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
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences

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The infonnation contained in this document, particularly unpublished data, is the property or 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 .... ................ ............. . 
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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.

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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 
CONFIDENTIAL 
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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 
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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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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 
investigational medicinal product.

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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 
consent is signed.

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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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Amendment 2
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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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Amendment 2
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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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Amendment 2
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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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Amendment 2
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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. 

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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· 

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Amendment 2
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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

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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
Page 78
28 November 2016
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
28 November 2016
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
28 November 2016
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
28 November 2016
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.

E/C/F/TAF
Protocol GS-US-292-1825
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 84
28 November 2016
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.
Amendment 2
CONFIDENTIAL
Page 85
28 November 2016
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
CONFIDENTIAL
Page 86
28 November 2016
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
CONFIDENTIAL
Page 87
28 November 2016
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
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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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences 
(eg, aspiration, choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences 
(eg, sepsis, circulatory 
failure, hemorrhage)
Proctitis 
(functional- symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability 
to perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences 
(eg, hypotensive shock)

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

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

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

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

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

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

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

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

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Appendix 6.
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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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)
{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}.