with study drug(s). 
Start with the lowest dose; gradual increase in dose 
may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s).
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: 
A dose decrease may be needed.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Opiates
Methadone:
Methadone exposures are unaffected upon 
coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required upon 
coadministration with study drug(s).
Meperidine (Pethidine):
Dosage increase and long-term use are not 
recommended due to increased levels of metabolite 
normeperidine, which has analgesic and 
CNS stimulant (eg, seizures) activities.
Buprenorphine:
Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and cobicistat, 
with no effect on opioid pharmacodynimcs.
The concentration changes are not considered 
clinically relevant and no dose adjustment of 
buprenorphine/naloxone is required upon
coadministration with study drug(s).
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil:
Caution should be exercised, including consideration 
of dose reduction, when coadministered for treatment 
of pulmonary arterial hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil:
It is recommended that a single dose of Sildenafil 
no more than 25 mg in 48 hours, Vardenafil no 
more than 2.5 mg in 72 hours, or Tadalafil no more 
than 10 mg in 72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem:
A dose decrease may be needed for these drugs. 
Clinical monitoring is recommended.

Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the Gilead Sciences 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 Sciences as soon as he/she is aware of 
the use of the disallowed medication.


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5.5.
Accountability for E/C/F/TAF
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. Accountability records (Study Drug Inventory Log) will be provided to each study site in 
order to:

Record the date received and the quantity of study drug bottles.

Record the date, subject number, subject initials, the study drug bottle number dispensed.

Record the date, quantity of used and unused study drug returned by the subject, along with 
the initials of the person recording the information.
The Investigator [or designee (e.g., study center pharmacist)] will acknowledge receipt of the 
study drugs from Gilead Sciences (or designee) after reviewing the shipment’s content and 
condition. The Investigator (or designee) will be responsible for maintaining an accurate 
inventory of the dates and quantities of all study drugs received, dispensed, and returned. 
Subjects should be instructed to return all unused study drug to the site at their study visits.  
Each dose of the study drug administered at the study center will be administered by qualified 
study center personnel. All doses of study drug administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Study Drug Inventory Logs provided by 
Gilead Sciences (or on equivalent documentation maintained by the study center), which 
indicates the date and quantity of all doses of study drug dispensed to individual subjects. 
The requirements of all applicable drug dispensing laws will apply to all doses of study drugs 
dispensed by the Investigator (or designee). 
The study drug inventory log must be available for inspection by the study monitor. Study drug
supplies, including partially used or empty bottles, must be accounted for by the study monitor 
prior to destruction or return.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions to the sites regarding the return of used and unused 
study drug. If return is not possible, the study monitor will evaluate each study center’s study 
drug disposal procedures and provide appropriate instruction for destruction of unused study 
drug. 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 study 
drug bottles in accordance with that site’s approved SOP. A copy of the site’s approved SOP will 
be obtained for central files.
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead. The study monitor will review study drug inventory and 
associated records at periodic intervals.


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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 described in the text that follows. 
The investigator must document any deviation from protocol procedures in the subject’s source 
documents and electronic Case Report Forms (eCRFs). In addition, the Sponsor and the 
Contract Research Organization (CRO) should be promptly notified of any protocol deviations. 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment. 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg 
(E/C/F/TAF), on Day 1. Please refer to Section 5.1 for details about enrollment and 
treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Day 1 visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events, substance use, 
family history of cardiovascular disease (i.e. myocardial infarction, stroke, peripheral 
vascular/arterial disease, and/or angina) and prior medications within 30 days of the 
screening visit

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) and weight

12-lead ECG performed supine

Height


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
Blood sample collection for the following laboratory analyses: 
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
FSH test is required for female subjects who have stopped menstruating for > 12 months 
but do not have documentation of ovarian hormonal failure.
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and parathyroid hormone (PTH)
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ T cell count
Plasma HIV-1 RNA (Taqman v2.0)
Hepatitis B virus surface antigen serology (HBsAg)
Hepatitis C virus (HCVAb) serology. If the antibody test result is positive, 
HCV RNA test will be performed to confirm HCV viremia.

HIV-TSQs (HIV Treatment Satisfaction Questionnaire Status) should be completed by the 
subject. Subject is to read the questionnaire by him/herself and write/mark answers directly 
onto the questionnaire.

Review of AEs and concomitant medications (adverse events related to protocol mandated 
procedures occurring after signing of the consent form)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for Day 1 assessments. 
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF). All other 


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untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF. See Section 7
Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments
The following evaluations are to be completed after confirmation of eligibility, and before the 
study drug is dispensed to the subject. Initiation of treatment with the study drug must take place 
within 24 hours after the Day 1 visit.

Obtain subject number and study drug bottle assignment from IWRS. The subject number 
assignment and enrollment may be performed up to 3 days prior to the in-clinic Day 1 visit 
provided that all screening procedures have been completed and subject eligibility has been 
confirmed.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, phosphorus, magnesium, potassium, sodium, uric acid, amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN) and PTH
Metabolic assessments: 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). 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
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Whole blood storage sample collection for virology analyses


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Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, VAS and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation. Study drug will be dispensed in an open-label fashion. Subjects 
must initiate dosing of study drug on the day of the Day 1 visit. 

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. On the days of hemodialysis, subjects should be instructed to take study 
drug after completion of hemodialysis. Subjects should also be counseled regarding the 
importance of adherence and taking their study drugs at approximately the same time each 
day.
6.3.
Treatment Assessments (Weeks 2-48)
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specific visit date through Week 12 and completed 
within ± 6 days of the protocol-specific visit date through Week 36. The visit window at 
Week 48 will be ± 6 weeks of the protocol-specific visit date, and this clinical visit window 
coincides with the Week 48 statistical analysis window for HIV RNA. Unless notified by the 
Sponsor, Week 48 visit should be completed within ± 6 days of the protocol-specific visit date. 
The following evaluations are to be completed at the end of Weeks 2, 4, 8, 12, 24, 36 and 48 
unless otherwise specified. 
Note: Regularly scheduled evaluations will be made on all subjects whether or not they continue 
to receive study drug. 

Pre-dose (within 30 minutes prior to study drug administration) whole blood samples
collection for plasma and PBMC samples (Week 4 or Week 12 only). 
Note: Week 4 or Week 12 visit should occur on the day of hemodialysis for this sample 
collection. Study drug administration should occur after completion of hemodialysis and 
should be observed on-site. 
PBMC sample processing will be performed by the central laboratory and plasma sample 
processing will be performed on-site. Details of the blood sampling procedures and 
sample management will be documented in the central laboratory manual. 


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
All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15) at or between Week 2 or Week 4 study visits, on a day prior to the 
day of hemodialysis and when the subject has administered three doses of E/C/F/TAF 
between two hemodialysis sessions. E/C/F/TAF administration prior to post-dose blood 
sample collection will be observed in-clinic. 
The ± 2 day window at Week 2 or Week 4 study visits does not apply to the PK 
sub-study visit. Please see Section 6.5.1 and Appendix 3, Pharmacokinetic (PK) 
Sub-study for additional details. 

Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24 and 48 only) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator)

Symptom-directed physical examination as needed (Weeks 2, 4, 8, 12 and 36)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, 
direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and PTH
Note: At Weeks 24 and 48, analyses of glucose will be done as part of the fasting 
metabolic assessments and not as part of the chemistry profile.
o
Chemistry profile will include PT/INR only at Week 24 and Week 48.
Metabolic assessments: 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). 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 (Weeks 24 and 48 only)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
o
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).


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CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
o
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 

Subject completed questionnaires:
SF-36 completed at Weeks 24 and 48 only
HIV-TSQs completed at Weeks 4, 24 and 48. HIV-TSQc (HIV Treatment Satisfaction 
Questionnaire Change) completed at Weeks 24 and 48.
VAS completed at all visits
The questionnaires should be completed by the subject. Subject is to read the questionnaire 
by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation (except at Week 2 and Week 48). Document study drug dispensation 
and accountability. 
At Day 1, study drug will be dispensed for 30 days. At the Week 2 visit, study drug will 
not be dispensed. 
At Week 48, study drug dispensation will not occur. Schedule the subject for a 30-Day 
Follow-Up visit. 
Note: At the Week 2 visit, provide the scheduled Week 4 visit date to the subject. Week 4 
visit should occur on day of hemodialysis. Instruct the subject to take study drug at Week 4 
on-site (after completion of hemodialysis).

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. 

Subjects should also be counseled regarding the importance of adherence and taking their 
study drugs at approximately the same time each day.


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6.4.
Post-treatment Assessments
6.4.1.
30-Day Follow-up Assessments
Subjects who complete the study through the Week 48 visit will be required to return to the 
clinic for a 30-Day Follow-Up Visit. 
Those subjects who permanently discontinue study drug and continue in the study through 
at least one subsequent visit after the Early Study Drug Discontinuation Visit will not be 
required to complete the 30-Day Follow-Up Visit.
Subjects who permanently discontinue study drug prior to the Week 48 visit and refuse to 
continue in the study through the Week 48 visit will be asked to return to the clinic 30 days after 
the completion of the ESDD Visit for 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 of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, 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) and PTH.
Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Serum pregnancy test (females of childbearing potential only)
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
At the 30 Day Follow Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.


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6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)
If the subject discontinues study drug prior to the Week 48 visit, the subject will be asked to 
return to the clinic within 72 hours of stopping study drug for the ESDD visit. 
Every attempt should be made to keep the subject in the study through Week 48 visit and 
continue to perform the required study-related follow-up and procedures (see Section 6.4.3, 
Criteria for Discontinuation of Study Treatment). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study.
Subjects who permanently discontinue study drug prior to the Week 48 visit and refuse to 
continue in the study through Week 48 visit will be asked to return to the clinic 30 days after the 
completion of ESDD visit for the 30-Day Follow-up visit.
At the Early Study Drug Discontinuation Visit, any evaluations showing abnormal results 
indicating that there is a possible or probable causal relationship with the study drug, 
should be repeated weekly (or as often as deemed prudent by the Investigator) until the 
abnormality is resolved, returns to baseline, or is otherwise explained.
The following evaluations are to be completed at the Early Study Drug Discontinuation Visit

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, 
direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, 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) and PTH
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
o
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).


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CD4+ T cell count
Plasma sample for virology testing or pharmacokinetic testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, HIV-TSQc and VAS questionnaires should be completed by the subject. Subject is to 
read the questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Drug accountability
6.4.3.
Criteria for Discontinuation of Study Treatment
Study drug 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.

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Lack of efficacy

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.5.
Other Evaluations
6.5.1.
Pharmacokinetic (PK) Sub-study
All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). 
Intense blood sampling will be conducted at hours 0.5, 1, 2, 3, 4, 6, 8, and 24.


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PK sub-study visit must occur at or between Week 2 or Week 4 study visits, on a day prior to the 
day of hemodialysis and when the subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. The ± 2 day window at Week 2 or Week 4 study visits does not apply 
to the PK sub-study visit. Study drug administration will be observed in-clinic at the sub-study 
visit. The sub-study will include intensive PK profiling in plasma. Details of the blood sampling 
procedures and sample management will be documented in the central laboratory manual. 
6.5.2.
Blood Storage
From subjects who provide additional consent, a portion of the blood drawn at all visits 
(except the Screening Visit and Unscheduled Visits) will be frozen and stored. These stored 
blood samples may be used by the Sponsor or its research partners for future testing to learn 
more about how the study drug has worked against HIV-1 or clinical laboratory testing to 
provide additional safety data. No human genetic testing will be performed without expressed 
consent of study subjects. At the conclusion of this study, these samples may be retained in 
storage by Gilead Sciences, Inc. for a period up to 15 years.
6.6.
Virologic Failure
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure.
Subjects will be considered to have virologic rebound if they have confirmed HIV-1 RNA 
≥50 copies/mL (two consecutive tests) at a scheduled or unscheduled visit.
6.6.1.
Management of Virologic Failure

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-4 weeks after the date of the original test with HIV-1 RNA 
≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented. Assessments should include:
Adherence
Concomitant medication
Comorbidities (for example: active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed, and the HIV-1 RNA is < 400 copies/mL, subjects may 
remain on their current regimen at the discretion of the Investigator. Subject will return for a 
repeat within 2-4 weeks. 


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
If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 400 copies/mL, the blood samples from the confirmation visit will be used for 
HIV-1 genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and HIV-1 RNA should be repeated (2-4 weeks from the date of confirmed 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 
subjects source documents. Investigators who opt to discontinue study drugs for an 
individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.6.2.
Subjects with ≥400 copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at Week 24 or Week 48, or at the last visit while receiving study drugs 
(or within 72 hours of discontinuation of study treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.


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Figure 6-1. 
Schema for Management of Virologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
Day1 
~ 
I 
At any visit, a rebound in HIV -1 RNA to ~ 50 copies/mL 
I 
Unconfu·med 
Return for scheduled/unscheduled HIV-1 
vii·ologic rebound: 
.... 
RNA and potential genotype/phenotype 
remain on cmTent 
(2-4 week~ late1•) 
regimen• 
' 
Confi1·med virologic rebound and 
HIV-1 RNA to <!: 400 copies/mLb 
,, 
Remain on study 
I 
HIV-1 genotype/phenotype' I 
' 
' 
If no reverse transcriptase •·esi~tance 
If reve1·se transc.l"iptase, protease, 
detected, continue on studl d1·ugs. 
or mtegrase resistance detected, 
Repeat HIV-1 RNA ,d 
discontinue study drugs and 
constl·uct a new ARV regimen• 
a 
If virologic rebOlmd is not confmned, the subje-ct will remain on their cmrent regin1en. 
b 
If virologic rebotmd is confmned, and the HIV-1 RNA is< 400 copies/mL, subjects may remain on their cun·ent regimen at 
the discretion of the Investigator. Subject will rettun for a repeat within 2-4 weeks. If virologic rebom1d is confinned, and 
HIV -1 RNA is :::: 400 copies/mL, the HIV -1 genotype and phenotype (reverse transcriptase, protease, and, if applicable, 
integrase resistance) will be analyzed. 
c 
Base·d on the results of the genotype/phenotype assays, the subject will remain on study chugs or study drugs will be 
discontinued. If genotyping/phenotyping assay fails, a new AR V regin1en may be configm·ed at the discretion of the 
Investi2ator. 
d 
If no r.;istance detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews study dt·ug 
continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation. 
e 
A new ARV regimen will be configtu·ed, at the Investigator's discretion, and the subject will remain in the study. 
CONFIDENTIAL 
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13 October 2015 


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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 adverse event (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, lack of efficacy, 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.

Pre-existing 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 7.5)

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 pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (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

Persistent or significant disability/incapacity


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
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.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.6.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to 
study drug using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event 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 adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
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.
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 drug, the following types of events should 
be reported on the case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences 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 occurs 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 Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported. 
All SAEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study drug follow-up period) the SAE has not resolved, then the SAE will be 
followed up until the investigator and/or Gilead Sciences determine that the subject's condition is 
stable. However, Gilead Sciences may request that certain SAEs be followed until resolution.
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 study drug, he/she should promptly document and 
report the event to Gilead DSPH. 

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Serious Adverse Event Paper Reporting Process

Serious Adverse Event Paper Reporting Process (only to be used if EDC System is not available)
All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of:
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
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 DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If the SAE was reported via paper, it 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.


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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the 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 investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with the study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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.
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 


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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 complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the post study drug follow-up period, 
to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to 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 7.3.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. 
Gilead DSPH contact information is as follows: 
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications does 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 the CRF/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.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 as outlined below.

All clinically significant Grades 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of study drug for any Grade 3 and 4 laboratory abnormality that in the opinion 
of the Investigator is clinically significant and may pose a risk to the subject’s safety.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(refer to Appendix 5).

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the Investigator.
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued and the 
subject managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug may not require permanent discontinuation.


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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 study drug, study drug 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.
Study Drug may be continued without dose interruption for a clinically non-significant 
Grade 3-4 laboratory abnormality (e.g., CK elevation after strenuous exercise, or triglyceride 
elevation that is non-fasting or that can be medically managed) or a Grade 3-4 clinical event 
considered unrelated to study drug.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the safety and tolerability of the elvitegravir/cobicistat/emtricitabine/
tenofovir alafenamide (EVG/COBI/FTC/TAF; E/C/F/TAF) fixed dose combination (FDC) in 
HIV-1 infected adults with end stage renal disease (ESRD) on chronic hemodialysis (HD) at 
Week 48
The secondary objectives of this study are:

To evaluate the proportion of subjects with virologic response (HIV-1 RNA < 50 copies/mL, 
Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in HIV-1 
infected patients with ESRD on HD
8.1.2.
Primary Endpoint
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events at 
Week 48.
8.1.3.
Secondary Endpoints

Proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by 
the FDA snapshot algorithm

The pharmacokinetics parameters of EVG, COBI, FTC, TAF and TFV, including 
AUCtau/AUClast, Cmax, and Cmin for the sub-study.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
Full Analysis Set (FAS): The Full Analysis Set will include all the subjects who were enrolled
and received at least one dose of study drug. The FAS will exclude subjects with major protocol 
violations. The FAS analysis set is the primary analysis set for the efficacy analyses.


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8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses is defined as all subjects that received at least 
one dose of study drug.
All data collected during treatment will be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) analysis set will include all subjects in the safety analysis set who 
participated in the sub-study and for whom concentration data of any one analyte (e.g., TAF, EVG,
COBI, TFV and FTC) of interest are available.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index and HIV-1 infection.
8.4.
Primary and Secondary Analysis
8.4.1.
Primary Analysis
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events at 
Week 48. Treatment-emergent adverse events are defined in Section 8.5.2.
8.4.2.
Secondary Analyses
The proportion of subjects achieving HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 will be 
computed using the FDA snapshot algorithm. The measures of pharmacokinetics of EVG, COBI, 
FTC, TAF and TFV, AUC, Cmax, and Cmin, will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV), median, minimum, 
and maximum] for the sub-study.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be summarized. Data for pre-treatment period and the 
period post the date of last dose plus 30 days will be included in data listings.


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8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized. 
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug
administration, and summarized. Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for
Regulatory Activities (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.
Treatment-emergent adverse events are adverse events that meet one of the following criteria:

Adverse events with onset dates on or after the first dose date of study drug, and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and PT) will be provided. Additional summaries will include summaries for adverse 
events by grade, Investigator’s assessment of relationship to study drug, and effect on study drug 
dosing.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
drug plus 30 days, will be summarized. 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 drug or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.


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8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for using descriptive statistics 
(eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of the study drug over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation.
8.7.
Sample Size
A sample size of approximately 50 subjects is based on practical considerations and is 
considered to be sufficient to evaluate the primary objective of this study. The Grade 3 or higher 
AE rate in Study GS-US-292-0112 in subjects that had mild to moderate renal impairment was 
8.8% at Week 48 for the E/C/F/TAF arm. Therefore, with 50 subjects, and an assumed rate of 
Grade 3 or higher AEs being 10%, this study would provide 95% confidence for the primary 
endpoint to be (1.7%, 18.3%) assuming normal approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating the PK parameters in the 
sub-study for practical reasons. 
8.8.
Data Monitoring Committee
An external multidisciplinary independent data monitoring committee (IDMC) will review the 
progress of the study and perform interim reviews of safety, efficacy data and provide 
recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study drug warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications. The committee will convene after the first 25 subjects enrolled complete Week 12
of the study. The IDMC’s specific activities will be defined by a mutually agreed charter, which 
will define the IDMC’s membership, conduct and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with 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 Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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 an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.


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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 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC 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 IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, IRB or IEC, 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 
investigator brochure, this protocol, eCRF, the study drug, 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,
IRB or IEC and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.


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The required source data should include sequential notes containing at least the following 
information for each 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);

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 study drug, including dates of dispensing 
and return;

Record of all adverse events 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 (i.e. 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.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is completed in EDC. 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 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 coordinator 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.
Study Drug Accountability and Return
The study monitor will provide instructions for return of used and unused study drug. If return is 
not possible, the study monitor will evaluate each study center’s study drug disposal procedures 
and provide appropriate instruction for destruction of unused study drug 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 study drug supplies 
in accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead.
The study monitor will review study drug inventory 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, IRBs or IECs, or 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 must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB [or] IEC approval before 
modifications can be implemented.
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

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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Amendment 1
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10.
REFERENCES
1238
Centers for Disease Control and Prevention. 1993 revised classification system 
for HIV infection and expanded surveillance case definition for AIDS among 
adolescents and adults. MMWR 1992;41 (RR-17):1-19.
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
4256
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 
2000;30 (Suppl 2):S-171-S6.
4266
Stone VE JJ, Tolson J, Pilon T. Potential impact of once daily regimens on 
adherence to HAART [abstract]. . 40th Annual Meeting of the Infectious Disease 
Society of America; 2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
4887
Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. 
Age-related immune dysfunction in health and in human immunodeficiency virus 
(HIV) disease: association of age and HIV infection with naive CD8+ cell 
depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic 
volumes. J Infect Dis 2003;187 (12):1924-33.
7034
Maggiolo F MM, Maserati R, Rizzi L, Pan A, Rizzi A, et al. . Once-a-day 
treatment for HIV infection: Final 48-week results. [Abstract 320]. 8th 
Conference on Retroviruses and Opportunistic Infections; 2001 February 4-8; 
Chicago, IL. 
7035
Felizarta F BS, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence and 
efficacy with a once-daily efavirenz-based regimen: 48-week results from the 
Daily Antiretroviral Therapy II (DART II) Study [Poster 5842]. . XV 
International AIDS Conference; 2004 July 11-16; Bangkok, Thailand. 
7036
Arribas JR IJ, Knobel H, Ribera E, Rubio R, Viciana P, et al. . Adherence, 
treatment satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) 
antiretroviral therapy (AT), in a large prospective observational cohort (CUVA 
Study).  [Poster WePeB5780]. . XV International AIDS Conference; 2004 July 
11-16; Bangkok, Thailand. 
7415
Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. 
Selective intracellular activation of a novel prodrug of the human 
immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to 
preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents 
Chemother 2005;49 (5):1898-906.


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Amendment 1
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7896
Centers for Disease Control and Prevention. 1994 Revised Classification System 
for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of 
Age. MMWR 1994;43 (RR-12):1-28.
8510
Hoetelmans R, Kestens D, Stevens M, Peeters M, Williams P, Bastiaanse L, et al. 
Pharmacokinetic interaction between the novel non-nucleoside reverse 
transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate 
(TDF) in healthy volunteers [poster]. 6th International Workshop on Clinical 
Pharmacology of HIV Therapy; 2005 April 28-30; Québec City, Canada. Poster 
No. 2.11. 
11428
Hoetelmans RM, Marien K, De Pauw M, Hill A, Peeters M, Sekar V, et al. 
Pharmacokinetic interaction between TMC114/ritonavir and tenofovir disoproxil 
fumarate in healthy volunteers. Br J Clin Pharmacol 2007;64 (5):655-61.
13119
Birkus G, Kutty N, He GX, Mulato A, Lee W, McDermott M, et al. Activation of 
9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-
methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate 
prodrugs by human proteases. Mol Pharmacol 2008;74 (1):92-100.
15426
Luber AD, Condoluci DV, Slowinski PD, Andrews M, Olson K, Peloquin CA, et 
al. Steady-state amprenavir and tenofovir pharmacokinetics after coadministration 
of unboosted or ritonavir-boosted fosamprenavir with tenofovir disoproxil 
fumarate in healthy volunteers. HIV Med 2010;11 (3):193-9.
16557
Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-
daily antiretroviral regimens: a meta-analysis. Clin Infect Dis 2009;48 (4):484-8.
16560
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral 
Treatment Regimens and Correlation with Risk of Hospitalization Among 
Commercially Insured HIV Patients in the United States [Poster O113]. 10th 
International Congress on Drug Therapy in HIV Infection; 2010 November 7-11; 
Glasgow, UK. 
19661
World Health Organization, UNAIDS, UNICEF. Global HIV/AIDS Response: 
Epidemic update and health sector progress towards universal access. Progress 
Report 2011.  
19946
Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature 
age-related comorbidities among HIV-infected persons compared with the general 
population. Clin Infect Dis 2011;53 (11):1120-6.
19947
Center for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2005. 
Vol. 17. Rev ed. Atlanta: U.S. Department of Health and Human Services, 
Centers for Disease Control and Prevention; 2007: 1-54. Also available at: 
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.  


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19948
Linley L, Hall H, An Q, Wheeler W. HIV/AIDS diagnoses among persons fifty 
years and older in 33 states, 2001-2005 [Abstract B08-1]. Presented at: 2007 
National HIV Prevention Conference; 2007 December 2-5; Atlanta, GA. 
21762
VIREAD® (tenofovir disoproxil fumarate) Tablets and Powder for oral use. US 
Prescribing Information. Gilead Sciences, Inc. Foster City, CA. Revised August 
2012.  
22029
Birkus G, Kutty N, He G-X, Mulato A, Lee W, McDermott M, et al. Activation of 
GS-7340 and Other Tenofovir Phosphonoamidate Prodrugs by Human Proteases. 
Antiviral Res 2007;74:A57.
22031
Department of Health and Human Services (DHHS). HHS Panel on Antiretroviral 
Guidelines for Adults and Adolescents Recommends a Fixed-Dose Combination 
Product of Elvitegravir/Cobicistat/Tenofovir/Emtricitabine as an Alternative 
Regimen in Antiretroviral Treatment-Naive Individuals with HIV-1 Infection.  
2012:1-2. 
22551
Cailhol J, Nkurunziza B, Izzedine H, Nindagiye E, Munyana L, Baramperanye E, 
et al. Prevalence of chronic kidney disease among people living with HIV/AIDS 
in Burundi: a cross-sectional study. BMC nephrology 2011;12:40.
22552
Selik RM, Byers RH, Jr., Dworkin MS. Trends in diseases reported on U.S. death 
certificates that mentioned HIV infection, 1987-1999. J Acquir Immune Defic
Syndr 2002;29 (4):378-87.
22553
Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. 
Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal 
disease. J Am Soc Nephrol 2005;16 (8):2412-20.
35184
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity 
and Mortality Weekly Report (MMWR). Revised Surveillance Case Definition 
for HIV Infection - United States 2014. Centers for Disease Control and 
Prevention,  2014.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pharmacokinetic Sub-study
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}


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Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Efficacy ofE/C/F/TAF Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis 
GS-US-292-1825, Amendment 1, 13 October 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Devi SenGupta, MD (Printed) 
Medical Monitor 
Date 
PPU 
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 
Page 72 
13 October 201 S 


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Appendix 2.
Study Procedures Table
Study Procedure
Screena
Day 1b
Week 2 to Week 48c
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
Written Informed Consent
X
Medical History 
X
Complete Physical Examinationf
X
X
X
X
X
Symptom-directed Physical Examinationg
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
Xh
X
Height
X
12-Lead ECG
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
Xj
Xj
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/Phenotypem
X
X
X
X
X
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
X
X
Serum and Plasma Storage Sampleso
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologyp
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
SF-36q
X
X
X
X


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Study Procedure
Screena
Day 1b
Week 2 to Week 48c
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
HIV-TSQq
X
X
X
X
X
X
VAS
X
X
X
X
X
X
X
X
X
Health Utilization Assessmentr
X
X
X
X
X
X
X
X
X
Drug Dispensation and Accountability
X
Xs
X
X
X
X
X
Xs
Xs
Pre-dose Whole Blood Sample Collectiont
X
X
Post-dose PK Sub-studyu
X
X
Whole Blood Storage Samplev
X
a
Evaluations to be completed within 30 days prior to Day 1.
b
Subjects will be dispensed study drug on the Day 1 visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit.
c
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol 
specified date through Week 48, except Week 48. Weeks 48 visit window is ± 6 weeks of the protocol specified date. Week 48 visit should be completed within ± 6 day 
window, unless otherwise specified by the Sponsor.
d
Required for those subjects who complete Week 48 visit or those subjects who permanently discontinue study drug and do not continue in the study through at least 
one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Week 48, if the subject discontinues study drug prior to completion of Week 48 visit.
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom-directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. At Day 1, Weeks 24 and 48 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry profile. 
PT/INR will be included in the chemistry profile at Screening, Weeks 24 and 48 only.
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At Weeks 24 and 48 analyses of glucose will be done as part of fasting metabolic 
assessments and not as part of the chemistry profile. 
k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian 
hormonal failure.
l
If the HIV-1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening 
and baseline results). See Section 6.6.1.
m
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV-1 RNA value ≥ 400 copies/mL. Subjects should be 
managed according to the Virologic Rebound Schema (Section 6.6.1). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the 
criteria described in this section.


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n
CBC with differential and platelet count
o
For subjects who provide consent −serum and plasma storage samples for possible future testing will be collected.
p
See Section 4.2 to confirm subject eligibility prior to enrollment.
q
SF-36 is to be completed by subjects at Day 1, Week 24 and Week 48 visits. HIV-TSQs should be completed by the subjects at Screening, Day 1, Week 4, Week 24, Week 48 
and ESDD visits. HIV-TSQc should be completed by the subjects at Week 24, Week 48 and ESDD visits. 
r
Subjects will be asked about their health utilization at Day 1 visit and every visit thereafter, including the ESDD and Unscheduled Visits.
s
Drug accountability only; study drug will not be dispensed at these visit.
t
At Week 4 or Week 12, pre-dose whole blood sample will be collected for subjects enrolled in the study. Sample collection should occur within 30 minutes prior to the study 
drug administration which should be observed on-site. PBMC processing will be completed by the central laboratory. 
u
At or between Week 2 or Week 4 study visits on a day prior to the day of hemodialysis and when the subject has administered three doses of E/C/F/TAF between two 
hemodialysis sessions. The ± 2 day window at Week 2 or Week 4 does not apply to the PK sub-study visit. Subjects who are willing to consent will be eligible to participate 
in the pharmacokinetic sub-study (target n = 15). Please see Section 6.5.1 and Appendix 3 Pharmacokinetic (PK) Sub-study for additional details.
v
Whole blood storage sample collected at baseline visit for virology assessments.


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Appendix 3.
Pharmacokinetic Sub-study
Blood Sampling Time Points for Intensive PK:
Study Day
Time Point (hrs) Post-dose
0.5
1
2
3
4
6
8
24
At or between Week 2 or Week 4
X
X
X
X
X
X
X
X
1) All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). 
2) PK sub-study visit must occur at or between Week 2 or Week 4 on a day prior to the day of 
hemodialysis and when the subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. 
3) Study drug administration should be observed at the clinic prior to the 0.5 hour post-dose 
blood sample collection. 
4) Subject should be instructed to dose after the 24 hour post-dose blood sample collection is 
collected and after the completion hemodialysis. 
5) The sub-study will include intensive PK profiling in plasma. Details of the blood sampling 
procedures and sample management will be documented in the central laboratory manual. 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 77
13 October 2015
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Gradf 1 
L------G-'r-ad_f_2----~~ 
~~------G-·r-ad_f_3----~~ ~~---------G-r-·a_d_e_~---------" 
! 
! 
l\Iay coutinuf 
Rfpfat lab to 
dosing at rhf 
confirm toiicity 
discrfrion ofthf 
gradf' 
in\·~stigator 
1 
If confinnl'<l and possibly and/or probably rflatfd to 
inwsrigarionru mroicinal products: 
1. Withhold inwsrigational ml'<licinal products until~ Gradf 2 
2. 
Rfsrart. all inwstigational mfdicinal produc.rs at full dosf 
1 
lf Grade 3 or ~ rfcwTence that is confit1ned and possibly or 
probably relatfd to inwstigational mfclicinal pt·oducrs, 
discontinuf all inwstigatioual medicinal products dosing 
pHmaufntly 
1 
r---------, 
Rfpfat Jab to 
confirm to:ticity 
gradf 
· 
1 
lf co 
inw 
dos 
nfirmro and uw'flatfd to 
stigarionru mfdicinal products, 
mg may continue at the 
disc rfrion of thf in,·estigator 
If confit·ml'<l and 
possibly or probably 
-. rflatedto 
inYestigarionaJ 
medicinal products, 
cliscoutinue 
iuYestigarionaJ 
medicinal products 
dosing pmnanfntly 
and follow at periodic 
intervals at !fast 
wHklY until a retw·u 
to ba;eline or is 
otltftmsf explainfd 
If GraM 3 or 4 recwnncf that is considHro uw·flarfd to 
inYesrigational medidnaJ proclucr.s, continue all investigational 
medicinal products at tbf same dose at the discrftion of tbf 
in,·esrigatoJ· 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 78
13 October 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 79
13 October 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.  


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 80
13 October 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 81
13 October 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 82
13 October 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 83
13 October 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 84
13 October 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 85
13 October 2015
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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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


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Amendment 1
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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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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 1
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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 1
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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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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.
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.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of study drugs on 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. Data from clinical pharmacokinetic interaction studies of study drug 
have demonstrated that there is no reduction in the clinical efficacy of hormonal contraception or 
that the effect on hormonal contraception is insignificant. 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 
prior to study enrollment. A serum pregnancy test will be performed at all study visits and the 
end of relevant system exposure. In the event of a delayed menstrual period (over one month 
between menstruations), a serum 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)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
o
Diaphragm with spermicide
o
Cervical cap with spermicide
o
Male condom (with or without spermicide)
Hormonal methods (the hormonal contraceptive should contain at least 30 mcg of 
ethinyl estradiol)
o
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
Contraceptive vaginal ring
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.


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3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential. 
4) 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.
5) 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 30days 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. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.5.2.1.


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Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†


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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV§
*
Only among children aged < 6 years
†
Only among adults, adolescents, and children aged ≥ 6 years
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy 
and HIV wasting syndrome, are described in the following references {7896}, {1238}.

Prot_008.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Efficacy ofE/C/F/TAF Fixed Dose 
Combination (FDC) in HIV -1 Infected Subjects on Chronic 
Hemodialysis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
111,007 
2015-002713-30 
NCT02600819 
HIV -1 Infection 
GS-US-292-1825 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Fax: 
Original: 
Amendment 1: 
Amendment 2: 
PO 
PO 
Devi SenGu ta MD 
PO 
PO 
08 July2015 
13 October 2015 
28 November 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The inf01mation 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 inf01mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessa1y to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


EICIFITAF 
Protocol GS-US-292-1825 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
TABLE OF CONTENTS .... 
LIST OF IN-TEXT TABLES 
LIST OF IN-TEXT FIGURES 
PROTOCOL SYNOPSIS 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS. 
1. 
INTRODUCTION ..................... ................ .......... . 
1.1. 
1.2. 
1.3. 
1.4. 
1.5. 
Background ................................................ . 
Tenofovir Alafenamide (TAF, GS-7340) 
1.2.1. 
General Information ...................................... . 
1.2.2. 
Preclinical Pharmacology and Toxicology 
1.2.3. 
Nonclinical Pharmacokinetics ....................... . 
1.2.4. 
Nonclinical Toxicology .................................................................... . 
1.2.5. 
Clinical Trials of ElvitegraviriCobicistat/Emtricitabine!Tenofovir 
Alafenamide (EICIF IT AF) ................................................................ . 
Rationale for This Study ............................. . 
1.3.1. 
Rationale for Dose Selection 
Risk/Benefit Assessment for the Study 
Compliance ................................................. . 
2. 
OBJECTIVES 
3. 
4. 
STUDY DESIGN ............ . 
3. 1. 
Study Design ....... ........ . 
3.2. 
Study Treatments ................. . 
3.3. 
Duration of Treatment 
3.4. 
End of Study ........ ................ . 
3. 5. 
Post Study Care 
3.6. 
Source Data ......... ........ . 
3.7. 
PPD 
L---------------------------~ 
SUBJECT POPULATION ............... ................ ................ . 
4.1. 
4.2. 
4.3. 
Number of Subjects and Subject Selection 
Inclusion Criteria .. . . 
Exclusion Criteria .. . 
5. 
INVESTIGATIONAL :MEDICINAL PRODUCTS 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
Emollment ............ ................ ................ ..... . 
Description and Handling ofEIC/F!TAF FDC Tablets 
5. 2. 1. 
Formulation ........ ........ . 
5.2.2. 
Packaging and Labeling ..... ........ . 
5.2.3. 
Storage and Handling ......... ..... . 
Dosage and Administration of EICIF IT AF 
Prior and Concomitant Medications 
Accountability for EICIF IT AF 
5.5.1. 
Study Drug Return or Disposal 
6. 
STUDY PROCEDURES .. ................ ................ ..... . 
6.1. 
6.2. 
Subject Emollment and Treatment Assignment. 
Pretreatment Assessments .... ................ ............. . 
CONFIDENTIAL 
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6.2.1.
Screening Visit .....................................................................................................................37
6.2.2.
Day 1 Assessments...............................................................................................................39
6.3.
Treatment Assessments (Weeks 2-96) ...................................................................................................40
6.4.
Post-treatment Assessments ...................................................................................................................43
6.4.1.
30-Day Follow-up Assessments...........................................................................................43
6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)....................................................44
6.4.3.
Criteria for Discontinuation of Study Treatment..................................................................46
6.5.
Other Evaluations...................................................................................................................................46
6.5.1.
Pharmacokinetic (PK) Sub-study .........................................................................................46
6.5.2.
Blood Storage.......................................................................................................................46
6.6.
Virologic Failure....................................................................................................................................47
6.6.1.
Management of Virologic Failure ........................................................................................47
6.6.2.
Subjects with ≥ 400 copies/mL of HIV-1 in the Absence of VR .........................................47
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................49
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................49
7.1.1.
Adverse Events.....................................................................................................................49
7.1.2.
Serious Adverse Events........................................................................................................49
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................50
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................50
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................50
7.2.2.
Assessment of Severity ........................................................................................................51
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................51
7.3.1.
Adverse Events.....................................................................................................................51
7.3.2.
Serious Adverse Events........................................................................................................51
7.4.
Gilead Reporting Requirements.............................................................................................................53
7.5.
Special Situations Reports......................................................................................................................53
7.5.1.
Definitions of Special Situations..........................................................................................53
7.5.2.
Instructions for Reporting Special Situations.......................................................................54
7.6.
Toxicity Management ............................................................................................................................55
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................55
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................56
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................56
8.
STATISTICAL CONSIDERATIONS................................................................................................................57
8.1.
Analysis Objectives and Endpoints........................................................................................................57
8.1.1.
Analysis Objectives..............................................................................................................57
8.1.2.
Primary Endpoint .................................................................................................................57
8.1.3.
Secondary Endpoints............................................................................................................57
8.2.
Analysis Conventions.............................................................................................................................57
8.2.1.
Analysis Sets ........................................................................................................................57
8.3.
Demographic Data and Baseline Characteristics ...................................................................................58
8.4.
Primary and Secondary Analysis ...........................................................................................................58
8.4.1.
Primary Analysis..................................................................................................................58
8.4.2.
Secondary Analyses .............................................................................................................58
8.5.
Safety Analysis.......................................................................................................................................58
8.5.1.
Extent of Exposure...............................................................................................................59
8.5.2.
Adverse Events.....................................................................................................................59
8.5.3.
Laboratory Evaluations ........................................................................................................59
8.5.4.
Other Safety Evaluations......................................................................................................60
8.6.
Pharmacokinetic Analysis......................................................................................................................60
8.7.
Sample Size............................................................................................................................................60


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8.8.
Data Monitoring Committee ..................................................................................................................60
9.
RESPONSIBILITIES..........................................................................................................................................61
9.1.
Investigator Responsibilities ..................................................................................................................61
9.1.1.
Good Clinical Practice..........................................................................................................61
9.1.2.
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................61
9.1.3.
Informed Consent.................................................................................................................61
9.1.4.
Confidentiality......................................................................................................................62
9.1.5.
Study Files and Retention of Records ..................................................................................62
9.1.6.
Case Report Forms...............................................................................................................63
9.1.7.
Study Drug Accountability and Return ................................................................................64
9.1.8.
Inspections............................................................................................................................64
9.1.9.
Protocol Compliance............................................................................................................64
9.2.
Sponsor Responsibilities ........................................................................................................................65
9.2.1.
Protocol Modifications.........................................................................................................65
9.2.2.
Study Report and Publications .............................................................................................65
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................65
9.3.1.
Payment Reporting...............................................................................................................65
9.3.2.
Access to Information for Monitoring..................................................................................66
9.3.3.
Access to Information for Auditing or Inspections ..............................................................66
9.3.4.
Study Discontinuation..........................................................................................................66
10.
REFERENCES ...................................................................................................................................................67
11.
APPENDICES ....................................................................................................................................................70
Appendix 1.
Investigator Signature Page....................................................................................................71
Appendix 2.
Study Procedures Table..........................................................................................................72
Appendix 3.
Pharmacokinetic Sub-study....................................................................................................74
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................75
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............76
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {Selik et al 2014} ......................101
LIST OF IN-TEXT TABLES
Table 1-1.
Comparison of Plasma TFV Exposures After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis Versus TDF-Containing Regimens in 
Patients with Normal Renal Function.....................................................................................20
Table 4-1.
Disallowed Agents .................................................................................................................29
Table 5-1.
Prior and Concomitant Medications.......................................................................................32
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted Steady-State TFV PK Profile After Administration of E/C/F/TAF in 
ESRD Subjects on Chronic Hemodialysis..............................................................................19
Figure 3-1.
Study Schema.........................................................................................................................24
Figure 6-1.
Schema for Management of Virologic Failure .......................................................................48


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy of E/C/F/TAF 
Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002713-30
NCT02600819
Study Centers Planned:
Approximately 25 study sites in North America and Europe
Objectives:
The primary objective of this study is as follows:

To evaluate the safety and tolerability of the 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
(EVG/COBI/FTC/TAF; E/C/F/TAF) fixed-dose combination 
(FDC) in HIV-1 infected adults with end stage renal disease 
(ESRD) on chronic hemodialysis (HD) at Week 48
The secondary objectives of this study are as follows: 

To evaluate the safety and tolerability of the 
EVG/COBI/FTC/TAF; E/C/F/TAF FDC) in HIV-1 infected 
adults with ESRD on chronic HD at Week 96

To evaluate the proportion of subjects achieving virologic 
response (HIV-1 RNA < 50 copies/mL, as defined by the FDA
Snapshot analysis) at Weeks 24, 48, and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, 
FTC, TAF and TFV in HIV-1 infected patients with ESRD on
chronic HD
Study Design:
Open-label, multicenter, single-arm study to assess the safety, 
tolerability, pharmacokinetics, and efficacy of E/C/F/TAF FDC
dosed once daily in HIV-infected adult subjects with ESRD on 
chronic HD. 
All subjects will switch from their current antiretroviral (ARV) 
regimen to E/C/F/TAF on Day 1. The treatment duration will be at 
least 96 weeks.


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Number of Subjects 
Planned:
Approximately 50 subjects with ESRD on chronic HD will be 
enrolled.
Target Population:
HIV-1 infected adults (≥18 years) with ESRD on chronic HD for 
≥6 months prior to screening, and HIV-1 RNA < 50 copies/mL on 
a stable antiretroviral (ARV) regimen for ≥ 6 consecutive months 
prior to screening.
Duration of Treatment:
Subjects will be treated for at least 96 weeks.
Diagnosis and Main 
Eligibility Criteria:
HIV-1-infected adults who meet the following criteria:

No documented history of HIV-1 resistance to EVG, FTC, 3TC 
or TFV

Currently receiving a stable antiretroviral regimen for 
≥6 consecutive months prior to screening 

Plasma HIV-1 RNA < 50 copies/mL for at least 6 months 
preceding the screening visit

CD4+ T cell count of ≥ 200 cells/μL

ESRD with eGFR < 15 mL/min by Cockcroft-Gault, on 
chronic HD for ≥ 6 months prior to screening

Hepatitis C (HCV) infection allowed 

Hepatitis B (HBV) infection not allowed
Study Procedures/
Frequency:
Following Screening, eligible subjects will be required to return for 
study visits at Day 1, Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 
96. After the Week 96 visit, subjects will stop study drug and 
complete a 30-Day Follow-up visit to complete their participation 
in the study.
For all subjects, HBV and HCV serologies will be analyzed at 
Screening. Adverse events, concomitant medications, complete or 
symptom-directed physical examinations, laboratory analyses 
(hematology and chemistry), fasting lipids and glucose, 
HIV-1 RNA, CD4+ T cell count and estimated GFR will be 
performed at the Screening, Day 1, and all subsequent study visits.
Pre-dose blood draw for plasma and PBMC samples will be 
collected from all subjects at Week 4 or Week 12, which must be 
the day of hemodialysis. 
All subjects who provide consent will be eligible to participate in 
the pharmacokinetic sub-study (target n = 15).


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Test Product, Dose, and 
Mode of Administration:
FDC of elvitegravir 150 mg / cobicistat 150 mg /
emtricitabine 200 mg / tenofovir alafenamide 10 mg administered
orally once daily with food until the next hemodialysis. On the 
day of hemodialysis, study drug should be administered after 
completion of hemodialysis. 
Reference Therapy, 
Dose, and Mode of 
Administration:
N/A
Criteria for Evaluation:
Safety:
Safety evaluations will include reporting of adverse events, clinical 
laboratory tests, physical examinations, and vital signs. 
An Independent Data Monitoring Committee (IDMC) will be 
convened after the first 25 subjects enrolled in the study complete 
Week 12 of the study. 
Efficacy:
Virologic response will be determined using the percentagesof
subjects with HIV-1 RNA < 50 copies/mL at Weeks 24, 48, and 96
(FDA snapshot analysis).
Pharmacokinetics:
At Week 4 or Week 12, on the day of hemodialysis, pre-dose 
(within 30 minutes prior to study drug administration) blood draws
for plasma and PBMC samples will be collected from all subjects. 
Study drug administration will be observed. Plasma concentrations 
of EVG, COBI, FTC, TAF and TFV and intracellular 
concentrations of TFV-DP may be explored.
Pharmacokinetic (PK) Sub-study
All subjects who provide consent will be eligible to participate in 
the PK sub-study (target n = 15). For the PK sub-study, intense 
blood sampling will be conducted at or between Week 2 or Week 4
study visits, on a day prior to the day of hemodialysis and when the 
subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. The PK of EVG, COBI, FTC, TAF and 
TFV will be evaluated. Study drug administration will be observed 
in-clinic at the sub-study visit. 
Health Related 
Questionnaires:
SF-36, VAS (visual analogues scale), HIV-TSQ (HIV Treatment
Satisfaction Questionnaire) and Health Utilization Questionnaire 
will be administered per the information provided in the study 
procedures section of this protocol.


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Statistical Methods:
The primary endpoint will be the incidence of treatment-emergent 
Grade 3 or higher adverse events up to Week 48.
The proportions of subjects with virologic response (HIV-1 RNA 
< 50 copies/mL, as defined by the FDA snapshot analysis) and the 
associated 95% confidence intervals at Weeks 24, 48, and 96, 
respectively will be constructed.
Concentrations and PK parameters of EVG, COBI, FTC, TAF and 
TFV for the sub-study, and intracellular PBMC concentrations of 
TFV-DP will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV),
median, minimum, and maximum].
A sample size of approximately 50 subjects is based on practical 
consideration and is considered to be sufficient to evaluate the 
primary objective of this study. The Grade 3 or higher AE rate in 
Study GS-US-292-0112 subjects that had mild to moderate renal 
impairment was 8.8% at Week 48 analysis for the E/C/F/TAF arm. 
Therefore, with 50 subjects, and an assumed rate of Grade 3 or 
higher AEs being 10%, this study would provide 95% confidence 
for the primary endpoint to be (1.7%, 18.3%) assuming normal 
approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating 
the PK parameters in the sub-study for practical reasons. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


E/C/F/TAF
Protocol GS-US-292-1825
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C 
degrees Celsius
°F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time 
curve
bsAP
serum bone specific alkaline phosphatase
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CG
Cockcroft-Gault
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration 
of drug
Cmin
minimum plasma concentration
CNS
central nervous system
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
E/C/F/TAF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir alafenamide (TAF) 10 mg fixed-dose combination, Genvoya®
E/C/F/TDF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg / 
tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination, Stribild®
ESRD
End stage renal disease
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed-dose combination


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FS
failure to suppress
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GS-7340 
tenofovir alafenamide, TAF, L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester
HAART
highly active antiretroviral therapy
HBsAg
hepatitis B virus surface antigen serology
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus serology
HD
Hemodialysis
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-TSQ
HIV Treatment Satisfaction Questionnaire
HIV-TSQs
HIV Treatment Satisfaction Questionnaire Status
HIV-TSQc
HIV Treatment Satisfaction Questionnaire Change
HMG-CoA
5-hydroxy-3-methylglutaryl-coenzyme A
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
DMC
Data Monitoring Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IRB
institutional review board
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MH
Mantel-Haenszel
Min
minute
mmHg
millimeters mercury
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OC
osteocalcin
P1NP
procollagen Type 1 N-terminal propeptide
PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor


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PK
pharmacokinetic
PT
preferred term 
PTH
parathyroid hormone
QD
once daily 
RNA
ribonucleic acid
SAE
serious adverse event
SVR
suboptimal virologic response
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
ULN
upper limit of the normal range
US
United States
VR
virologic rebound


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 infection is a life-threatening and serious disease of major 
public health significance, with approximately 34 million people infected with HIV worldwide 
{World Health Organization (WHO) 2011}. The goals of highly active antiretroviral therapy 
(HAART) for HIV-1 infection are to delay disease progression and prolong survival by 
achieving maximal and durable suppression of HIV-1 replication. Prompt antiretroviral therapy 
(ART) initiation after diagnosis is based on growing evidence that untreated HIV infection or 
uncontrolled viremia is associated with development of non- acquired immune deficiency 
syndrome (AIDS)-defining diseases, including cardiovascular disease (CVD), kidney disease, 
liver disease, neurologic complications, and malignancies. The success of ART has shifted 
clinical attention towards regimens that optimize long-term adherence, tolerability and safety. 
Adherence to ART is required to prevent development of drug resistance and subsequent loss of 
virologic suppression, and adherence to ART is improved by reducing pill burden and dosing 
frequency {Chesney 2000, Stone et al 2002}. Once-daily, single tablet regimens are associated 
with high adherence, better clinical outcomes, including fewer hospitalizations, improved patient 
satisfaction, and excellent virologic outcomes {Arribas et al 2004, Felizarta et al 2004, 
Maggiolo et al 2001, Parienti et al 2009, Sax et al 2010}.
Despite current therapy that effectively suppresses viremia, HIV disease remains a serious 
condition due to non-AIDS associated comorbidities. As treatment guidelines recommend early 
treatment of HIV-1 infection, there is a need for regimens offering enhanced product safety and 
tolerability, effectiveness, and convenience for long-term treatment.
Though antiretroviral drugs have led to dramatic improvements in survival and disease 
progression, complications such as kidney, liver, and cardiac disease have become increasingly 
important causes of morbidity and mortality for HIV patients taking effective therapy 
{Center for Disease Control and Prevention 2007, Linley et al 2007, Selik et al 2002}. Recent 
data has shown that even with treatment, HIV patients experience more age-related 
co-morbidities, such as renal and bone disease, which manifest earlier than their age-matched 
HIV-uninfected peers {Guaraldi et al 2011}. Moreover, the prevalence and incidence of chronic 
kidney disease (CKD) and end stage renal disease (ESRD) in the US are expected to rise as the 
prevalence of HIV infection continues to rise {Schwartz et al 2005}. Worldwide, prevalence may 
be even greater; one cross-sectional study in the East African Republic of Burundi reported 
46% of HIV-positive adults fulfilled criteria for CKD {Cailhol et al 2011}.
Patients with HIV are at risk for acute and chronic kidney disease from a wide spectrum of 
etiologies, including HIV-associated nephropathy, immune complex kidney disease, thrombotic 
microangiopathy, and kidney disease associated with comorbidities such as diabetes, hypertension, 
hepatitis B and hepatitis C coinfections, as well as medications associated with nephrotoxicity. 
Clearly, new therapies that improve on the current standard of care are needed, so that life-long 
antiviral therapy is more effective, more tolerable, and safer for patients. Since the majority of 
currently available nucleos(t)ide backbones are prescribed as fixed-dose combinations, 
HIV-positive patients with chronic kidney disease have particularly limited therapeutic options.


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The availability of a single tablet regimen composed of potent agents with improved tolerability 
and long-term safety, that does not require dose adjustment at eGFR < 50 mL/min, would 
represent an important therapeutic innovation in this special patient population, providing more 
convenient dosing and potentially improving patient adherence.
Tenofovir alafenamide (TAF) has a unique metabolism that provides enhanced lymphatic 
delivery of tenofovir, resulting in higher intracellular levels of the active phosphorylated 
metabolite, tenofovir-diphosphate (TFV-DP), and lower circulating levels of TFV 
{Birkus et al 2007, Birkus et al 2008, Lee et al 2005}. The distinct metabolism of TAF offers an 
improved clinical profile compared with TDF, which is associated with nephrotoxicity and 
decreased bone mineral density {Department of Health and Human Services (DHHS) 2012, 
Gilead Sciences Inc 2012}. Compared with TDF, TAF is characterized by lower systemic 
exposures and higher intracellular levels of TFV. Additionally, TFV exposures achieved with 
TAF in subjects with severe renal impairment are comparable to those with normal renal 
functions receiving TDF 300 mg, indicating that TAF can be administered to HIV-1 infected 
patients with renal impairment without dose modification. 
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is an prodrug of TFV, 
a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolized intracellularly 
to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 reverse transcriptase (RT) 
that terminates the elongation of the viral deoxyribonucleic acid (DNA) chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids. 
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
Tenofovir alafenamide is metabolized to TFV, a nucleotide analog (ie, a nucleoside 
monophosphate analog) which is not dependent on an intracellular nucleoside kinase activity 
for the first step in the conversion to the active metabolite, TFV-DP. The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{Kalayjian et al 2003} and nucleotide diphosphate kinase, which are highly active and 
ubiquitous. AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV 
mediated most efficiently by AK2.


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The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T cells, natural killer (NK) 
cells, B-cells and macrophages/monocytes. TAF is metabolized inside host cells to the active 
metabolite TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all 
cell populations.
1.2.2.2.
Safety Pharmacology
Single doses of TAF did not induce pharmacologic effects on the central nervous system of the 
rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the cardiovascular system of the 
dog (100 mg/kg).
1.2.3.
Nonclinical Pharmacokinetics
All nonclinical PK experiments were performed using TAF monofumarate (GS-7340-02), and all 
study data described in this section reflect the dosage of the monofumarate. For reference, 
100 mg of TAF monofumarate is equivalent to 80 mg of the GS-7340 free base (TAF).
Key results from nonclinical absorption, distribution, metabolism, and excretion studies of TAF 
are as follows: 

Following oral administration in dogs and monkeys, TAF demonstrated rapid absorption, 
with peak plasma concentrations between 0.25 and 0.5 hours. Thereafter, TAF plasma 
concentrations declined rapidly with a terminal half-life of less than 1 hour. 
Tenofovir alafenamide exposure (Cmax and AUC values) was nonlinear with dose and greater 
than expected with increasing dose. Repeat-dose studies in rats and monkeys showed no 
change in pharmacokinetics over time. 

Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. 

Following oral administration of [14C]-radiolabeled TAF to dogs, a mean total recovery of 
radioactivity at 24 hours of 63% was demonstrated. Radioactivity was detected in all tissues 
except brain with the majority present in the contents of the gastrointestinal tract, liver, 
kidney, and large intestine. Tissue concentrations were the highest in kidney, peripheral 
blood mononuclear cells (PBMCs), liver, large intestine, and bile. Additional studies in dogs, 
TFV concentrations in PBMCs following oral administration of TAF were approximately 
50-fold greater than observed in plasma, with an estimated t½ of greater than 24 hours. 

The major route of elimination of TAF-related radioactivity was via feces, with 
approximately 35% of the dose recovered in feces through 48 hours postdose. The primary 
route of elimination of TFV is renal excretion of unchanged drug based on IV studies of 
TFV.


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
Tenofovir alafenamide has been found to be a substrate for intestinal efflux transport and in 
nonclinical studies its intestinal absorption was increased by the transport inhibitor 
cyclosporin A. 

No significant inhibition of human drug metabolizing cytochrome P450 (CYP) enzymes, 
uridine diphosphate glucuronyltransferase (UGT) 1A1 or transporters including 
P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide 
(OATP)1B1 and OATP1B3 was observed with TAF in vitro. 

Tenofovir alafenamide did not activate human pregnane X receptor (hPXR) or 
aryl hydrocarbon receptor (AhR).

Tenofovir alafenamide was not a substrate for drug-metabolizing CYP enzymes except for 
CYP3A4, which metabolized the compound slowly. 
1.2.4.
Nonclinical Toxicology
Key results from nonclinical toxicology studies of TAF are as follows:

Based on TFV exposure, the no observed adverse effect levels (NOAELs) in the 6-month rat, 
9-month dog, and 1-month monkey studies provide 14-, 4-, and 22-fold safety margins, 
respectively, for a human dose of 25 mg/day.

In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment with TAF 
100 mg/kg/day; however, effects were not seen at lower doses. Tenofovir alafenamide also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above.

In chronic studies in dogs after 9 months of treatment at doses up to TAF 18/12 mg/kg/day 
(the high dose was reduced from 18 to 12 mg/kg/day due to the occurrence of death, severe 
clinical signs and reduced body weight), the primary target organs were kidney 
(slight to moderate renal tubular degeneration and karyomegaly) and bone 
(decreased bone mineral density [BMD] in metaphyseal cancellous bone). 

Tenofovir alafenamide had no discernable electrocardiograph effect at the low dose of 
2 mg/kg/day. There was some evidence at 6 and 18/12 mg/kg/day for an effect to slightly 
prolong PR intervals. 

After 9 months of treatment, some dogs administered the highest dose of TAF 
(18/12 mg/kg/day) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given 
lower doses and it has not occurred in other animal studies. 


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
There were no clear treatment-related effects observed in monkeys following 28 days of 
TAF treatment at 3 and 30 mg/kg/day, including no changes in mitochondrial function and 
mitochondrial DNA (mtDNA) content in the liver, kidney, and skeletal muscle, and 
characterization of lymphocyte populations.

Tenofovir alafenamide was not genotoxic in either in vitro or in vivo assays. 
Tenofovir alafenamide had no adverse effects on male or female fertility parameters in rats. 
There was no effect on fetal viability or fetal development in pregnant rats administered 
doses of TAF up to 250 mg/kg/day or in pregnant rabbits administered TAF up to 
100 mg/kg/day; the highest doses were maternally toxic.
1.2.5.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
(E/C/F/TAF)
Emtricitabine and TAF have been combined with the integrase inhibitor EVG and its 
pharmacoenhancer COBI in the E/C/F/TAF FDC, which has been designed to be a complete 
treatment regimen for HIV-1 infection and is being evaluated in a broad clinical development 
program. The details of the key clinical studies are provided below:

GS-US-292-0102, a randomized, double-blinded controlled Phase 2 study in which 
E/C/F/TAF is compared to Stribild® (STB), as initial treatment of HIV-infection in 
ART-naive patients. This is a single-variable clinical comparison of the 2 tenofovir prodrugs, 
TAF and TDF 

GS-US-292-0104 and GS-US-292-0111, Phase 3 randomized, double-blinded studies of the 
safety and efficacy of E/C/F/TAF versus E/C/F/TDF in HIV-1 infected, antiretroviral 
treatment-naive adults. The interim Week 48 key conclusions from pooled data are as 
follows: 1) E/C/F/TAF once daily was noninferior to STB once daily when administered
for 48 weeks to HIV-infected, ART-naive adults, as assessed using the US Food and Drug
Administration (FDA)-defined snapshot algorithm with HIV-1 RNA < 50 copies/mL 
(E/C/F/TAF 92.4%; STB 90.4%; difference in percentages: 2.0%, 95% CI: −0.7% to 4.7%), 
2) administration of E/C/F/TAF resulted in > 90% lower plasma TFV and higher intracellular 
TFV-DP relative to STB, 3) E/C/F/TAF showed an improved renal and bone safety profile 
with significantly less decline in hip and spine BMD, less increase in serum creatinine and 
reduction in estimated glomerular filtration rate (eGFR), 4) Increases from baseline in fasting 
total cholesterol fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides 
were noted in the E/C/F/TAF group. At Week 96 86.6% in the TAF arm and 85.2% in the 
TDF arm maintained HIV-RNA <50 c/ML.


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
GS-US-292-0112, a Phase 3 open-label safety study of E/C/F/TAF in HIV-1 positive patients 
with mild to moderate renal impairment; Week 48 results demonstrated that patients who 
switched to E/C/F/TAF had no change in eGFR, and had significant improvements in 
measures of renal function including proteinuria, albuminuria, retinol binding protein and 
beta-2-microglobulin. These subjects also had improvements in measures of bone mineral
density. Importantly, because FTC was given without dose adjustment to patients with 
eGFR 30-50 mL/min, these patients had comparable safety profile to patients with 
eGFR 50-69 mL/min, with no increased rate of potential FTC related drug reactions, 
supporting the safety of FTC at higher exposures. In addition, 92% of study participants 
maintained virologic suppression (HIV-1 RNA < 50 copies/ml) at Week 48 after switching to 
E/C/F/TAF. The virologic suppression rate was 88% at Week 96.

GS-US-292-0109, a Phase 3 study designed to evaluate the safety, efficacy, and tolerability 
of switching to E/C/F/TAF in individuals who are virologically suppressed on regimens 
containing TDF. The interim Week 48 key conclusions from this study are as follows: 
1) switching to E/C/F/TAF was noninferior to maintaining FTC/TDF+3rd Agent 
(STB, efavirenz/emtricitabine/tenofovir DF (ATR), atazanavir (ATV)/boosted+Truvada®) as 
assessed using the FDA snapshot algorithm (Week 48 FAS) with HIV-1 RNA cutoff at 
50 copies/mL (E/C/F/TAF 95.6%; FTC/TDF+3rd Agent 92.9%; difference in percentages: 
2.7%, 95.01% CI: −0.3% to 5.6%), 2) An improved renal and bone safety profile was 
observed in subjects who switched to E/C/F/TAF, 3) there were no differences in ocular 
findings between treatment groups and no reported cases of uveitis.
1.3.
Rationale for This Study
Because of the increasing average age of HIV-infected patients, the high prevalence of chronic 
kidney disease, and the increasing prevalence of co-morbid conditions that require medical 
management, medical regimens in ESRD patients are complex and can impact a patient’s overall 
risk of morbidity and mortality. The availability of a single-tablet regimen composed of potent 
agents with improved tolerability and long-term safety that does not require dose adjustment at 
eGFR < 15 mL/min, would represent an important therapeutic innovation for HIV infected
patients with ESRD. EVG, COBI, and TAF are not renally eliminated, while the metabolite of 
TAF (TFV) and FTC, are renally eliminated. 
The E/C/F/TAF FDC was recently shown to be safe and efficacious in HIV-infected patients 
with mild to moderate chronic kidney disease (CKD; eGFR 30-69 mL/min) in study 
GS-US-292-0112 through 48 weeks. The long-term safety of E/C/F/TAF remains to be 
established in subjects at more advanced stages of renal impairment, including those with ESRD 
on hemodialysis. The present study will provide the pharmacokinetic data describing TFV and 
FTC exposures in these patients when administered as the E/C/F/TAF FDC, dosed once daily, as 
well as safety and efficacy data in this special population through 96 weeks. 


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1.3.1.
Rationale for Dose Selection
The E/C/F/TDF FDC containing EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg),
has been approved for use once daily for the treatment of human immunodeficiency virus type 1 
(HIV-1) infection in adults and pediatric patients 12 years of age and older without any known 
resistance to the individual components and with an eGFR ≥ 30 mL/min. This FDC contains the 
equivalent doses of EVG and COBI in the marketed product, Stribild®. The FTC (200 mg) in the 
E/C/F/TAF FDC represents the marketed dose in several approved FDC products: 
emtricitabine/tenofovir DF, efavirenz/emtricitabine/tenofovir DF, and 
emtricitabine/rilpivirine/tenofovir DF for the treatment of HIV-1 infection.
EVG, COBI, and TAF are not renally eliminated, while the metabolite of TAF (TFV) and FTC, 
are renally eliminated. 
TAF and TFV
The Phase 3 study GS-US-292-0112 demonstrated that patients with moderate renal impairment 
(baseline eGFR 30-50 mL/min) who switched to E/C/F/TAF had no change in eGFR, and had 
significant improvements in measures of renal function including proteinuria, albuminuria, 
retinol binding protein and beta-2-microglobulin. These subjects also had improvements in 
measures of bone mineral density. TAF PK in subjects with screening eGFR 30-69 mL/min was 
consistent with data following administration of E/C/F/TAF in non-renally-impaired 
HIV-infected subjects in Phase 2 and Phase 3 studies. 
Data from GS-US-120-0108 demonstrated that in HIV uninfected subjects with an eGFR of 
15-29 mL/min, plasma TAF exposures increased < 2-fold. Study GS-US-292-1825 will evaluate 
TAF (as well as TFV and FTC) PK in the setting of daily administration of E/C/F/TAF FDC in 
treatment-experienced subjects with eGFR < 15 mL/min on chronic hemodialysis.
To support TAF dosing in ESRD patients, simulation for TFV exposures was conducted using an 
established population pharmacokinetic model for TFV following administration of E/C/F/TAF 
and with information from previously conducted Gilead Study (GS-01-919) where TDF was 
administered in ESRD subjects (Figure 1-1).


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Figure 1-1.
Predicted Steady-State TFV PK Profile After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis
Figure 1-1 shows the simulated TFV PK profile following E/C/F/TAF once-daily for two weeks in subjects with ESRD on 
chronic hemodialysis three-times per week. IPRED represents the model predicted plasma concentration of TFV. The double 
blue arrows represent a four-hour hemodialysis session.
In subjects with ESRD on chronic hemodialysis three-times per week, systemic TFV exposures 
are expected to be higher following administration of E/C/F/TAF, relative to E/C/F/TAF in 
subjects with eGFR > 30 mL/min, due to the renal elimination pathway for TFV. In subjects with 
ESRD on chronic hemodialysis, E/C/F/TAF administered once daily is predicted to result in a 
mean (% CV) TFV exposure of 3610 (21.6) h•ng/mL. Given the extensive safety data available 
for TDF, TFV exposures follow administration of E/C/F/TAF in ESRD subjects on chronic 
hemodialysis are expected to be in the range of those following TDF-containing regimens in 
patients with normal renal function (Table 1-1) and, as such, would not require TAF dose 
modification. 


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Table 1-1.
Comparison of Plasma TFV Exposures After Administration of 
E/C/F/TAF in ESRD Subjects on Chronic Hemodialysis Versus 
TDF-Containing Regimens in Patients with Normal Renal Function
TFV AUC (Mean [%CV])
E/C/F/TAF regimen
3610 (21.6)
TDF-Containing Regimens in Normal Renal Function
Atazanavir+Ritonavira
3940 (30)
Darunavir+Ritonavirb
4630 (16)
Fosamprenavir+Ritonavirc
2930 (1780, 4280)
Lopinavir+Ritonavird
3500 (27)
Saquinavir+Ritonavire
3110 (24)
Rilpivirinef
3590 (22)
Emtricitabine+TDFg
2870 (25)
Efavirenz/Emtricitabine/TDFh,i
2270 (19)
Elvitegravir/Cobicistat/Emtricitabine/TDFh
3940 (20)
a
Study GS-US-216-0114
b
{Hoetelmans et al 2007}
c
mean (90% CI) {Luber et al 2010}
d
Studies 00-909 and 01-943
e
Study GS-US-104-0236
f
{Hoetelmans et al 2005}
g
Studies GS-US-236-0101 and GS-US-236-0110
h
Studies GS-US-236-0120 
i
Study GS-US-334-0131
FTC
The FTC dose (200 mg) in the E/C/F/TAF FDC represents the marketed dose as part of the 
approved products FTC (Emtriva®), FTC/TDF (Truvada®), efavirenz/FTC/TDF (Atripla®), 
FTC/rilpivirine/TDF (Complera® or Eviplera®), and E/C/F/TDF (Stribild®) for the treatment of 
HIV-1 infection. Emtricitabine is principally eliminated by the kidney and higher exposures are 
observed in patients with moderate to severe renal impairment. For eGFR of 30-49 mL/min, 
Emtriva prescribing information recommends dose interval adjustment of the 200 mg oral 
capsule to q48h. However, available clinical experience suggests the plasma FTC may not 
require dose adjustment in the setting of renal impairment. In study GS-US-292-0112, FTC was 
given without dose adjustment to patients with eGFR 30-50 mL/min, and these patients had 
comparable safety profile to patients with eGFR 50-69 mL/min, with no increased rate of 
potential FTC related drug reactions, supporting the safety of FTC at higher exposures. 
In Study FTC-107, an open-label, parallel-group study of single-dose emtricitabine 200 mg in 
HIV uninfected subjects with varying degrees of renal impairment, 6 subjects with moderate 
renal impairment (30-49 mL/min), 5 subjects with severe renal impairment (< 30 mL/min) and 
6 subjects on dialysis were treated. Of note, subjects with baseline eGFR of 30-49 mL/min had 


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only twice the mean FTC systemic exposure (mean (%CV) AUCinf: 25.08 hr•μg/mL (23)) 
compared to subjects with eGFR > 80 mL/min (mean (%CV) AUCinf: 11.78 (25) hr•μg/mL. 
Subjects on dialysis had an AUCinf of 53.22 hr•μg/mL (19). In all cohorts, the overall incidence 
of adverse events was low and there was no apparent relationship between the incidence of AEs 
and the degree of renal impairment. 
In Study GS-US-104-0235, the safety and tolerability of FTC+TDF (200/300 mg) in 
treatment-naïve and treatment-experienced HIV infected subjects with various degrees of renal 
impairment were assessed. One subject in this study assigned to the mild impairment group was 
later found to have moderate impairment (eGFR ≥30 and < 50 mL/min) and one subject 
assigned to moderate impairment was found to have severe impairment (eGFR < 30 mL/min) 
after 40 days of treatment. Based on PK analyses of these subjects, the subject with moderate 
renal impairment was continued on FTC 200 mg daily because FTC exposures remained within 
the predicted range for subjects without renal impairment and the subject with severe renal 
impairment continued to receive FTC 200 mg every 48 hours based upon appropriate FTC 
systemic exposures. 
Consistent with the renal impairment Study FTC-107 described above, results from the PK 
sub-study of GS-US-292-0112 (n = 30) showed that FTC exposure was slightly higher in 
subjects with mild to moderate renal impairment as compared with historical data on FTC in 
subjects with normal renal function (mean [%CV] FTC AUCtau 20968.6 [25.5] ng•h/mL versus 
11,714.1 [16.6] ng•h/mL in Phase 2 Study GS-US-292-0102 of non-renally-impaired 
HIV-infected subjects), as expected due to the renal elimination of FTC. Further population PK 
analysis on all subjects treated in Study GS-US-292-0112 with available FTC data (n = 241), 
confirmed the findings from the PK sub-study, showing slightly higher FTC exposures in 
subjects with baseline eGFRCG < 50 mL/min, as compared with subjects with baseline 
eGFRCG ≥50 mL/min. Importantly, these observed differences in FTC exposure by 
renal impairment subgroup did not result in a different safety profile. The incidence of adverse 
events that occurred in ≥ 5% of subjects and of treatment-related adverse events that occurred in 
≥1% of subjects was similar between groups after 48 weeks of treatment. Adverse reactions 
from the Emtriva SmPC were also specifically evaluated. Despite higher FTC exposure in this 
study, incidence of these events was similar in subjects with eGFRCG < 50 mL/min and in 
subjects with eGFRCG ≥50 mL/min. The current study will evaluate FTC exposures and safety, 
and an IDMC will be convened to monitor safety data.
1.4.
Risk/Benefit Assessment for the Study
Potential risks of a patient’s study involvement include switching to an unfamiliar regimen with 
potential loss of virologic control and/or new adverse events, the inconvenience of more frequent 
clinic visits and laboratory blood draws and the associated pain and discomfort of phlebotomy. 
Strategies to mitigate these risks include close monitoring of viral load, CD4+ T cell count and 
other lab values as well as monitoring of adverse events. Parameters for discontinuation of the 
study drug due to adverse events or lack of efficacy will be well-defined and closely followed. 
In addition, an independent data monitoring committee will be convened at Week 12 to evaluate 
safety data and determine whether the risks/benefits warrant continuation of the study. 


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Potential benefits may include the patient receiving a FDC antiretroviral regimen that is more 
convenient leading to improved adherence, with potentially fewer adverse events than the current 
regimen, E/C/F/TAF may provide an alternative treatment for a patient population with fewer 
therapeutic options than the general HIV-1-infected population. 
Considering the above, the benefit-risk balance for this study is considered positive.
1.5.
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 safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with
ESRD on chronic HD at Week 48
The secondary objectives of this study are:

To evaluate the safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with 
ESRD on chronic HD at Week 96

To evaluate the proportion of subjects achieving virologic response (defined as HIV-1 RNA
< 50 copies/mL, as defined by the FDA Snapshot analysis) at Weeks 24, 48, and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in 
HIV-1 infected patients with ESRD on chronic HD


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3. 
STUDY DESIGN 
3.1. 
Study Design 
Final 
Amendment 2 
This is an open-label, multicenter, single-rum study to assess the safety, tolerability, 
phrumacokinetics, and efficacy ofEICIFITAF FDC in HIV-1 infected adult subjects with 
ESRD on chronic HD. 
Approximately 50 subjects with ESRD on chronic HD will be emolled. All subjects will switch 
from their cunent antiretroviral regimen to EICIFITAF on Day 1. The total treatment dmation 
will be at least 96 weeks. After the Week 96 visit, all subjects will stop study dmg and complete 
a 30-Day Follow-up visit. 
Figure 3-1. 
Screening 
Study Schema 
Day 1 
Week48 
(Prima1y Endpoint) 
~ 30 days 
prior to 
Baseline 
96 Weeks of Treatment on EICIFITAF 
(n = approximately 50/ 
30-Day 
Follow-upb,c 
a 
Following the Day 1 visit, subjects will retmn for study visits at Weeks 2, 4, 8, 12, 24, 36,48, 60, 72, 84, and 96. 
b 
After 96 weeks, subjects will stop study dmg and c.omplete a 30-Day Follow-up visit to end their participation in the study. 
c 
Subjects who discontinue study drug administration before their Week 96 visit, will complete an ESDD visit. These subjects 
may remain on the study off study dmg up to the Week 96 visit. Upon completion of Week 96 visit, subjects may be 
require·d to retmn to the clinic for a 30-Day Follow-up visit to complete their participation in the study. 
3.2. 
Study Treatments 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg I cobicistat 150 mg I emtricitabine 200 mg I tenofovir alafenamide 10 mg 
(EICIFITAF), on Day 1. 
Study dmg will be administered orally once daily with food at approximately the same time 
every day. On the day of hemodialysis, study dmg administration should occm after completion 
of hemodialysis. 
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3.3. 
Duration of Treatment 
Final 
Amendment 2 
The study will consist of a 30-day screening period (within 30 days before Day 1 visit), followed 
by a 96 week treatment period. After Day 1, subjects will retmn for study visits at 
Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. 
After Week 96, subjects will stop study dmg and complete a 30-Day Follow-up visit. 
3.4. 
End of Study 
End of the study will occur when the last subject emolled in the study has completed their 
last observation (or visit). 
3.5. 
Post Study Care 
After a subject has completed/te1minated their participation in the study, long-tenn care for the 
subject will remain the responsibility of their primmy treating physician. 
3.6. 
Source Data 
Sponsor will provide somce document worksheets for all study visits. 
3.7. 
PPD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects who meet the eligibility criteria will be enrolled. 
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 screening procedures
2) Age ≥ 18 years
3) Currently receiving a stable antiretroviral regimen for ≥ 6 consecutive months prior to 
screening 
4) Documented plasma HIV-1 RNA concentrations < 50 copies/mL for at least 6 months 
preceding the screening visit (measured at least twice using the same assay) and have 
HIV-1 RNA < 50 copies/mL at screening
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
≥50 copies/mL and < 400 copies/mL) is acceptable, only if HIV-1 RNA is 
< 50 copies/mL immediately before and after the blip. 
b) To determine virologic suppression in the preceding 6 months prior to screening, the 
lower limit of quantification (LLOQ) by the local HIV-1 RNA assay may be used, only if 
its LLOQ is greater than 50 copies/mL (e.g. LLOQ of 75 copies/mL)
5) No documented history of HIV-1 resistance to EVG, FTC, 3TC or TFV and no history of 
switching off EVG, FTC, 3TC or TFV due to concern for resistance
6) CD4+ T cell count of ≥200 cells/μL
7) ESRD with eGFR < 15 mL/min by Cockcroft-Gault formula for creatinine clearance 
{Cockcroft et al 1976}
Male:
(140 – age in years) × (wt in kg) Clcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 Clcr (mL/min)
72 × (serum creatinine in mg/dL)
8) On chronic HD for ≥ 6 months prior to screening


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9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Chronic Hepatitis C (HCV) infection allowed if liver function is stable for ≥6 months prior to 
screening: ALT ≤ 10 × ULN, AST ≤ 10 × ULN, total bilirubin ≤ 2.5, or normal direct 
bilirubin (subjects with documented Gilbert’s Syndrome or hyperbilirubinemia due to 
atazanavir therapy may have total bilirubin up to 5 × ULN), INR ≤ 1.5 and albumin ≥3 g/dL; 
no evidence of cirrhosis or hepatocellular carcinoma by imaging in the last 12 months
11) Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; 
platelets ≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
12) Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤ 5 × ULN)
13) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant confirmed by a negative serum pregnancy test (unless permanently sterile 
or greater than two years post-menopausal)
b) Of non-child bearing potential (i.e. women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for ≥ 12 months) of previously occurring menses
Female subjects who have stopped menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure must have a serum follicle stimulating 
hormone (FSH) level at screening within the post-menopausal range based on the 
Central Laboratory Reference range. 
c) Of childbearing potential and agrees to utilize the protocol specified method of 
contraception or be non-heterosexually active or practice abstinence from screening 
throughout the duration of the study treatment and for 30 days following study drug 
discontinuation (as defined in Appendix 6)
d) Female subjects who utilize hormonal contraception as one of the birth control methods 
must have used the same method for at least three months prior to the study dosing. 
14) Male subjects must agree to use protocol specified method(s) of contraception from 
screening throughout the duration of study treatment and for 30 days following 
discontinuation of study drugs (Appendix 6).
15) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days 
after the last study drug dose.
16) Lactating females must agree to discontinue nursing before the study drug is administered.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Hepatitis B surface antigen (HBsAg) positive
2) Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
3) Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening
4) Treatment with radiation, cytotoxic chemotherapeutic agents, or any immunomodulator 
within 30 days of screening
5) Any other clinical history, condition, or test result that, in the opinion of the Investigator, 
would make the subject unsuitable for the study or unable to comply with dosing 
requirements
6) Administration of other investigational agents (unless approved by Gilead Sciences). 
Participation in any other clinical trial, including observational trials, without prior approval 
from the sponsor is prohibited while participating in this trial.
7) History or presence of allergy or intolerance to the study drugs or their components
8) A new AIDS-defining condition (excluding CD4+ T cell count and percentage criteria) 
diagnosed within the 30 days prior to screening, with the exception of 
oropharyngeal candidiasis (see Appendix 7)
9) Have an implanted defibrillator or pacemaker
10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
carcinoma
12) Received solid organ or bone marrow transplant
13) Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures
14) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1
15) Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use]), immunosuppressant, or 
immunomodulating agents
16) Subjects receiving ongoing therapy with any of the following medications in the Table 4-1
below, including drugs not to be used with EVG, COBI, FTC, TAF


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Table 4-1.
Disallowed Agents
Drug Class
Agents Disalloweda
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Calcium Channel Blockers
Bepridil
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
Inhaled Beta Agonist
Salmeterol
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a
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. 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label, single arm study. All eligible subjects will receive open-label E/C/F/TAF.
Enrollment and Day 1 visit cannot occur until subject eligibility has been confirmed.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment. Once eligibility is confirmed, each subject will be assigned a unique subject 
number using 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 may be performed up to 3 days prior to the in-clinic Day 1 visit, provided that all 
other screening procedures have been completed and subject eligibility has been confirmed. 
Eligibility must be confirmed and all Day 1 tests and procedures must be completed prior 
to the administration of the first dose of study drug.
IWRS will assign study drug bottle numbers at each study visit. Initiation of study drug must 
take place on the day of Day 1 visit. 
5.2.
Description and Handling of E/C/F/TAF FDC Tablets
5.2.1.
Formulation
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets and are debossed with “GSI” on
one side of the tablet and “510” on the other side of the tablet. E/C/F/TAF tablets contain 150 mg
of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of TAF fumarate).
The E/C/F/TAF tablet core contains silicon dioxide, croscarmellose sodium, hydroxypropyl
cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine aluminum 
lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.2.2.
Packaging and Labeling
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle
contains 30 tablets, silica gel desiccant and polyester packaging material. Each bottle is enclosed
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
Study drug to be distributed to centers in the US and other participating countries shall be labeled 
to meet applicable requirements of the United States Food and Drug Administration (FDA), 
EU Guideline to Good Manufacturing Practice −Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.


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5.2.3.
Storage and Handling
E/C/F/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). Storage conditions are specified on 
the label. Until dispensed to the subjects, all bottles of study drug should be stored in a securely
locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration of E/C/F/TAF
E/C/F/TAF FDC tablets will be provided by Gilead Sciences.
E/C/F/TAF FDC tablets containing 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 
10 mg of TAF will be provided to all eligible subjects at Day 1. Study drug will be administered
orally at approximately the same time each day with food. 
On the day of hemodialysis study drug administration should occur after completion of 
completion of hemodialysis. 
Subjects will be instructed to bring all study drug in the original container at each clinic visit for 
drug accountability (unless otherwise specified in the study procedures sections of this protocol). 
The Investigator will be responsible for maintaining accurate records for all study drug bottles 
dispensed and tablets returned. The inventory and dispensing logs must be available for 
inspection by the study monitor. Study drug supplies, including partially used or empty bottles, 
must be accounted for by the study monitor prior to destruction or return.
5.4.
Prior and Concomitant Medications

For subjects receiving hormonal contraceptives, investigators and/or the subject’s healthcare 
providers should consider additional methods of contraception, as concentrations of ethinyl 
estradiol may decrease and progestin level may increase on co-administration with study 
drug. 

The use of medications for the treatment of HIV, other than study drug, is prohibited.

For subjects receiving concomitant medications that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious adverse 
events, investigators and/or the subject’s healthcare providers should consider alternative 
concomitant medications.


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
During the study, subjects may not receive any of the following concomitant medications:
Competitors of renal excretion (e.g., probenecid; high-dose non-steroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin and pentamidine)

Medications listed in the following table and use of herbal/natural supplements are excluded 
or should be used with caution while subjects are participating in the study. Any concomitant 
medication requiring adjustment or discontinuation due to renal impairment or a change in 
renal function on study should be managed per that drug’s prescribing information.
Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Concentration of study drug may decrease with 
antacids. Subjects may not take antacids 
(eg, Tums, Mylanta); the ulcer medication 
sucralfate (Carafate); or vitamin or mineral 
supplements that contain calcium, iron or zinc for a 
minimum of 2 hours before and 2 hours after any 
dose of study drug.
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: Concentrations may 
increase with study drug(s); clinical monitoring is
recommended.
Antiarrhythmics
Amiodarone, Flecainide Quinidine, Propafenone, 
Systemic Lidocaine, Mexiletine, Disopyramide: 
Concentrations may increase with study drug(s) 
resulting in a potential for cardiac arrhythmias; 
clinical and ECG monitoring is recommended.
Calcium Channel Blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, Verapamil, 
Diltiazem, Amlodipine: Concentrations may 
increase with study drug(s). Clinical and ECG 
monitoring of subjects is recommended
Digoxin
Digoxin: Concomitant use may result in increased 
levels; use with caution and with appropriate 
monitoring of serum digoxin levels. Digoxin 
therapy should be initiated at the lower dose, and 
the dose should be titrated to clinical response.
Antibacterials
Clarithromycin and Telithromycin: Concentrations 
may be altered with study drug(s); consider an 
alternative.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR (International
Normalized Ratio) monitoring is recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics: Concentrations may increase or decrease 
with study drug(s). Concentration monitoring is 
recommended to ensure adequate clinical response.
Trazodone: Concomitant use with 
CYP3A inhibitors results in increased 
concentrations and adverse events; dose reduction 
should be considered.
Antifungals
Ketoconazole and Itraconazole: Concomitant use 
with study drug may result in an increase in 
concentrations. Daily dose of ketoconazole and 
itraconazole should be restricted to 200 mg. 
Subjects receiving ketoconazole or itraconazole 
should be monitored for adequate clinical response.
Voriconazole: Concomitant use with study drug 
may result in an increase in concentrations. 
Clinical monitoring may be needed.
Antigout
Colchicine: Concentrations may increase with 
study drug(s). Dose reductions of colchicine may be 
required. Should not be coadministered in patients 
with renal or hepatic impairment.
Treatment of Gout Flare:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg 
(half tablet) 1 hour later. Treatment course may be 
repeated no earlier than 3 days.
Prophylaxis of Gout Flares:
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:
Maximum daily dose of 0.6 mg 
(may be given as 0.3 mg twice a day).
Antihistamines
Astemizole, Terfenadine


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol: Clinical and ECG monitoring 
of subjects is recommended. A dose decrease 
may be needed.
Corticosteroids: 
Inhaled/Nasal
Concomitant use of inhaled fluticasone and study 
drug(s) may increase plasma concentrations of 
fluticasone. Use is not recommended unless the 
potential benefit to the subject outweighs the risks 
of corticosteroid side effects. Alternatives should be 
considered, particularly for long-term use.
Corticosteroids: Systemic
Systemic dexamethasone, a CYP3A inducer, may 
significantly decrease elvitegravir and cobicistat 
plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative corticosteroids should be considered.
Use of Prednisone as a steroid burst (≤1 week of 
use) should be monitored appropriately.
Endothelin receptor 
antagonists
Bosentan: coadministration may lead to decreased 
elvitegravir exposures and loss of therapeutic effect 
and development of resistance. Alternative 
endothelin receptor antagonists may be considered.
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin
Atorvastatin: Concentrations may increase with 
study drug(s). Start with the lowest dose; gradual 
increase in dose may be tailored to clinical 
response. Careful monitoring for signs and 
symptoms of muscle weakness or myopathy, 
including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s).
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: A dose 
decrease may be needed.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Opiates
Methadone: Methadone exposures are unaffected 
upon coadministration with elvitegravir and 
cobicistat. No dose adjustment of methadone is 
required upon coadministration with study drug(s).
Meperidine (Pethidine): Dosage increase and 
long-term use are not recommended due to 
increased levels of metabolite normeperidine, 
which has analgesic and CNS stimulant 
(eg, seizures) activities.
Buprenorphine: Concentrations of buprenorphine 
and norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and 
cobicistat, with no effect on opioid 
pharmacodynimcs. The concentration changes are 
not considered clinically relevant and no dose 
adjustment of buprenorphine/naloxone is required 
upon coadministration with study drug(s).
Phosphodiesterase-5 
Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil: Caution should be exercised, including 
consideration of dose reduction, when 
coadministered for treatment of pulmonary arterial 
hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil: It is recommended 
that a single dose of Sildenafil no more than 25 mg 
in 48 hours, Vardenafil no more than 2.5 mg in 
72 hours, or Tadalafil no more than 10 mg in 
72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem: A dose decrease may be 
needed for these drugs. Clinical monitoring 
is recommended.

Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the Gilead Sciences 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 Sciences as soon as he/she is aware of 
the use of the disallowed medication.


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5.5.
Accountability for E/C/F/TAF
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. Accountability records (Study Drug Inventory Log) will be provided to each study site in 
order to:

Record the date received and the quantity of study drug bottles.

Record the date, subject number, subject initials, the study drug bottle number dispensed.

Record the date, quantity of used and unused study drug returned by the subject, along with 
the initials of the person recording the information.
The Investigator [or designee (e.g., study center pharmacist)] will acknowledge receipt of the 
study drugs from Gilead Sciences (or designee) after reviewing the shipment’s content and 
condition. The Investigator (or designee) will be responsible for maintaining an accurate 
inventory of the dates and quantities of all study drugs received, dispensed, and returned. 
Subjects should be instructed to return all unused study drug to the site at their study visits.  
Each dose of the study drug administered at the study center will be administered by qualified 
study center personnel. All doses of study drug administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Study Drug Inventory Logs provided by 
Gilead Sciences (or on equivalent documentation maintained by the study center), which 
indicates the date and quantity of all doses of study drug dispensed to individual subjects. 
The requirements of all applicable drug dispensing laws will apply to all doses of study drugs 
dispensed by the Investigator (or designee). 
The study drug inventory log must be available for inspection by the study monitor. Study drug
supplies, including partially used or empty bottles, must be accounted for by the study monitor 
prior to destruction or return.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions to the sites regarding the return of used and unused 
study drug. If return is not possible, the study monitor will evaluate each study center’s study 
drug disposal procedures and provide appropriate instruction for destruction of unused study 
drug. 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 study 
drug bottles in accordance with that site’s approved SOP. A copy of the site’s approved SOP will 
be obtained for central files.
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead. The study monitor will review study drug inventory and 
associated records at periodic intervals.


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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 described in the text that follows. 
The investigator must document any deviation from protocol procedures in the subject’s source 
documents and electronic Case Report Forms (eCRFs). In addition, the Sponsor and the 
Contract Research Organization (CRO) should be promptly notified of any protocol deviations. 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment. 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg 
(E/C/F/TAF), on Day 1. Please refer to Section 5.1 for details about enrollment and 
treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Day 1 visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events, substance use, 
family history of cardiovascular disease (i.e. myocardial infarction, stroke, peripheral 
vascular/arterial disease, and/or angina) and prior medications within 30 days of the 
screening visit

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) and weight

12-lead ECG performed supine

Height


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
Blood sample collection for the following laboratory analyses: 
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
FSH test is required for female subjects who have stopped menstruating for > 12 months 
but do not have documentation of ovarian hormonal failure.
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and parathyroid hormone (PTH)
■
Sample should be drawn prior to hemodialysis 
○
Timing of draw and timing of hemodialysis should be recorded
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ T cell count
Plasma HIV-1 RNA (Taqman v2.0)
Hepatitis B virus surface antigen serology (HBsAg)
Hepatitis C virus (HCVAb) serology. If the antibody test result is positive, 
HCV RNA test will be performed to confirm HCV viremia.

HIV-TSQs (HIV Treatment Satisfaction Questionnaire Status) should be completed by the 
subject. Subject is to read the questionnaire by him/herself and write/mark answers directly 
onto the questionnaire.

Review of AEs and concomitant medications (adverse events related to protocol mandated 
procedures occurring after signing of the consent form)


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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for Day 1 assessments. 
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF). All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF. See Section 7
Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments
The following evaluations are to be completed after confirmation of eligibility, and before the 
study drug is dispensed to the subject. Initiation of treatment with the study drug must take place 
within 24 hours after the Day 1 visit.

Obtain subject number and study drug bottle assignment from IWRS. The subject number 
assignment and enrollment may be performed up to 3 days prior to the in-clinic Day 1 visit 
provided that all screening procedures have been completed and subject eligibility has been 
confirmed.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, phosphorus, magnesium, potassium, sodium, uric acid, amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN) and PTH
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Metabolic assessments: 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). 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


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Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Whole blood storage sample collection for virology analyses
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, VAS and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation. Study drug will be dispensed in an open-label fashion. Subjects 
must initiate dosing of study drug on the day of the Day 1 visit. 

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. On the days of hemodialysis, subjects should be instructed to take study 
drug after completion of hemodialysis. Subjects should also be counseled regarding the 
importance of adherence and taking their study drugs at approximately the same time each 
day.
6.3.
Treatment Assessments (Weeks 2-96)
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specific visit date through Week 12 and completed 
within ± 6 days of the protocol-specific visit date through Week 36. The visit window at 
Week 48 will be ± 6 weeks of the protocol-specific visit date, and this clinical visit window 
coincides with the Week 48 statistical analysis window for HIV-1 RNA. Unless notified by the 
Sponsor, Week 48 visit should be completed within ± 6 days of the protocol-specific visit date. 
Following the Week 48 visit, study visits are to be completed within ± 6 days of the 
protocol-specific visit date through Week 84. The visit window at Week 96 will be ± 6 weeks of 
the protocol-specific visit date. Unless notified by the Sponsor, Week 96 visit should be 
completed within ± 6 days of the protocol-specific visit date.


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The following evaluations are to be completed at the end of Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 
84, and 96, unless otherwise specified. 
Note: Regularly scheduled evaluations will be made on all subjects whether or not they continue 
to receive study drug. 

Pre-dose (within 30 minutes prior to study drug administration) whole blood samples
collection for plasma and PBMC samples (Week 4 or Week 12 only). 
Note: Week 4 or Week 12 visit should occur on the day of hemodialysis for this sample 
collection. Study drug administration should occur after completion of hemodialysis and 
should be observed on-site. 
PBMC sample processing will be performed by the central laboratory and plasma sample 
processing will be performed on-site. Details of the blood sampling procedures and 
sample management will be documented in the central laboratory manual. 

All subjects who are willing to provide written consent to participate in the study will be 
eligible to participate in the pharmacokinetic sub-study (target n = 15) at or between Week 2 
or Week 4 study visits, on a day prior to the day of hemodialysis and when the subject has 
administered three doses of E/C/F/TAF between two hemodialysis sessions. E/C/F/TAF 
administration prior to post-dose blood sample collection will be observed in-clinic. 
The ± 2 day window at Week 2 or Week 4 study visits does not apply to the PK 
sub-study visit. Please see Section 6.5.1 and Appendix 3, Pharmacokinetic (PK) 
Sub-study for additional details. 

Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24, 48, and 96 only) (urogenital/anorectal exams 
will be performed at the discretion of the Investigator)

Symptom-directed physical examination as needed (Weeks 2, 4, 8, 12, 36, 60, 72, and 84)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

12-lead ECG performed supine (Weeks 48 and 96)


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
Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, 
direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and PTH
Note: At Weeks 24, 48, 72, and 96, analyses of glucose will be done as part of the fasting 
metabolic assessments and not as part of the chemistry profile.
■
Chemistry profile will include PT/INR only at Week 24 and Week 48
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Metabolic assessments: 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). 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 (Weeks 24, 48, 72, and 96 only)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).
CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing
Serum and plasma storage samples for possible additional clinical testing (for subjects
who provide consent)
Serum pregnancy test (females of childbearing potential only). 
■
Serum pregnancy testing may be performed more frequently if required by local 
regulations. 


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
Subject completed questionnaires:
SF-36 completed at Weeks 24, 48, 72, and 96 only
HIV-TSQs completed at Weeks 4, 24, 48, 72, and 96. HIV-TSQc (HIV Treatment 
Satisfaction Questionnaire Change) completed at Weeks 24, 48, 72, and 96.
VAS completed at all visits
The questionnaires should be completed by the subject. Subject is to read the questionnaire 
by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation (except at Week 2 and Week 96). Document study drug dispensation 
and accountability. 
At Day 1, study drug will be dispensed for 30 days. At the Week 2 visit, study drug will 
not be dispensed. 
At Week 96, study drug dispensation will not occur. Schedule the subject for a 30-Day 
Follow-Up visit. 
Note: At the Week 2 visit, provide the scheduled Week 4 visit date to the subject. Week 4 
visit should occur on day of hemodialysis. Instruct the subject to take study drug at Week 4 
on-site (after completion of hemodialysis).

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. 

Subjects should also be counseled regarding the importance of adherence and taking their 
study drugs at approximately the same time each day.
6.4.
Post-treatment Assessments
6.4.1.
30-Day Follow-up Assessments
Subjects who complete the study through the Week 96 visit will be required to return to the 
clinic for a 30-Day Follow-Up Visit. 
Those subjects who prematurely discontinue study drug and continue in the study through 
at least one subsequent visit after the Early Study Drug Discontinuation Visit will not be 
required to complete the 30-Day Follow-Up Visit.
Subjects who prematurely discontinue study drug prior to the Week 96 visit and refuse to 
continue in the study through the Week 96 visit will be asked to return to the clinic 30 days after 
the completion of the ESDD Visit for the 30-Day Follow-Up Visit.


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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 of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, 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) and PTH.
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Serum pregnancy test (females of childbearing potential only)
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
At the 30 Day Follow Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)
If the subject discontinues study drug prior to the Week 96 visit, the subject will be asked to 
return to the clinic within 72 hours of stopping study drug for the ESDD visit. 
Every attempt should be made to keep the subject in the study through Week 96 visit and 
continue to perform the required study-related follow-up and procedures (see Section 6.4.3, 
Criteria for Discontinuation of Study Treatment). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study.
Subjects who prematurely discontinue study drug prior to the Week 96 visit and refuse to 
continue in the study through Week 96 visit will be asked to return to the clinic 30 days after the 
completion of ESDD visit for the 30-Day Follow-up visit.


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At the Early Study Drug Discontinuation Visit, any evaluations showing abnormal results 
indicating that there is a possible or probable causal relationship with the study drug, 
should be repeated weekly (or as often as deemed prudent by the Investigator) until the 
abnormality is resolved, returns to baseline, or is otherwise explained.
The following evaluations are to be completed at the Early Study Drug Discontinuation Visit

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, 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)
and PTH
■
Sample should be drawn prior to hemodialysis
○
Timing of draw and timing of hemodialysis should be recorded
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
■
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).
CD4+ T cell count
Plasma sample for virology testing or pharmacokinetic testing
Serum and plasma storage samples for possible additional clinical testing (for subjects 
who provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, HIV-TSQc and VAS questionnaires should be completed by the subject. Subject is to 
read the questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Drug accountability


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6.4.3.
Criteria for Discontinuation of Study Treatment
Study drug 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.

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Lack of efficacy

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.5.
Other Evaluations
6.5.1.
Pharmacokinetic (PK) Sub-study
All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). 
Intense blood sampling will be conducted at hours 0.5, 1, 2, 3, 4, 6, 8, and 24.
PK sub-study visit must occur at or between Week 2 or Week 4 study visits, on a day prior to the 
day of hemodialysis and when the subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. The ± 2 day window at Week 2 or Week 4 study visits does not apply 
to the PK sub-study visit. Study drug administration will be observed in-clinic at the sub-study 
visit. The sub-study will include intensive PK profiling in plasma. Details of the blood sampling 
procedures and sample management will be documented in the central laboratory manual. 
6.5.2.
Blood Storage
From subjects who provide additional consent, a portion of the blood drawn at all visits 
(except the Screening Visit and Unscheduled Visits) will be frozen and stored. These stored 
blood samples may be used by the Sponsor or its research partners for future testing to learn 
more about how the study drug has worked against HIV-1 or clinical laboratory testing to 
provide additional safety data. No human genetic testing will be performed without expressed 
consent of study subjects. At the conclusion of this study, these samples may be retained in 
storage by Gilead Sciences, Inc. for a period up to 15 years.


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6.6.
Virologic Failure
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure.
Subjects will be considered to have virologic rebound if they have confirmed HIV-1 RNA 
≥50 copies/mL (two consecutive tests) at a scheduled or unscheduled visit.
6.6.1.
Management of Virologic Failure

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-4 weeks after the date of the original test with HIV-1 RNA 
≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented. Assessments should include:
Adherence
Concomitant medication
Comorbidities (for example: active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed, and the HIV-1 RNA is < 400 copies/mL, subjects may 
remain on their current regimen at the discretion of the Investigator. Subject will return for a 
repeat within 2-4 weeks. 

If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 400 copies/mL, the blood samples from the confirmation visit will be used for 
HIV-1 genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and HIV-1 RNA should be repeated (2-4 weeks from the date of confirmed 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 
subjects source documents. Investigators who opt to discontinue study drugs for an 
individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.6.2.
Subjects with ≥400 copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at Week 24, Week 48, Week 96, or at the last visit while receiving study drugs 
(or within 72 hours of discontinuation of study treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.


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Amendment 2 
Figure 6-1. 
Schema for Management of Virologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
Dayl 
~ 
I 
At any visit, a rebound in HIV -1 RNA to ~ 50 copies/mL 
I 
Unconfu·med 
Return for scheduled/unscheduled HIV-1 
vii·ologic rebound: 
.... 
RNA and potential genotype/phenotype 
remain on cmTent 
(2-4 week~ late1•) 
regimen• 
' 
Confi1·med virologic rebound and 
HIV-1 RNA to <!: 400 copies/mLb 
,, 
Remain on study 
I 
HIV-1 genotype/phenotype' I 
' 
' 
If no reverse transcriptase •·esi~tance 
If reve1·se transc.l"iptase, protease, 
detected, continue on studl d1·ugs. 
or mtegrase resistance detected, 
Repeat HIV-1 RNA ,d 
discontinue study drugs and 
constl·uct a new ARV regimen• 
a 
If virologic rebotmd is not confmned, the subject will remain on their current regimen. 
b 
If virologic rebotmd is confmned, and the HIV-1 RNA is< 400 copies/mL, subjects may remain on their cun·ent regimen at 
the discretion of the Investigator. Subject will rettUll for a repeat within 2-4 weeks. If virologic rebound is confinned, and 
HlV -1 RNA is :::: 400 copies/mL, the HlV -1 genotype and phenotype (reverse transcriptase, protease, and, if applicable, 
integrase resistance) will be analyzed. 
c 
Base-d on the results of the genotype/phenotype assays, the subject will remain on study dmgs or study drugs will be 
discontinued. If genotyping/phenotyping assay fails, a new ARV regimen may be configured at the discretion of the 
Investi2ator. 
d 
If no r.;istance detected, HIV-1 RNA will be repeated (2-4 weeks latet'). Investigator reviews study dmg 
continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation. 
e 
A new AR V regimen will be configtu·ed, at the Investigator's discretion, and the subject will remain in the study. 
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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 adverse event (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, lack of efficacy, 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.

Pre-existing 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 7.5)

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 pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (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

Persistent or significant disability/incapacity


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
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.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.6.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to 
study drug using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event 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 adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
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.
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 drug, the following types of events should 
be reported on the case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences 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 occurs 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 Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported. 
All SAEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study drug follow-up period) the SAE has not resolved, then the SAE will be 
followed up until the investigator and/or Gilead Sciences determine that the subject's condition is 
stable. However, Gilead Sciences may request that certain SAEs be followed until resolution.
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 study drug, he/she should promptly document and 
report the event to Gilead DSPH. 

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Serious Adverse Event Paper Reporting Process

Serious Adverse Event Paper Reporting Process (only to be used if EDC System is not 
available)
All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of:
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
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 DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If the SAE was reported via paper, it 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.


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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the 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 investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with the study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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.
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 


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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 complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the post study drug follow-up period, 
to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to 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 7.3.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. 
Gilead DSPH contact information is as follows: 
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does 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 the CRF/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.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 as outlined below.

All clinically significant Grades 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of study drug for any Grade 3 and 4 laboratory abnormality that in the opinion 
of the Investigator is clinically significant and may pose a risk to the subject’s safety.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(refer to Appendix 5).

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the Investigator.


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7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued and the 
subject managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug 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 study drug, study drug 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.
Study Drug may be continued without dose interruption for a clinically non-significant 
Grade 3-4 laboratory abnormality (e.g., CK elevation after strenuous exercise, or triglyceride 
elevation that is non-fasting or that can be medically managed) or a Grade 3-4 clinical event 
considered unrelated to study drug.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the safety and tolerability of the elvitegravir/cobicistat/emtricitabine/
tenofovir alafenamide (EVG/COBI/FTC/TAF; E/C/F/TAF) fixed-dose combination (FDC) in 
HIV-1 infected adults with end stage renal disease (ESRD) on chronic hemodialysis (HD) at 
Week 48
The secondary objectives of this study are:

To evaluate the safety and tolerability of the EVG/COBI/FTC/TAF; E/C/F/TAF FDC in 
HIV-1 infected adults with ESRD on chronic HD at Week 96

To evaluate the proportion of subjects with virologic response (HIV-1 RNA < 50 copies/mL, 
as defined by the FDA Snapshot analysis) at Weeks 24, 48 and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in HIV-1 
infected patients with ESRD on chronic HD
8.1.2.
Primary Endpoint
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events up 
to Week 48.
8.1.3.
Secondary Endpoints

Incidence of treatment-emergent grade 3 or higher adverse events up to Week 96

Proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24, 48, and 96 as defined 
by the FDA snapshot algorithm

The pharmacokinetics parameters of EVG, COBI, FTC, TAF and TFV, including 
AUCtau/AUClast, Cmax, and Cmin for the sub-study.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
Full Analysis Set (FAS): The Full Analysis Set will include all the subjects who were enrolled
and received at least one dose of study drug. The FAS will exclude subjects with major protocol 
violations. The FAS analysis set is the primary analysis set for the efficacy analyses.


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8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses is defined as all subjects that received at least 
one dose of study drug.
All data collected during treatment will be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) analysis set will include all subjects in the safety analysis set who 
participated in the sub-study and for whom concentration data of any one analyte (e.g., TAF, EVG,
COBI, TFV and FTC) of interest are available.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index and 
HIV-1 infection.
8.4.
Primary and Secondary Analysis
8.4.1.
Primary Analysis
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events up 
to Week 48. Treatment-emergent adverse events are defined in Section 8.5.2.
8.4.2.
Secondary Analyses
The proportion of subjects achieving HIV-1 RNA < 50 copies/mL at Weeks 24, 48, and 96 will 
be computed using the FDA snapshot algorithm. The measures of pharmacokinetics of EVG, 
COBI, FTC, TAF and TFV, AUC, Cmax, and Cmin, will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV), median, minimum, 
and maximum] for the sub-study.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be summarized. Data for pre-treatment period and the 
period post the date of last dose plus 30 days will be included in data listings.


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8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized. 
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug
administration, and summarized. Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (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.
Treatment-emergent adverse events are adverse events that meet one of the following criteria:

Adverse events with onset dates on or after the first dose date of study drug, and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
HLT [if applicable], and PT) will be provided. Additional summaries will include summaries for 
adverse events by grade, Investigator’s assessment of relationship to study drug, and effect on 
study drug dosing.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
drug plus 30 days, will be summarized. 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 drug or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.


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8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for using descriptive statistics 
(eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of the study drug over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation.
8.7.
Sample Size
A sample size of approximately 50 subjects is based on practical considerations and is 
considered to be sufficient to evaluate the primary objective of this study. The Grade 3 or higher 
AE rate in Study GS-US-292-0112 in subjects that had mild to moderate renal impairment was 
8.8% at Week 48 analysis for the E/C/F/TAF arm. Therefore, with 50 subjects, and an assumed 
rate of Grade 3 or higher AEs being 10%, this study would provide 95% confidence for the 
primary endpoint to be (1.7%, 18.3%) assuming normal approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating the PK parameters in the 
sub-study for practical reasons. 
8.8.
Data Monitoring Committee
An external multidisciplinary independent data monitoring committee (IDMC) will review the 
progress of the study and perform interim reviews of safety, efficacy, and PK data and provide 
recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study drug warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications. The committee will convene after the first 25 subjects enrolled complete Week 12
of the study. The IDMC’s specific activities will be defined by a mutually agreed charter, which 
will define the IDMC’s membership, conduct and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with 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 Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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 an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC approved consent form for documenting written 


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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 IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, IRB or IEC, 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 
investigator brochure, this protocol, eCRF, the study drug, 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,
IRB or IEC 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 study drug, including dates of dispensing 
and return;

Record of all adverse events 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 (i.e. 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 will be completed by an authorized study staff member 
whose training for this function is completed in EDC. 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 source data verification within 


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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 coordinator 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.
Study Drug Accountability and Return
The study monitor will provide instructions for return of used and unused study drug. If return is 
not possible, the study monitor will evaluate each study center’s study drug disposal procedures 
and provide appropriate instruction for destruction of unused study drug 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 study drug supplies 
in accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead.
The study monitor will review study drug inventory 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, IRBs or IECs, or 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 must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB [or] IEC approval before 
modifications can be implemented.
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

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
Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P. Adherence, treatment
satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) 
antiretroviral therapy (AT), in a large prospective observational cohort (CUVA 
Study).  [Poster WePeB5780]. . XV International AIDS Conference; 2004 July 
11-16; Bangkok, Thailand. 
Birkus G, Kutty N, He G-X, Mulato A, Lee W, McDermott M, et al. Activation of GS-7340 and 
Other Tenofovir Phosphonoamidate Prodrugs by Human Proteases. Antiviral Res 
2007;74:A57.
Birkus G, Kutty N, He GX, Mulato A, Lee W, McDermott M, et al. Activation of 9-[(R)-2-[[(S)-
[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-
methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate 
prodrugs by human proteases. Mol Pharmacol 2008;74 (1):92-100.
Cailhol J, Nkurunziza B, Izzedine H, Nindagiye E, Munyana L, Baramperanye E, et al. 
Prevalence of chronic kidney disease among people living with HIV/AIDS in 
Burundi: a cross-sectional study. BMC nephrology 2011;12:40.
Center for Disease Control and Prevention. HIV/AIDS Surveillance Report. Rev ed. Atlanta: 
U.S. Department of Health and Human Services, Centers for Disease Control and 
Prevention. Also available at: 
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.  2007.
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and 
adults. MMWR 1992;41 (RR-17):1-19.
Centers for Disease Control and Prevention. 1994 Revised Classification System for Human 
Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. 
MMWR 1994;43 (RR-12):1-28.
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30 
(Suppl 2):S-171-S6.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Department of Health and Human Services (DHHS). HHS Panel on Antiretroviral Guidelines for 
Adults and Adolescents Recommends a Fixed-Dose Combination Product of 
Elvitegravir/Cobicistat/Tenofovir/Emtricitabine as an Alternative Regimen in 
Antiretroviral Treatment-Naive Individuals with HIV-1 Infection.  2012:1-2. 


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Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L. Adherence and efficacy with a 
once-daily efavirenz-based regimen: 48-week results from the Daily 
Antiretroviral Therapy II (DART II) Study [Poster 5842]. . XV International 
AIDS Conference; 2004 July 11-16; Bangkok, Thailand. 
Gilead Sciences Inc. VIREAD® (tenofovir disoproxil fumarate) Tablets and Powder for oral use. 
US Prescribing Information. Foster City, CA. Revised August 2012:
Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related 
comorbidities among HIV-infected persons compared with the general 
population. Clin Infect Dis 2011;53 (11):1120-6.
Hoetelmans R, Kestens D, Stevens M, Peeters M, Williams P, Bastiaanse L, et al. 
Pharmacokinetic interaction between the novel non-nucleoside reverse 
transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate 
(TDF) in healthy volunteers [poster]. 6th International Workshop on Clinical 
Pharmacology of HIV Therapy; 2005 April 28-30; Québec City, Canada. Poster 
No. 2.11. 
Hoetelmans RM, Marien K, De Pauw M, Hill A, Peeters M, Sekar V, et al. Pharmacokinetic 
interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in 
healthy volunteers. Br J Clin Pharmacol 2007;64 (5):655-61.
Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. Age-related 
immune dysfunction in health and in human immunodeficiency virus (HIV) 
disease: association of age and HIV infection with naive CD8+ cell depletion, 
reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect 
Dis 2003;187 (12):1924-33.
Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective intracellular 
activation of a novel prodrug of the human immunodeficiency virus reverse 
transcriptase inhibitor tenofovir leads to preferential distribution and 
accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005;49 
(5):1898-906.
Linley L, Hall H, An Q, Wheeler W. HIV/AIDS diagnoses among persons fifty years and older 
in 33 states, 2001-2005 [Abstract B08-1]. Presented at: 2007 National HIV 
Prevention Conference; 2007 December 2-5; Atlanta, GA. 
Luber AD, Condoluci DV, Slowinski PD, Andrews M, Olson K, Peloquin CA, et al. Steady-state 
amprenavir and tenofovir pharmacokinetics after coadministration of unboosted 
or ritonavir-boosted fosamprenavir with tenofovir disoproxil fumarate in healthy 
volunteers. HIV Med 2010;11 (3):193-9.


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Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A. Once-a-day treatment for HIV 
infection: Final 48-week results. [Abstract 320]. 8th Conference on Retroviruses 
and Opportunistic Infections; 2001 February 4-8; Chicago, IL. 
Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-daily 
antiretroviral regimens: a meta-analysis. Clin Infect Dis 2009;48 (4):484-8.
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral Treatment Regimens 
and Correlation with Risk of Hospitalization Among Commercially Insured HIV 
Patients in the United States [Poster O113]. 10th International Congress on Drug 
Therapy in HIV Infection; 2010 November 7-11; Glasgow, UK. 
Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active 
antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am 
Soc Nephrol 2005;16 (8):2412-20.
Selik RM, Byers RH, Jr., Dworkin MS. Trends in diseases reported on U.S. death certificates 
that mentioned HIV infection, 1987-1999. J Acquir Immune Defic Syndr 2002;29 
(4):378-87.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to 
HAART [abstract]. . 40th Annual Meeting of the Infectious Disease Society of 
America; 2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
World Health Organization (WHO). World Health Organization, UNAIDS, UNICEF. Global 
HIV/AIDS Response: Epidemic update and health sector progress towards 
universal access. Progress Report 2011.  2011.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pharmacokinetic Sub-study
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {Selik et al 2014}


EICIF!TAF 
Protocol GS-US-292-1825 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Efficacy ofE/C/F/TAF Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis 
GS-US-292-1825, Amendment 2, 28 November 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Devi SenGupta, MD (Printed) 
Medical Monitor 
Date 
PPD 
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 
Page 71 
28 November 2016 


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Appendix 2.
Study Procedures Table
Study Procedure
Screena
Day 1b
Week 2 to Week 96c
30-Day Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Written Informed Consent
X
Medical History 
X
Complete Physical Examinationf
X
X
X
X
X
X
Symptom-directed Physical Examinationg
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Height
X
12-Lead ECG
X
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
Xj
Xj
Xj
Xj
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/Phenotypem
X
X
X
X
X
X
X
X
X
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum and Plasma Storage Sampleso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologyp
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36q
X
X
X
X
X
X
HIV-TSQq
X
X
X
X
X
X
X
X
VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Utilization Assessmentr
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Dispensation and Accountability
X
Xs
X
X
X
X
X
X
X
X
X
Xs
Xs
Pre-dose Whole Blood Sample Collectiont
X
X


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Study Procedure
Screena
Day 1b
Week 2 to Week 96c
30-Day Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Post-dose PK Sub-studyu
X
X
Whole Blood Storage Samplev
X
a
Evaluations to be completed within 30 days prior to Day 1.
b
Subjects will be dispensed study drug on the Day 1 visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit.
c
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol specified date 
through Week 48, except Week 48. Weeks 48 visit window is ± 6 weeks of the protocol specified date. Week 48 visit should be completed within ± 6 day window, unless otherwise 
specified by the Sponsor. Following the Week 48 visit, study visits are to be completed within ± 6 days of the protocol specified date through Week 84. The visit window at Week 96 
will be ± 6 weeks of the protocol-specific visit date. Unless notified by the Sponsor, Week 96 visit should be completed within ± 6 days of the protocol-specific visit date.
d
Required for those subjects who complete Week 96 visit or those subjects who prematurely discontinue study drug and do not continue in the study through at least one subsequent visit 
after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through Week 96, if 
the subject discontinues study drug prior to completion of Week 96 visit.
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom-directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN) and PTH. At 
Day 1, Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry profile. PT/INR will be included in the 
chemistry profile at Screening, Weeks 24 and 48 only. This sample should be drawn prior to hemodialysis. The timing of draw and timing of hemodialysis should be recorded.
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of fasting metabolic assessments and not as 
part of the chemistry profile. 
k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure.
l
If the HIV-1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening and baseline 
results). See Section 6.6.1.
m
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV-1 RNA value ≥ 400 copies/mL. Subjects should be managed according 
to the Virologic Rebound Schema (Section 6.6.1). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the criteria described in this section.
n
CBC with differential and platelet count
o
For subjects who provide consent −serum and plasma storage samples for possible future testing will be collected.
p
See Section 4.2 to confirm subject eligibility prior to enrollment.
q
SF-36 is to be completed by subjects at Day 1, Week 24, Week 48, Week 72, and Week 96 visits. HIV-TSQs should be completed by the subjects at Screening, Day 1, Week 4, 
Week 24, Week 48, Week 72, Week 96 and ESDD visits. HIV-TSQc should be completed by the subjects at Week 24, Week 48, Week 72, Week 96 and ESDD visits. 
r
Subjects will be asked about their health utilization at Day 1 visit and every visit thereafter, including the ESDD and Unscheduled Visits.
s
Drug accountability only; study drug will not be dispensed at these visits.
t
At Week 4 or Week 12, pre-dose whole blood sample will be collected for subjects enrolled in the study. Sample collection should occur within 30 minutes prior to the study drug 
administration which should be observed on-site. PBMC processing will be completed by the central laboratory. 
u
At or between Week 2 or Week 4 study visits on a day prior to the day of hemodialysis and when the subject has administered three doses of E/C/F/TAF between two hemodialysis 
sessions. The ± 2 day window at Week 2 or Week 4 does not apply to the PK sub-study visit. Subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). Please see Section 6.5.1 and Appendix 3 Pharmacokinetic (PK) Sub-study for additional details.
v
Whole blood storage sample collected at baseline visit for virology assessments.


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Appendix 3.
Pharmacokinetic Sub-study
Blood Sampling Time Points for Intensive PK:
Study Day
Time Point (hrs) Post-dose
0.5
1
2
3
4
6
8
24
At or between Week 2 or Week 4
X
X
X
X
X
X
X
X
1) All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). 
2) PK sub-study visit must occur at or between Week 2 or Week 4 on a day prior to the day of 
hemodialysis and when the subject has administered three doses of E/C/F/TAF between 
two hemodialysis sessions. 
3) Study drug administration should be observed at the clinic prior to the 0.5 hour post-dose 
blood sample collection. 
4) Subject should be instructed to dose after the 24 hour post-dose blood sample collection is 
collected and after the completion hemodialysis. 
5) The sub-study will include intensive PK profiling in plasma. Details of the blood sampling 
procedures and sample management will be documented in the central laboratory manual. 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 75
28 November 2016
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Gradf 1 
L------G-'r-ad_f_2----~~ 
~~------G-·r-ad_f_3----~~ ~~---------G-r-·a_d_e_~---------" 
! 
! 
l\Iay coutinuf 
Rfpfat lab to 
dosing at rhf 
confirm toiicity 
discrfrion ofthf 
gradf' 
in\·~stigator 
1 
If confinnl'<l and possibly and/or probably rflatfd to 
inwsrigarionru mroicinal products: 
1. Withhold inwsrigational ml'<licinal products until~ Gradf 2 
2. 
Rfsrart. all inwstigational mfdicinal produc.rs at full dosf 
1 
lf Grade 3 or ~ rfcwTence that is confit1ned and possibly or 
probably relatfd to inwstigational mfclicinal pt·oducrs, 
discontinuf all inwstigatioual medicinal products dosing 
pHmaufntly 
1 
r---------, 
Rfpfat Jab to 
confirm to:ticity 
gradf 
· 
1 
lf co 
inw 
dos 
nfirmro and uw'flatfd to 
stigarionru mfdicinal products, 
mg may continue at the 
disc rfrion of thf in,·estigator 
If confit·ml'<l and 
possibly or probably 
-. rflatedto 
inYestigarionaJ 
medicinal products, 
cliscoutinue 
iuYestigarionaJ 
medicinal products 
dosing pmnanfntly 
and follow at periodic 
intervals at !fast 
wHklY until a retw·u 
to ba;eline or is 
otltftmsf explainfd 
If GraM 3 or 4 recwnncf that is considHro uw·flarfd to 
inYesrigational medidnaJ proclucr.s, continue all investigational 
medicinal products at tbf same dose at the discrftion of tbf 
in,·esrigatoJ· 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 76
28 November 2016
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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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.  


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 79
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 80
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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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 81
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 82
28 November 2016
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 83
28 November 2016
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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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


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Amendment 2
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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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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 2
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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 2
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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
Gilead Sciences, Inc.
Amendment 2
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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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Amendment 2
CONFIDENTIAL
Page 90
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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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Amendment 2
CONFIDENTIAL
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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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Amendment 2
CONFIDENTIAL
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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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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 93
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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


E/C/F/TAF
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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 94
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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]


E/C/F/TAF
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Amendment 2
CONFIDENTIAL
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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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Amendment 2
CONFIDENTIAL
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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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28 November 2016
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.
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.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of study drugs on 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. Data from clinical pharmacokinetic interaction studies of study drug 
have demonstrated that there is no reduction in the clinical efficacy of hormonal contraception or 
that the effect on hormonal contraception is insignificant. 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 
prior to study enrollment. A serum pregnancy test will be performed at all study visits and the 
end of relevant system exposure. In the event of a delayed menstrual period (over one month 
between menstruations), a serum 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)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods (the hormonal contraceptive should contain at least 30 mcg of 
ethinyl estradiol)
■
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
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.


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Amendment 2
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3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential. 
4) 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.
5) 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 30days 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. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.5.2.1.


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Gilead Sciences, Inc.
Amendment 2
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Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines)
{Selik et al 2014}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†


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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV§
*
Only among children aged < 6 years
†
Only among adults, adolescents, and children aged ≥ 6 years
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy 
and HIV wasting syndrome, are described in the following references {Centers for Disease Control and 
Prevention 1992, Centers for Disease Control and Prevention 1994}.

Prot_006.pdf: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy ofE/C/F/TAF 
Fixed Dose Combination (FDC) in HIV -1 Infected Subjects on 
Chronic Hemodialysis 
Sponsor: 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
IND Number: 
111,007 
EudraCT Number: 
2015-002713-30 
Clinical Trials.gov Identifier: Not Available 
Indication: 
HIV -1 Infection 
Protocol ID: 
GS-US-292-1825 
Clinical Program Manager: 
Name: 
Telephone: 
Fax: 
Gilead Medical Monitor: 
Name: 
Telephone: 
Fax: 
Protocol Version/Date: 
Original: 
PPD 
PPD 
PPD 
Devi SenGupta, MD 
PD 
PPD 
08 July2015 
CONFIDENTIALITY STATEMENT 
I 
The infonnation contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The infmmation 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 infmmation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessruy to obtain infmmed consent from those 
persons to whom the dmg may be administered. 


EICIFITAF 
Protocol GS-US-292-1825 
Gilead Sciences, Inc. 
TABLE OF CONTENTS 
Final 
Original 
TABLE OF CONTENTS ........ ................... ............... ............... ............... ............... ............... ............... ................ 2 
LIST OF IN-TEXT TABLES 
...... 4 
LIST OF IN-TEXT FIGURES 
.4 
PROTOCOL SYNOPSIS 
.. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . 
. 5 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS. 
.9 
1. 
INTRODUCTION .................................................... ............... ............... ............... ............... ................... .. .. 12 
1.1. 
1.2. 
1.3. 
1.4. 
1.5. 
Background ................... ................ ................ .. . 
Tenofovir Alafenamide (TAF, GS-7340) 
1.2.1. 
General Information .. .. .............. .. .............. ... .. 
1.2.2. 
Preclinical Pharmacology and Toxicology 
1.2.3. 
Nonclinical Pharmacokinetics ...................... .. 
1.2.4. 
Nonclinical Toxicology ............. .. .............. .. .............. .. .............. .. .. .. .. 
1. 2. 5. 
Clinical Trials of ElvitegraviriCobicistat/Em tricitabine/T enofovir 
.. .. 12 
.. .. 13 
.. .. 13 
.. .. 13 
.. .. 14 
.. .. 15 
Alafenamide (EIC/F IT AF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. ... 16 
Rationale for This Study .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. . .. . .. .. .. . .. .. . .. . .. .. .. . .. .. . .. . .. 
.. .. 17 
1.3.1. 
Rationale for Dose Selection ...................... ............... ............... ............... ................... .. .. 18 
Risk/Benefit Assessment for the Study ........................ ............... ............... ............... ................... .. .. 20 
Compliance 
.. .. .. .. .. .. .. . .. .. .. .. .. .. .. . 
. .............. ............... ............... ............... ................... .. .. 20 
2. 
OBJECTIVES 
.. .. 21 
.. .. 22 
.. .. 22 
.. .. 22 
.. .. 23 
.. .. 23 
.. .. 23 
.. .. 23 
.. .. 23 
3. 
4. 
5. 
STUDY DESIGN ........... .. 
3. 1. 
Study Design 
3.2. 
Study Treatments ............ .. 
3.3. 
Duration of Treatment 
3.4. 
End of Study ................ ... .. 
3. 5. 
Post Study Care 
3.6. 
Source Data ............ .. 
3.7. 
PPD 
~--------------------------~ 
SUBJECT POPULATION .......................................... .. 
4.1. 
4.2. 
4.3. 
Number of Subjects and Subject Selection 
Inclusion Criteria ......... .. .. ............ .. .. ............ ....... .. 
Exclusion Criteria ................................................ . 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
Emollment.. .. .. 
Description and Handling ofEIC/F/TAF FDC Tablets .. 
5. 2. 1. 
Formulation .. 
5.2.2. 
Packaging and Labeling 
5.2.3. 
Storage and Handling ... 
Dosage and Administration of EICIF IT AF 
Prior and Concomitant Medications 
Accountability for EICIF IT AF 
5.5.1. 
Study Drug Return or Disposal 
6. 
STUDY PROCEDURES .... 
6.1. 
6.2. 
Subject Emollment and Treatment Assignment. 
Pretreatment Assessments ............ .. .............. .. ... . 
CONFIDENTIAL 
Page 2 
.. .. 24 
.... 24 
.. .. 24 
.. .. 26 
.... 28 
.... 28 
.. .. 28 
.. .. 28 
.... 28 
.. .. 29 
.. .. 29 
.. .. 29 
.. .. 35 
.... 35 
.. .. 36 
........ 36 
. ....... 36 
08 July 2015 


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6.2.1.
Screening Visit .....................................................................................................................36
6.2.2.
Day 1 Assessments...............................................................................................................38
6.3.
Treatment Assessments (Weeks 2-48) ...................................................................................................39
6.4.
Post-treatment Assessments ...................................................................................................................41
6.4.1.
30-Day Follow-up Assessments...........................................................................................41
6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)....................................................42
6.4.3.
Criteria for Discontinuation of Study Treatment..................................................................44
6.5.
Other Evaluations...................................................................................................................................44
6.5.1.
Pharmacokinetic (PK) Sub-study .........................................................................................44
6.5.2.
Blood Storage.......................................................................................................................44
6.6.
Virologic Failure....................................................................................................................................45
6.6.1.
Management of Virologic Failure ........................................................................................45
6.6.2.
Subjects with ≥ 400 Copies/mL of HIV-1 in the Absence of VR ........................................45
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................47
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events....................................47
7.1.1.
Adverse Events.....................................................................................................................47
7.1.2.
Serious Adverse Events........................................................................................................47
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................48
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................48
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................48
7.2.2.
Assessment of Severity ........................................................................................................49
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................49
7.3.1.
Adverse Events.....................................................................................................................49
7.3.2.
Serious Adverse Events........................................................................................................49
7.4.
Gilead Reporting Requirements.............................................................................................................51
7.5.
Special Situations Reports......................................................................................................................51
7.5.1.
Definitions of Special Situations..........................................................................................51
7.5.2.
Instructions for Reporting Special Situations.......................................................................52
7.6.
Toxicity Management ............................................................................................................................53
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................53
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................53
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................54
7.6.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management in Subjects Co-infected with Hepatitis B........................................................54
8.
STATISTICAL CONSIDERATIONS................................................................................................................56
8.1.
Analysis Objectives and Endpoints........................................................................................................56
8.1.1.
Analysis Objectives..............................................................................................................56
8.1.2.
Primary Endpoint .................................................................................................................56
8.1.3.
Secondary Endpoints............................................................................................................56
8.2.
Analysis Conventions.............................................................................................................................56
8.2.1.
Analysis Sets ........................................................................................................................56
8.3.
Demographic Data and Baseline Characteristics ...................................................................................57
8.4.
Primary and Secondary Analysis ...........................................................................................................57
8.4.1.
Primary Analysis..................................................................................................................57
8.4.2.
Secondary Analyses .............................................................................................................57
8.5.
Safety Analysis.......................................................................................................................................57
8.5.1.
Extent of Exposure...............................................................................................................58
8.5.2.
Adverse Events.....................................................................................................................58
8.5.3.
Laboratory Evaluations ........................................................................................................58
8.5.4.
Other Safety Evaluations......................................................................................................59


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8.6.
Pharmacokinetic Analysis......................................................................................................................59
8.7.
Sample Size............................................................................................................................................59
8.8.
Data Monitoring Committee ..................................................................................................................59
9.
RESPONSIBILITIES..........................................................................................................................................60
9.1.
Investigator Responsibilities ..................................................................................................................60
9.1.1.
Good Clinical Practice..........................................................................................................60
9.1.2.
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................60
9.1.3.
Informed Consent.................................................................................................................61
9.1.4.
Confidentiality......................................................................................................................61
9.1.5.
Study Files and Retention of Records ..................................................................................61
9.1.6.
Case Report Forms...............................................................................................................63
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................63
9.1.8.
Inspections............................................................................................................................63
9.1.9.
Protocol Compliance............................................................................................................64
9.2.
Sponsor Responsibilities ........................................................................................................................64
9.2.1.
Protocol Modifications.........................................................................................................64
9.2.2.
Study Report and Publications .............................................................................................64
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................64
9.3.1.
Payment Reporting...............................................................................................................64
9.3.2.
Access to Information for Monitoring..................................................................................65
9.3.3.
Access to Information for Auditing or Inspections ..............................................................65
9.3.4.
Study Discontinuation..........................................................................................................65
10.
REFERENCES ...................................................................................................................................................66
11.
APPENDICES ....................................................................................................................................................69
Appendix 1.
Investigator Signature Page....................................................................................................70
Appendix 2.
Study Procedures Table..........................................................................................................71
Appendix 3.
Pharmacokinetic Substudy .....................................................................................................74
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................75
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............76
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}.....................................101
LIST OF IN-TEXT TABLES
Table 4-1.
Disallowed Agents .................................................................................................................27
Table 5-1.
Prior and Concomitant Medications.......................................................................................31
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................22
Figure 6-1.
Schema for Management of Virologic Failure .......................................................................46


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b Open-Label Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Efficacy of E/C/F/TAF 
Fixed Dose Combination (FDC) in HIV-1 Infected Subjects on 
Chronic Hemodialysis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002713-30
Not available 
Study Centers Planned:
Approximately 50 study sites in North America and Europe
Objectives:
The primary objective of this study is as follows:

To evaluate the safety and tolerability of the
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
(EVG/COBI/FTC/TAF; E/C/F/TAF) fixed dose combination 
(FDC) in HIV-1 infected adults with end stage renal disease 
(ESRD) on chronic hemodialysis (HD) at Week 48
The secondary objectives of this study are as follows: 

To evaluate the proportion of subjects achieving virologic 
response (defined as HIV-1 RNA < 50 copies/mL, 
Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, 
FTC, TAF and TFV in HIV-1 infected patients with ESRD on 
HD
Study Design:
Open-label, multicenter, single-arm study to assess the safety, 
tolerability, pharmacokinetics, and efficacy of E/C/F/TAF FDC
dosed once daily in HIV-infected adult subjects with ESRD on 
chronic HD. 
All subjects will switch from their current antiretroviral (ARV) 
regimen to E/C/F/TAF on Day 1. The treatment duration will be 
48 weeks.
Number of Subjects 
Planned:
Approximately 50 subjects with ESRD on chronic HD will be 
enrolled.


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Target Population:
HIV-1 infected adults (≥18 years) with ESRD on chronic HD for 
≥6 months prior to screening, and HIV-1 RNA < 50 copies/mL on 
a stable antiretroviral (ARV) regimen for ≥ 6 consecutive months 
prior to screening.
Duration of Treatment:
Subjects will be treated for 48 weeks.
Diagnosis and Main 
Eligibility Criteria:
HIV-1-infected adults who meet the following criteria:

No documented history of HIV-1 resistance to EVG, FTC,
3TC or TFV

Currently receiving a stable antiretroviral regimen for 
≥6 consecutive months prior to screening

Plasma HIV-1 RNA < 50 copies/mL for at least 6 months 
preceding the screening visit

CD4+ T cell count of ≥ 200 cells/μL

ESRD with eGFR < 15 mL/min by Cockcroft-Gault, 
on chronic HD for ≥ 6 months prior to screening

Chronic Hepatitis B (HBV) infection allowed 

Hepatitis C (HCV) infection allowed 
Study Procedures/
Frequency:
Following Screening, eligible subjects will be required to return 
for study visits at Day 1, Weeks 2, 4, 8, 12, 24, 36 and 48. After 
the Week 48 visit, subjects will stop study drug and complete a 
30-Day Follow-up visit to complete their participation in the study.
For all subjects, HBV and HCV serologies will be analyzed at 
Screening. Adverse events, concomitant medications, complete or 
symptom-directed physical examinations, laboratory analyses 
(hematology and chemistry), fasting lipids and glucose, 
HIV-1 RNA, CD4+ T cell count and estimated GFR will be 
performed at the Screening, Day 1, and all subsequent study visits.
A single pre-dose blood draw for PBMCs will be collected from
all subjects at Week 4 or Week 12, which must be the day of 
hemodialysis. 
All subjects who provide consent will be eligible to participate in 
the pharmacokinetic sub-study (target n = 15).


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Test Product, Dose, and 
Mode of Administration:
FDC of elvitegravir 150 mg / cobicistat 150 mg /
emtricitabine 200 mg / tenofovir alafenamide 10 mg 
administered orally once daily with food until the next 
hemodialysis. On the day of hemodialysis, study drug should be 
administered two to four hours following completion of 
hemodialysis. 
Reference Therapy, 
Dose, and Mode of 
Administration:
N/A
Criteria for Evaluation:
Safety:
Safety evaluations will include reporting of adverse events,
clinical laboratory tests, physical examinations, and vital signs. 
An Independent Data Monitoring Committee (IDMC) will be 
convened after the first 25 subjects enrolled in the study complete 
Week 12 of the study. 
Efficacy:
Virologic response will be determined using the percentages of
subjects with HIV-1 RNA < 50 copies/mL at Week 24 and 48
(snapshot analysis).
Pharmacokinetics:
At Week 4 or Week 12, on the day of hemodialysis, observed 
study drug administration will occur 2 to 4 hours after the 
completion of hemodialysis. A pre-dose (within 30 minutes prior 
to study drug administration) PBMC blood sample will be 
collected from all subjects. Plasma concentrations of EVG, COBI, 
FTC, TAF and TFV and intracellular concentrations of TFV-DP 
may be explored.
Pharmacokinetic (PK) Sub-study
All subjects who provide consent will be eligible to participate in 
the PK sub-study (target n = 15). For the PK sub-study, post-dose 
blood samples will be collected at or between Week 4 or Week 8, 
on the day of hemodialysis. The PK of EVG, COBI, FTC, TAF 
and TFV will be evaluated. Study drug administration will be 
observed in-clinic at the sub-study visit. 
Health Related 
Questionnaires:
SF-36, VAS (visual analogues scale), HIV-TSQ 
(HIV Treatment Satisfaction Questionnaire) and 
Health Utilization Questionnaire will be administered per the 
information provided in the study procedures section of this 
protocol.


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Original
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Statistical Methods:
The primary endpoint will be the incidence of treatment-emergent 
Grade 3 or higher adverse events at Week 48.
The proportions of subjects with virologic response 
(HIV-1 RNA < 50 copies/mL, snapshot analysis) and the 
associated 95% confidence intervals at Weeks 24 and 48, 
respectively will be constructed.
Concentrations and PK parameters of EVG, COBI, FTC, TAF and 
TFV for the sub-study, and intracellular PBMC concentrations of 
TFV-DP will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV),
median, minimum, and maximum].
A sample size of approximately 50 subjects is based on practical 
consideration and is considered to be sufficient to evaluate the 
primary objective of this study. The grade 3 or higher AE rate in 
Study GS-US-292-0112 in subjects that had mild to moderate
renal impairment was 8.8% at Week 48 for the E/C/F/TAF arm. 
Therefore, with 50 subjects, and an assumed rate of Grade 3 or 
higher AEs being 10%, this study would provide 95% confidence 
for the primary endpoint to be (1.7%, 18.3%) assuming normal 
approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating 
the PK parameters in the sub-study for practical reasons. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time curve
bsAP
serum bone specific alkaline phosphatase
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration
of drug
Cmin
minimum plasma concentration
CNS
central nervous system
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
E/C/F/TAF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir alafenamide (TAF) 10 mg fixed dose combination
ESRD
End stage renal disease
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FS
failure to suppress
FTC
emtricitabine
GCP
Good Clinical Practice (Guidelines)


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GS-7340 
tenofovir alafenamide, TAF, L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester
HAART
highly active antiretroviral therapy
HBsAg
hepatitis B virus surface antigen serology
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus serology
HD
hemodialysis
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HMG-CoA
5-hydroxy-3-methylglutaryl-coenzyme A
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
DMC
Data Monitoring Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IRB
institutional review board
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MH
Mantel-Haenszel
Min
minute
mmHg
millimeters mercury
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OC
osteocalcin
P1NP
procollagen Type 1 N-terminal propeptide
PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term 
PTH
parathyroid hormone
QD
once daily 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SAE
serious adverse event
SVR
suboptimal virologic response
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
ULN
upper limit of the normal range
US
United States
VR
virologic rebound


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 infection is a life-threatening and serious disease of major 
public health significance, with approximately 34 million people infected with HIV worldwide 
{19661}. The goals of highly active antiretroviral therapy (HAART) for HIV-1 infection are to 
delay disease progression and prolong survival by achieving maximal and durable suppression of 
HIV-1 replication. Prompt antiretroviral therapy (ART) initiation after diagnosis is based on 
growing evidence that untreated HIV infection or uncontrolled viremia is associated with 
development of non- acquired immune deficiency syndrome (AIDS)-defining diseases, including 
cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and 
malignancies. The success of ART has shifted clinical attention towards regimens that optimize 
long-term adherence, tolerability and safety. Adherence to ART is required to prevent 
development of drug resistance and subsequent loss of virologic suppression, and adherence to 
ART is improved by reducing pill burden and dosing frequency {4266}, {4256}. Once-daily, 
single tablet regimens are associated with high adherence, better clinical outcomes, including 
fewer hospitalizations, improved patient satisfaction, and excellent virologic outcomes {7034}, 
{7035}, {7036}, {16557}, {16560}.
Despite current therapy that effectively suppresses viremia, HIV disease remains a serious 
condition due to non-AIDS associated comorbidities. As treatment guidelines recommend early 
treatment of HIV-1 infection, there is a need for regimens offering enhanced product safety and 
tolerability, effectiveness, and convenience for long-term treatment.
Though antiretroviral drugs have led to dramatic improvements in survival and disease 
progression, complications such as kidney, liver, and cardiac disease have become increasingly 
important causes of morbidity and mortality for HIV patients taking effective therapy {19947}, 
{19948}, {22552}. Recent data has shown that even with treatment, HIV patients experience more 
age-related co-morbidities, such as renal and bone disease, which manifest earlier than their 
age-matched HIV-uninfected peers {19946}. Moreover, the prevalence and incidence of chronic 
kidney disease (CKD) and end stage renal disease (ESRD) in the US are expected to rise as the 
prevalence of HIV infection continues to rise {22553}. Worldwide, prevalence may be even
greater; one cross-sectional study in the East African Republic of Burundi reported 
46% of HIV-positive adults fulfilled criteria for CKD {22551}.
Patients with HIV are at risk for acute and chronic kidney disease from a wide spectrum of 
etiologies, including HIV-associated nephropathy, immune complex kidney disease, thrombotic 
microangiopathy, and kidney disease associated with comorbidities such as diabetes, 
hypertension, hepatitis B and hepatitis C coinfections, as well as medications associated with 
nephrotoxicity. Clearly, new therapies that improve on the current standard of care are needed, 
so that life-long antiviral therapy is more effective, more tolerable, and safer for patients. 
Since the majority of currently available nucleos(t)ide backbones are prescribed as fixed dose 
combinations, HIV-positive patients with chronic kidney disease have particularly limited 
therapeutic options.


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The availability of a single tablet regimen composed of potent agents with improved tolerability 
and long-term safety, that does not require dose adjustment at eGFR < 50 mL/min, would 
represent an important therapeutic innovation in this special patient population, providing more 
convenient dosing and potentially improving patient adherence.
Tenofovir alafenamide (TAF) has a unique metabolism that provides enhanced lymphatic 
delivery of tenofovir, resulting in higher intracellular levels of the active phosphorylated 
metabolite, tenofovir-diphosphate (TFV-DP), and lower circulating levels of TFV {7415}, 
{13119}, {22029}. The distinct metabolism of TAF offers an improved clinical profile compared 
with TDF, which is associated with nephrotoxicity and decreased bone mineral density {21762}, 
{22031}. Compared with TDF, TAF is characterized by lower systemic exposures and higher 
intracellular levels of TFV. Additionally, TFV exposures achieved with TAF in subjects with 
severe renal impairment are comparable to those with normal renal functions receiving 
TDF 300 mg, indicating that TAF can be administered to HIV-1 infected patients with renal 
impairment without dose modification. 
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is an prodrug of TFV, 
a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolized intracellularly 
to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 reverse transcriptase (RT) 
that terminates the elongation of the viral deoxyribonucleic acid (DNA) chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids. 
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
Tenofovir alafenamide is metabolized to TFV, a nucleotide analog (ie, a nucleoside 
monophosphate analog) which is not dependent on an intracellular nucleoside kinase activity 
for the first step in the conversion to the active metabolite, TFV-DP. The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{4887} and nucleotide diphosphate kinase, which are highly active and ubiquitous. AK exists as 
multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most efficiently by 
AK2.


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The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in different 
human blood lymphocyte subpopulations, CD4+ and CD8+ T cells, natural killer (NK) cells,
B-cells and macrophages/monocytes. TAF is metabolized inside host cells to the active 
metabolite TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all 
cell populations.
1.2.2.2.
Safety Pharmacology
Single doses of TAF did not induce pharmacologic effects on the central nervous system of the 
rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the cardiovascular system of the 
dog (100 mg/kg).
1.2.3.
Nonclinical Pharmacokinetics
All nonclinical PK experiments were performed using TAF monofumarate (GS-7340-02), and all 
study data described in this section reflect the dosage of the monofumarate. For reference, 
100 mg of TAF monofumarate is equivalent to 80 mg of the GS-7340 free base (TAF).
Key results from nonclinical absorption, distribution, metabolism, and excretion studies of TAF 
are as follows: 

Following oral administration in dogs and monkeys, TAF demonstrated rapid absorption, 
with peak plasma concentrations between 0.25 and 0.5 hours. Thereafter, TAF plasma 
concentrations declined rapidly with a terminal half-life of less than 1 hour. 
Tenofovir alafenamide exposure (Cmax and AUC values) was nonlinear with dose and greater 
than expected with increasing dose. Repeat-dose studies in rats and monkeys showed no 
change in pharmacokinetics over time. 

Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. 

Following oral administration of [14C]-radiolabeled TAF to dogs, a mean total recovery of 
radioactivity at 24 hours of 63% was demonstrated. Radioactivity was detected in all tissues 
except brain with the majority present in the contents of the gastrointestinal tract, liver, 
kidney, and large intestine. Tissue concentrations were the highest in kidney, peripheral 
blood mononuclear cells (PBMCs), liver, large intestine, and bile. Additional studies in dogs, 
TFV concentrations in PBMCs following oral administration of TAF were approximately 
50-fold greater than observed in plasma, with an estimated t½ of greater than 24 hours. 

The major route of elimination of TAF-related radioactivity was via feces, with 
approximately 35% of the dose recovered in feces through 48 hours postdose. The primary 
route of elimination of TFV is renal excretion of unchanged drug based on IV studies of 
TFV. 


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
Tenofovir alafenamide has been found to be a substrate for intestinal efflux transport and in 
nonclinical studies its intestinal absorption was increased by the transport inhibitor 
cyclosporin A. 

No significant inhibition of human drug metabolizing cytochrome P450 (CYP) enzymes, 
uridine diphosphate glucuronyltransferase (UGT) 1A1 or transporters including 
P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide 
(OATP)1B1 and OATP1B3 was observed with TAF in vitro.

Tenofovir alafenamide did not activate human pregnane X receptor (hPXR) or 
aryl hydrocarbon receptor (AhR).

Tenofovir alafenamide was not a substrate for drug-metabolizing CYP enzymes except for 
CYP3A4, which metabolized the compound slowly. 
1.2.4.
Nonclinical Toxicology
Key results from nonclinical toxicology studies of TAF are as follows:

Based on TFV exposure, the no observed adverse effect levels (NOAELs) in the 6-month rat, 
9-month dog, and 1-month monkey studies provide 14-, 4-, and 22-fold safety margins, 
respectively, for a human dose of 25 mg/day.

In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment with TAF 
100 mg/kg/day; however, effects were not seen at lower doses. Tenofovir alafenamide also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above.

In chronic studies in dogs after 9 months of treatment at doses up to TAF 18/12 mg/kg/day 
(the high dose was reduced from 18 to 12 mg/kg/day due to the occurrence of death, severe 
clinical signs and reduced body weight), the primary target organs were kidney 
(slight to moderate renal tubular degeneration and karyomegaly) and bone 
(decreased bone mineral density [BMD] in metaphyseal cancellous bone). 

Tenofovir alafenamide had no discernable electrocardiograph effect at the low dose of 
2 mg/kg/day. There was some evidence at 6 and 18/12 mg/kg/day for an effect to slightly 
prolong PR intervals. 

After 9 months of treatment, some dogs administered the highest dose of TAF 
(18/12 mg/kg/day) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given 
lower doses and it has not occurred in other animal studies. 


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
There were no clear treatment-related effects observed in monkeys following 28 days of 
TAF treatment at 3 and 30 mg/kg/day, including no changes in mitochondrial function and 
mitochondrial DNA (mtDNA) content in the liver, kidney, and skeletal muscle, and 
characterization of lymphocyte populations.

Tenofovir alafenamide was not genotoxic in either in vitro or in vivo assays. 
Tenofovir alafenamide had no adverse effects on male or female fertility parameters in rats. 
There was no effect on fetal viability or fetal development in pregnant rats administered 
doses of TAF up to 250 mg/kg/day or in pregnant rabbits administered TAF up to 
100 mg/kg/day; the highest doses were maternally toxic.
1.2.5.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
(E/C/F/TAF)
Emtricitabine and TAF have been combined with the integrase inhibitor EVG and its 
pharmacoenhancer COBI in the E/C/F/TAF FDC, which has been designed to be a complete 
treatment regimen for HIV-1 infection and is being evaluated in a broad clinical development 
program. The details of the key clinical studies are provided below:

GS-US-292-0102, a randomized, double-blinded controlled Phase 2 study in which 
E/C/F/TAF is compared to Stribild® (STB), as initial treatment of HIV-infection in 
ART-naive patients. This is a single-variable clinical comparison of the 2 tenofovir prodrugs, 
TAF and TDF 

GS-US-292-0104 and GS-US-292-0111, Phase 3 randomized, double-blinded studies of the 
safety and efficacy of E/C/F/TAF versus E/C/F/TDF in HIV-1 infected, antiretroviral 
treatment-naive adults. The interim Week 48 key conclusions from pooled data are as 
follows: 1) E/C/F/TAF once daily was noninferior to STB once daily when administered
for 48 weeks to HIV-infected, ART-naive adults, as assessed using the US Food and Drug
Administration (FDA)-defined snapshot algorithm with HIV-1 RNA < 50 copies/mL 
(E/C/F/TAF 92.4%; STB 90.4%; difference in percentages: 2.0%, 95% CI: -0.7% to 4.7%), 
2) administration of E/C/F/TAF resulted in > 90% lower plasma TFV and higher intracellular 
TFV-DP relative to STB, 3) E/C/F/TAF showed an improved renal and bone safety profile 
with significantly less decline in hip and spine BMD, less increase in serum creatinine and 
reduction in estimated glomerular filtration rate (eGFR), 4) Increases from baseline in fasting 
total cholesterol fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides 
were noted in the E/C/F/TAF group;


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
GS-US-292-0112, a Phase 3 open-label safety study of E/C/F/TAF in HIV-1 positive patients 
with mild to moderate renal impairment; Week 48 results demonstrated that patients who 
switched to E/C/F/TAF had no change in eGFR, and had significant improvements in 
measures of renal function including proteinuria, albuminuria, retinol binding protein and 
beta-2-microglobulin. These subjects also had improvements in measures of bone mineral 
density. Importantly, because FTC was given without dose adjustment to patients with 
eGFR 30-50 mL/min, these patients had comparable safety profile to patients with 
eGFR 50-69 mL/min, with no increased rate of potential FTC related drug reactions, 
supporting the safety of FTC at higher exposures. In addition, 92% of study participants 
maintained virologic suppression (HIV-1 RNA < 50 copies/ml) at Week 48 after switching to 
E/C/F/TAF.

GS-US-292-0109, a Phase 3 study designed to evaluate the safety, efficacy, and tolerability 
of switching to E/C/F/TAF in individuals who are virologically suppressed on regimens 
containing TDF. The interim Week 48 key conclusions from this study are as follows: 
1) switching to E/C/F/TAF was noninferior to maintaining FTC/TDF + 3rd Agent 
(STB, efavirenz/emtricitabine/tenofovir DF (ATR), atazanavir (ATV)/boosted + Truvada®) 
as assessed using the FDA snapshot algorithm (Week 48 FAS) with HIV-1 RNA cutoff at 
50 copies/mL (E/C/F/TAF 95.6%; FTC/TDF + 3rd Agent 92.9%; difference in percentages: 
2.7%, 95.01% CI: -0.3% to 5.6%), 2) An improved renal and bone safety profile was 
observed in subjects who switched to E/C/F/TAF, 3) there were no differences in ocular 
findings between treatment groups and no reported cases of uveitis.
1.3.
Rationale for This Study
Because of the increasing average age of HIV-infected patients, the high prevalence of chronic 
kidney disease, and the increasing prevalence of co-morbid conditions that require medical 
management, medical regimens in ESRD patients are complex and can impact a patient’s overall 
risk of morbidity and mortality. The availability of a single-tablet regimen composed of potent 
agents with improved tolerability and long-term safety that does not require dose adjustment at 
eGFR < 15 mL/min, would represent an important therapeutic innovation for HIV infected
patients with ESRD. EVG, COBI, and TAF are not renally eliminated, while the metabolite of 
TAF (TFV) and FTC, are renally eliminated. 
The E/C/F/TAF FDC was recently shown to be safe and efficacious in HIV-infected patients 
with mild to moderate chronic kidney disease (CKD; eGFR 30-69 mL/min) in study 
GS-US-292-0112 through 48 weeks. The long-term safety of E/C/F/TAF remains to be 
established in subjects at more advanced stages of renal impairment, including those with ESRD 
on hemodialysis. The present study will provide the pharmacokinetic data describing TFV and 
FTC exposures in these patients when administered as the E/C/F/TAF FDC, dosed once daily, as 
well as safety and efficacy data in this special population through 48 weeks. 


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1.3.1.
Rationale for Dose Selection
The E/C/F/TDF FDC containing EVG (150 mg), COBI (150 mg), FTC (200 mg), and TAF (10 mg),
is currently under review for use once daily for the treatment of human immunodeficiency virus 
type 1 (HIV-1) infection in adults and pediatric patients 12 years of age and older without any 
known resistance to the individual components. This FDC contains the equivalent doses of 
EVG and COBI in the marketed product, Stribild®. The FTC (200 mg) in the E/C/F/TAF FDC 
represents the marketed dose in several approved FDC products: emtricitabine/tenofovir DF, 
efavirenz/emtricitabine/tenofovir DF, and emtricitabine/rilpivirine/tenofovir DF for the treatment 
of HIV-1 infection.
EVG, COBI, and TAF are not renally eliminated, while the metabolite of TAF (TFV) and FTC, 
are renally eliminated. 
TAF
The Phase 3 study GS-US-292-0112 demonstrated that patients with moderate renal impairment 
(baseline eGFR 30-50 mL/min) who switched to E/C/F/TAF had no change in eGFR, and had 
significant improvements in measures of renal function including proteinuria, albuminuria, 
retinol binding protein and beta-2-microglobulin. These subjects also had improvements in 
measures of bone mineral density. TAF PK in subjects with screening eGFR 30-69 mL/min was 
consistent with data following administration of E/C/F/TAF in nonrenally-impaired 
HIV-infected subjects in Phase 2 and Phase 3 studies. 
Data from GS-US-120-0108 demonstrated that in HIV uninfected subjects with an eGFR of 
15-29 mL/min, plasma TAF exposures increased < 2-fold. Study GS-US-292-1825 will evaluate 
TAF (as well as TFV and FTC) PK in the setting of daily administration of E/C/F/TAF STR in 
treatment-experienced subjects with eGFR < 15 mL/min on chronic hemodialysis.
TFV
In subjects with ESRD, systemic TFV exposures are expected to be higher, but not as high as 
TDF 300 mg. Data from several studies have demonstrated ~90% lower AUC and ~95% lower Cmax
of TFV following administration of TAF vs. TDF (GS-US-120-1101, GS-US-120-0104), 
and the renal impairment study (GS-US-120-0108) showed a mean (% CV) TFV AUCinf of
2074.4 (47.1) ng•h/mL in severe renal impairment, which is within or lower than the range of 
TFV exposures observed in subjects with normal renal function receiving TDF 300 mg once 
daily (2020-2480 ng•h/mL). Given the extensive safety data available for TDF at these 
therapeutic exposures, TFV exposures in renally impaired subjects in the range of those from 
TDF in patients with normal renal function would not require TAF dose modification. PK 
modeling of TAF in ESRD in hemodialysis also indicates that the mean TFV AUC for a daily 
TAF dose of 25 mg is equivalent to a TDF dose of 300 mg plus atazanavir boosted with ritonavir 
in a subject with CrCl > 50 mL/min.


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FTC
The FTC dose (200 mg) in the E/C/F/TAF FDC represents the marketed dose as part of the 
approved products FTC (Emtriva®), FTC/TDF (Truvada®), efavirenz/FTC/TDF (Atripla®), 
FTC/rilpivirine/TDF (Complera® or Eviplera®), and E/C/F/TDF (Stribild®) for the treatment of 
HIV-1 infection. Emtricitabine is principally eliminated by the kidney and higher exposures are 
observed in patients with moderate to severe renal impairment. For eGFR of 30-49 mL/min, 
Emtriva prescribing information recommends dose interval adjustment of the 200 mg oral 
capsule to q48h. However, available clinical experience suggests the plasma FTC may not 
require dose adjustment in the setting of renal impairment. In study GS-US-292-0112, FTC was 
given without dose adjustment to patients with eGFR 30-50 mL/min, and these patients had 
comparable safety profile to patients with eGFR 50-69 mL/min, with no increased rate of 
potential FTC related drug reactions, supporting the safety of FTC at higher exposures. 
In Study FTC-107, an open-label, parallel-group study of single-dose emtricitabine 200 mg in 
HIV uninfected subjects with varying degrees of renal impairment, 6 subjects with moderate 
renal impairment (30-49 mL/min), 5 subjects with severe renal impairment (< 30 mL/min) and 
6 subjects on dialysis were treated. Of note, subjects with baseline eGFR of 30-49 mL/min had 
only twice the mean FTC systemic exposure (mean (%CV) AUCinf: 25.08 hr•μg/mL (23)) 
compared to subjects with eGFR > 80 mL/min (mean (%CV) AUCinf: 11.78 (25) hr•μg/mL. 
Subjects on dialysis had an AUCinf of 53.22 hr•μg/mL (19). In all cohorts, the overall incidence 
of adverse events was low and there was no apparent relationship between the incidence of AEs 
and the degree of renal impairment. 
In study GS-US-104-0235, the safety and tolerability of FTC+TDF (200/300 mg) in 
treatment-naïve and treatment-experienced HIV infected subjects with various degrees of renal 
impairment were assessed. One subject in this study assigned to the mild impairment group was 
later found to have moderate impairment (eGFR ≥30 and < 50 mL/min) and one subject 
assigned to moderate impairment was found to have severe impairment (eGFR < 30 mL/min) 
after 40 days of treatment. Based on PK analyses of these subjects, the subject with moderate 
renal impairment was continued on FTC 200 mg daily because FTC exposures remained within 
the predicted range for subjects without renal impairment and the subject with severe renal 
impairment continued to receive FTC 200 mg every 48 hours based upon appropriate FTC 
systemic exposures. 
Consistent with the renal impairment Study FTC-107 described above, results from the PK sub-
study of GS-US-292-0112 (n = 30) showed that FTC exposure was slightly higher in subjects 
with mild to moderate renal impairment as compared with historical data on FTC in subjects 
with normal renal function (mean [%CV] FTC AUCtau 20968.6 [25.5] ng•h/mL versus 
11,714.1 [16.6] ng•h/mL in Phase 2 Study GS-US-292-0102 of non-renally-impaired 
HIV-infected subjects), as expected due to the renal elimination of FTC. Further population PK 
analysis on all subjects treated in Study GS-US-292-0112 with available FTC data (n = 241), 
confirmed the findings from the PK sub-study, showing slightly higher FTC exposures in 
subjects with baseline eGFRCG < 50 mL/min, as compared with subjects with baseline 
eGFRCG ≥50 mL/min. Importantly, these observed differences in FTC exposure by 


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renal impairment subgroup did not result in a different safety profile. The incidence of adverse 
events that occurred in ≥ 5% of subjects and of treatment-related adverse events that occurred in 
≥1% of subjects was similar between groups after 48 weeks of treatment. Adverse reactions 
from the Emtriva SmPC were also specifically evaluated. Despite higher FTC exposure in this 
study, incidence of these events was similar in subjects with eGFRCG < 50 mL/min and in 
subjects with eGFRCG ≥50 mL/min. The current study will evaluate FTC exposures and safety, 
and an IDMC will be convened to monitor safety data.
1.4.
Risk/Benefit Assessment for the Study
Potential risks of a patient’s study involvement include switching to an unfamiliar regimen with 
potential loss of virologic control and/or new adverse events, the inconvenience of more frequent 
clinic visits and laboratory blood draws and the associated pain and discomfort of phlebotomy. 
Strategies to mitigate these risks include close monitoring of viral load, CD4+ T cell count and 
other lab values as well as monitoring of adverse events. Parameters for discontinuation of the 
study drug due to adverse events or lack of efficacy will be well-defined and closely followed. 
In addition, an independent data monitoring committee will be convened at Week 12 to evaluate 
safety data and determine whether the risks/benefits warrant continuation of the study. 
Potential benefits may include the patient receiving a FDC antiretroviral regimen that is more 
convenient leading to improved adherence, with potentially fewer adverse events than the current 
regimen, E/C/F/TAF may provide an alternative treatment for a patient population with fewer 
therapeutic options than the general HIV-1-infected population. 
Considering the above, the benefit-risk balance for this study is considered positive.
1.5.
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 safety and tolerability of E/C/F/TAF FDC in HIV-1 infected adults with
ESRD on chronic HD at Week 48
The secondary objectives of this study are:

To evaluate the proportion of subjects achieving virologic response (defined as 
HIV-1 RNA < 50 copies/mL, Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in 
HIV-1 infected patients with ESRD on HD


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3. 
STUDY DESIGN 
3.1. 
Study Design 
This is an open-label, multicenter, single-rum study to assess the safety, tolerability, 
phrumacokinetics, and efficacy ofEICIFITAF FDC in HIV-1 infected adult subjects with 
ESRD on chronic HD. 
Final 
Original 
Approximately 50 subjects with ESRD on chronic HD will be enrolled. All subjects will switch 
from their cunent antiretroviral regimen to EICIFITAF on Day 1. The total treatment dmation 
will be 48 weeks. After Week 48 visit, all subjects will stop study dmg and complete a 30-Day 
Follow-up visit. 
Figure 3-1. 
Screening 
:::; 30 days 
prior to 
Baseline 
Study Schema 
Day 1 
Week48 
(Primmy Endpoint) 
48 Weeks of Treatment on EICIFITAF 
(n = approximately sot 
30-Day 
Follow-upb.c 
a 
Following the Day 1 visit, subjects will retmn for study visits at Weeks 2, 4, 8, 12, 24, 36 and 48. 
b 
After 48 weeks, subjects will stop study dmg and c.omplete a 30-Day Follow-up visit to end their patticipation in the study. 
c 
Subjects who discontinue study dmg administration before their Week 48 visit, will complete and ESDD visit. 
These subjects may remain on the study off study dtug up to the Week 48 visit. Upon completion of Week 48 visit, subjects 
may be required to rehun to d1e clinic for a 30-Day Follow-up visit to complete their patticipation in d1e study. 
3.2. 
Study Treatments 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg I cobicistat 150 mg I emtricitabine 200 mg I tenofovir alafenamide 10 mg 
(EICIFITAF), on Day 1. 
Study dmg will be administered orally once daily with food at approximately the same time 
every day. On the day of hemodialysis, study chug administration should occm 2 hours following 
the completion ofhemodialysis. 
CONFIDENTIAL 
Page22 
08 July 2015 


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3.3. 
Duration of Treatment 
Final 
Original 
The study will consist of a 30-day screening period (within 30 days before Day 1 visit), followed 
by a 48 weeks treatment period. After Day 1, subjects will retum for study visits at 
Weeks 2, 4, 8, 12, 24, 36 and 48. 
After Week 48, subjects will stop study dmg and complete a 30-Day Follow-up visit. 
3.4. 
End of Study 
End of the study will occur when the last subject emolled in the study has completed Week 48 
visit followed by a 30-Day Follow-up visit. 
3.5. 
Post Study Care 
After a subject has completed/te1minated their participation in the study, long-tenn care for the 
subject will remain the responsibility of their primmy treating physician. 
3.6. 
Source Data 
Sponsor will provide somce document worksheets for all study visits. 
3.7. 
~PD 
PD 
CONFIDENTIAL 
Page23 
08 July 2015 


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects who meet the eligibility criteria will be enrolled. 
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 screening procedures
2) Age ≥ 18 years
3) Currently receiving a stable antiretroviral regimen for ≥ 6 consecutive months prior to 
screening
4) Documented plasma HIV-1 RNA concentrations < 50 copies/mL for at least 6 months 
preceding the screening visit (measured at least twice using the same assay) and have 
HIV-1 RNA < 50 copies/mL at screening
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
≥50 copies/mL and < 400 copies/mL) is acceptable, only if HIV-1 RNA is 
< 50 copies/mL immediately before and after the blip. 
b) To determine virologic suppression in the preceding 6 months prior to screening, the 
lower limit of quantification (LLOQ) by the local HIV-1 RNA assay may be used, only if 
its LLOQ is greater than 50 copies/mL (e.g. LLOQ of 75 copies/mL)
5) No documented history of HIV-1 resistance to EVG, FTC, 3TC or TFV and no history of 
switching off EVG, FTC, 3TC or TFV due to concern for resistance
6) CD4+ T cell count of ≥200 cells/μL
7) ESRD with eGFR < 15 mL/min by Cockcroft-Gault formula for creatinine clearance {2202}
Male:
(140 – age in years) (wt in kg) Clcr (mL/min)
72 (serum creatinine in mg/dL)
Female:
(140 – age in years) (wt in kg) 0.85 Clcr (mL/min)
72 (serum creatinine in mg/dL)
8) On chronic HD for ≥ 6 months prior to screening


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9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Hepatitis B (HBV) infection allowed if liver function is stable for ≥ 6 months prior to 
screening: ALT ≤ 10 × ULN, AST ≤ 10 × ULN, total bilirubin ≤ 2.5, or normal direct 
bilirubin (subjects with documented Gilbert’s Syndrome or hyperbilirubinemia due to 
atazanavir therapy may have total bilirubin up to 5 × ULN), INR ≤ 1.5 and albumin ≥3 g/dL; 
no evidence of cirrhosis or hepatocellular carcinoma by imaging in the last 12 months
11) Chronic Hepatitis C (HCV) infection allowed if liver function is stable (see above for criteria)
12) Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; 
platelets ≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
13) Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤ 5 × ULN)
14) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant confirmed by a negative serum pregnancy test (unless permanently sterile 
or greater than two years post-menopausal)
b) Of non-child bearing potential (i.e. women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for ≥ 12 months) of previously occurring menses
Female subjects who have stopped menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure must have a serum follicle stimulating 
hormone (FSH) level at screening within the post-menopausal range based on the 
Central Laboratory Reference range. 
c) Of childbearing potential and agrees to utilize the protocol specified method of 
contraception or be non-heterosexually active or practice abstinence from screening 
throughout the duration of the study treatment and for 30 days following study drug 
discontinuation (as defined in Appendix 6)
d) Female subjects who utilize hormonal contraception as one of the birth control methods 
must have used the same method for at least three months prior to the study dosing. 
15) Male subjects must agree to use protocol specified method(s) of contraception from 
screening throughout the duration of study treatment and for 30 days following 
discontinuation of study drugs (Appendix 6).
16) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days 
after the last study drug dose.
17) Lactating females must agree to discontinue nursing before the study drug is administered.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
2) Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening
3) Treatment with radiation, cytotoxic chemotherapeutic agents, or any immunomodulator 
within 30 days of screening
4) Any other clinical history, condition, or test result that, in the opinion of the Investigator, 
would make the subject unsuitable for the study or unable to comply with dosing 
requirements
5) Administration of other investigational agents (unless approved by Gilead Sciences). 
Participation in any other clinical trial, including observational trials, without prior approval 
from the sponsor is prohibited while participating in this trial.
6) History or presence of allergy or intolerance to the study drugs or their components
7) A new AIDS-defining condition (excluding CD4+ T cell count and percentage criteria) 
diagnosed within the 30 days prior to screening, with the exception of 
oropharyngeal candidiasis (see Appendix 7)
8) Have an implanted defibrillator or pacemaker
9) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
10) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
carcinoma
11) Received solid organ or bone marrow transplant
12) Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures
13) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1
14) Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use]), immunosuppressant, or 
immunomodulating agents
15) Subjects receiving ongoing therapy with any of the following medications in the Table 4-1
below, including drugs not to be used with EVG, COBI, FTC, TAF


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Table 4-1.
Disallowed Agents
Drug Class
Agents Disallowed*
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Calcium Channel Blockers
Bepridil
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
*
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. 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label, single arm study. All eligible subjects will receive open-label E/C/F/TAF.
Enrollment and Day 1 visit cannot occur until subject eligibility has been confirmed.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment. Once eligibility is confirmed, each subject will be assigned a unique subject 
number using 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 may be performed up to 3 days prior to the in-clinic Day 1 visit, provided that all 
other screening procedures have been completed and subject eligibility has been confirmed. 
Eligibility must be confirmed and all Day 1 tests and procedures must be completed prior 
to the administration of the first dose of study drug.
IWRS will assign study drug bottle numbers at each study visit. Initiation of study drug must 
take place within 24 hours after Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF FDC Tablets
5.2.1.
Formulation
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets and are debossed with “GSI” on
one side of the tablet and “510” on the other side of the tablet. E/C/F/TAF tablets contain 150 mg
of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of TAF fumarate).
The E/C/F/TAF tablet core contains silicon dioxide, croscarmellose sodium, hydroxypropyl
cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine aluminum 
lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.2.2.
Packaging and Labeling
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle
contains 30 tablets, silica gel desiccant and polyester packaging material. Each bottle is enclosed
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
Study drug to be distributed to centers in the US and other participating countries shall be labeled 
to meet applicable requirements of the United States Food and Drug Administration (FDA), 
EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.


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5.2.3.
Storage and Handling
E/C/F/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). Storage conditions are specified on 
the label. Until dispensed to the subjects, all bottles of study drug should be stored in a securely
locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration of E/C/F/TAF
E/C/F/TAF FDC tablets will be provided by Gilead Sciences.
E/C/F/TAF FDC tablets containing 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 
10 mg of TAF will be provided to all eligible subjects at Day 1. Study drug will be administered
orally at approximately the same time each day with food. 
On the day of hemodialysis study drug administration should occur two to four hours 
following the completion of hemodialysis. 
Subjects will be instructed to bring all study medication in the original container at each clinic 
visit for drug accountability (unless otherwise specified in the study procedures sections of this 
protocol). The Investigator will be responsible for maintaining accurate records for all study drug 
bottles dispensed and tablets returned. The inventory and dispensing logs must be available for 
inspection by the study monitor. Study medication supplies, including partially used or empty 
bottles, must be accounted for by the study monitor prior to destruction or return.
5.4.
Prior and Concomitant Medications

Subjects receiving hormonal contraceptives should consider additional methods of 
contraception as concentrations of ethinyl estradiol may decrease and progestin level may 
increase on co-administration with study drug. 

The use of medications for the treatment of HIV, other than study drug, is prohibited.

Subjects receiving concomitant medications that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious adverse 
events should consider alternative concomitant medications.


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
During the study, subjects may not receive any of the following concomitant medications:
Competitors of renal excretion (e.g., probenecid; high-dose non-steroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin and pentamidine)

Medications listed in the following table and use of herbal/natural supplements are excluded 
or should be used with caution while subjects are participating in the study. Any concomitant 
medication requiring adjustment or discontinuation due to renal impairment or a change in 
renal function on study should be managed per that drug’s prescribing information.


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Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Concentration of study drug may decrease with 
antacids. Subjects may not take antacids 
(eg, Tums, Mylanta); the ulcer medication sucralfate
(Carafate); or vitamin or mineral supplements that 
contain calcium, iron or zinc for a minimum of 2 hours 
before and 2 hours after any dose of study drug.
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antiarrhythmics
Amiodarone, Flecainide Quinidine, Propafenone, 
Systemic Lidocaine, Mexiletine, Disopyramide: 
Concentrations may increase with study drug(s) 
resulting in a potential for cardiac arrhythmias; 
clinical and ECG monitoring is recommended.
Calcium Channel Blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, Verapamil, 
Diltiazem, Amlodipine:
Concentrations may increase with study drug(s). 
Clinical and ECG monitoring of subjects is 
recommended
Digoxin
Digoxin:
Concomitant use may result in increased levels; use 
with caution and with appropriate monitoring of 
serum digoxin levels. Digoxin therapy should be 
initiated at the lower dose, and the dose should be 
titrated to clinical response.
Antibacterials
Clarithromycin and Telithromycin: 
Concentrations may be altered with study drug(s); 
consider an alternative.
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR 
(International Normalized Ratio) monitoring 
is recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine:
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics:
Concentrations may increase or decrease with study 
drug(s). Concentration monitoring is recommended 
to ensure adequate clinical response.
Trazodone:
Concomitant use with CYP3A inhibitors results in 
increased concentrations and adverse events; dose 
reduction should be considered.
Antifungals
Ketoconazole and Itraconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Daily dose of 
ketoconazole and itraconazole should be restricted 
to 200 mg. Subjects receiving ketoconazole or 
itraconazole should be monitored for adequate 
clinical response.
Voriconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Clinical monitoring may 
be needed.
Antigout
Colchicine:
Concentrations may increase with study drug(s). 
Dose reductions of colchicine may be required. 
Should not be coadministered in patients with 
renal or hepatic impairment.
Treatment of Gout Flare:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg 
(half tablet) 1 hour later. Treatment course may be 
repeated no earlier than 3 days.
Prophylaxis of Gout Flares:
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:
Maximum daily dose of 0.6 mg 
(may be given as 0.3 mg twice a day).
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
Corticosteroids: Inhaled/Nasal
Concomitant use of inhaled fluticasone and study 
drug(s) may increase plasma concentrations of 
fluticasone. Use is not recommended unless the 
potential benefit to the subject outweighs the risks 
of corticosteroid side effects. Alternatives should be 
considered, particularly for long-term use.
Corticosteroids: Systemic
Systemic dexamethasone, a CYP3A inducer, may 
significantly decrease elvitegravir and cobicistat 
plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative corticosteroids should be considered.
Use of Prednisone as a steroid burst (≤1 week of use)
should be monitored appropriately.
Endothelin receptor antagonists
Bosentan:
coadministration may lead to decreased elvitegravir 
exposures and loss of therapeutic effect and 
development of resistance. Alternative endothelin 
receptor antagonists may be considered.
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Atorvastatin:
Concentrations may increase with study drug(s). 
Start with the lowest dose; gradual increase in dose 
may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s).
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol:
Concentrations may increase with study drug. 
Coadministration of salmeterol with study drug may 
result in increased risk of cardiovascular adverse 
events associated with salmeterol, including QT 
prolongation, palpitations, and sinus tachycardia.
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: 
A dose decrease may be needed.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Opiates
Methadone:
Methadone exposures are unaffected upon 
coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required upon 
coadministration with study drug(s).
Meperidine (Pethidine):
Dosage increase and long-term use are not 
recommended due to increased levels of metabolite 
normeperidine, which has analgesic and 
CNS stimulant (eg, seizures) activities.
Buprenorphine:
Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and cobicistat, 
with no effect on opioid pharmacodynimcs.
The concentration changes are not considered 
clinically relevant and no dose adjustment of 
buprenorphine/naloxone is required upon
coadministration with study drug(s).
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil:
Caution should be exercised, including consideration 
of dose reduction, when coadministered for treatment 
of pulmonary arterial hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil:
It is recommended that a single dose of Sildenafil 
no more than 25 mg in 48 hours, Vardenafil no 
more than 2.5 mg in 72 hours, or Tadalafil no more 
than 10 mg in 72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem:
A dose decrease may be needed for these drugs. 
Clinical monitoring is recommended.

Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the Gilead Sciences 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 Sciences as soon as he/she is aware of 
the use of the disallowed medication.


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5.5.
Accountability for E/C/F/TAF
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. Accountability records (Study Drug Inventory Log) will be provided to each study site in 
order to:

Record the date received and the quantity of study drug bottles.

Record the date, subject number, subject initials, the study drug bottle number dispensed.

Record the date, quantity of used and unused study drug returned by the subject, along with 
the initials of the person recording the information.
The Investigator [or designee (e.g., study center pharmacist)] will acknowledge receipt of the 
study drugs from Gilead Sciences (or designee) after reviewing the shipment’s content and 
condition. The Investigator (or designee) will be responsible for maintaining an accurate 
inventory of the dates and quantities of all study drugs received, dispensed, and returned. 
Subjects should be instructed to return all unused study drug to the site at their study visits.  
Each dose of the study drug administered at the study center will be administered by qualified 
study center personnel. All doses of study drug administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Study Drug Inventory Logs provided by 
Gilead Sciences (or on equivalent documentation maintained by the study center), which 
indicates the date and quantity of all doses of study drug dispensed to individual subjects. 
The requirements of all applicable drug dispensing laws will apply to all doses of study drugs 
dispensed by the Investigator (or designee). 
The study drug inventory log must be available for inspection by the study monitor. 
Study medication supplies, including partially used or empty bottles, must be accounted for by 
the study monitor prior to destruction or return.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions to the sites regarding the return of used and unused 
study drug. If return is not possible, the study monitor will evaluate each study center’s study 
drug disposal procedures and provide appropriate instruction for destruction of unused study 
drug. 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 study 
drug bottles in accordance with that site’s approved SOP. A copy of the site’s approved SOP will 
be obtained for central files.
If the study drug is destroyed on site, the investigator must maintain accurate records for all 
study drug 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 study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. The study monitor will review study drug inventory and associated records at 
periodic intervals.


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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 described in the text that follows. 
The investigator must document any deviation from protocol procedures in the subject’s source 
documents and electronic Case Report Forms (eCRFs). In addition, the Sponsor and the Contract 
Research Organization (CRO) should be promptly notified of any protocol deviations. 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment. 
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg 
(E/C/F/TAF), on Day 1. Please refer to Section 5.1 for details about enrollment and 
treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Day 1 visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events, substance use and 
prior medications within 30 days of the screening visit

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) and weight

12-lead ECG performed supine

Height

Blood sample collection for the following laboratory analyses: 
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
FSH test is required for female subjects (age > 54 years) who have stopped menstruating 
for > 12 months but do not have documentation of ovarian hormonal failure.


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Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium,
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, 
PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and parathyroid hormone (PTH)
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance:
Male:
(140 – age in years) (wt in kg) CLcr (mL/min)
72 (serum creatinine in mg/dL)
Female:
(140 – age in years) (wt in kg) 0.85 CLcr (mL/min)
72 (serum creatinine in mg/dL)
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ T cell count
Plasma HIV-1 RNA (Taqman v2.0)
Hepatitis B virus surface antigen serology (HBsAg)
Hepatitis C virus (HCVAb) serology. If the antibody test result is positive, 
HCV RNA test will be performed to confirm HCV viremia.

Review of AEs and concomitant medications (adverse events related to protocol mandated 
procedures occurring after signing of the consent form)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for Day 1 assessments. 
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (eCRF). All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history eCRF. See Section 7
Adverse Events and Toxicity Management for additional details.


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6.2.2.
Day 1 Assessments
The following evaluations are to be completed after confirmation of eligibility and before the 
study drug is dispensed to the subject. Initiation of treatment with the study drug must take place 
within 24 hours after the Day 1 visit.

Obtain subject number and study drug bottle assignment from IWRS. The subject number 
assignment and enrollment may be performed up to 3 days prior to the in-clinic Day 1 visit 
provided that all screening procedures have been completed and subject eligibility has been 
confirmed.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, phosphorus, magnesium, potassium, sodium, uric acid, amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN) and PTH
Metabolic assessments: 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). 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
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
Plasma HBV DNA (only required if HBV DNA positive at screening visit)
CD4+ T cell count
Whole blood storage sample collection for virology analyses
Plasma storage sample for virology, safety and/or PK testing


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Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, VAS and HIV-TSQs should be completed by the subject. Subject is to read the 
questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation. Study drug will be dispensed in an open-label fashion. Subjects 
must initiate dosing of study drug within 24 hours after the Day 1 visit.

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. On the days of hemodialysis, subjects should be instructed to take study 
drug 2 to 4 hours following hemodialysis. Subjects should also be counseled regarding the 
importance of adherence and taking their study drugs at approximately the same time each 
day.
6.3.
Treatment Assessments (Weeks 2-48)
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specific visit date through Week 12 and completed 
within ± 6 days of the protocol-specific visit date through Week 36. The visit window at 
Week 48 will be ± 6 weeks of the protocol-specific visit date, and this clinical visit window 
coincides with the Week 48 statistical analysis window for HIV RNA. Unless notified by the 
Sponsor, Week 48 visit should be completed within ± 6 days of the protocol-specific visit date. 
The following evaluations are to be completed at the end of Weeks 2, 4, 8, 12, 24, 36 and 48 
unless otherwise specified. 
Note: Regularly scheduled evaluations will be made on all subjects whether or not they continue 
to receive study drug. 

Single, pre-dose (within 30 minutes prior to study drug administration) whole blood sample 
collection (Week 4 or Week 12 only). PBMC sample processing will be performed by the 
central laboratory. 
Note: Week 4 or Week 12 visit should occur on the day of hemodialysis for this sample 
collection. Study drug administration should occur 2 to 4 hours following the completion 
of hemodialysis and should be observed on-site. 

All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15) at or between Week 4 or Week 8. Please see Section 6.5.1 and 
Appendix 3, Pharmacokinetic (PK) Sub-study for additional details. 


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
Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24 and 48 only) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator)

Symptom-directed physical examination as needed (Weeks 2, 4, 8, 12 and 36)

12-lead ECG performed supine

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, 
direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, PT/INR, amylase (reflex lipase testing is performed in subjects with 
total amylase > 1.5 × ULN) and PTH
o
Note: At Weeks 24 and 48, analyses of glucose will be done as part of the fasting 
metabolic assessments and not as part of the chemistry profile.
o
Chemistry profile will include PT/INR only at Week 24 and Week 48.
Metabolic assessments: 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). 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 (Weeks 24 and 48 only)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula for 
creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
o
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).
Plasma HBV DNA (only required if HBV DNA positive at screening visit)
CD4+ T cell count
Plasma storage sample for virology, safety and/or PK testing


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Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
Serum pregnancy test (females of childbearing potential only)

Subject completed questionnaires:
SF-36 and HIV-TSQc completed at Weeks 24 and 48 only
VAS completed at all visits
The questionnaires should be completed by the subject. Subject is to read the questionnaire 
by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Study drug dispensation (except at Week 2 and Week 48). Document study drug dispensation 
and accountability. 
At Day 1, study drug will be dispensed for 30 days. At the Week 2 visit, study drug will 
not be dispensed. 
At Week 48, study drug dispensation will not occur. Schedule the subject for a 30-Day 
Follow-Up visit. 

Note: At the Week 2 visit, provide the scheduled Week 4 visit date to the subject. Week 4 
visit should occur on day of hemodialysis. Instruct the subject to take study drug at Week 4 
on-site, 2 to 4 hours following hemodialysis.

Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day.

Subjects should also be counseled regarding the importance of adherence and taking their 
study drugs at approximately the same time each day.
6.4.
Post-treatment Assessments
6.4.1.
30-Day Follow-up Assessments
Subjects who complete the study through the Week 48 visit will be required to return to the 
clinic for a 30-Day Follow-Up Visit. 
Those subjects who permanently discontinue study drug and continue in the study through 
at least one subsequent visit after the Early Study Drug Discontinuation Visit will not be 
required to complete the 30-Day Follow-Up Visit.


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Subjects who permanently discontinue study drug prior to the Week 48 visit and refuse to 
continue in the study through the Week 48 visit will be asked to return to the clinic 30 days after 
the completion of the ESDD Visit for 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 of AEs and changes in concomitant medications

Symptom-directed physical examination as needed 

Weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, 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) and PTH.
Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
CD4+ T cell count
Serum pregnancy test (females of childbearing potential only)
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
At the 30 Day Follow Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.4.2.
Early Study Drug Discontinuation Assessments (ESDD)
If the subject discontinues study drug prior to the Week 48 visit, the subject will be asked to 
return to the clinic within 72 hours of stopping study drug for the ESDD visit. 
Every attempt should be made to keep the subject in the study through Week 48 visit and 
continue to perform the required study-related follow-up and procedures (see Section 6.4.3, 
Criteria for Discontinuation of Study Treatment). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study.
Subjects who permanently discontinue study drug prior to the Week 48 visit and refuse to 
continue in the study through Week 48 visit will be asked to return to the clinic 30 days after the 
completion of ESDD visit for the 30-Day Follow-up visit.


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At the Early Study Drug Discontinuation Visit, any evaluations showing abnormal results 
indicating that there is a possible or probable causal relationship with the study drug, 
should be repeated weekly (or as often as deemed prudent by the Investigator) until the 
abnormality is resolved, returns to baseline, or is otherwise explained.
The following evaluations are to be completed at the Early Study Drug Discontinuation Visit

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Vital signs (blood pressure, pulse, respiration rate, and temperature) and weight

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, 
direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, 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) and PTH
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance
Hematology profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA (Taqman v2.0)
o
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of Suspected Virologic Failure (Section 6.6.1).
Plasma HBV DNA (only required if HBV DNA positive at screening visit)
CD4+ T cell count
Plasma sample for virology testing or pharmacokinetic testing
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
Serum pregnancy test (females of childbearing potential only)

SF-36, HIV-TSQc and VAS questionnaires should be completed by the subject. Subject is to 
read the questionnaire by him/herself and write/mark answers directly onto the questionnaire.

Site-administered questions for Health Utilization Assessment to be completed

Drug accountability


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6.4.3.
Criteria for Discontinuation of Study Treatment
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.

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Therapeutic failure 

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.5.
Other Evaluations
6.5.1.
Pharmacokinetic (PK) Sub-study
All subjects who are willing to consent will be eligible to participate in the pharmacokinetic sub-
study (target n = 15). 
Post-dose blood sample collection will be performed at hours 0.5, 1, 2, 3, 4, 6, 8, and 24.
PK sub-study visit must occur at or between Week 4 or Week 8, on the day of hemodialysis. 
Study drug administration will be observed in-clinic at the sub-study visit. The sub-study will 
include intensive PK profiling in plasma. Details of the blood sampling procedures and sample 
management will be documented in the Pharmacokinetic Sample Collection, Processing, 
Storage, and Shipment Manual. 
6.5.2.
Blood Storage
From subjects who provide additional consent, a portion of the blood drawn at all visits 
(except the Screening Visit and Unscheduled Visits) will be frozen and stored. These stored 
blood samples may be used by the Sponsor or its research partners for future testing to learn 
more about how the study drug has worked against HIV-1 or clinical laboratory testing to 
provide additional safety data. No human genetic testing will be performed without expressed 
consent of study subjects. At the conclusion of this study, these samples may be retained in 
storage by Gilead Sciences, Inc. for a period up to 15 years.


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6.6.
Virologic Failure
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure.
Subjects will be considered to have virologic rebound if they have confirmed HIV-1 RNA 
≥50 copies/mL (two consecutive tests) at a scheduled or unscheduled visit.
6.6.1.
Management of Virologic Failure

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-4 weeks after the date of the original test with HIV-1 RNA ≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented. Assessments should include:
Adherence
Concomitant medication
Comorbidities (for example: active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed, and the HIV-1 RNA is < 400 copies/mL, subjects may 
remain on their current regimen at the discretion of the Investigator. Subject will return for a 
repeat within 2-4 weeks. 

If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 400 copies/mL, the blood samples from the confirmation visit will be used for 
HIV-1 genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and HIV-1 RNA should be repeated (2-4 weeks from the date of confirmed 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 
subjects source documents. Investigators who opt to discontinue study drugs for an 
individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.6.2.
Subjects with ≥ 400 Copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at Week 24 or Week 48, or at the last visit while receiving study drugs 
(or within 72 hours of discontinuation of study treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.


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Figure 6-1. 
Schema for Management of Virologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
D ayl 
~ 
I 
At any visit, a rebound in HIV-1 RNA to ~ 50 copies/mL 
I 
Unconfu·med 
Return for scheduled/unscheduled HIV-1 
vii·ologic rebound: 
.... 
RNA and potential genotype/phenotype 
remain on cmTent 
(2-4 weeks later) 
regimen• 
' 
Confit•med virologic rebound and 
HIV-1 RNA to <!: 400 copies/mLb 
,, 
Remain on study 
I 
HIV-1 genotype/phenotype' I 
' 
' 
If no revet·se transcriptase t•esistance 
If reverse transc.riptase, protease, 
detected, continue on study drugs. 
or integrase resistance detected, 
Repeat HIV-1 RNAb,d 
discontinue study drugs and 
constt·uct a new ARV regimen• 
a 
If virologic rebOlmd is not confmned, the subje.ct will remain on their cmrent regin1en. 
b 
If virologic rebotmd is confmned, and the HIV-1 RNA is< 400 copies/mL, subjects may remain on their cun·ent regimen at 
the discretion of the Investigator. Subject will rettun for a repeat within 2-4 weeks. If virologic rebom1d is confinned, and 
HIV -1 RNA is :::: 400 copies/mL, the HIV -1 genotype and phenotype (reverse transcriptase, protease, and, if applicable, 
integrase resistance) will be analyzed. 
c 
Base·d on the results of the genotype/phenotype assays, the subject will remain on study chugs or study drugs will be 
discontinued. If genotyping/phenotyping assay fails, a new ARV regin1en may be configm·ed at the discretion of the 
Investi2ator. 
d 
If no r.;istance detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews study dt·ug 
continuation/discontinuation options and discuss with Medical Monitor prior to study dt·ug discontinuation. 
e 
A new ARV regimen will be configtu·ed, at the Investigator's discretion, and the subject will remain in the study. 
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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 adverse event (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, lack of efficacy, 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.

Pre-existing 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 7.5)

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 pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (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

Persistent or significant disability/incapacity


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
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.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.6.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to 
study drug using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 


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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 adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
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.
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 case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences 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 occurs 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 Drug Safety and Public Health (DSPH) 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. 


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All SAEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the SAE has not resolved, then the SAE 
will be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain SAEs be followed until 
resolution.
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 study drug, he/she should promptly document and 
report the event to Gilead DSPH. 

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
Serious Adverse Event Paper Reporting Process

Serious Adverse Event Paper Reporting Process (only to be used if EDC System is not available)
All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of:
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
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 DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If the SAE was reported via paper, it 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 onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.


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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 investigator’s brochure or relevant local label as applicable. 
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.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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.
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 complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to 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 7.3.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. 
Gilead DSPH contact information is as follows: 
Gilead Sciences DSPH:
Fax:
E-mail:
+1 (650) 522 5477
safety_fc@gilead.com
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH 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 does 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. 


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Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the CRF/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.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 as outlined below.

All clinically significant Grades 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of investigational medicinal product for any Grade 3 and 4 laboratory 
abnormality that in the opinion of the Investigator is clinically significant and may pose a 
risk to the subject’s safety.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(refer to Appendix 5).

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to Grade 3 following re-challenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.


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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 investigational medicinal product, 
investigational medicinal product 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 3-4 laboratory abnormality (e.g., CK elevation after strenuous exercise, or 
triglyceride elevation that is non-fasting or that can be medically managed) or a Grade 3-4 
clinical event considered unrelated to investigational medicinal product.
7.6.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management in Subjects Co-infected with Hepatitis B
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × Day 1 value
and >10 × ULN, with or without associated symptoms
7.6.4.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT > 2 × Day 1 value and > 10 × ULN, the following 
is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after
initial laboratory results were drawn). During the visit, a clinical assessment of the subject 
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status.

If the ALT elevation is confirmed, request the central clinical laboratory to conduct reflex
testing for plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM, and 
HCV serology.
Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and serum 
albumin. Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable Relative to Day 1 Liver Function Tests
If ALT levels are elevated (i.e., > 2 × Day 1 and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to Day 1, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or Day 1 level. During monitoring, 
if the ALT values remain persistently elevated, the Investigator should discuss with the 
Gilead Medical Monitor whether the study drug should be discontinued.  


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For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on an HIV regimen containing commercially available HBV therapy if 
study drug is discontinued.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × Day 1 and > 10 × ULN), and total bilirubin is confirmed to 
be 2 × Day 1 value, and INR is 0.5 above Day 1, provided both are > ULN, the investigator 
should consider discontinuing study medication (upon discussion with the Gilead Medical Monitor,
unless the safety of the patient is of immediate concern). The subject should be monitored 
weekly as long as ALT, total bilirubin, and INR values remain elevated or above Day 1 values.
During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the Investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on an HIV regimen containing commercially available HBV therapy if 
study drug is discontinued.
7.6.4.2.
Management of Exacerbation of Hepatitis in Subjects Who Have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation > 2 × Day 1 and > 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function
(total bilirubin 2 × Day 1, INR 0.5 above Day 1, provided both are > ULN) and the subject is on 
no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject.

Check the following laboratory parameters: serum ALT and AST, bilirubin, INR, and
albumin.

If the ALT elevation is confirmed, request the clinical laboratory to conduct reflex testing 
for plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM and HCV.
If serum HBV DNA is increasing, the investigator should consider immediate initiation of 
approved therapy.

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or Day 1 up to a maximum of 6 months after the initial occurrence of the event.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the safety and tolerability of the elvitegravir/cobicistat/emtricitabine/
tenofovir alafenamide (EVG/COBI/FTC/TAF; E/C/F/TAF) fixed dose combination (FDC) in 
HIV-1 infected adults with end stage renal disease (ESRD) on chronic hemodialysis (HD) at 
Week 48
The secondary objectives of this study are:

To evaluate the proportion of subjects with virologic response (HIV-1 RNA < 50 copies/mL, 
Snapshot analysis) at Weeks 24 and 48

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF and TFV in HIV-1 
infected patients with ESRD on HD
8.1.2.
Primary Endpoint
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events at
Week 48.
8.1.3.
Secondary Endpoints

Proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by 
the FDA snapshot algorithm

The pharmacokinetics parameters of EVG, COBI, FTC, TAF and TFV, including 
AUCtau/AUClast, Cmax, and Cmin for the sub-study.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
Full Analysis Set (FAS): The Full Analysis Set will include all the subjects who were enrolled
and received at least one dose of study drug. The FAS will exclude subjects with major protocol 
violations. The FAS analysis set is the primary analysis set for the efficacy analyses.


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8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses is defined as all subjects that received at least 
one dose of study medication.
All data collected during treatment will be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) analysis set will include all subjects in the safety analysis set who 
participated in the sub-study and for whom concentration data of any one analyte (e.g., TAF, EVG,
COBI, TFV and FTC) of interest are available.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index and HIV-1 infection.
8.4.
Primary and Secondary Analysis
8.4.1.
Primary Analysis
The primary endpoint is the incidence of treatment-emergent grade 3 or higher adverse events at 
Week 48. Treatment-emergent adverse events are defined in Section 8.5.2.
8.4.2.
Secondary Analyses
The proportion of subjects achieving HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 will be 
computed using the FDA snapshot algorithm. The measures of pharmacokinetics of EVG, COBI, 
FTC, TAF and TFV, AUC, Cmax, and Cmin, will be summarized using descriptive statistics 
[N, mean, standard deviation, percent coefficient of variation (%CV), median, minimum, 
and maximum] for the sub-study.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that study medication was first dispensed up to the 
date of last dose of study medication plus 30 days will be summarized. Data for pre-treatment 
period and the period post the date of last dose plus 30 days will be included in data listings.


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8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration data. Exposure data will be summarized.
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug
administration, and summarized. Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (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.
Treatment-emergent adverse events are adverse events that meet one of the following criteria:

Adverse events with onset dates on or after the first dose date of study drug, and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and PT) will be provided. Additional summaries will include summaries for adverse 
events by grade, Investigator’s assessment of relationship to study drug, and effect on study drug 
dosing.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
drug plus 30 days, will be summarized. 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 drug or after the subject has
been discontinued from treatment plus 30 days will be included in a data listing.


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8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for using descriptive statistics 
(eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of the study drug over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation.
8.7.
Sample Size
A sample size of approximately 50 subjects is based on practical considerations and is 
considered to be sufficient to evaluate the primary objective of this study. The Grade 3 or higher 
AE rate in Study GS-US-292-0112 in subjects that had mild to moderate renal impairment was 
8.8% at Week 48 for the E/C/F/TAF arm. Therefore, with 50 subjects, and an assumed rate of 
Grade 3 or higher AEs being 10%, this study would provide 95% confidence for the primary 
endpoint to be (1.7%, 18.3%) assuming normal approximation to binomial proportions. 
A sample size of at least 15 subjects is considered for estimating the PK parameters in the sub-
study for practical reasons. 
8.8.
Data Monitoring Committee
An external multidisciplinary independent data monitoring committee (IDMC) will review the 
progress of the study and perform interim reviews of safety, efficacy data and provide 
recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study drug warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications. The committee will convene after the first 25 subjects enrolled complete Week 12
of the study. The IDMC’s specific activities will be defined by a mutually agreed charter, which 
will define the IDMC’s membership, conduct and meeting schedule.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with 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 Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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 an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.


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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 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC 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 IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, IRB or IEC, 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 
investigator brochure, 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,
IRB or IEC and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.


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The required source data should include sequential notes containing at least the following 
information for each 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);

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 adverse events 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 (i.e. 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.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), 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. The eCRF capture the data required per the protocol 
schedule of events and procedures. 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 
coordinator 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). 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, IRBs or IECs, or regulatory authority or health authority 
inspectors.


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB [or] IEC approval before 
modifications can be implemented.
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

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
1238
Centers for Disease Control and Prevention. 1993 revised classification system 
for HIV infection and expanded surveillance case definition for AIDS among 
adolescents and adults. MMWR 1992;41 (RR-17):1-19.
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
4256
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 
2000;30 (Suppl 2):S-171-S6.
4266
Stone VE JJ, Tolson J, Pilon T. Potential impact of once daily regimens on 
adherence to HAART [abstract]. . 40th Annual Meeting of the Infectious Disease 
Society of America; 2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
4887
Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. 
Age-related immune dysfunction in health and in human immunodeficiency virus 
(HIV) disease: association of age and HIV infection with naive CD8+ cell 
depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic 
volumes. J Infect Dis 2003;187 (12):1924-33.
7034
Maggiolo F MM, Maserati R, Rizzi L, Pan A, Rizzi A, et al. . Once-a-day 
treatment for HIV infection: Final 48-week results. [Abstract 320]. 8th 
Conference on Retroviruses and Opportunistic Infections; 2001 February 4-8; 
Chicago, IL. 
7035
Felizarta F BS, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence and 
efficacy with a once-daily efavirenz-based regimen: 48-week results from the 
Daily Antiretroviral Therapy II (DART II) Study [Poster 5842]. . XV 
International AIDS Conference; 2004 July 11-16; Bangkok, Thailand. 
7036
Arribas JR IJ, Knobel H, Ribera E, Rubio R, Viciana P, et al. . Adherence, 
treatment satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) 
antiretroviral therapy (AT), in a large prospective observational cohort (CUVA 
Study).  [Poster WePeB5780]. . XV International AIDS Conference; 2004 July 
11-16; Bangkok, Thailand. 
7415
Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. 
Selective intracellular activation of a novel prodrug of the human 
immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to 
preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents 
Chemother 2005;49 (5):1898-906.


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7896
Centers for Disease Control and Prevention. 1994 Revised Classification System 
for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of 
Age. MMWR 1994;43 (RR-12):1-28.
13119
Birkus G, Kutty N, He GX, Mulato A, Lee W, McDermott M, et al. Activation of 
9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-
methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate 
prodrugs by human proteases. Mol Pharmacol 2008;74 (1):92-100.
16557
Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-
daily antiretroviral regimens: a meta-analysis. Clin Infect Dis 2009;48 (4):484-8.
16560
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral 
Treatment Regimens and Correlation with Risk of Hospitalization Among 
Commercially Insured HIV Patients in the United States [Poster O113]. 10th 
International Congress on Drug Therapy in HIV Infection; 2010 November 7-11; 
Glasgow, UK. 
19661
World Health Organization, UNAIDS, UNICEF. Global HIV/AIDS Response: 
Epidemic update and health sector progress towards universal access. Progress 
Report 2011.  
19946
Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature 
age-related comorbidities among HIV-infected persons compared with the general 
population. Clin Infect Dis 2011;53 (11):1120-6.
19947
Center for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2005. 
Vol. 17. Rev ed. Atlanta: U.S. Department of Health and Human Services, 
Centers for Disease Control and Prevention; 2007: 1-54. Also available at: 
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/.  
19948
Linley L, Hall H, An Q, Wheeler W. HIV/AIDS diagnoses among persons fifty 
years and older in 33 states, 2001-2005 [Abstract B08-1]. Presented at: 2007 
National HIV Prevention Conference; 2007 December 2-5; Atlanta, GA. 
21762
VIREAD® (tenofovir disoproxil fumarate) Tablets and Powder for oral use. US 
Prescribing Information. Gilead Sciences, Inc. Foster City, CA. Revised August 
2012.  
22029
Birkus G, Kutty N, He G-X, Mulato A, Lee W, McDermott M, et al. Activation of 
GS-7340 and Other Tenofovir Phosphonoamidate Prodrugs by Human Proteases. 
Antiviral Res 2007;74:A57.


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22031
Department of Health and Human Services (DHHS). HHS Panel on Antiretroviral 
Guidelines for Adults and Adolescents Recommends a Fixed-Dose Combination 
Product of Elvitegravir/Cobicistat/Tenofovir/Emtricitabine as an Alternative 
Regimen in Antiretroviral Treatment-Naive Individuals with HIV-1 Infection.  
2012:1-2. 
22551
Cailhol J, Nkurunziza B, Izzedine H, Nindagiye E, Munyana L, Baramperanye E, 
et al. Prevalence of chronic kidney disease among people living with HIV/AIDS 
in Burundi: a cross-sectional study. BMC nephrology 2011;12:40.
22552
Selik RM, Byers RH, Jr., Dworkin MS. Trends in diseases reported on U.S. death 
certificates that mentioned HIV infection, 1987-1999. J Acquir Immune Defic 
Syndr 2002;29 (4):378-87.
22553
Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. 
Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal 
disease. J Am Soc Nephrol 2005;16 (8):2412-20.
35184
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity 
and Mortality Weekly Report (MMWR). Revised Surveillance Case Definition 
for HIV Infection - United States 2014. Centers for Disease Control and 
Prevention,  2014.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pharmacokinetic Substudy
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Open-Label Study to Evaluate the Safety, Tolerability, Phrumacokinetics and 
Efficacy of E/C/F/T AF Fixed Dose Combination (FDC) in HlV -1 Infected Subjects on 
Chronic Hemodialysis 
GS-US-292-1825, Original, 08 July 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Devi SenGupta, MD (Printed) 
Medical Monitor 
Date 
PPD 
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 aJI 
information provided by Gilead Sciences, Inc. I will discuss this material with them to enswe 
that they are fuJiy informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 70 
08 July 2015 


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Appendix 2.
Study Procedures Table
Study Procedure
Screena
Day 1b
Week 2 to Week 48c
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
Written Informed Consent
X
Medical History 
X
Complete Physical Examinationf
X
X
X
X
X
Symptom-directed Physical Examinationg
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
Xh
X
Height
X
12-Lead ECG
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
Xj
Xj
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Genotype/Phenotypem
X
X
X
X
X
X
X
X
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
X
X
Serum Storage Sampleso
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologyp
X


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Study Procedure
Screena
Day 1b
Week 2 to Week 48c
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
SF-36 and HIV-TSQq
X
X
X
X
VAS
X
X
X
X
X
X
X
X
Health Utilization Assessmentr
X
X
X
X
X
X
X
X
X
Drug Dispensation and Accountability
X
Xs
X
X
X
X
X
Xs
Xs
Single Pre-dose Whole Blood Sample Collectiont
X
X
Post-dose PK Sub-studyu
X
X
Whole Blood Storage Samplev
X
Plasma HBV DNAw
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Day 1.
b
Subjects will be dispensed study drug on the Day 1 visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit.
c
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol 
specified date through Week 48, except Week 48. Weeks 48 visit window is ± 6 weeks of the protocol specified date. Week 48 visit should be completed within ± 6 day 
window, unless otherwise specified by the Sponsor.
d
Required for those subjects who complete Week 48 visit or those subjects who permanently discontinue study drug and do not continue in the study through at least 
one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Week 48, if the subject discontinues study drug prior to completion of Week 48 visit.
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom-directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR and amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN). At Day 1, Weeks 24 and 48 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry profile. PT/INR will 
be included in the chemistry profile at Screening, Weeks 24 and 48 only.
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At Weeks 24 and 48 analyses of glucose will be done as part of the chemistry profile. 


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k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian 
hormonal failure.
l
If the HIV-1 RNA value is ≥50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening 
and baseline results). See Section 6.6.1.
m
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV-1 RNA value ≥ 400 copies/mL. Subjects should be 
managed according to the Virologic Rebound Schema (Section 6.6.1). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the 
criteria described in this section.
n
CBC with differential and platelet count
o
For subjects who provide consent −serum storage samples for possible future testing will be collected.
p
See Section 4.2 to confirm subject eligibility prior to enrollment.
q
SF-36 and HIV-TSQ are to be completed by subjects at Day 1, Week 24 and Week 48 visits. HIV-TSQs to be completed by the subjects at Day 1 visit, HIV-TSQc to be 
completed by the subjects at Week 24 and Week 48 visits. 
r
Subjects will be asked about their health utilization at Day 1 visit and every visit thereafter, including the ESDD and Unscheduled Visits.
s
Drug accountability only; study drug will not be dispensed at these visit.
t
At Week 4 or Week 12, a single pre-dose whole blood sample will be collected for subjects enrolled in the study. Sample collection should occur within 30 minutes prior to 
the study drug administration which should be observed on-site. PBMC processing will be completed by the central laboratory. 
u
At or between Week 4 or Week 8, subjects who are willing to consent will be eligible to participate in the pharmacokinetic sub-study (target n = 15). Please see Section 6.5.1
and Appendix 3 Pharmacokinetic (PK) Sub-study for additional details.
v
Whole blood storage sample collected at baseline visit for virology assessments.
w
Plasma HBV DNA testing required only subject tests HBV positive at screening visit. 


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Appendix 3.
Pharmacokinetic Sub-study
Blood Sampling Time Points for Intensive PK:
Study Day
Time Point (hrs) Post-dose
0.5
1
2
3
4
6
8
24
At or between 
Week 4 or 
Week 8
X
X
X
X
X
X
X
X
1) All subjects who are willing to consent will be eligible to participate in the pharmacokinetic 
sub-study (target n = 15). 
2) PK sub-study visit must occur at or between Week 4 or Week 8 on the day of hemodialysis. 
3) Subject should be instructed to dose 2 to 4 hours after the completion hemodialysis. 
Study drug administration should be observed in-clinic. 
4) The sub-study will include intensive PK profiling in plasma. Details of the blood sampling 
procedures and sample management will be documented in the Pharmacokinetic Sample 
Collection, Processing, Storage, and Shipment Manual. 


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Appendix 4.
Management of Clinical and Laboratory Adverse Events
Gradf 1 
L------G-'r-ad_f_2----~~ 
~~------G-·r-ad_f_3----~~ ~~---------G-r-·a_d_e_~---------" 
! 
! 
l\Iay coutinuf 
Rfpfat lab to 
dosing at rhf 
confirm toiicity 
discrfrion ofthf 
gradf' 
in\·~stigator 
1 
If confinnl'<l and possibly and/or probably rflatfd to 
inwsrigarionru mroicinal products: 
1. Withhold inwsrigational ml'<licinal products until~ Gradf 2 
2. 
Rfsrart. all inwstigational mfdicinal produc.rs at full dosf 
1 
lf Grade 3 or ~ rfcwTence that is confit1ned and possibly or 
probably relatfd to inwstigational mfclicinal pt·oducrs, 
discontinuf all inwstigatioual medicinal products dosing 
pHmaufntly 
1 
r---------, 
Rfpfat Jab to 
confirm to:ticity 
gradf 
· 
1 
lf co 
inw 
dos 
nfirmro and uw'flatfd to 
stigarionru mfdicinal products, 
mg may continue at the 
disc rfrion of thf in,·estigator 
If confit·ml'<l and 
possibly or probably 
-. rflatedto 
inYestigarionaJ 
medicinal products, 
cliscoutinue 
iuYestigarionaJ 
medicinal products 
dosing pmnanfntly 
and follow at periodic 
intervals at !fast 
wHklY until a retw·u 
to ba;eline or is 
otltftmsf explainfd 
If GraM 3 or 4 recwnncf that is considHro uw·flarfd to 
inYesrigational medidnaJ proclucr.s, continue all investigational 
medicinal products at tbf same dose at the discrftion of tbf 
in,·esrigatoJ· 


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 76
08 July 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 77
08 July 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.  


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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08 July 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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08 July 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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.
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 83
08 July 2015
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.


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
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CONFIDENTIAL
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08 July 2015
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


E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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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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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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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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


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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.
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.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of study drugs on 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. Data from clinical pharmacokinetic interaction studies of study drug 
have demonstrated that there is no reduction in the clinical efficacy of hormonal contraception or 
that the effect on hormonal contraception is insignificant. 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 
prior to study enrollment. A serum pregnancy test will be performed at all study visits and the 
end of relevant system exposure. In the event of a delayed menstrual period (over one month 
between menstruations), a serum 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)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
o
Diaphragm with spermicide
o
Cervical cap with spermicide
o
Male condom (with or without spermicide)
Hormonal methods (the hormonal contraceptive should contain at least 30 mcg of 
ethinyl estradiol)
o
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
Contraceptive vaginal ring
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.


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3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential. 
4) 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.
5) 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 30days 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. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.5.2.1.


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Appendix 7.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†


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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV§
*
Only among children aged < 6 years
†
Only among adults, adolescents, and children aged ≥ 6 years
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy 
and HIV wasting syndrome, are described in the following references {7896}, {1238}.

SAP_005.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3b Open-label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Efficacy of E/C/F/TAF Fixed Dose 
Combination (FDC) in HIV-1 Infected Subjects on Chronic 
Hemodialysis
Name of Test Drugs:
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) Fixed-Dose Combination
Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF)
Fixed-Dose Combination
Study Number:
GS-US-292-1825
Protocol Version:
Amendment 2.1
Protocol Date:
01 May 2018
Analysis Type:
Final
Analysis Plan Version:
Version 1
Analysis Plan Date:
02 December 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAiJ 
-


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Data Monitoring Committee Analyses...................................................................................................11
2.2.
Week 24 Analysis ..................................................................................................................................11
2.3.
Week 48 Analysis ..................................................................................................................................11
2.4.
Week 96 Analysis ..................................................................................................................................11
2.5.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Enrolled Subjects Analysis Set.......................................................................................13
3.1.2.
B/F/TAF Enrolled Subjects Analysis Set.............................................................................13
3.1.3.
E/C/F/TAF Full Analysis Set ...............................................................................................13
3.1.4.
B/F/TAF Full Analysis Set...................................................................................................13
3.1.5.
E/C/F/TAF Safety Analysis Set............................................................................................13
3.1.6.
B/F/TAF Safety Analysis Set...............................................................................................13
3.1.7.
B/F/TAF Plasma PK Analysis Set........................................................................................13
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subgroups........................................................................................................14
3.5.
Multiple Comparisons............................................................................................................................14
3.6.
Missing Data and Outliers......................................................................................................................14
3.6.1.
Missing Data ........................................................................................................................14
3.6.2.
Outliers.................................................................................................................................14
3.7.
Data Handling Conventions and Transformations .................................................................................15
3.8.
Analysis Windows .................................................................................................................................15
3.8.1.
Definition of Study Day .......................................................................................................15
3.8.2.
Analysis Windows................................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in a Window .......................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment and Disposition.......................................................................................................22
4.1.1.
Subject Enrollment...............................................................................................................22
4.1.2.
Subject Disposition ..............................................................................................................22
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................23
4.2.1.
Duration of Exposure to E/C/F/TAF Study Drug.................................................................23
4.2.2.
Duration of Exposure to B/F/TAF Study Drug ....................................................................23
4.2.3.
Adherence with Study Drug.................................................................................................23
4.3.
Protocol Deviations................................................................................................................................24
5.
BASELINE CHARACTERISTICS....................................................................................................................25


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5.1.
Demographics and Baseline Characteristics ..........................................................................................25
5.2.
Baseline Disease Characteristics............................................................................................................25
5.3.
Medical History......................................................................................................................................26
6.
ANALYSES OF PRIMARY ENDPOINT..........................................................................................................27
6.1.
Definition of the Primary Endpoint........................................................................................................27
7.
EFFICACY ANALYSES ...................................................................................................................................28
7.1.
Efficacy Endpoints as Secondary Study Endpoints................................................................................28
7.2.
Analysis of Efficacy Endpoints..............................................................................................................28
7.2.1.
Analysis of the Proportion of Subjects with HIV-1 RNA < 50 copies/mL 
at Week 96 as Determined by US FDA-defined Snapshot Algorithm .................................28
7.2.2.
Analysis of Other Efficacy Endpoints..................................................................................29
7.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................30
8.
SAFETY ANALYSES........................................................................................................................................31
8.1.
Adverse Events Up to Week 96 .............................................................................................................31
8.2.
Analysis of Adverse Events Up to Week 96 ..........................................................................................32
8.3.
Adverse Events and Deaths....................................................................................................................32
8.3.1.
Adverse Event Dictionary ....................................................................................................32
8.3.2.
Adverse Event Severity........................................................................................................32
8.3.3.
Relationship of Adverse Events to Study Drug....................................................................32
8.3.4.
Serious Adverse Events........................................................................................................33
8.3.5.
Treatment-Emergent Adverse Events...................................................................................33
8.3.6.
Summaries of Adverse Events and Deaths...........................................................................34
8.3.7.
Additional Analysis of Adverse Events ...............................................................................35
8.4.
Laboratory Evaluations ..........................................................................................................................37
8.4.1.
Summaries of Numeric Laboratory Results .........................................................................37
8.4.2.
Graded Laboratory Values ...................................................................................................38
8.4.3.
Metabolic Laboratory Evaluations .......................................................................................40
8.4.4.
Liver-Related Laboratory Evaluations .................................................................................41
8.5.
Vital Signs and Body Weight.................................................................................................................42
8.6.
Prior and Concomitant Medications.......................................................................................................42
8.6.1.
Nonstudy-Drug Antiretroviral (ARV) Medications .............................................................42
8.6.2.
Concomitant Non-ARV Medications...................................................................................43
8.7.
Electrocardiogram Results .....................................................................................................................43
8.8.
Healthcare Utilization Assessment.........................................................................................................43
8.9.
Other Safety Analysis ............................................................................................................................44
8.10.
Changes From Protocol-Specified Safety Analyses...............................................................................44
9.
PHARMACOKINETIC ANALYSES ................................................................................................................45
10.
PATIENT REPORTED OUTCOMES................................................................................................................46
10.1.
Medication Adherence Questionnaire....................................................................................................46
10.2.
HIV Treatment Satisfaction Questionnaire ............................................................................................47
10.3.
SF-36 (Version 2) Health Survey...........................................................................................................48
10.3.1.
Scoring the SF-36.................................................................................................................48
10.3.2.
SF-36 Statistical Analysis Method .......................................................................................48
11.
REFERENCES ...................................................................................................................................................49
12.
SOFTWARE.......................................................................................................................................................50
13.
SAP REVISION..................................................................................................................................................51
14.
APPENDICES ....................................................................................................................................................52


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Appendix 1.
Study Procedures Table (E/C/F/TAF Phase)..........................................................................53
Appendix 2.
Study Procedures Table (Open Label Rollover Extension)....................................................56
Appendix 3.
Flowchart of US FDA-defined Snapshot Algorithm for Switch Trial....................................58
Appendix 4.
Cardiovascular or Cerebrovascular Events.............................................................................59
Appendix 5.
Hepatic Events........................................................................................................................60
Appendix 6.
TFL Mocks.............................................................................................................................61
Appendix 7.
Programming Specifications...................................................................................................68
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for HIV-1 RNA, CD4 Cell Count, CD4%, Hematologya, 
Chemistryb, eGFRCG, Vital Signs, Weight, Visual Analogue Scale (VAS), and 
Healthcare Utilization Assessment (E/C/F/TAF Phase).........................................................17
Table 3-2.
Analysis Windows for Fasting Glucose and Lipid Panel (E/C/F/TAF Phase) .......................17
Table 3-3.
Analysis Windows for prothrombin time and INR (E/C/F/TAF Phase).................................18
Table 3-4.
Analysis Windows for SF-36 and HIV-TSQc (E/C/F/TAF Phase) ........................................18
Table 3-5.
Analysis Windows for HIV-TSQs (E/C/F/TAF Phase)..........................................................18
Table 3-6.
Analysis Windows for Safety ECG (E/C/F/TAF Phase) ........................................................19
Table 3-7.
Analysis Windows for HIV-1 RNA, CD4 Cell Count, CD4%, Hematologya, 
Chemistryb, eGFRCG, Vital Signs, and Weight (B/F/TAF OL Extension Phase) ...................19
Table 3-8.
Analysis Windows for Fasting Glucose and Lipid Panel (B/F/TAF OL Extension 
Phase) .....................................................................................................................................19
Table 3-9.
Analysis Windows for SF-36 and HIV-TSQ (B/F/TAF OL Extension Phase) ......................20
Table 3-10.
Analysis Windows for Safety ECG (B/F/TAF OL Extension Phase) ....................................20


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LIST OF ABBREVIATIONS
ABC
abacavir
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARV 
antiretroviral 
AST
aspartate aminotransferase
B/F/TAF
bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg fixed-dose
combination, Biktarvy®
BMI
body mass index
BLQ
below the limit of quantitation
CDER
Center for Drug Evaluation and Research
CG
Cockcroft-Gault 
CI
confidence interval 
COBI
cobicistat (Tybost®)
CPK
creatine phosphokinase
CRF
case report form
CV
coefficient of variation
E/C/F/TAF
single-tablet regimen of elvitegravir (EVG) 150 mg/ cobicistat (COBI) 150 mg / 
emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10mg; coformulated; 
Genvoya®
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
eGFRCG
estimated glomerular filtration rate calculated using the Cockcroft-Gault formula
ESDD
early study drug discontinuation
ESRD
end stage renal disease
EVG
elvitegravir
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDC
fixed-dose combination
FTC
emtricitabine (Emtriva®)
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
HD
hemodialysis
HDL
high-density lipoprotein
HIV-1
human immunodeficiency virus (type 1) 
HLGT
high level group terms
HLT
high level term


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Statistical Analysis Plan
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IDMC
independent data monitoring committee
INR
international normalized ratio of prothrombin time
LOCF
last observation carried forward 
LDL
low-density lipoprotein
LLT
lowest level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
OL
open label
PBMC
peripheral blood mononuclear cell
PK
pharmacokinetic
PT
preferred term
PTH
parathyroid hormone
Q
quartile
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
Scr
serum creatinine concentration
SD
standard deviation 
SMQ
Standardised MedDRA Query
SOC
system organ class
STB
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, coformulated; Stribild®
STR
single-tablet regimen 
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate (Viread®)
TEAE
Treatment-emergent adverse event
TFL
tables, figures, and listings
TFV
tenofovir
ULN
upper limit of normal
VAS
visual analogue scale
WHO
World Health Organization


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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-292-1825, which will be performed when all subjects have completed the study or 
prematurely discontinued from the study. This SAP is based on the study Protocol Amendment 
2.1, dated 01 May 2018, and electronic case report form (eCRF). The SAP will be finalized 
before database finalization. Any changes made to the analyses after the finalization of the SAP 
will be documented in the final clinical study report. Analyses that were performed as part of 
interim clinical study reports will not be repeated for the final analysis unless otherwise 
specified.
1.1.
Study Objectives
The primary objective of this study is as follows: 

To evaluate the safety and tolerability of elvitegravir/cobicistat/emtricitabine/tenofovir 
alafenamide (EVG/COBI/FTC/TAF; E/C/F/TAF) fixed-dose combination (FDC) in HIV-1 
infected adults with end stage renal disease (ESRD) on chronic hemodialysis (HD) at 
Week 48
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of the E/C/F/TAF FDC in HIV-1 infected adults with 
ESRD on chronic HD at Week 96

To evaluate the proportion of subjects receiving E/C/F/TAF FDC achieving virologic 
response (HIV-1 RNA < 50 copies/mL, as defined by the FDA snapshot analysis) at 
Weeks 24, 48, and 96

To evaluate plasma pharmacokinetics (PK) of EVG, COBI, FTC, TAF, and tenofovir (TFV)
in HIV-1 infected patients with ESRD on chronic HD

To evaluate the safety and tolerability of bictegravir/emtricitabine/tenofovir alafenamide
(B/F/TAF) FDC in HIV-1 infected adults with ESRD on chronic HD in the open-label 
extension phase
1.2.
Study Design
Design Configuration and Subject Population
GS-US-292-1825 is an open-label, multicenter, single-arm study to assess the safety, tolerability, 
PK, and efficacy of the E/C/F/TAF FDC dosed once daily in HIV-infected adult subjects with 
ESRD on chronic HD. 


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All subjects will switch from their current antiretroviral (ARV) regimen to E/C/F/TAF on Day 1. 
The treatment duration for E/C/F/TAF will be at least 96 weeks. 
After Week 96, subjects in the US will continue to take their study drug and attend visits every 
12 weeks until the End of E/C/F/TAF visit. At Week 96 or the End of E/C/F/TAF Visit, subjects 
will discontinue E/C/F/TAF FDC and be given the option to receive open-label (OL) B/F/TAF 
FDC. All subjects participating in the OL extension of B/F/TAF FDC will return for study visits 
at B/F/TAF Week 4 OL, Week 12 OL, and every 12 weeks thereafter for at least 48 weeks.
Subjects who do not wish to participate in the B/F/TAF OL extension phase will discontinue 
study drug at Week 96.
Approximately 50 subjects with ESRD on chronic HD will be enrolled.
Treatment Groups
All enrolled subjects will receive the following treatment:

FDC of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 
10 mg administered orally, once daily with food until the next hemodialysis. On the day of 
hemodialysis, study drug should be administered after completion of hemodialysis.
Subjects who enroll into the B/F/TAF OL extension phase will receive the following treatment:

FDC of bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg administered 
orally, once daily without regard to food until the next hemodialysis. On the day of 
hemodialysis, study drug should be administered after completion of hemodialysis.
Key Eligibility Criteria 
HIV-infected adults who meet the following criteria:

No documented history of HIV-1 resistance to EVG, FTC, lamivudine (3TC), or TFV

Currently receiving a stable ARV regimen for ≥ 6 consecutive months prior to screening

Plasma HIV-1 RNA < 50 copies/mL for at least 6 months preceding the screening visit

CD4 cell count of ≥ 200 cells/μL

ESRD with eGFR < 15 mL/min by Cockcroft-Gault (CG)

On chronic HD for ≥ 6 months prior to screening

Hepatitis C virus (HCV) infection allowed

Hepatitis B virus (HBV) infection not allowed


Genvoya/B iktarvy 
GS-US-292- 1825 
Statistical Analysis Plan 
Studv Periods / Phases 
Version I 
The study will consist of a 30-day screening period (within 30 days before Day 1 visit), followed 
by a 96-week EiC/FIT AF treatment period. 
After Week 96, all subjects participating in the B/F/f AF OL extension phase will receive 
B/F/f AF FDC for at least 48 weeks. 
End of the study will occur when the last subject enrolled in the study has completed their 
last observation ( or visit). 
After a subject has completed/tenninated their participation in the study, long-tenn care of the 
subject will remain the responsibility of their primary treating physician. 
Schedule of Assessments {E/C/Fff AF Phase) 
Following Screening, eligible subjects will be required to return for study visits at Day 1 and 
Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. After the Week 96 visit, subjects who are not 
pla1ming to participate in the B/F ff AF OL extension phase will stop study drug and complete a 
30-day Follow-up visit to complete their participation in the study. Subjects who plan to 
participate in the B/F/TAF OL extension phase will continue to take E/C/F/f AF and attend visits 
every 12 weeks until the End of E/C/F/TAF visit. 
For all subjects, HBV and HCV serologies will be analyzed at Screening. Adverse events (AEs), 
concomitant medications, complete or symptom-directed physical examinations, laboratory 
analyses (hematology and chemistry), HIV-1 RNA, and CD4 cell count will be assessed at 
Screening, Day 1, and all subsequent study visits. eGFR will be assessed at Screening, Day 1, 
and all subsequent study visits except the 30-day Follow-up visit. Fasting lipids and glucose will 
be assessed at Day 1 and every 24 weeks thereafter m1til Week 96 or End of E/C/F/f AF visit. 
Predose whole blood draw for plasma and peripheral blood mononuclear cell (PBMC) samples 
will be collected from all subjects at Week 4 or Week 12, which must be the day of hemodialysis. 
Schedule of Assessments {B/Fff AF OL Extension Phase) 
All subjects participating in the B/F/f AF OL extension phase will return for study visits at 
B/F/fAF Week 4 OL, Week 12 OL, and every 12 weeks thereafter for at least 48 weeks. 
Adverse events, concomitant medications, complete or symptom-directed physical examinations, 
laboratory analyses (hematology and chemistry), HIV-1 RNA, and CD4 cell count will be 
assessed at each visit. eGFR will be assessed at each visit except the 30-day Follow-up visit. 
Fasting lipids and glucose will be assessed every 24 weeks. 
CONFIDENTIAL 
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Genvoya/B iktarvy 
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Statistical Analysis Plan 
Site and Stratum Enrollment Limits 
Approximately 25 study sites in North America and Europe will participate. There is no 
enrollment limit for individual sites. 
1.3. 
Sample Size and Power 
Version I 
A sample size of approximately 50 subjects is based on practical considerations and is 
considered to be sufficient to evaluate the primary objective of this study. The primary endpoint 
is the incidence of treatment-emergent Grade 3 or higher AEs up to Week 48. The Grade 3 or 
higher AE rate in Study GS-US-292-0112 in subjects that had mild to moderate renal impainnent 
was 8.8% at Week 48 for the E/C/F/TAF ann. Therefore, with 50 subjects, and an assumed rate 
of Grade 3 or higher AEs being 10%, this study would provide 95% confidence for the primary 
endpoint to be within (1.7%, 18.3%) assuming nonnal approximation to binomial proportions. 
CONFIDENTIAL 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
The Week 12 Independent Data Monitoring Committee (IDMC) analysis was conducted after the 
first 25 subjects enrolled completed their Week 12 visit of the study or prematurely discontinued 
the study drug. The IDMC’s role and responsibilities and the scope of analysis provided to the 
IDMC were provided in a mutually agreed upon charter, which defines the IDMC membership, 
meeting logistics, and meeting frequency.
2.2.
Week 24 Analysis
A Week 24 analysis was conducted after all subjects enrolled either completed their Week 24
visit of the study or prematurely discontinued study drug.
2.3.
Week 48 Analysis
A Week 48 analysis was conducted after all subjects enrolled either completed their Week 48 
visit of the study or prematurely discontinued study drug.
2.4.
Week 96 Analysis
A Week 96 analysis was conducted after all subjects enrolled either completed their Week 96
visit of the study or prematurely discontinued from the study.
2.5.
Final Analysis
The final statistical analysis will be conducted after all subjects either complete the study or 
prematurely discontinue from the study. 
This SAP describes the analysis plan for the final analysis.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
The final analysis will include all data collected from the E/C/F/TAF and the B/F/TAF OL 
extension phases of the study. Separate tables and figures will be created for each phase unless 
otherwise specified. Data collected from both phases will be included in data listings. Data 
included in each phase are defined as follows:
E/C/F/TAF Phase Data

For subjects who are never treated in the B/F/TAF OL extension phase of the study, all 
available data are considered as the E/C/F/TAF phase data. 

For subjects treated in the B/F/TAF OL extension phase of the study, E/C/F/TAF phase data 
are defined as data collected up to the B/F/TAF OL extension phase first dose date except for 
data on adverse events (AEs), concomitant medications, pregnancy, and death. For AEs, 
concomitant medications, pregnancy, and death, only data collected prior to the B/F/TAF 
OL extension phase first dose date are included. 
B/F/TAF OL Extension Phase Data 

B/F/TAF OL extension phase data are only available from subjects who enter the B/F/TAF 
OL extension phase of the study. B/F/TAF OL extension phase data are defined as data 
collected after the B/F/TAF OL extension phase first dose date except for data on AEs, 
concomitant medications, pregnancy, and death. For AEs, concomitant medications, 
pregnancy, and death, data collected on or after the extension phase first dose date are 
included. 
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 Subjects 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 a 
subject. 
In general, age (in years) on the date of the first dose of E/C/F/TAF study drug will be used for 
analyses and presentation in listings. For screen failures, age on the date the informed consent 
was signed will be used. If only birth year is collected on the eCRF, “01 January” will be used 
for the unknown birth day and month for the purpose of age calculation; similarly, if only birth 
year and month are collected on the eCRF, “01” will be used for the unknown birth day for the 
purpose of age calculation. 
In general, permanent discontinuation of study drug refers to premature discontinuation of study 
drug or completion of study drug.


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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 and will be identified in a subtitle of each table, figure, and listing. A summary of the 
number and percentage of subjects in each analysis set will be provided. 
3.1.1.
All Enrolled Subjects Analysis Set
The All Enrolled Subjects Analysis Set will include all subjects who are enrolled into the study.
This is the primary analysis set for by-subject listings.
3.1.2.
B/F/TAF Enrolled Subjects Analysis Set
The B/F/TAF Enrolled Subjects Analysis Set will include all subjects who enrolled into the 
B/F/TAF OL extension phase of the study. This is the analysis set for by-subject listings that 
pertain to the B/F/TAF OL extension phase only.
3.1.3.
E/C/F/TAF Full Analysis Set
The E/C/F/TAF Full Analysis Set (FAS) will include all subjects who (1) were enrolled in the 
study and (2) received at least 1 dose of E/C/F/TAF study drug. This is the primary analysis set 
for the E/C/F/TAF efficacy analyses.
3.1.4.
B/F/TAF Full Analysis Set
The B/F/TAF Full Analysis Set (FAS) will include all subjects who (1) were enrolled in the 
study and (2) received at least 1 dose of B/F/TAF study drug. This is the primary analysis set for 
the B/F/TAF efficacy analyses.
3.1.5.
E/C/F/TAF Safety Analysis Set
The E/C/F/TAF Safety Analysis Set will include all subjects who received at least 1 dose of 
E/C/F/TAF study drug. This is the primary analysis set for the E/C/F/TAF safety analyses.
3.1.6.
B/F/TAF Safety Analysis Set
The B/F/TAF Safety Analysis Set will include all subjects who received at least 1 dose of 
B/F/TAF study drug. This is the primary analysis set for the B/F/TAF safety analyses.
3.1.7.
B/F/TAF Plasma PK Analysis Set
The B/F/TAF Plasma PK Analysis Set will include all subjects who (1) were enrolled into the 
study, (2) received at least 1 dose of B/F/TAF study drug, and (3) have at least 1 nonmissing 
plasma PK concentration value for any analyte of interest reported by the PK lab. The B/F/TAF 
Plasma PK Analysis Set will be used for general B/F/TAF plasma PK analyses.


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3.2.
Subject Grouping
For all analyses, subjects will be grouped by treatment received. All subjects received 
E/C/F/TAF. Subjects who enrolled into the B/F/TAF OL extension phase also received B/F/TAF. 
Subjects will be grouped under “GEN” for the E/C/F/TAF phase and under “GEN to OL 
B/F/TAF” for the B/F/TAF OL extension phase. In the subject listings, subjects who received 
only E/C/F/TAF will have treatment group of “GEN” and subjects who received E/C/F/TAF and 
OL B/F/TAF will have treatment group of “GEN to OL B/F/TAF”.
3.3.
Strata and Covariates
This study did not use a stratified randomization schedule when enrolling subjects. No covariates 
will be included in efficacy or safety analyses.
3.4.
Examination of Subject Subgroups
No subgroup analyses are planned.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
A missing datum for a given study analysis window may be due to any of the following reasons:

A visit occurring in the window but data were not collected or were unusable

A visit not occurring in the window

A subject permanently discontinuing from the study before reaching the window
In general, values for missing data will not be imputed, unless methods for handling missing data 
are specified.
For missing last dose date of study drug, imputation rules are described in Section 3.8.1. The 
handling of missing or incomplete dates for AE onset is described in Section 8.3.5.2, and for 
concomitant medication in Section 8.6.2.
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.


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3.7.
Data Handling Conventions and Transformations
Laboratory data that are continuous in nature but less than the lower limit of quantitation 
(LLOQ) or above the upper limit of quantitation will be imputed as follows:

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 49 
and 4.9, respectively, will be used for calculation of 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 for calculation of summary statistics. 

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “x” (where x is considered the limit of quantitation).
Logarithm (base 10) transformation will be applied to HIV-1 RNA data for efficacy analyses. 
HIV-1 RNA results of “No HIV-1 RNA detected” and “< 20 copies/mL HIV-1 RNA detected” 
will be imputed as 19 copies/mL for analysis purposes.
3.8.
Analysis Windows
3.8.1.
Definition of Study Day
Study Day 1 is defined as the day when the first dose of E/C/F/TAF study drug was taken, as 
recorded on the Study Drug Administration eCRF form.
B/F/TAF Study Day 1 is defined as the day when the first dose of B/F/TAF study drug was 
taken, as recorded on the Study Drug Administration eCRF form.
Study Days are calculated relative to Study Day 1 and B/F/TAF Study Day 1. For events that 
occurred on or after Study Day 1, study days are calculated as (visit date minus Study Day 1 
plus 1). For events that occurred prior to Study Day 1, study days are calculated as (visit date 
minus Study Day 1).
E/C/F/TAF Last Dose Date is the latest of E/C/F/TAF study drug end dates recorded on the 
Study Drug Administration eCRF form with “Permanently Withdrawn” box checked for subjects 
who prematurely discontinued study drug or who completed study drug according to the Study 
Drug Completion eCRF. 


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If the date of E/C/F/TAF last dose is missing (eg, only year of last dose is known or completely 
missing due to lost to follow-up) for subjects who prematurely discontinued or completed study 
drug, the latest of the E/C/F/TAF study drug start dates and end dates, the clinic visit dates, and 
the laboratory visit dates, excluding the date of the 30-day follow-up visit and any dates on or 
after the first dose of B/F/TAF if applicable, will be used to impute the last dose date. For other 
partial missing last dose dates, please see programming specifications (Appendix 7) for 
imputation rule details. 
B/F/TAF Last Dose Date is the latest of B/F/TAF study drug end dates recorded on the Study 
Drug Administration eCRF form with “Permanently Withdrawn” box checked for subjects who 
prematurely discontinued study drug or who completed study drug according to the Study Drug 
Completion eCRF. 
If the date of B/F/TAF last dose is missing (eg, only year of last dose is known or completely 
missing due to lost to follow-up) for subjects who prematurely discontinued or completed study 
drug, the latest of the B/F/TAF study drug start dates and end dates, the clinic visit dates, and the 
laboratory visit dates, excluding the date of the 30-day follow-up visit and any dates before the 
first dose of B/F/TAF, will be used to impute the last dose date. For other partial missing last 
dose dates, please see programming specifications (Appendix 7) for imputation rule details. 
Last Study Date is the latest of E/C/F/TAF or B/F/TAF study drug start date and end date, clinic 
visit dates, and laboratory visit dates, including the 30-day follow-up visit date, for subjects who 
prematurely discontinued the study or who completed the study according to Study Completion 
eCRF.
Baseline value for the E/C/F/TAF phase is defined as the last value obtained on or prior to Study 
Day 1 for all assessments. Baseline value for the B/F/TAF OL extension phase is defined as the 
last value obtained on or prior to B/F/TAF Study Day 1 for all assessments. 
3.8.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purposes of analysis, 
observations will be assigned to analysis windows.
3.8.2.1.
Analysis Windows for E/C/F/TAF Phase
The analysis windows for HIV-1 RNA, CD4 cell count, CD4%, hematology (excluding INR),
chemistry, eGFRCG, vital signs, weight, visual analogue scale (VAS), and healthcare utilization 
assessment are presented in Table 3-1.


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Table 3-1.
Analysis Windows for HIV-1 RNA, CD4 Cell Count, CD4%, 
Hematologya, Chemistryb, eGFRCG, Vital Signs, Weight, Visual 
Analogue Scale (VAS), and Healthcare Utilization Assessment
(E/C/F/TAF Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 2
14
2
21
Week 4
28
22
42
Week 8
56
43
70
Week 12
84
71
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
Week 60
420
379
462
Week 72
504
463
546
Week 84
588
547
630
Week 96
672
631
714
Week 108
756
715
798
Week 120
840
799
882
a
Hematology panel excluding INR and prothrombin time.
b
Chemistry profile includes alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, 
albumin, LDH, CPK, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, 
uric acid, and amylase. 
Note: The above analysis windows will also be used for bone biomarker of parathyroid hormone (PTH). 
The analysis windows for fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, 
triglycerides, and total cholesterol to HDL ratio) are presented in Table 3-2.
Table 3-2.
Analysis Windows for Fasting Glucose and Lipid Panel (E/C/F/TAF
Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 24
168
2
252
Week 48
336
253
420
Week 72
504
421
588
Week 96
672
589
756
Week 120
840
757
924


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The analysis windows for prothrombin time and INR are presented in Table 3-3. 
Table 3-3.
Analysis Windows for prothrombin time and INR (E/C/F/TAF Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 24
168
2
252
Week 48
336
253
588
Week 120
840
589
1092
The analysis windows for SF-36 and HIV-TSQc are presented in Table 3-4. 
Table 3-4.
Analysis Windows for SF-36 and HIV-TSQc (E/C/F/TAF Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baselinea
1
Week 24
168
2
252
Week 48
336
253
420
Week 72
504
421
588
Week 96
672
589
756
Week 120
840
757
924
a
HIV TSQc does not have a baseline assessment so analysis window at baseline does not apply. 
The analysis windows for HIV-TSQs are presented in Table 3-5. 
Table 3-5.
Analysis Windows for HIV-TSQs (E/C/F/TAF Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
98
Week 24
168
99
252
Week 48
336
253
420
Week 72
504
421
588
Week 96
672
589
756
Week 120
840
757
924


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The analysis windows for safety ECG are presented in Table 3-6.
Table 3-6.
Analysis Windows for Safety ECG (E/C/F/TAF Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 48
336
2
504
Week 96
672
505
840
3.8.2.2.
Analysis Windows for B/F/TAF OL Extension Phase
The analysis windows for HIV-1 RNA, CD4 cell count, CD4%, hematology, chemistry, 
eGFRCG, vital signs, and weight are presented in Table 3-7.
Table 3-7.
Analysis Windows for HIV-1 RNA, CD4 Cell Count, CD4%,
Hematologya, Chemistryb, eGFRCG, Vital Signs, and Weight (B/F/TAF
OL Extension Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
56
Week 12
84
57
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
Week 60
420
379
462
a
Hematology panel including PT/INR.
b
Chemistry profile includes alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, 
albumin, LDH, CPK, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, 
uric acid, and amylase. 
Note: The above analysis windows will also be used for bone biomarker of parathyroid hormone (PTH).
The analysis windows for fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, 
triglycerides, and total cholesterol to HDL ratio) are presented in Table 3-8.
Table 3-8.
Analysis Windows for Fasting Glucose and Lipid Panel (B/F/TAF OL 
Extension Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 24
168
2
252
Week 48
336
253
420


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The analysis windows for SF-36 and HIV-TSQ are presented in Table 3-9.
Table 3-9.
Analysis Windows for SF-36 and HIV-TSQ (B/F/TAF OL Extension
Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
98
Week 24
168
99
252
Week 48
336
253
420
The analysis windows for safety ECG are presented in Table 3-10.
Table 3-10.
Analysis Windows for Safety ECG (B/F/TAF OL Extension Phase)
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 48
336
2
504
3.8.3.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rule(s) will be used.
If multiple nonmissing numeric observations exist in a window, records will be chosen as follows:

For baseline, the latest available record on or prior to the first dose of E/C/F/TAF or 
B/F/TAF study drug, as appropriate, will be selected. If there are multiple records with the 
same time or no time recorded on the same day, average will be used for the baseline value, 
except for HIV-1 RNA (see below). 

For postbaseline visits: 
For CD4 cell count and CD4%, the record(s) collected on the latest day in the window 
will be selected for analysis.
For other numeric observations (except HIV-1 RNA), the record(s) collected on the day
closest to the nominal day for that visit will be selected. If there are 2 records equidistant 
from the nominal day, the later day will be selected.
For any numeric observations except HIV-1 RNA, if there are multiple records on the 
selected day, the average will be taken.


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
For baseline and postbaseline HIV-1 RNA, the latest (considering both date and time) 
record(s) in the window 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.
If multiple valid nonmissing categorical observations exist in a window, records will be chosen 
as follows:

For baseline, the last available record on or prior to the first dose of E/C/F/TAF or B/F/TAF 
study drug, as appropriate, will be selected. If there are multiple records with the same time 
or no time recorded on the same day, the value with the lowest severity will be selected 
(eg, normal will be selected over abnormal for safety ECG findings).

For postbaseline visits, the most conservative value within the window will be selected for 
categorical observations other than patient reported outcomes (eg, abnormal will be selected 
over normal for safety ECG findings).

For patient-reported outcomes collected at postbaseline visits, the record closest to the 
nominal day for that visit will be selected. If there are 2 records equidistant from the nominal 
day, the later will be selected.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
4.1.1.
Subject Enrollment
The number and percentage of subjects enrolled for each country and investigator will be 
summarized using the E/C/F/TAF Safety Analysis Set and the B/F/TAF Safety Analysis Set. The 
denominator for these summaries will be the number of subjects in the respective Safety 
Analysis Set.
A listing of subject enrollment including date of informed consent signed and met all eligibility 
criteria will be provided (see Appendix Listing 1). 
4.1.2.
Subject Disposition
A summary of subject disposition will be provided (see Appendix Table 1). 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, subjects enrolled but not 
treated, subjects in the E/C/F/TAF Safety Analysis Set, subjects in the B/F/TAF Safety Analysis 
Set, subjects in the E/C/F/TAF FAS, and subjects in the B/F/TAF FAS.
In addition, the number and percentage of subjects in the following categories will be 
summarized:

Completed E/C/F/TAF study treatment

Prematurely discontinued E/C/F/TAF study treatment (with summary of reasons for 
discontinuing study drug)

Enrolled in the B/F/TAF OL extension phase of the study

Completed B/F/TAF OL study treatment

Prematurely discontinued B/F/TAF OL study treatment (with summary of reasons for 
discontinuing study drug)

Completed the study

Prematurely discontinued from the study (with summary of reasons for discontinuing study) 
The denominator for the percentages of subjects in each category, except for the categories of 
“completed B/F/TAF OL study treatment” and “prematurely discontinued B/F/TAF OL study 
treatment”, will be the number of subjects in the E/C/F/TAF Safety Analysis Set. The 
denominator for the percentage of subjects in the categories of “completed B/F/TAF OL study 
treatment” and “prematurely discontinued B/F/TAF OL study treatment” will be the number of 
subjects in the B/F/TAF Safety Analysis Set.


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No inferential statistics will be generated. Data listings of reasons for premature study drug
discontinuation and premature study discontinuation will be provided.
4.2.
Extent of Study Drug Exposure and Adherence
4.2.1.
Duration of Exposure to E/C/F/TAF Study Drug
Duration of exposure to E/C/F/TAF study drug will be defined as (the last E/C/F/TAF dose date 
Study Day 1 + 1), regardless of temporary interruptions in study drug administration, and will 
be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
Duration of exposure to E/C/F/TAF study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and as the number and percentage of 
subjects exposed for specified periods, ie, ≥2 weeks (14 days), ≥ 4 weeks (28 days), ≥8 weeks
(56 days), ≥12 weeks (84 days), ≥24 weeks (168 days), ≥36 weeks (252 days), ≥48 weeks 
(336 days), ≥60 weeks (420 days), ≥72 weeks (504 days), ≥84 weeks (588 days), ≥96 weeks 
(672 days), ≥108 weeks (756 days), etc.
Summaries will be provided for subjects in the E/C/F/TAF Safety Analysis Set. No inferential 
statistics will be provided.
Time to premature discontinuation of E/C/F/TAF study drug will be analyzed using the 
Kaplan-Meier (KM) method based on the E/C/F/TAF Safety Analysis Set. Subjects who 
completed E/C/F/TAF study treatment will be censored on the last E/C/F/TAF dose date. A plot 
of KM estimates for time to premature discontinuation of E/C/F/TAF study drug will be 
generated. 
4.2.2.
Duration of Exposure to B/F/TAF Study Drug
Duration of exposure to B/F/TAF study drug will be defined as (the last B/F/TAF dose date 
B/F/TAF Study Day 1 + 1), regardless of temporary interruptions in study drug administration, 
and will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
Duration of exposure to B/F/TAF study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and as the number and percentage of 
subjects exposed for specified periods, ie, ≥2 weeks (14 days), ≥ 4 weeks (28 days), ≥8 weeks 
(56 days), ≥ 12 weeks (84 days), ≥ 24 weeks (168 days), ≥36 weeks (252 days), and ≥48 weeks 
(336 days).
Summaries will be provided for subjects in the B/F/TAF Safety Analysis Set. No inferential 
statistics will be provided.
4.2.3.
Adherence with Study Drug
Study drug adherence will be computed based on pill counts. The numbers of pills of study drug 
dispensed and returned are captured on the Study Drug Accountability eCRF. 


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Adherence (%) to E/C/F/TAF study drug will be calculated as follows:
prescribed
pills
of
No.
Total
 taken
pills
of
No.
Total
100
(%)
Adherence


period
dispensing
each
at 
prescribed
pills
of
No.
period
dispensing
each
at 
 taken
pills
of
No.
100
[2]
[1]



[1]
Number of pills taken at a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number 
of pills prescribed for the study drug multiplied by the duration of treatment at the dispensing period, and (b) the number of 
pills taken for the study drug (number of pills dispensed minus the number of pills returned). Total number of pills taken is 
determined by summing the number of pills taken from all evaluable dispensing periods.
[2]
Number of pills prescribed at a distinct dispensing period for a study drug is calculated as the daily number of pills 
prescribed for the study drug multiplied by the duration of treatment at the dispensing period. Total number of pills 
prescribed is determined by summing the number of pills prescribed from all evaluable dispensing periods.
The duration of treatment at each dispensing period is calculated as the minimum of (a) the 
last returned date of study drug at a dispensing period, (b) date of premature discontinuation of 
the study drug, and (c) next pill dispensing date of the study drug, minus dispensing date of the 
study drug. 
The next pill dispensing date is the following dispensing date of the study drug regardless of the 
bottle return date.
For a record where the number of pills returned was missing (with “Yes” answered for 
“Was Bottle returned?” question), it is assumed the number of pills returned was zero. If the 
number of pills dispensed was missing or any study drug bottle was not returned, or the bottle 
return status was unknown, then all records in that dispensing period will be excluded from both 
denominator and numerator calculation.
Adherence will be calculated using all data from the entire dosing period up to the date of 
permanent discontinuation of the E/C/F/TAF study drug for subjects who prematurely 
discontinued study drug or completed E/C/F/TAF study drug. 
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) along with the 
number and percentage of subjects belonging to adherence categories (ie, < 80%, ≥80% to 
< 90%, 90% to < 95%, 95%) will be provided for subjects who return at least 1 bottle and 
have calculable adherence during the study in the E/C/F/TAF Safety Analysis Set. No inferential 
statistics will be provided.
Adherence will be calculated in a similar manner for the B/F/TAF Safety Analysis Set.
4.3.
Protocol Deviations
A listing will be provided for subjects in the All Enrolled Subjects analysis set who violated at 
least 1 inclusion or exclusion criterion. The listing will include the criteria not met.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex at birth, race, and ethnicity) and baseline characteristics 
(eg, body weight, height, and body mass index [BMI]) will be summarized using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous data and by 
the number and percentage of subjects for categorical data. The summaries of demographic data 
and baseline characteristics will be provided for the E/C/F/TAF Safety Analysis Set and the 
B/F/TAF Safety Analysis Set. Baseline for each phase is defined in Section 3.8.1.
5.2.
Baseline Disease Characteristics
The following baseline disease characteristics collected at enrollment will be summarized:

Mode of infection (HIV risk factors)

HIV disease status at study entry

HCV antibody status at study entry

Medical history at study entry: Type I or II diabetes (Yes/No), cardiovascular disease
(Yes/No), hypertension (Yes/No), and hyperlipidemia (Yes/No) (see Appendix 7 for details) 

Smoking status at study entry: (a) Never Smoked, (b) Former Smoker, and (c) Current 
Smoker (see Appendix 7 for details)

Duration of hemodialysis at study entry (years)

Pre-switch ARV categories: (a) Containing TDF, (b) Containing ABC, and (c) Containing 
Neither

Pre-switch ARV categories: (a) Containing 3TC, (b) Containing ABC, (c) Containing TDF, 
(d) Containing FTC

Pre-switch ARV 3rd Agent Category: (a) INSTI, (b) PI, (c) NNRTI, (d) CCR5 Antagonist
The following baseline disease characteristics collected prior to E/C/F/TAF administration and 
prior to B/F/TAF administration will be summarized for the E/C/F/TAF Safety Analysis Set and 
the B/F/TAF Safety Analysis Set, respectively:

HIV-1 RNA categories (copies/mL): (a) < 50 and (b) ≥ 50

CD4 cell count (/μL)

CD4 cell count categories (/μL): (a) < 50, (b) ≥ 50 to < 200, (c) ≥ 200 to < 350, 
(d) ≥350 to < 500, and (e) ≥500


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
CD4%

eGFRCG (mL/min)
No inferential statistics will be provided.
5.3.
Medical History
Subjects’ answers to the following questions prespecified on the Medical History CRF will be 
listed: 

Does the Subject have diabetes? (Type I or II)

Have any first-degree relatives experienced MI or stroke before the age of 50?
In addition, subjects’ kidney transplant registration status collected by the Transplant History 
CRF will be listed. 
General medical history data will be collected at screening and listed only. General medical 
history data will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA).


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6.
ANALYSES OF PRIMARY ENDPOINT
6.1.
Definition of the Primary Endpoint
The primary endpoint of this study is the incidence of treatment-emergent Grade 3 or higher AEs
in subjects receiving E/C/F/TAF up to Week 48. The analysis of the primary endpoint was 
conducted for the Week 48 clinical study report and will not be repeated for this final analysis.


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7.
EFFICACY ANALYSES
The proportions of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by 
the US FDA-defined snapshot algorithm were summarized as part of the Week 48 clinical study 
report and will not be repeated for the final analysis. 
7.1.
Efficacy Endpoints as Secondary Study Endpoints
Secondary efficacy endpoints for the final analysis include the following: 

The proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 96 as defined by the 
US FDA-defined snapshot algorithm

The proportion of subjects with HIV-1 RNA < 50 copies/mL by visit

The change from baseline in CD4 cell count and CD4% by visit
7.2.
Analysis of Efficacy Endpoints
7.2.1.
Analysis of the Proportion of Subjects with HIV-1 RNA < 50 copies/mL at 
Week 96 as Determined by US FDA-defined Snapshot Algorithm
US FDA-Defined Snapshot Algorithm
The analysis window at Week 96 is defined as from Study Day 631 to Study Day 714, inclusive.
All HIV-1 RNA data collected on-treatment (ie, data collected up to 1 day after the last dose date 
of E/C/F/TAF study drug) will be used in the US FDA-defined snapshot algorithm. Virologic 
outcome for Week 96 will be defined using the following categories:

HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the analysis window

HIV-1 RNA ≥ 50 copies/mL: this includes subjects
1) Who have the last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the analysis 
window , or
2) Who do not have on-treatment HIV-1 RNA data in the analysis window and
a) Who discontinue study drug prior to or in the analysis window due to lack of efficacy, 
or
b) Who discontinue study drug prior to or in the analysis window due to AE or death 
and have the last available on-treatment HIV-1 RNA ≥50 copies/mL, or
c) Who discontinue study drug prior to or in the analysis window due to reasons other 
than AE, death, or lack of efficacy and have the last available on-treatment HIV-1 
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
No Virologic Data in Window: this includes subjects who do not have on-treatment HIV-1 
RNA data in the analysis window because of the following:
3) Discontinuation of study drug prior to or in the analysis window due to AE or death and 
the last available on-treatment HIV-1 RNA < 50 copies/mL, or
4) Discontinuation of study drug prior to or in the analysis window due to reasons other than 
AE, death, or lack of efficacy and the last available on-treatment HIV-1 RNA is 
< 50 copies/mL, or
5) Missing data during the window but on study drug
The flowchart of the snapshot algorithm is provided in Appendix 3.
The number and percentage of subjects with HIV-1 RNA < 50 copies/mL, HIV-1 RNA 
≥50 copies/mL, and reasons for no virologic data at Week 96 will be summarized using the 
E/C/F/TAF FAS. The 95% confidence intervals (CIs) for percentages of subjects with HIV-1 
RNA < 50 copies/mL and HIV-1 RNA ≥ 50 copies/mL will be constructed using the Exact 
method (see Appendix Table 1Appendix Table 2). 
The same analysis will be repeated for proportion of subjects with HIV-1 RNA < 20 copies/mL 
at Week 96 as defined by US FDA-defined snapshot algorithm.
The Week 96 virologic outcomes for the US FDA-defined snapshot algorithm will be listed 
(see Appendix Listing 2).
7.2.2.
Analysis of Other Efficacy Endpoints
7.2.2.1.
By-Visit Analysis of the Proportion of Subjects with HIV-1 RNA < 50 copies/mL 
by Missing  Failure and Missing  Excluded Approaches
The proportion of subjects with HIV-1 RNA < 50 copies/mL will be summarized using the 
following 2 methods for imputing missing HIV-1 RNA values: 

Missing  Failure (M  F) 
In this approach, all missing data will be treated as HIV-1 RNA 50 copies/mL. The 
denominator for percentages is the number of subjects in the E/C/F/TAF FAS.

Missing
Excluded (M  E)
In this approach, all missing data will be excluded in the computation of the percentages 
(ie, missing data points will be excluded from both the numerator and denominator in the 
computation). The denominator for percentages at a visit is the number of subjects in the FAS 
with nonmissing HIV-1 RNA value at that visit.


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For both M  F and M
E analyses, the number and percentage of subjects with HIV-1 RNA in 
the following categories will be summarized (see Appendix Table 3 ):

< 50 copies/mL
< 20 copies/mL
■
< 20 Not Detectable
■
< 20 Detectable

20 to < 50 copies/mL 

≥ 50 copies/mL 
The 95% CIs of the proportion of subjects with HIV-1 RNA < 50 copies/mL will be provided 
using the Exact method.
Separate summaries will be provided for the E/C/F/TAF FAS and the B/F/TAF FAS.
7.2.2.2.
Analysis of CD4 Cell Count and CD4 %
Values and changes from baseline in CD4 cell count and CD4% will be summarized at each 
postbaseline visit using descriptive statistics based on observed on-treatment values. On-treatment 
values include data collected after the first dose date up to the applicable last dose date + 1 day for 
subjects who permanently discontinued the applicable study drug.
In addition, values and changes from baseline in CD4 cell counts with missing values imputed 
using the last observation carried forward (LOCF) method will be summarized at each 
postbaseline visit. The algorithm for LOCF is as follows:

If a value is missing in an analysis visit window, the missing value will be replaced with the 
last on-treatment value (ie, up to 1 day after the last dose date of applicable study drug) 
observed before the analysis visit window that has the missing value.

Baseline values will not be used for imputation; subjects who had no postbaseline CD4 
assessment will be excluded from the postbaseline summaries.
The mean and 95% CI and median (Q1, Q3) of values and change from baseline in CD4 cell 
count over time will be plotted using observed data.
Separate summaries will be provided for the E/C/F/TAF FAS and the B/F/TAF FAS.
7.3.
Changes From Protocol-Specified Efficacy Analyses
There are no changes from the protocol-specified efficacy analyses.


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8.
SAFETY ANALYSES
Safety data will be summarized for the subjects in the E/C/F/TAF Safety Analysis Set and the 
B/F/TAF Safety Analysis Set. All safety data will be included in data listings.
The primary endpoint of the incidence of treatment-emergent Grade 3 or higher AEs up to 
Week 48 was conducted for the Week 48 clinical study report and will not be repeated for this
final analysis.
The secondary endpoint of the incidence of treatment-emergent Grade 3 or higher AEs up to 
Week 96 is defined in a similar manner to the primary endpoint included in the Week 48 clinical 
study report (See Section 8.1).
E/C/F/TAF Phase
For subjects who do not participate in the B/F/TAF OL extension phase, all safety data collected
from the first dose of E/C/F/TAF up to 30 days after permanent discontinuation of E/C/F/TAF 
study drug will be summarized, unless specified otherwise. For subjects who participate in the 
B/F/TAF OL extension phase, all safety data collected up to the date of the first B/F/TAF study 
drug dose will be summarized, unless specified otherwise.
B/F/TAF OL Extension Phase
All safety data collected from the first dose of B/F/TAF up to 30 days after permanent 
discontinuation of B/F/TAF study drug will be summarized, unless specified otherwise.
8.1.
Adverse Events Up to Week 96
Adverse events up to Week 96, or adverse events on or prior to Week 96, refers to those adverse 
events with onset date (if applicable) on or prior to the date of the Week 96 visit, as recorded on 
the Visit Date CRF, for subjects who had the Week 96 visit performed according to the 
Visit Date CRF. 
If the onset date of an AE is partially missing (with only year and month or year alone), the event 
is considered on or prior to Week 96 if the month and year (or year alone) of the AE onset date is 
the same as or before the month and year (or year) of the Week 96 visit date recorded on the 
Visit Date CRF. 
If the onset date of an AE in completely missing, the event is considered on or prior to the 
Week 96 if any of the following three criteria are met: 

The AE stop date is on or prior to the Week 96 visit date; or

The AE stop date is partially missing, with the month and year (or year alone) on or prior to 
the Week 96 visit date; or 

The AE stop date is completely missing, including the case when AE is still ongoing. 


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For subjects who prematurely discontinued the study prior to the Week 96 visit, all adverse 
events will be considered AEs on or prior to Week 96. 
8.2.
Analysis of Adverse Events Up to Week 96
The number and percentage of subjects who experienced at least 1 Grade 3 or 4 
treatment-emergent AE will be provided by system organ class (SOC) and preferred term (PT) 
using the E/C/F/TAF Safety Analysis set. For those AEs that occurred more than once in an 
individual subject during the specified time frame, the most severe grade will be used.
Multiple events will be counted only once per subject in the summaries. Adverse events will be 
summarized and listed first in alphabetical order of SOC, and then by PT in descending order of 
total frequency within each SOC. Grade 3 or 4 treatment-emergent AEs will also be summarized 
by PT only, in descending order of total frequency.
Grade 3 or 4 treatment-emergent study-drug related AEs by Week 96 will be summarized by 
SOC and PT. 
The general safety summaries described in Section 8.3 will present all TEAEs (or subset of 
TEAEs).
8.3.
Adverse Events and Deaths
8.3.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
Medical Dictionary for Regulatory Activities (MedDRA). SOC, high-level group term (HLGT), 
high level term (HLT), PT, and lowest-level term (LLT) will be provided in the AE dataset.
8.3.2.
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 study 
protocol. The severity grade of events for which the investigator did not record severity will be 
left as “missing” for data listings. 
8.3.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment”. 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.


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8.3.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs meet the 
definition of SAE specified in the study protocol. Serious adverse events captured and stored in 
the clinical database will be reconciled with the SAE database from the Gilead 
Pharmacovigilance & Epidemiology Department before data finalization. 
8.3.5.
Treatment-Emergent Adverse Events
8.3.5.1.
Definition of Treatment-Emergent Adverse Events
E/C/F/TAF phase treatment-emergent AEs are defined as 1 or both of the following:

Any AEs with an onset date on or after the E/C/F/TAF study drug start date and no later than 
30 days after permanent discontinuation of the E/C/F/TAF study drug for subjects who do 
not participate in the B/F/TAF OL extension phase or the day prior to the date of the first 
B/F/TAF study drug dose for subjects who participate in the B/F/TAF OL extension phase, 
or

Any AEs leading to premature discontinuation of E/C/F/TAF study drug.
B/F/TAF OL extension phase treatment-emergent AEs are defined as 1 or both of the following:

Any AEs with an onset date on or after the B/F/TAF study drug start date and no later than 
30 days after permanent discontinuation of the B/F/TAF study drug, or

Any AEs leading to premature discontinuation of B/F/TAF study drug.
8.3.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dose date of 
E/C/F/TAF study drug, then 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 for the E/C/F/TAF phase if both of the following 2 
criteria are met: 

The month and year (or year) of the AE onset is the same as or after the month and year 
(or year) of the first dose date of E/C/F/TAF study drug, and 

The month and year (or year) of the AE onset is the same as or before the month and year 
(or year) of the date corresponding to the minimum of (1) the last dose of E/C/F/TAF study 
drug plus 30 days AND (2) the first dose of B/F/TAF study drug minus 1 day 


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The event is considered treatment emergent for the B/F/TAF OL extension phase if both of the 
following 2 criteria are met: 

The month and year (or year) of the AE onset is after the month and year (or year) of the 
first dose date of B/F/TAF study drug, and

The month and year (or year) of the AE onset is the same as or before the month and year 
(or year) of the date corresponding to 30 days after the date of last dose of B/F/TAF study 
drug
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date on or after the first dose date of E/C/F/TAF study drug, will be considered to be treatment
emergent for the E/C/F/TAF phase. 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 dose date of E/C/F/TAF study drug will be considered treatment emergent. 
8.3.6.
Summaries of Adverse Events and Deaths
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, and PT separately for the E/C/F/TAF Safety Analysis Set and 
B/F/TAF Safety Analysis Set. For other AEs described below, summaries will be provided by 
SOC and PT separately for the E/C/F/TAF Safety Analysis Set and B/F/TAF Safety Analysis 
Set: 

Any Grade 2, 3, or 4 treatment-emergent AE

Any Grade 3 or 4 treatment-emergent AE

All treatment-emergent study-drug-related AEs

Any Grade 2, 3, or 4 treatment-emergent study-drug-related AE

Any Grade 3 or 4 treatment-emergent study-drug-related AE

All treatment-emergent SAEs

All treatment-emergent study-drug-related SAEs

All treatment-emergent AEs that caused premature discontinuation from study drug
A brief, high-level summary of AEs described above will be provided by the number and 
percentage of subjects who experienced the above AEs. Treatment-emergent deaths observed in 
the study will also be included in this summary. 


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For the E/C/F/TAF Safety Analysis Set summary, treatment-emergent death refers to a death that 
occurred between the first E/C/F/TAF dose date and the last E/C/F/TAF dose date plus 30 days 
(inclusive) for subjects who do not participate in the B/F/TAF OL extension phase or the day 
prior to the date of the first B/F/TAF study drug dose for subjects who participate in the 
B/F/TAF OL extension phase. 
For the B/F/TAF Safety Analysis Set summary, treatment-emergent death refers to a death that 
occurred between the first B/F/TAF dose date and the last B/F/TAF dose date plus 30 days 
(inclusive). 
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetical order of SOC and HLT within each SOC 
(if applicable), 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 treatment-emergent AEs will be summarized by PT 
only, in descending order of total frequency. 
In addition, data listings will be provided for the following: 

All AEs (with a variable indicating whether the event is treatment-emergent)

Grade 3 and 4 AEs

Study-drug-related AEs

SAEs

Study-drug-related SAEs

Deaths reported

AEs leading to premature discontinuation of study drug.
8.3.7.
Additional Analysis of Adverse Events
8.3.7.1.
Stage 3 Opportunistic Illnesses in HIV
On an ongoing basis, AEs will be reviewed for events that might meet the definition of stage 3 
opportunistic illnesses in HIV that are indicative of an AIDS-defining diagnosis (see Protocol 
Appendix 8). The Gilead medical monitor will review the possible stage 3 opportunistic illnesses
and approve the events that meet the definition. Events that meet the stage 3 opportunistic 
illnesses definition diagnosis will be listed for all enrolled subjects. 


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8.3.7.2.
Common Adverse Events Included in the FTC Prescribing Information
The common treatment-emergent AEs in the FTC Prescribing Information will be summarized 
by PT, in descending order of total frequency. The associated PTs are the following:

Headache 

Diarrhea

Nausea 

Fatigue 

Dizziness

Depression

Insomnia

Abnormal dreams

Rash

Abdominal pain

Asthenia

Cough

Rhinitis.
A by-subject listing will be provided for AEs with PT terms above for all enrolled subjects. 
8.3.7.3.
Cardiovascular or Cerebrovascular Events
Preferred terms for cardiovascular or cerebrovascular events are from relevant Standardised 
MedDRA Query (SMQ). The selected PT listing was provided by Gilead PVE and reviewed by 
Gilead medical monitors (see details in Appendix 4).
A data listing of cardiovascular or cerebrovascular events will be provided for the B/F/TAF 
Safety Analysis Set.
8.3.7.4.
Hepatic Events
Preferred terms for hepatic events are from 15 relevant SMQs, which are identified as 
non-infectious and non-congenital hepatobiliary disorders. The selected PT listing was provided 
by Gilead PVE and reviewed by Gilead medical monitors (see details in Appendix 5).


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A data listing of hepatic events will be provided for the B/F/TAF Safety Analysis Set.
8.4.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
E/C/F/TAF Safety Analysis Set and B/F/TAF Safety Analysis Set. The analysis will be based on 
values reported in conventional units. When values are below the lower limit of quantitation 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. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology and serum chemistry separately. 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.
8.4.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided for each laboratory test specified in the study protocol as 
follows:

Baseline value 

Value at each postbaseline analysis window

Change from baseline at each postbaseline analysis window 
In addition, percentage change from baseline at each postbaseline analysis window will also be 
provided for biomarker PTH.
A baseline laboratory value for the E/C/F/TAF phase will be defined as the last nonmissing value 
obtained on or prior to the date of first dose of E/C/F/TAF study drug. A baseline laboratory 
value for the B/F/TAF OL phase will be defined as the last nonmissing value obtained on or 
prior to the date of first dose of B/F/TAF study drug. Change from baseline to a postbaseline 
visit will be defined as the postbaseline value minus the baseline value. 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.


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Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized. The following formula will 
be used when both serum calcium and albumin results for a given blood draw are available and 
serum albumin value is < 4.0 g/dL. 

Calcium corrected for albumin (mg/dL)  serum calcium (mg/dL) + 0.8 (4.0 albumin (g/dL)). 
Toxicity grading for calcium will be applied based on the corrected values.
Estimated GFR
The following formula will be used to calculate eGFRCG: 

eGFRCG (mL/min)  [(140  age(yrs)) weight (kg) (0.85 if female)] / (SCr (mg/dL) 72),
where weight is total body mass in kilograms, and SCr is serum creatinine. 
8.4.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grade (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 normal reference ranges 
(eg, Grade 1 scale overlaps with normal reference range), laboratory values within normal range 
will be Grade 0 except for lipid tests.
For triglycerides, LDL, and cholesterol, the protocol-specified toxicity grade scale is for fasting 
test values, so nonfasting lipid results (or lipid results without known fasting status) will not be 
graded or summarized by toxicity grades.
For international normalized ratio (INR) of prothrombin time, protocol-specified toxicity grade 
scale depends on the upper limit of normal range (ULN). While the ULN of INR depends on 
whether a subject is taking anticoagulant medication or not (ie, Not taking oral anticoagulant: 
0.8 - 1.2; Taking oral anticoagulant: 2.0 3.0), the information is not collected in Covance lab. 
As a result, INR will be graded by assuming the subject is not taking oral anticoagulant, which is 
a more conservative approach and may lead to over-reporting abnormalities for INR. Since INR 
and prothrombin time are reflex tests; only an absolute value and not the toxicity grade is needed 
for patient management purposes; most importantly, the toxicity grades for INR may be 
over-reported. INR and prothrombin time will not be included in the laboratory abnormalities 
summary tables but will be included in a listing. 


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8.4.2.1.
Treatment-Emergent Laboratory Abnormalities
E/C/F/TAF treatment-emergent laboratory abnormalities are defined as values that increase at 
least 1 toxicity grade from baseline at any postbaseline time point up to 30 days after the 
permanent discontinuation of E/C/F/TAF study drug for subjects who do not participate in the 
B/F/TAF OL extension phase or up to the date of the first B/F/TAF study drug dose for subjects 
who participate in the B/F/TAF OL extension phase. 
B/F/TAF treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point up to 30 days after the permanent 
discontinuation of B/F/TAF study drug. 
If the relevant baseline 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 result 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 postbaseline grade, 
instead of treatment-emergent grade, for nonfasting glucose will be summarized, as nonfasting 
glucose was not assessed at baseline visit for most of the subjects; therefore, whether an 
abnormality is treatment-emergent or not cannot be determined for these subjects. 
8.4.2.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test; subjects will be categorized according to most severe 
postbaseline abnormality grade for a given lab test:

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 or 4 laboratory abnormalities
For all summaries of E/C/F/TAF laboratory abnormalities, the denominator is the number of 
subjects with any nonmissing postbaseline values up to 30 days after the last E/C/F/TAF dose
date for subjects who do not participate in the B/F/TAF OL extension phase or up to the date of 
the first B/F/TAF study drug dose for subjects who participate in the B/F/TAF OL extension
phase. 
For all summaries of B/F/TAF laboratory abnormalities, the denominator is the number of 
subjects with any nonmissing postbaseline values up to 30 days after the last B/F/TAF dose date. 
By-subject listings of treatment-emergent graded abnormalities and Grade 3 or 4 laboratory 
abnormalities will be provided by subject ID number and visit in chronological order.


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8.4.3.
Metabolic Laboratory Evaluations
For metabolic assessments, including fasting glucose and the lipid panel (ie, total cholesterol, 
triglycerides, LDL, HDL, total cholesterol to HDL ratio), only those measurements under fasting 
status will be summarized. 
Fasting lipid data will also be analyzed by using the following National Cholesterol Education 
Program (NCEP) ATP III categories {National Cholesterol Education Program (NCEP) 2001}:

For total cholesterol (mg/dL): < 200, 200-239, ≥ 240

For LDL (mg/dL): <100, 100-129, 130-159, 160-189, and ≥ 190 

For HDL (mg/dL): < 40, ≥40 to < 60, and ≥ 60 

For triglycerides (mg/dL): < 150, 150-199, 200-499, and ≥ 500
The number and proportion of subjects for the above categories of each lipid parameter will be 
summarized by its baseline category at Weeks 24, 48, 72, and 96 for the E/C/F/TAF Safety 
Analysis Set and at Weeks 24 and 48 for the B/F/TAF Safety Analysis Set.
In addition, the number and proportion of subjects in the E/C/F/TAF Safety Analysis Set who 
took lipid modifying medication at study entry and initiated medication during the E/C/F/TAF 
phase and the number and proportion of subjects in the B/F/TAF Safety Analysis Set who took 
lipid modifying medication at the start of the B/F/TAF OL extension phase and initiated 
medication during the B/F/TAF OL extension phase will be provided. 
A lipid modifying medication is defined as a medication with drug class (Anatomical 
Therapeutic Chemical drug class Level 2)  “LIPID MODIFYING AGENTS” and CMDECOD 
containing the wording of “STATIN”.
A sensitivity analysis of fasting lipid tests (including total cholesterol, LDL, HDL, triglycerides, 
and total cholesterol to HDL ratio) will be performed using the E/C/F/TAF Safety Analysis Set 
by excluding subjects who took lipid modifying medication at study entry or initiated lipid 
modifying medication during the study prior to Week 96: baseline, postbaseline, and changes 
from baseline at Week 96 will be summarized. Only subjects with both baseline and Week 96 
postbaseline values will be included in the analysis. 
A sensitivity analysis of fasting lipid tests (including total cholesterol, LDL, HDL, triglycerides, 
and total cholesterol to HDL ratio) will be performed using the B/F/TAF Safety Analysis Set by 
excluding subjects who took lipid modifying medication at the start of the B/F/TAF OL 
extension phase or initiated lipid modifying medication during the B/F/TAF OL extension phase: 
baseline, postbaseline, and changes from baseline at Weeks 24 and 48 will be summarized. Only 
subjects with both baseline and Week 48 postbaseline values will be included in the analysis. 


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Median (Q1, Q3) of change from baseline in fasting metabolic assessments over time will be 
plotted. 
8.4.4.
Liver-Related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements (see Appendix Table 4):
Individual Test:

Aspartate aminotransferase (AST): (a) > 3 ULN, (b) > 5 ULN, (c) > 10 ULN, 
(d) > 20 ULN

Alanine aminotransferase (ALT): (a) > 3 ULN, (b) > 5 ULN, (c) > 10 ULN,
(d) > 20 ULN

AST or ALT: (a) > 3 ULN, (b) > 5 ULN, (c) > 10 ULN, (d) > 20 ULN

Total bilirubin: (a) > 1 ULN, (b) > 2 ULN

Alkaline Phosphatase (ALP): > 1.5 ULN

AST or ALT > 3 ULN and total bilirubin: (a) > 1.5 ULN, (b) > 2 ULN

AST or ALT > 3 ULN and total bilirubin > 2 ULN and ALP < 2 ULN
The E/C/F/TAF summary will use data from all postbaseline visits up to 30 days after the 
last dose of E/C/F/TAF study drug for subjects who do not participate in the B/F/TAF OL 
extension phase or up to the date of the first B/F/TAF study drug dose for subjects who 
participate in the B/F/TAF OL extension phase. 
The B/F/TAF summary will use data from all postbaseline visits up to 30 days after the last dose 
of B/F/TAF study drug.
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline value. For both the composite endpoint of AST or ALT and total bilirubin, and the 
composite endpoint of AST or ALT, total bilirubin, and ALP, subjects will be counted once 
when the criteria are met at the same postbaseline visit date. The denominator is the number of 
subjects in the E/C/F/TAF Safety Analysis Set or B/F/TAF Safety Analysis Set with nonmissing 
postbaseline values of the tests in evaluation at the same postbaseline visit date. 
In addition, baseline, postbaseline, and change from baseline in AST, ALT, ALP, and total 
bilirubin will be summarized by visit using descriptive statistics.
Subjects with AST or ALT > 3 ULN will also be listed. 


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8.5.
Vital Signs and Body Weight
Descriptive statistics will be provided for vital signs and body weight as follows: 

Baseline value

Value at each postbaseline analysis window

Change from baseline to each postbaseline analysis window
A baseline value for the E/C/F/TAF phase will be defined as the last nonmissing value obtained 
on or prior to the date of first dose of E/C/F/TAF study drug. A baseline value for the B/F/TAF 
OL phase will be defined as the last nonmissing value obtained on or prior to the date of first 
dose of B/F/TAF study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
A by-subject listing of vital signs, body weight, height, and BMI will be provided by subject ID 
number and visit in chronological order. 
8.6.
Prior and Concomitant Medications
8.6.1.
Nonstudy-Drug Antiretroviral (ARV) Medications
Any nonstudy-drug ARV medications used prior to, during, or after the study (if collected) will 
be coded using the GSI-modified World Health Organization (WHO) Drug Dictionary for ARV 
medications. The WHO preferred name and drug code will be attached to the clinical database. 
All nonstudy-drug ARV medications will be listed. No inferential statistics will be provided.
8.6.1.1.
Nonstudy-Drug ARV Medication Received at Baseline
Nonstudy-drug ARV medication with an end date 1 or 2 days before the first dose date of 
E/C/F/TAF study drug will be considered as nonstudy-drug ARV medication received 
immediately prior to the first E/C/F/TAF dose date of study drug (or prior ARV used at baseline
[pre-switch]). 
Nonstudy-drug ARV medication received immediately prior to the first dose date of E/C/F/TAF 
study drug will be summarized by preferred name for subjects in the E/C/F/TAF Safety Analysis 
Set. Multiple drug use (by preferred name) will be counted only once per subject. Preferred 
names will be presented by descending order of the total frequency. No inferential statistics will 
be provided. 
8.6.1.2.
Nonstudy-Drug ARV Medication Received Prior to the First Dose Date of Study 
Drug
Nonstudy-drug ARV medication received prior to the first dose date of E/C/F/TAF study drug 
will also be summarized as a separate table. Results will be summarized in the same way as 
described for prior ARV used at baseline in Section 8.6.1.1. 


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8.6.2.
Concomitant Non-ARV 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 non-ARV 
medications from Study Day 1 up to the date of last dose of E/C/F/TAF study drug will be 
summarized (number and percentage of subjects) by preferred name for the E/C/F/TAF Safety 
Analysis Set. Use of concomitant non-ARV medications from B/F/TAF Study Day 1 up to the 
date of last dose of B/F/TAF study drug will be summarized (number and percentage of subjects) 
by preferred name for the B/F/TAF Safety Analysis Set. Multiple drug use (by preferred name) 
will be counted once only per subject. The summary will be presented by decreasing total 
frequency.
If the start or stop date of a non-ARV medication is incomplete, the month and year (or year 
alone if month is not recorded) of start or stop date determine whether the non-ARV is
concomitant or not. The medication is concomitant if the month and year of start or stop (or year 
of the start or stop) of the medication does not meet either of the following criteria:

The month and year of start of the medication is after the date of the last dose of study drug

The month and year of stop of the medication is before the date of the first dose of study drug 
If the start and stop date of a non-ARV medication is complete, the start date is not after the 
last dose date, and the stop date is not before the first dose date, or the non-ARV medication is
marked as ongoing and start date is on or before the last dose date, the non-ARV medication is
concomitant.
Subjects with any non-ARV concomitant medications will be listed. No inferential statistics will 
be provided.
8.7.
Electrocardiogram Results
A shift table of the investigators’ assessment of ECG results at each scheduled postbaseline visit 
(Weeks 48 and 96 for the E/C/F/TAF Safety Analysis Set and Week 48 for the B/F/TAF Safety 
Analysis Set) compared with baseline values will be presented using the following categories: 
normal; abnormal, not clinically significant; abnormal, clinically significant; and 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 baseline or postbaseline will not be included in the 
denominator for percentage calculation. No inferential statistics will be provided. 
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
8.8.
Healthcare Utilization Assessment
The number of hospitalizations, unplanned visits for a healthcare issue, and unplanned specialty 
care provider visits for a healthcare issue since the last study visit were summarized for the 
Week 96 analysis and will not be repeated for the final analysis.


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A listing of healthcare utilization assessment data will be provided by subject.
8.9.
Other Safety Analysis
A data listing will be provided for subjects experiencing pregnancy during the study. Physical 
examination data were not collected in the eCRF; therefore, there is no analysis for these data.
8.10.
Changes From Protocol-Specified Safety Analyses
No change from protocol-specified safety analyses is planned.


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Statistical Analysis Plan 
9. 
PHARMACOKINETIC ANALYSES 
Version I 
During the B/F/f AF OL extension phase, at Weeks 4 OL, 24 OL, and 48 OL, on the day of 
hemodialysis, a sparse timed blood sample was to be collected from all subjects within 10 
minutes prior to hemodialysis initiation. Predose (within 30 minutes prior to study drug 
administration) blood draws for plasma samples were also collected at these visits. 
Plasma concentrations of bictegravir from the pre-hemodialysis and pre-dose (post-
hemodialysis) PK draws at Weeks 4 OL, 24 OL, and 48 OL will be listed for all subjects for the 
BIF ff AF Plasma PK Analysis Set. 
Concentration samples will be smmnarized using descriptive statistics (sample size, mean, SD, 
coefficient of variation [%CV], minimum, median, maximum, Q 1, Q3, geometric mean, and its 
95% CI) for the B/F/TAF Plasma PK Analysis Set. For concentration values below the limit of 
quantitation (BLQ), the nmnber of subjects with values BLQ will be presented. 
Plasma PK sampling details and study drug administration records for plasma PK samples for the 
B/F/f AF OL extension phase will be listed. 
CONFIDENTIAL 
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10.
PATIENT REPORTED OUTCOMES
Patient reported outcomes (PRO) include the following assessments:

Medication Adherence Questionnaire (assessed at all protocol planned visits through 
Week 96 for E/C/F/TAF phase)

HIV Treatment Satisfaction Questionnaire Status (HIV-TSQs) (assessed at baseline, 
Weeks 4, 24, 48, 72, 96, and End of E/C/F/TAF Visit for E/C/F/TAF phase and at Weeks 4
OL, 24 OL, and 48 OL for B/F/TAF OL extension phase)

HIV Treatment Satisfaction Questionnaire Change (HIV-TSQc) (assessed at Weeks 24, 48, 
72, 96, and End of E/C/F/TAF Visit for E/C/F/TAF phase)

Medical Outcome Study Short Form (SF-36) (assessed at Baseline, Weeks 24, 48, 72, 96, and 
End of E/C/F/TAF Visit for E/C/F/TAF phase and at Weeks 4 OL, 24 OL, and 48 OL for 
B/F/TAF OL extension phase)
The Medication Adherence Questionnaire will be listed only.
The HIV-TSQs, HIV-TSQc, and SF-36 results will be summarized using the E/C/F/TAF Safety 
Analysis Set. Data collected up to 30 days after the last dose date of E/C/F/TAF study drug for 
subjects who do not participate in the B/F/TAF OL extension or up to the date of the first 
B/F/TAF study drug dose for subjects who participate in the B/F/TAF OL extension will be 
included in summaries. 
The HIV-TSQs and SF-36 results will also be summarized using the B/F/TAF Safety Analysis 
Set. Data collected up to 30 days after the last dose date of B/F/TAF study drug will be included 
in summaries.
Unless otherwise stated, multiple responses and out of range responses will be set to missing and
missing responses will not be imputed. The PRO data will be listed.
10.1.
Medication Adherence Questionnaire
Adherence was assessed by the medication adherence questionnaire that includes a VAS and 2 
additional questions.
For the VAS, the subject is asked to describe their adherence to their ARV regimen by using a 
linear scale (0%
100%) to indicate what percent of medication was taken in the last 30 days 
(0%  taken none of prescribed anti-HIV medication, and 100%  taken all doses of prescribed 
anti-HIV medication). The 2 additional questions ask how many days the subject has missed 
medication in the last 30 days and how many days the subject has missed medication in the 
last 4 days. 


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A listing will be provided for subject response to the VAS questionnaire. 
10.2.
HIV Treatment Satisfaction Questionnaire
Both HIV-TSQs and HIV-TSQc forms have 10 questions about the current treatment regimen.
For the Status form, the responses to those questions range from (6) very satisfied, to (0) very 
dissatisfied; for the Change form, the responses to those questions range from (3) much more 
satisfied now, to (-3) much less satisfied now, with the exception of the following questions:
a) How well controlled do you feel your HIV has been recently? For Status form: (6) very well 
controlled, to (0) very poorly controlled; for Change form: (3) much better controlled now, to 
(-3) much worse controlled now;
b) How convenient have you been finding your treatment to be recently? For Status form: 
(6) very convenient, to (0) very inconvenient; for Change form: (3) much more convenient 
now, to (-3) much less convenient now;
c) How flexible have you been finding your treatment to be recently? For Status form: 
(6) very flexible, to (0) very inflexible; for Change form: (3) much more flexible now, to 
(-3) much less flexible now;
d) On Status form only: Would you recommend your present treatment to someone else with 
HIV? (6) Yes, I would definitely recommend the treatment, to (0) No, I would definitely not 
recommend the treatment.
e) On Change form only: How likely would you be to recommend your present treatment to 
someone else with HIV? (3) much more likely to recommend the treatment now, to 
(-3) much less likely to recommend the treatment now.
A treatment satisfaction scale total will be calculated as the sum of the responses to the 
10 question items on the Status form, ranging from 0 to 60, and on the Change form, ranging
from 30 to 30. If the number of missing responses is ≥ 2 then the treatment satisfaction scale 
total will be set to missing; otherwise, the missing item score will be imputed by the average of 
the non-missing item responses from the same subject at the same visit and the treatment 
satisfaction scale total will be calculated.
A descriptive summary of the number and percent of subjects with responses to each question 
and the treatment satisfaction scale total will be provided for HIV-TSQs form and the HIV-TSQc
form by visit.
Two listings will be provided for subject responses to HIV-TSQs and HIV-TSQc forms at all 
visits for each subject, respectively. 


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10.3.
SF-36 (Version 2) Health Survey
The SF-36 Version 2 is a self-reported, generic, comprehensive, and widely used questionnaire 
that is designed to measure health-related quality of life in the general population, as well as in 
subject groups with diverse chronic diseases including HIV/AIDS. Responses from the 36 items 
are used to construct 8 health domains including physical functioning, social functioning, general 
health, vitality, bodily pain, mental health, role capacity-physical, and role capacity-emotional. 
Furthermore, 2 summary scores, the Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores, aggregate information from the 8 SF-36 domains in a way 
that captures 80% to 85% of the variance in the 8 domains. 
10.3.1.
Scoring the SF-36
The 8 domains and 2 component summary scores of the SF-36 will be calculated according to 
“How to Score Version 2 of the SF-36 Health Survey (Chapters 6 and 7)” {Maruish 2011}
published by QualityMetric Inc. Scores for each of the 8 domains, including PCS and MCS,
range from 0 to 100 with a higher score indicating a better functioning. 
10.3.2.
SF-36 Statistical Analysis Method
Scores and change from baseline for each domain, PCS, and MCS will be summarized by visit 
using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum). 
A by-subject listing for the scores for each domain, PCS, and MCS will be provided. 


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11.
REFERENCES
Maruish ME. User's manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality Metric 
Incorporated.; 2011. 
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. 
National Institute of Health  May, 2001.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Silver Spring, MD.  November, 2015.


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12.
SOFTWARE
SAS(SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, 
listings, and figures.
nQuery Advisor(Statistical Solutions Ltd., Version 6.0, Cork, Ireland) was used for the sample 
size and power calculation.


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13.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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14.
APPENDICES
Appendix 1.
Study Procedures Table (E/C/F/TAF Phase)
Appendix 2.
Study Procedures Table (Open Label Rollover Extension)
Appendix 3.
Flowchart of US FDA-defined Snapshot Algorithm for Switch Trial
Appendix 4.
Cardiovascular or Cerebrovascular Events
Appendix 5.
Hepatic Events
Appendix 6.
TFL Mocks
Appendix 7.
Programming Specifications


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Appendix 1.
Study Procedures Table (E/C/F/TAF Phase)
Study Procedure
Screena
Day 
1b
Week 2 to Week 96c
Post 
Week 96
End of 
E/C/F/TAF 
Visit
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Written Informed Consent
X
Medical History 
X
Complete Physical 
Examinationf
X
X
X
X
X
X
Symptom directed Physical 
Examinationg
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Height
X
12 Lead ECG
X
X
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
Xj
Xj
Xj
Xj
Xw
X
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV 1 RNAl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV 1 Genotype/Phenotypem
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologyp
X
CCI


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Study Procedure
Screena
Day 
1b
Week 2 to Week 96c
Post 
Week 96
End of 
E/C/F/TAF 
Visit
30-Day 
Follow-upd
ESDDe
2
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF 36q
X
X
X
X
X
X
X
HIV TSQq
X
X
X
X
X
X
X
X
X
VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Utilization Assessmentr
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Dispensation and 
Accountability
X
Xs
X
X
X
X
X
X
X
X
X
X
X
Xx
Xs
Pre dose Whole Blood Sample 
Collectiont
X
X
Whole Blood Storage Samplev
X
a
Evaluations to be completed within 30 days prior to Day 1.
b
Subjects will be dispensed study drug on the Day 1 Visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 Visit.
c
All study visits are to be scheduled relative to the Day 1 Visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol 
specified date through Week 48, except Week 48. Weeks 48 Visit window is ± 6 weeks of the protocol specified date. Week 48 Visit should be completed within ± 6 day 
window, unless otherwise specified by the Sponsor. Following the Week 48 Visit, study visits are to be completed within ± 6 days of the protocol specified date through 
Week 84. The visit window at Week 96 will be ± 6 weeks of the protocol specific visit date. Unless notified by the Sponsor, Week 96 Visit should be completed within 
± 6 days of the protocol specific visit date.
d
Required for those subjects who complete Week 96 Visit or those subjects who prematurely discontinue study drug and do not continue in the study through at least 
one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30 Day Follow Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation Visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Week 96, if the subject discontinues study drug prior to completion of Week 96 Visit.
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. At Day 1, Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry 
profile. PT/INR will be included in the chemistry profile at Screening, Weeks 24 and 48 only. This sample should be drawn prior to hemodialysis. The timing of draw and 
timing of hemodialysis should be recorded.
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Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At Weeks 24, 48, 72, and 96 analyses of glucose will be done as part of fasting metabolic 
assessments and not as part of the chemistry profile. 
k 
Females of childbearing potential only. FSH test is re.quired for female subjects who have stopped menstmating for 2:: 12 months but do not have documentation of ovarian 
hom10nal failure. 
If the HIV I RNA value is 2:: 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2 4 weeks after the date of the original test (except for screening 
and baseline results). See Protocol Section 6. 7. 1. 
m 
HIV I genotype/phenotype resistance testing only conducted for subjects with confim1ed virologic rebound with HIV I RNA value 2:: 400 copies/mL. Subjects should be 
managed according to the Virologic Rebound Schema (see Protocol Section 6. 7. 1 ). HIV I genotype/phenotype sample collection to occur if subject's HIV I RNA lab values 
meet the criteria described in this section. 
n 
CBC with differential and latelet count 
I' 
p 
See Protocol Sectton 4.2 to con m11 subject eligibility prior to enrollment. 
q 
SF 36 is to be completed by subjects at Day I, Week 24, Week 48, Week 72, and Week 96 Visits. HIV TSQs should be completed by the subjects at Screening, Day I, 
Week 4, Week 24, Week 48, Week 72, Week 96 and ESDD Visits. HIV TSQc should be completed by the subjects at Week 24, Week 48, Week 72, Week 96 and ESDD 
Visits. 
r 
Subjects will be asked about their health utilization at Day I Visit and every visit thereafter, including the ESDD and Unscheduled Visits. 
s 
Dmg accountability only; study dmg will not be dispensed at these visits. 
t 
At Week 4 or Week 12, pre dose whole blood sample will be collected for subjects enrolled in the study. Sample collection should occur within 30 minutes prior to the study 
dmg administration which should be observed on site. PBMC rocessing will be com leted b the central laborato . 
I' 
V 
w 
X 
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Appendix 2.
Study Procedures Table (Open Label Rollover Extension)
Study Procedure
End of E/C/F/TAF 
Visit
End of Weeka, c
30-Day Follow-upd
ESDDe
Week 4 OL
Week 12 OL
Week 24 OL
Week 36 OL
Week 48 OL
Complete Physical Examinationf
X
X
Symptom directed Physical 
Examinationg
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
Xh
X
12 Lead ECG
X
X
X
Chemistry Profilei
X
X
X
X
X
X
X
X
Metabolic Assessmentsj
X
X
X
Serum Pregnancy Testk
X
X
X
X
X
X
X
X
CD4+ T Cell Count
X
X
X
X
X
X
X
X
Plasma HIV 1 RNAl
X
X
X
X
X
X
X
X
HIV 1 Genotype/Phenotypem
X
X
X
X
X
X
X
PK Samplingp
X
X
X
Estimated eGFR
X
X
X
X
X
X
X
Hematology profilen
X
X
X
X
X
X
X
X
Plasma Storage Samples
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
SF 36 
X
X
X
X
X
HIV TSQ
X
X
X
X
X
Drug Dispensation and 
Accountability
X
X
X
X
X
X
Xb
a
Open label study drug, B/F/TAF FDC will be dispensed to subjects participating in the Open Label Rollover extension for at least 48 weeks.
b
Drug accountability only; study drug will not be dispensed at these visits
c
All study visits are to be scheduled based upon the Week 96 Visit or End of E/C/F/TAF Visit date (whichever occurs later). The Week 4 OL Visit should be completed within 
±2 days of the protocol specified visit date. All other Study visits are to be completed within ± 6 days of the protocol specified visit date, unless otherwise specified by the 
Sponsor.
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d
Required for those subjects who complete End of E/C/F/TAF Visit or those subjects who prematurely discontinue study drug during the Open Label extension phase. For the 
purpose of scheduling a 30 Day Follow Up Visit, a ± 6 days window may be used.
e
Early Study Drug Discontinuation Visit to occur within 72 hours of last dose of study drug. 
f
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator).
g
Symptom directed physical examination as needed
h
Weight only
i
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, PT/INR, amylase (reflex lipase testing is performed in subjects with total amylase 
> 1.5 × ULN) and PTH. At End of E/C/F/TAF Visit, Week 24 OL, and Week 48 OL analyses of glucose will be done as part of the fasting metabolic assessments and not as 
part of the chemistry profile. This sample should be drawn prior to hemodialysis. The timing of draw and timing of hemodialysis should be recorded.
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 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. At End of E/C/F/TAF Visit, Week 24 OL, and Week 48 OL analyses of glucose will be 
done as part of fasting metabolic assessments and not as part of the chemistry profile. 
k
Females of childbearing potential only. FSH test is required for female subjects who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian 
hormonal failure.
l
If the HIV 1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2 3 weeks after the date of the original test (except for screening 
and baseline results). See Protocol Section 6.7.3.
m
HIV 1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic rebound with HIV 1 RNA value ≥ 200 copies/mL. Subjects should be managed 
according to the Virologic Rebound Schema (see Protocol Section 6.7.3). HIV 1 genotype/phenotype sample collection to occur if subject’s HIV 1 RNA lab values meet the 
criteria described in this section.
n
CBC with differential and platelet count
p
At Week 4 OL, Week 24 OL and Week 48 OL study visits, on the day of hemodialysis, a sparse timed blood sample will be collected within 10 minutes before hemodialysis 
initiates from all subjects. Pre dose (within 30 minutes prior to study drug administration) blood draws for plasma samples will also be collected at these visits. Study drug 
administration will be observed. Plasma concentrations of BIC may be determined. Plasma concentrations of other analytes may also be explored.
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Statistical Analysis Plan 
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Appendix 3. 
Flowchart of US FDA-defined Snapshot Algorithm for Switch Trial 
The following flowchart for US FDA-defined snapshot algorithm in based on the US FDA 
Guidance on Hmnan Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for 
Treatment {U.S. Department of Health and Human Services 2015} 
Yes 
Is there at least I on-
treatment* HIV- l RNA 
collected in the Snapshot 
window? 
Is the last available on-treatment* 
HIV- I RNA in the Snapshot 
window< 50 copies/mL? 
0 
Is study drug prematurely 
discontinued on or prior to the 
upper limit of the Snapshot 
window? 
Yes 
Yes 
Is discontinuation of the study 
drug due to Lack of Efficacy? 
HIV-1 RNA < 
50 copies/mL 
HIV-I RNA~ 
50 copies/mL 
No 
Is discontinuation of the study 
drug due to AE/Death? 
Yes 
Is the last available on-
ls the last available on-
treatment* HIV-I RNA < treatment* HIV-I RNA < 
50 copies/mL 
50 copies/mL 
Yes 
No Virologic Data: 
iscontinued Study Drug 
Due to Other Reasons 
and Last HJV-1 RNA < 
50 copies/mL 
No Virologic Data: 
Discontinued Study 
Drug Due to AE/Death 
and Last HIV-1 RNA < 
50 copies/m L 
No 
No Virologic Data: 
Missing Data During 
Window but on Study 
Drug 
* On-treatment values include 1) data collected up to 1 day after the last dose date for subjects who 
prematurely discontinued or completed study drug or 2) all the data for subjects who were ongoing 
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Appendix 4.
Cardiovascular or Cerebrovascular Events
An adverse event record will be flagged as a cardiovascular or cerebrovascular event if its 
MedDRA PT is included in the pre-specified PT list, which includes all PTs from the narrow 
search of the following 3 SMQs under MedDRA v22.0 provided by Gilead PVE (search name: 
Ischemic cardiac and cerebral events narrow) and reviewed by Gilead medical monitors.
SMQ Source
Cardiovascular or Cerebrovascular 
Events
Ischaemic central nervous system vascular conditions (SMQ) – Narrow 
Scope Term
Myocardial infarction (SMQ) - Narrow Scope Term
Other ischaemic heart disease (SMQ) - Narrow Scope Term


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Appendix 5.
Hepatic Events
An adverse event record will be flagged as a hepatic event if its MedDRA PT is included in this
pre-specified PT list, which includes all PTs from the broad search of the following 15 SMQs 
under MedDRA v22.0 provided by Gilead PVE (search name: Non-infectious, non-congenital 
hepatobiliary disorders) and reviewed by Gilead medical monitors.
SMQ Source
Hepatic Events (HEP)
Biliary neoplasms benign (incl cysts and polyps) (SMQ)
Biliary malignant tumours (SMQ)
Biliary tumours of unspecified malignancy (SMQ)
Biliary system related investigations, signs and symptoms (SMQ)
Biliary tract disorders (SMQ)
Gallbladder related disorders (SMQ)
Gallstone related disorders (SMQ)
Cholestasis and jaundice of hepatic origin (SMQ)
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions (SMQ)
Hepatitis, non-infectious (SMQ)
Liver neoplasms, benign (incl cysts and polyps) (SMQ)
Liver malignant tumours (SMQ)
Liver tumours of unspecified malignancy (SMQ)
Liver related investigations, signs and symptoms (SMQ)
Liver-related coagulation and bleeding disturbances (SMQ)


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Appendix 6.
TFL Mocks
Appendix Table 1.
Subject Disposition, All Screened Subjects
Visit
GEN
Subjects Screened
75
Screen Failure Subjects Who Were Not Enrolled
15
Subjects Met All Eligibility Criteria and Not Enrolled*
5
Subjects Enrolled
55
Subjects Enrolled and Never Treated
0
Subjects in E/C/F/TAF Safety Analysis Set
55
Subjects in E/C/F/TAF Full Analysis Set
55
Subjects Completing E/C/F/TAF Study Treatment
xx (xx.x%)
Subjects Prematurely Discontinuing E/C/F/TAF Study Treatment
xx (xx.x%)
Reasons for Prematurely Discontinuing E/C/F/TAF Study 
Treatment
Reason 1
xx (xx.x%)
Reason 2
xx (xx.x%)
Reason x
xx (xx.x%)
Subjects Enrolling in B/F/TAF Open Label Extension Phase
xx 
Subjects in B/F/TAF Safety Analysis Set
xx
Subjects in B/F/TAF Full Analysis Set
xx
Subjects Completing B/F/TAF Study Treatment
xx (xx.x%)
Subjects Prematurely Discontinuing B/F/TAF Study Treatment
xx (xx.x%)
Reasons for Prematurely Discontinuing B/F/TAF Study Treatment
Reason 1
xx (xx.x%)
Reason 2
xx (xx.x%)
Reason x
xx (xx.x%)
Subjects Completing Study
xx (xx.x%)
Subjects Prematurely Discontinuing from Study 
xx (xx.x%)
Reasons for Prematurely Discontinuing from Study
Reason 1
xx (xx.x%)
Reason 2
xx (xx.x%)
Reason x
xx (xx.x%)
The denominator for percentages of subjects is the number of subjects in the E/C/F/TAF Safety Analysis Set except for the 
categories related to the B/F/TAF Open Label Extension Phase for which the denominator is the number of subjects in the 
B/F/TAF Safety Analysis Set.
The number of screen failures is counted by unique subject based on the date of birth, race, ethnicity, sex, country, and initials.
*
Among 5 subjects who met all eligibility criteria but were not enrolled, the reasons (N) were: withdrew consent (4) and 
outside of visit window (1).


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Appendix Table 2.
Virologic Outcome at Week 96 (HIV-1 RNA Cutoff at 50 copies/mL, Snapshot Algorithm), 
Full Analysis Set
GEN
(N = xxx)
HIV-1 RNA < 50 copies/mL
xx (xx.x%)
95% CI
xx.x% to xx.x%
HIV-1 RNA ≥ 50 copies/mL
xx (xx.x%)
95% CI
xx.x% to xx.x%
HIV-1 RNA ≥ 50 copies/mL in Week 96 Window
xx (xx.x%)
Discontinued Study Drug Due to Lack of Efficacy
xx (xx.x%)
Discontinued Study Drug Due to AE/Death and Last Available 
HIV-1 RNA ≥ 50 copies/mL
xx (xx.x%)
Discontinued Study Drug Due to Other Reasons* and Last Available 
HIV-1 RNA ≥ 50 copies/mL
xx (xx.x%)
No Virologic Data in Week 48 Window
xx (xx.x%)
Discontinued Study Drug Due to AE/Death and Last Available 
HIV-1 RNA < 50 copies/mL
xx (xx.x%)
Discontinued Study Drug Due to Other Reasons* and Last Available 
HIV-1 RNA < 50 copies/mL
xx (xx.x%)
Missing Data During Window but on Study Drug
xx (xx.x%)
Week 96 window is between Day 631 and 714 (inclusive).
*
Other reasons include subjects who discontinued study drug due to investigator’s discretion, subject decision, lost to follow up, noncompliance with study drug, protocol 
violation, pregnancy, and study terminated by sponsor.


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Appendix Table 3.
Number and Percentage of Subjects with HIV-1 RNA < 50 copies/mL by Visit, Missing Excluded
GEN
(N = xx)
HIV-1 RNA at Week XX
< 50 copies/mL
95% CI
< 20 copies/mL
< 20 copies/mL Not Detectable
< 20 copies/mL Detectable
20 to < 50 copies/mL 
≥ 50 copies/mL 
The denominator for percentages is the number of subjects in the E/C/F/TAF Full Analysis Set.
The 95% CI for percentage estimate of HIV 1 RNA < 50 copies/mL was obtained using Exact method.


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Appendix Table 4.
Liver-Related Laboratory Test Abnormalities
GEN
(N = xx)
AST
> 3 x ULN
xx/xx (xx.x%)
> 5 x ULN
xx/xx (xx.x%)
> 10 x ULN
xx/xx (xx.x%)
> 20 x ULN
xx/xx (xx.x%)
ALT
> 3 x ULN
xx/xx (xx.x%)
> 5 x ULN
xx/xx (xx.x%)
> 10 x ULN
xx/xx (xx.x%)
> 20 x ULN
xx/xx (xx.x%)
AST or ALT
> 3 x ULN
xx/xx (xx.x%)
> 5 x ULN
xx/xx (xx.x%)
> 10 x ULN
xx/xx (xx.x%)
> 20 x ULN
xx/xx (xx.x%)
Total Bilirubin
> 1 x ULN
xx/xx (xx.x%)
> 2 x ULN
xx/xx (xx.x%)
Alkaline Phosphatase (ALP)
> 1.5 x ULN
xx/xx (xx.x%)


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GEN
(N = xx)
AST or ALT > 3 x ULN 
xx/xx (xx.x%)
Total Bilirubin > 1.5 x ULN
xx/xx (xx.x%)
Total Bilirubin > 2 x ULN
xx/xx (xx.x%)
Total Bilirubin > 2 x ULN and ALP < 2 x ULN
xx/xx (xx.x%)
ULN  upper limit of normal.
Denominator for percentage for individual test is the number of subjects in the E/C/F/TAF Safety Analysis Set with at least 1 postbaseline laboratory value.
The most severe postbaseline value per subject was summarized for each laboratory test. For AST, ALT, AST or ALT, and total bilirubin, subjects may be counted in multiple 
categories, eg, subject would be counted in > 3 ULN, > 5 ULN and > 10 ULN if the worst value was > 10 ULN.
For the composite endpoint of AST or ALT, and total bilirubin with or without alkaline phosphatase (ALP), subjects were counted once when the criteria were met at the same 
postbaseline visit date. The denominator is the number of subjects in the Safety Analysis set with nonmissing postbaseline values of the tests in evaluation at the same postbaseline 
visit date.


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Appendix Table 5.
Individual Data and Summary Statistics of Plasma Bictegravir Concentration (ng/mL) at 
Protocol-Specified Sampling Times
Subject ID
Week 4
Sparse
Week 4
Predose
Week 24
Sparse
Week 24
Predose
Week 48
Sparse
Week 48
Predose
#####-####
#####-####
N
Mean 
SD 
% CV
Median 
Min 
Max 
Q1
Q3
N (LN-scale) 
Geom. Mean 
95% CI(L) 
95% CI(U) 
# BLQ
BLQ  Below Limit of Quantitation.
Geom. Mean  Geometric Mean. LN  Natural log.


PPD


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Appendix 7.
Programming Specifications
1) AGE is calculated as follows:
a) AGE (years) is calculated from the number of days between the date of birth (DOB) and 
Day 1 (first E/C/F/TAF 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 Day 1 have the month in common and the birthday is later in the month 
than the date of Study Day 1, then subtract one from the AGE result above.
For subjects enrolled and never dosed with study drug, age will be calculated from the date 
of enrollment.
Age for laboratory test reference range will be based on the age at the sample collection date.
2) All screened subjects refer to all subjects who are screened and have a screening number. For 
summarization, same subject is counted only once. DOB and other demographic information 
such as sex, race, ethnicity, country, and initials will be used for identifying unique screened
subjects. 
3) Screen failure subjects are the subjects who were 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) Subjects in the All Enrolled analysis set are defined as subjects enrolled into the study. 
IXRSENRL is the source to determine whether the subject is enrolled.
5) In disposition table, the reasons for premature discontinuation are displayed in the order as 
they appear on the eCRF.
6) Body mass index (BMI) is calculated from height in meters (eg, height in cm/100) and 
weight in kilograms as:

BMI will be calculated at baseline. Baseline height and weight will be used for the 
Calculation: Height will be obtained from Vital Signs Performed eCRF at screening visit; 
Weight will be obtained from Vital Signs Performed eCRF at the baseline visit; if it is 
missing, Weight at the screening visit from Vital Signs Performed eCRF will be used. For 
B/F/TAF baseline, the last nonmissing Weight value obtained on or prior to the date of 
first B/F/TAF study drug will be used.


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BMI  (weight [kg]) / (height [meters]2) 
7) Please note, “Not Permitted”, “Unknown”, or missing categories will be excluded for 
percentage calculation. Except for Mode of infection (HIV Risk Factors), where “Unknown” 
will be included for percentage calculation, since a subject may fit more than 1 HIV risk 
factors, therefore percentage may add to more than 100%. 
Subjects with Race  “Not Permitted” will also be excluded to define Race subgroup 
(ie, black vs. nonblack) for efficacy subgroup analysis. 
8) Baseline disease characteristics 
Baseline disease characteristics in Section 5.2 will be summarized for both the E/C/F/TAF 
Safety Analysis Set and the B/F/TAF Safety Analysis Set. Baseline disease characteristics 
collected at enrollment include mode of infection, HIV disease status, HCV antibody status, 
medical history (including Type I or II diabetes, cardiovascular disease, hypertension, 
hyperlipidemia), smoking status, duration of hemodialysis, and pre-switch ARVs. These 
characteristics are defined prior to the first dose of E/C/F/TAF. 
The following baseline characteristics will be re-defined for the B/F/TAF summary:

HIV-1 RNA categories (copies/mL): (a) < 50 and (b) ≥ 50

CD4 cell count (/μL)

CD4 cell count categories (/μL): (a) < 50, (b) ≥ 50 to < 200, (c) ≥ 200 to < 350, 
(d) ≥350 to < 500, and (e) ≥500

CD4%

eGFRCG (mL/min)
9) Medical history of interest at study entry
Medical history of diabetes, hypertension, cardiovascular disease, and hyperlipidemia will be 
summarized at study entry (E/C/F/TAF baseline) as baseline disease characteristics. A 
subject who had medical history of one of these diseases is a subject who experienced at least 
one selected medical history reported in the Medical History eCRF, including keywords as 
below.


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Hypertension
Diabetes
Cardiovascular Disease
Hyperlipidemia
HYPERTENSION
DIABETES
CEREBRAL VASCULAR 
ACCIDENT
HYPERLIPIDEMIA
HIGH BLOOD 
PRESSURE
DIABETIC
CEREBROVASCULAR 
ACCIDENT
DYSLIPIDEMIA
MYOCARDIAL INFARCTION
HYPERCHOLESTEREMIA
CONGESTIVE HEART FAILURE
HYPERCHOLESTEROLEMIA
CORONARY ARTERY DISEASE
HIGH CHOLESTEROL
CORONARY ARTERY 
CALCIFICATION
HIGH TRIGLYCERIDES
PERIPHERAL VASCULAR 
DISEASE
ELEVATED CHOLESTEROL
CARDIOMYOPATHY
HYPERGLYCERIDAEMIA
HEART DISEASE
TRANSIENT ESCHEMIC 
ATTACK
AGINA
ARTERY BLOCKAGE
CARDIOVASCULAR DISEASE
In addition, subject who experienced hypertension before starting study drug according to 
Adverse Event eCRF with reported term includes the key word “HYPERTENSION”. 
10) To calculate years on hemodialysis at study entry, please use the Medical History CRF to 
find the earliest (according to MH start date on Medical History CRF) hemodialysis medical 
record containing any of the following keywords: 
a) “ESRD”
b) “END” + “STAGE” + “RENAL”/“KIDNEY” + “DISEASE”/“FAILURE”
c) “RENAL”/“KIDNEY”/“HEMO” + “DIALYSIS”
d) “RENAL”/“KIDNEY” + “DISEASE”/“FAILURE” + “SEVERE”/“STAGE_VI”
For each subject, year on HD  year of first E/C/F/TAF dose date start year of the 
hemodialysis medical record captured as above + 1. 


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11) Smoking status at study entry
Smoking status at baseline (ie, never smoked, former smoker, and current smoker) will be 
summarized as part of the baseline disease characteristics. 
Former smoker at baseline refers to the subjects who have stopped the use of any Cigarettes 
or Cigars before study day 1 (ie, the first E/C/F/TAF dose date).
Current Smoker at baseline refers to the smokers who have used any Cigarettes or Cigars at 
study day 1.
Never smoker at baseline refers to subjects who have no record with Type of Substance Use  
“Cigarettes” or “Cigars” on or prior to study day 1.
How to classify a subject as never smoker, former smoker, or current smoker at baseline is 
specified as follows:
a) First select only records with Type of Substance Use
 “Cigarettes” or “Cigars”. Records 
with Type of Substance Use
 “Other” (including chew tobacco, e-cigarettes, etc) will not 
be considered as smoking.
b) Second, for each selected substance use record, flag whether it is “Prior”, “Present”, or 
“Post” relative to the first E/C/F/TAF dose date according to the algorithm below. 
c) Finally, (1) the subject will be flagged as “Never” smoker, if the subject has no record 
with Type of Substance Use
 “Cigarettes” or “Cigars” or all selected records have a flag 
of “Post”; (2) the subject will be flagged as a “Former” smoker, if any selected record has 
flag of “Prior” and no record of “Present”; (3) Otherwise, the subject will be flagged as a 
“Current” smoker, if any selected records has a flag of “Present”. 
Selected Substance Use Records
Prior
No
No
Yes
Yes
Yes
No
No
Yes
Present
No
No
No
No
Yes
Yes
Yes
Yes
Post
No
Yes
No
Yes
No
No
Yes
Yes
Smoking Status 
Never
Never
Former
Former
Current
Current
Current
Current


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Algorithm to flag whether a selected record is “Prior”, “Present”, or “Post” relative to 
the first E/C/F/TAF dose date:
a) The start and stop dates of the selected record are not completely missing (ie, at least year 
is known) or the start date is not missing and record is ongoing. The complete start or 
stop dates will be used to compare with the first dose date whenever possible. Otherwise, 
the month and year (or year alone if month is not recorded) of the start or stop dates will 
be used to compare with the first dose date when the start or stop date of the selected 
record is incomplete:
i)
The record is flagged as “Prior”, if the stop date is before the first dose date; 
ii) The record is flagged as “Present”, if the start date is on or before the first dose date 
and the stop date is on or after the first dose date, or the selected record is marked as 
ongoing and the start date is on or before the first dose date; 
iii) The record is flagged as “Post”, if the start date is after the first dose date
b) The start date of the selected record is completely missing. We assume that the start date 
is before the first dose date, the stop date (or the month and/or year of the stop date, if
stop date is incomplete) or “ongoing” will be used to determine whether the selected 
record is “Prior” or “Present” as follows:
i)
The record is flagged as “Prior”, if the stop date is before the first dose date or the 
stop date is completed missing and the record is not marked as ongoing. 
ii) The record is flagged as “Present”, if the stop date is on or after the first dose date or 
the selected record is marked as ongoing.
c) The start date of the selected record is before the first dose date, but the stop date is 
completely missing and the record is not marked as ongoing. We assume that the end date 
is before the first dose date, the record is flagged as “Prior”.
d) The start date of the selected record is on or after the first dose date, but the stop date is 
completely missing and the record is not marked as ongoing. This is a data issue, should 
be queried first. However, this record is flagged as “Present” if the start date is on the 
first dose; this record is flagged as “Post” if the start date is after the first dose.
12) Clarification for defining Pre-ARV Categories.
Subjects are grouped by the pre-ARV at baseline (pre-switch). Pre-switch ARVs include 
ARVs that the subject was receiving 1 or 2 days before the first dose date. For each subject, 
classify them in each ARV category per Appendix Table 6.


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Appendix Table 6.
ARV Category 
Pre-ARV Categories
CMTRT3
ABBR
INGRED
TDF containing ARV
NRTI/INI: Stribild 
(EVG+COBI+FTC+TDF)
STB
EVG COBI FTC TDF
NRTI/NNRTI: Atripla 
(EFV+FTC+TDF)
ATR
EFV FTC TDF
NRTI/NNRTI: Complera 
(FTC+RPV+TDF)
CPA
FTC RPV TDF
NRTI: Tenofovir DF (TDF)
TDF
TDF
NRTI: Truvada (FTC+TDF)
TVD
FTC TDF
COBI/RTV/RPV containing ARV
NRTI/INI: Stribild 
(EVG+COBI+FTC+TDF)
STB
EVG COBI FTC TDF
NRTI/NNRTI: Complera 
(FTC+RPV+TDF)
CPA
FTC RPV TDF
NNRTI: Rilpivirine (RPV)
RPV
RPV
PI: Kaletra (LPV+RTV)
LPV/r
LPV RTV
PI: Ritonavir (RTV)
RTV
RTV
Other
COBI
COBI
ABC containing ARV
NRTI: Abacavir (ABC)
ABC
ABC
NRTI: Epzicom/Kivexa (ABC+3TC)
EPZ
ABC 3TC
NRTI: Trizivir (ABC+AZT+3TC)
TZV
ABC AZT 3TC
FTC containing ARV
NRTI/INI: Stribild 
(EVG+COBI+FTC+TDF)
STB
EVG COBI FTC TDF
NRTI/INI: Genvoya 
(EVG+COBI+FTC+TAF)
E-C-F-
TAF
EVG COBI FTC TAF
NRTI/NNRTI: Atripla 
(EFV+FTC+TDF)
ATR
EFV FTC TDF
NRTI/NNRTI: Complera 
(FTC+RPV+TDF)
CPA
FTC RPV TDF
NRTI: Emtricitabine (FTC)
FTC
FTC
NRTI: Truvada (FTC+TDF)
TVD
FTC TDF
3TC containing ARV
NRTI: Lamivudine (3TC)
3TC
3TC
NRTI: Epzicom/Kivexa (ABC+3TC)
EPZ
ABC 3TC
NRTI: Trizivir (ABC+AZT+3TC)
TZV
ABC AZT 3TC
NRTI: Combivir (AZT+3TC)
CBV
AZT 3TC
FTC containing ARV
NRTI/INI: Stribild 
(EVG+COBI+FTC+TDF)
STB
EVG COBI FTC TDF


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13) Last Dose Dates and Last Study Date:
a) Last Dose Date is defined in SAP Section 3.8.1. If the last dose date is incomplete or 
missing, the last dose date will be imputed as follows, using E/C/F/TAF or B/F/TAF 
dosing information as appropriate:

If the last dose date is missing day (ie, month and year of the last dose are known), 
the latest of dispensing dates of study drug bottles, study drug start dates and end 
dates, and imputed last dose date (day imputed as 15) will be used to impute the 
last dose date. However, if the month of the dispensing date is after the month of the 
last dose date, data query is needed. If subject died and the death date is complete 
(ie, not partial date) and before the imputed last dose date, the complete death date 
should be used as the imputed last dose date. 

If the last dose date is missing day and month or completely missing (eg, due to lost 
to follow-up), the latest of study drug start dates and end dates, clinical visit dates, 
and laboratory visit dates (excluding the date of 30-day follow-up visit date) will be 
used to impute the last dose date. 
b) Last Study Date is the maximum of nonmissing study drug start dates and end dates, 
clinic visit and laboratory visit dates, including the 30-day follow-up visit date for 
subjects who prematurely discontinued study or who completed study according to study 
completion eCRF. Please note: if study drug start date or end date is partially missing, the 
imputed date (day imputed as 15) will be used. If subject died and the death date is 
complete (ie, not partial date) and before the imputed last study date, the complete death 
date should be used as the imputed last study date. Note that last visit date and last lab 
date include the 30-day follow-up visit.
14) Toxicity Grades:
a) With regards to Triglycerides and Hypercholesterolemia, if the fasting status is not ‘Y’, 
in other words it is blank or ‘N’, then the lab result value would not be graded as 
non-fasting values are not interpretable.
b) For toxicity grade summary, we will include all postbaseline graded results up to 30 days 
after the last dose of study drug, not just those at summarized visits.
15) Clarification of the following LOCF algorithms:

Baseline values will not be carried forward.

For CD4: If a value is missing in an analysis visit window, replace the missing value with 
the last on- treatment value observed before the analysis visit window that has the 
missing value.


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16) For safety ECGs at postbaseline visits, the most conservative (worst) value within the 
window will be selected, eg, abnormal will be selected over normal for safety ECG or 
clinically significant abnormal will be selected over not clinically significant normal if there 
are multiple abnormal findings.
17) Treatment-Emergent Adverse Events 
Events with Missing Onset Day and/or Month
The event is treatment emergent for the E/C/F/TAF phase if the following 3 criteria are met:

The month and year (or year) of onset date is the same as or after the month and year 
(or year) of the first dose of E/C/F/TAF study drug, and

The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of the date corresponding to the minimum of (1) the last dose of 
E/C/F/TAF study drug plus 30 days AND (2) the first dose of B/F/TAF study drug minus 
1 day, and

End date is as follows: 
The (complete) end date is on or after the first E/C/F/TAF dose date, or
The month and year (or year) of end date is the same or after the month and year 
(or year) of the first dose of E/C/F/TAF study drug, or
End date is completely missing
The event is treatment emergent for the B/F/TAF OL extension phase if the following 3 
criteria are met:

The month and year (or year) of onset date is after the month and year (or year) of the 
first dose of B/F/TAF study drug, and

The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of the date corresponding to the last dose of B/F/TAF study drug plus 
30 days, and

End date is as follows: 
The (complete) end date is on or after the first B/F/TAF dose date, or
The month and year (or year) of end date is the same or after the month and year 
(or year) of the first dose of B/F/TAF study drug, or
End date is completely missing


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Events with Completely Missing Onset Date
An AE with a completely missing onset date is defined as TEAE for the E/C/F/TAF phase 
if end date is as follows:

The (complete) end date is on or after the first E/C/F/TAF dose date, or

The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of E/C/F/TAF study drug, or

End date is completely missing
18) Calculation of ratios 
To calculate laboratory ratios (eg, fasting total cholesterol to HDL ratio), lab value of each 
test in the ratio needs to be from the same accession number; if any test value used for the 
ratio calculation from the same accession number is missing, the ratio is not calculable 
(ie, missing).
19) 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)


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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 (Fasting) 
Decrease
Serum Glucose (Fasting, Hypoglycemia)
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)
20) Concomitant nonstudy-drug ARV medications (ie, ARV medications other than study drug 
that are taken while receiving study drug) will be flagged in “Nonstudy-Drug Antiviral 
Medication” listing. The logic to define concomitant nonstudy-drug ARV is similar to 
concomitant non-ARV Medications (see details in Section 8.6.2)
21) Lipid modifying medication analyses:

Lipid modifying medication is defined to be the concomitant medication with ACLAS
 
“LIPID MODIFYING AGENTS” and CMDECOD contains wording of “STATIN” in the 
ADCM dataset.

Subjects who took lipid modifying medications at study entry refer to the subjects who 
have any use of the lipid modifying agents at study day 1 (ie, the first E/C/F/TAF dose 
date).
a) More specifically, subjects with “Lipid Modifying Agent Use at Study Entry” include 
those subjects in E/C/F/TAF Safety Analysis set meeting both the following criteria: 
1) any selected CM record with the start date ≤ the first E/C/F/TAF dose date, and 
2) the end date of the selected CM record ≥the first E/C/F/TAF dose date or the end 
date of the selected CM record is ongoing
b) For lipid modifying medications with the start date completely unknown, we assume 
the start date is on or before the E/C/F/TAF first dose date, lipid modifying 
medication was considered as being taken at study entry if the end date is not prior to 
the first E/C/F/TAF dose date (ie, the end date is on or after the first E/C/F/TAF dose 
date, completely unknown, or ongoing).


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c) Lipid modifying medications with the start date prior to the first E/C/F/TAF dose date 
and the end date unknown (completely missing) were considered as being taken at 
study entry (the unknown end date is assumed on or after the first E/C/F/TAF dose 
date).

Subjects who initiated lipid modifying medications during the E/C/F/TAF phase refers to 
the subjects in the E/C/F/TAF Safety Analysis set who did not take lipid modifying 
medications at study entry and met the following criteria: 1) any selected CM record 
started after the first E/C/F/TAF dose date and on and prior to the last E/C/F/TAF dose 
date.

Subjects who took lipid modifying medications at the start of the B/F/TAF OL extension 
phase refer to the subjects who have any use of the lipid modifying agents at B/F/TAF 
Study Day 1 (ie, the first B/F/TAF dose date).
d) More specifically, subjects with “Lipid Modifying Agent Use at Entry in B/F/TAF 
OL Extension Phase” include those subjects in the B/F/TAF Safety Analysis set 
meeting both the following criteria: 1) any selected CM record with the start date 
≤the first B/F/TAF dose date, and 2) the end date of the selected CM 
record ≥the first B/F/TAF dose date or the end date of the selected CM record is 
ongoing 
e) For lipid modifying medications with the start date completely unknown, we assume 
the start date is on or before the B/F/TAF first dose date, lipid modifying medication 
was considered as being taken at start of B/F/TAF OL extension phase if the end date 
is not prior to the first B/F/TAF dose date (ie, the end date is on or after the first 
B/F/TAF dose date, completely unknown, or ongoing).
f)
Lipid modifying medications with the start date prior to the first B/F/TAF dose date 
and the end date unknown (completely missing) were considered as being taken at the 
start of the B/F/TAF OL extension phase (the unknown end date is assumed on or 
after the first B/F/TAF dose date).

Subjects who initiated lipid modifying medications during the B/F/TAF OL extension
phase refers to the subjects in the B/F/TAF Safety Analysis set who did not take lipid 
modifying medications at the start of the B/F/TAF OL extension phase and met the 
following criteria: 1) any selected CM record started after the first B/F/TAF dose date 
and on and prior to the last B/F/TAF dose date.
22) For figures, if at a visit where n (sample size) for any treatment group ≤5, data for that 
treatment group will not be displayed at the visit in figure (except the Kaplan-Meier figure), 
but all data will be included in the corresponding table summary.


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23) LDL: Conversions between 2nd and 3rd generations
LDL was analyzed by 2 different assays in the study: 2nd generation (RCT2394) and 
3rd generation (RCT3870). Samples collected at earlier visits were analyzed using LDL 
2nd generation assay. Samples collected at later visits were analyzed using LDL 
3rd generation assay. The conversion formulas are as follow:
2nd Gen (mmol/L)  (3rd Gen - 0.0626)/0.882
3rd Gen (mmol/L)  (0.882 x 2nd Gen) + 0.0626
For this analysis, since LDL samples were analyzed by 2nd generation assay at Baseline, 
only conversion from 3rd generation to 2nd generation will be performed.
For the analysis of change from baseline in fasting direct LDL: the sample analyzed by LDL 
3rd generation assay will be converted to 2nd generation as a new record with test codes of 
LIP.LDL.00.02 in raw data. During ADaM stage, a derived parameter code (FLDL2) for
“Fasting LDL Cholesterol 2ND GEN Combined” will be generated to pool the records from 
both original and converted (LIP.LDL.00.02) 2nd generation results to calculate the change 
from baseline in fasting direct LDL.
For the analysis of toxicity grade for fasting direct LDL: toxicity grade will be based on the 
Gilead grading results (ie, toxgrg) from the original values before conversion. In another 
words, during ADaM programming stage, a derived parameter code (FLDLTOX) for 
“Fasting LDL Cholesterol for Toxicity” will be generated to pool the records from 
2nd generation and 3rd generation to derive treatment-emergent toxicity grades, maximum 
postbaseline toxicity grades, etc.
24) Plasma concentrations
During the B/F/TAF OL extension phase, at Weeks 4, 24, and 48, on the day of 
hemodialysis, a sparse timed blood sample was to be collected from all subjects within 
10 minutes prior to hemodialysis initiation. Predose (within 30 minutes prior to study drug 
administration) blood draws for plasma samples were also collected at these visits. For the 
summary table, all values will be listed; however only trough values will be included in the 
summary statistics. Values not included in the summary statistics should be flagged.
In general, intensive PK concentration values that are BLQ will be treated as 0 at predose 
timepoints and one-half the value of the LLOQ at postdose time points for summary 
purposes. Other PK concentration values (including trough, predose, postdose, anytime PK 
concentration) that are BLQ will be treated as one-half of the LLOQ.


SAP Final GS-US-292-1825
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Project Team
Leader eSigned
03-Dec-2019
11:13:38
Biostatistics eSigned
03-Dec-2019
17:27:06
Project Team
Leader eSigned
05-Dec-2019
01:44:24
PPD
PPD
PPD
--