A Phase 3b, Randomized, Open-Label Study to Evaluate Switching From a Tenofovir Disoproxil Fumarate (TDF) Containing Regimen to Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 60 Years
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Randomized, Open-Label Study to Evaluate 
Switching from a Tenofovir Disoproxil Fumarate (TDF) 
Containing Regimen to Elvitegravir/Cobicistat/Emtricitabine/ 
Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination 
(FDC) in Virologically-Suppressed, HIV -1 Infected Subjects 
Aged :::: 60 Years 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Clinical Trials.gov Identifier: 
111007 
2015-002712-32 
TBD 
Indication: 
Protocol ID: 
Gilead Clinical Program 
Manager: 
Gilead Medical Monitor: 
Gilead Study Director: 
Protocol Version/Date: 
HIV -1 h1fection 
GS-US-292-1826 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Mobile: 
Name: 
Telephone: 
Mobile: 
Original: 
Richard Haubrich, MD 
PPD 
PPD 
Ian McNicholl, PharmD 
PD 
PD 
22 July 2015 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, particularly unpublished data, is the property or 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 necessaty to obtain inf01med consent from those 
persons to whom the dmg may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................15
1.2.3.
Clinical Trials of E/C/F/TAF ...............................................................................................17
1.3.
Rationale for This Study ........................................................................................................................19
1.4.
Risk/Benefit Assessment........................................................................................................................19
1.5.
Compliance ............................................................................................................................................19
2.
OBJECTIVES.....................................................................................................................................................20
3.
STUDY DESIGN................................................................................................................................................21
3.1.
Endpoints ...............................................................................................................................................21
3.2.
Study Design..........................................................................................................................................21
3.3.
Study Treatments ...................................................................................................................................21
3.4.
Duration of Treatment............................................................................................................................21
3.5.
End of Study...........................................................................................................................................21
3.6.
Post Study Care......................................................................................................................................22
3.7.
Source Data............................................................................................................................................22
3.8.
Samples for Optional Exploratory Assessments ....................................................................................22
4.
SUBJECT POPULATION..................................................................................................................................23
4.1.
Number of Subjects and Subject Selection ............................................................................................23
4.2.
Inclusion Criteria....................................................................................................................................23
4.3.
Exclusion Criteria...................................................................................................................................24
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................27
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................27
5.2.
Description and Handling of E/C/F/TAF FDC ......................................................................................27
5.2.1.
Formulation..........................................................................................................................27
5.2.2.
Packaging and Labeling .......................................................................................................28
5.2.3.
Storage and Handling...........................................................................................................28
5.3.
Dosage and Administration of E/C/F/TAF FDC....................................................................................28
5.4.
Prior and Concomitant Medications.......................................................................................................28
5.5.
Accountability for Study Drug...............................................................................................................33
5.5.1.
Study Drug Return or Disposal ............................................................................................34
6.
STUDY PROCEDURES ....................................................................................................................................35
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................35
6.2.
Pretreatment Assessments......................................................................................................................35
6.2.1.
Screening Visit .....................................................................................................................35
6.2.2.
Day 1 Visit ...........................................................................................................................37
6.3.
Randomization .......................................................................................................................................38

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6.4.
Treatment Assessments..........................................................................................................................39
6.4.1.
Treatment Visits (Weeks 4-48) ............................................................................................39
6.5.
Post-Treatment Assessments..................................................................................................................41
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................41
6.5.2.
30 Day Follow-Up Visit.......................................................................................................42
6.6.
Assessments for Premature Discontinuation from Study.......................................................................43
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................43
6.8.
Other Evaluations...................................................................................................................................43
6.8.1.
Blood and Urine Storage......................................................................................................43
6.8.2.
Bone Mineral Density Evaluations.......................................................................................44
6.8.3.
Bone Safety and Inflammation.............................................................................................44
6.8.4.
Markers of Platelet Function and Coagulation.....................................................................44
6.8.5.
Markers of Renal Tubular Function .....................................................................................44
6.9.
End of Study...........................................................................................................................................44
6.10.
Post Study Care......................................................................................................................................44
6.11.
Virologic Failure....................................................................................................................................44
6.11.1.
Management of Virologic Failure ........................................................................................45
6.11.2.
Resistance Analysis at Subjects Last Visit...........................................................................45
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................47
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events....................................47
7.1.1.
Adverse Events.....................................................................................................................47
7.1.2.
Serious Adverse Events........................................................................................................47
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................48
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................48
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................48
7.2.2.
Assessment of Severity ........................................................................................................49
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................49
7.4.
Gilead Reporting Requirements.............................................................................................................51
7.5.
Special Situations Reports......................................................................................................................51
7.5.1.
Definitions of Special Situations..........................................................................................51
7.5.2.
Instructions for Reporting Special Situations.......................................................................52
7.6.
Toxicity Management ............................................................................................................................53
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................53
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................53
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................54
7.6.4.
Management of Bone Evaluation.........................................................................................54
7.6.5.
Management of Potential Nephrotoxicity.............................................................................54
7.6.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................55
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 Endpoint .............................................................................................................57
8.2.
Analysis Conventions.............................................................................................................................58
8.2.1.
Analysis Sets ........................................................................................................................58
8.3.
Data Handling Conventions ...................................................................................................................58
8.4.
Demographic Data and Baseline Characteristics ...................................................................................59
8.5.
Primary Analysis....................................................................................................................................59
8.5.1.
Spine BMD...........................................................................................................................59

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8.5.2.
Secondary Analyses .............................................................................................................59
8.6.
Statistical Testing Procedure..................................................................................................................60
8.7.
Safety Analysis.......................................................................................................................................60
8.7.1.
Extent of Exposure...............................................................................................................60
8.7.2.
Adverse Events.....................................................................................................................60
8.7.3.
Laboratory Evaluations ........................................................................................................61
8.7.4.
Other Safety Evaluations......................................................................................................61
8.8.
Sample Size............................................................................................................................................61
9.
RESPONSIBILITIES..........................................................................................................................................62
9.1.
Investigator Responsibilities ..................................................................................................................62
9.1.1.
Good Clinical Practice..........................................................................................................62
9.1.2.
Independent Ethics Committee (IEC) Review and Approval...............................................62
9.1.3.
Informed Consent.................................................................................................................62
9.1.4.
Confidentiality......................................................................................................................63
9.1.5.
Study Files and Retention of Records ..................................................................................63
9.1.6.
Electronic Case Report Forms (eCRFs) ...............................................................................64
9.1.7.
Study Drug Accountability and Return ................................................................................65
9.1.8.
Inspections............................................................................................................................65
9.1.9.
Protocol Compliance............................................................................................................65
9.2.
Sponsor Responsibilities ........................................................................................................................65
9.2.1.
Protocol Modifications.........................................................................................................65
9.2.2.
Study Report and Publications .............................................................................................66
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................66
9.3.1.
Payment Reporting...............................................................................................................66
9.3.2.
Access to Information for Monitoring..................................................................................66
9.3.3.
Access to Information for Auditing or Inspections ..............................................................67
9.3.4.
Study Discontinuation..........................................................................................................67
10.
REFERENCES ...................................................................................................................................................68
11.
APPENDICES ....................................................................................................................................................70
Appendix 1.
Investigator Signature Page....................................................................................................71
Appendix 2.
Study Procedures Table..........................................................................................................72
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................75
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............76
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
Appendix 6.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}.......................................99
LIST OF IN-TEXT TABLES
Table 4-1.
Allowable Antiretroviral Agents of Current Regimen ...........................................................26
Table 4-2.
Disallowed Agents .................................................................................................................26
Table 5-1.
Prior and Concomitant Medications.......................................................................................29
LIST OF IN-TEXT FIGURES
Figure 6-1.
Management of Virologic Failure ..........................................................................................46

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b, Randomized, Open-Label Study to Evaluate 
Switching from a Tenofovir Disoproxil Fumarate (TDF) 
Containing Regimen to Elvitegravir/Cobicistat/Emtricitabine/
Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination 
(FDC) in Virologically-Suppressed, HIV-1 Infected Subjects 
Aged ≥60 Years
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002712-32
TBD
Study Centers Planned:
Approximately 30 centers in Europe
Objectives:
The primary objective of this study is:

To evaluate the safety of E/C/F/TAF FDC relative to 
unchanged current anti-retroviral therapy (ART) by assessing 
spine and hip bone mineral density (BMD) measured at 
Week 48 in virologically-suppressed, HIV-1 infected subjects 
aged ≥ 60 years
The secondary objectives of this study are as follows:

To evaluate spine and hip BMD at Week 24

To evaluate maintenance of HIV-1 RNA suppression 
< 50 copies/mL between regimens at Weeks 24 and 48

To evaluate the safety and tolerability of the 
two treatment groups through Week 48
Study Design:
Randomized, open-label, multicenter, active-controlled study to 
evaluate switching from TDF and FTC or 3TC-containing 
‘backbone’ regimen plus a third agent to E/C/F/TAF FDC in 
virologically-suppressed, HIV-1 infected subjects aged ≥ 60 years

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Subjects will be randomized in a 2:1 ratio to one of the following 
two treatment groups:

Treatment Group 1: FDC of elvitegravir 150 mg /
cobicistat 150 mg / emtricitabine 200 mg /
tenofovir alafenamide 10 mg (E/C/F/TAF) once daily (n = 100)

Treatment Group 2: Remain on current TDF and FTC or 
3TC-containing ‘backbone’ (maximum of 2 NRTIs) regimen 
plus continuing third agent (n = 50)
Randomization will be stratified based on a bivariate cut-point of 
the screening spine and hip BMD T-score < -1.00 or ≥ -1.00.
Subjects will be treated for 48 weeks in a randomized phase. 
Number of Subjects 
Planned:
150
Target Population:
HIV-1 infected subjects ≥ 60 years old who are 
virologically-suppressed (HIV-1 RNA < 50 copies/mL) on a 
stable TDF and FTC or 3TC-containing ‘backbone’ (maximum of 
2 NRTIs) regimen plus a third agent
Duration of Treatment:
A 42 day screening period followed by 48 weeks on study and a 
30 Day Follow-Up visit after completion of study
Diagnosis and Main 
Eligibility Criteria:
HIV-1 infected adults who meet the following criteria:

Age ≥60 years

Currently receiving a TDF and FTC or 3TC-containing 
‘backbone’ (maximum of 2 NRTIs) regimen plus a third agent 
continuously for ≥6 months preceding the screening visit. 
Subject must be on first or second ART regimen. Allowed 
third agents include: LPV/r, ATV + RTV, ATV + COBI 
(or ATV/COBI FDC), DRV + RTV, DRV + COBI 
(or DRV/COBI FDC), EFV, RPV, NVP, ETR, RAL, 
EVG + COBI, or DTG

Documented plasma HIV-1 RNA levels < 50 copies/mL for 
≥6 months preceding the screening visit (measured at least 
twice using the same assay). In the preceding 6 months 
prior to screening, one episode of “blip” (HIV-1 RNA 
> 50 and < 400 copies/mL) is acceptable, only if HIV-1 RNA 
is < 50 copies/mL immediately before and after the “blip”.

Plasma HIV-1 RNA < 50 copies/mL at screening visit

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
Documented historical genotype prior to starting initial ART 
showing no known resistance to TDF or FTC, including, but 
not limited to the presence of reverse transcriptase resistance 
mutations K65R, M184V/I, or thymidine analog-associated 
mutations (TAMs) that include M41L, L210W, D67N, K70R, 
T215Y/F, K219Q/E/N/R. If historical genotype is not 
available, subject will have proviral genotype resistance 
analysis prior to Day 1.

Adequate renal function defined as having an estimated 
glomerular filtration rate of ≥ 30 mL/min as calculated by 
Cockcroft-Gault (eGFRCG) and are on ART that are 
appropriately dose adjusted for renal function per 
package insert

No previous use of any approved or experimental integrase 
strand transfer inhibitor (INSTI) (for any length of time) if the 
current regimen contains a PI/r or NNRTI
Study Procedures/
Frequency:
After screening, study visits will occur at Day 1, Weeks 4, 8, 12, 
24, 36, and 48. 
Laboratory analyses (chemistry, hematology, and urinalysis), 
HIV-1 RNA, CD4+ cell count, assessment of adverse events and 
concomitant medications, and complete or symptom directed 
physical examinations will be performed at all study visits.
Blood and urine for selected evaluations of bone and renal safety, 
inflammation, and platelet and coagulation function will be 
collected at Day 1, Weeks 4, 12, 24, and 48. 
Dual-energy x-ray absorptiometry (DXA) scans will be performed 
at screening, Weeks 24 and 48. Scans will cover the spine and hip
to measure changes in BMD.
Test Product, Dose, and 
Mode of Administration:
Elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg /
tenofovir alafenamide 10 mg (E/C/F/TAF) FDC administered 
orally once daily with food
Reference Therapy, 
Dose, and Mode of 
Administration:
Current ART consisting of TDF and FTC or 3TC-containing 
‘backbone’ (maximum of 2 NRTIs) regimen plus a third agent

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Criteria for Evaluation:
Safety:
Primary Endpoints:

Percent change from Baseline to Week 48 in spine and hip BMD
Secondary Endpoints:

Percent change from Baseline to Week 24 in spine and hip BMD
Efficacy:
Secondary Endpoints:

Proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Weeks 24 and 48 as defined by the Food and Drug Administration 
(FDA) snapshot algorithm

Change from Baseline in CD4+ cell count at Weeks 24 and 48
Health Related 
Questionnaires:
Health related questionnaires will be administered, including the 
Visual Analogue Scale (VAS), HIV Treatment Satisfaction 
(HIVTSQ), EQ-5D, Medical Outcome Study Short Form-36 (SF-36),
and Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F).
Statistical Methods:
The primary endpoints are the percentage change from baseline in 
spine and hip BMD at Week 48. The primary objective would be 
met if either one of these endpoints are statistically significant; the 
Type I error rate will be controlled using the fallback procedure. 
The primary endpoints: percent change from baseline in spine (and 
hip) BMD at Week 48 will be conducted using an ANOVA model, 
including treatment group and baseline spine (hip) BMD T-score 
in (< -1.00 vs ≥ -1.00) as a fixed effect in the model.
Similar methods will be used at Week 24 for the BMD changes in 
hip and spine.
Sample Size:
In study GS-US-292-0109 (virologically-suppressed subjects 
switched from E/C/F/TDF to E/C/F/TAF) for subjects 55 or older, 
the mean percent change from baseline at Week 48 in hip BMD 
was +1.21 in the TAF group and -0.35 in the TDF group. The SD 
was 2.93 for the difference between the 2 groups resulting in an 
effect size of 0.53. The mean percent change from baseline at 
Week 48 in spine BMD was +1.71 in the TAF group 
and -1.32 in the TDF group. The SD was 4.24 for the difference 
between the 2 groups resulting in an effect size of 0.71. Given 
150 subjects in the present study, there is at least 90% power to 
detect an effect size of 0.71 in spine BMD at Week 48 with a 
Type I error rate of α = 0.03 and a power of 75% for hip BMD at 

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Week 48 with α = 0.02 (in the situation that spine BMD is not 
statistically significantly different or 85% with α = 0.05 in the 
situation that spine BMD is statistically significantly different) for 
an effect size of 0.53.
Descriptive statistics will summarize baseline characteristics, 
efficacy, and safety endpoints.
The secondary efficacy objective will assess maintenance of 
HIV-1 RNA suppression < 50 copies/mL by comparing the 
proportion of each group using the FDA snapshot algorithm. 
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
3TC
lamivudine 
ABC
abacavir
AE
adverse event
AIDS
Acquired Immune Deficiency Syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ANOVA
analysis of variance
ARV
antiretroviral
AST
aspartate aminotransferase
ATR
Atripla®; EFV/FTC/TDF
ATV
atazanavir 
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time curve
AUClast
area under the plasma concentration-time curve from time 0 to the last measurable concentration
AUCtau
area under the plasma concentration-time curve at the end of the dosing interval
AV
atrioventricular
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CK
creatine kinase
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration
of drug
CMH
Cochran-Mantel-Haenszel test
CNS
central nervous system
COBI, /co
cobicistat 
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CSR
clinical study report
CTX
type 1 collagen crosslinked C-telopeptide
CYP
cytochrome P450
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DRV
darunavir

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DSPH
Drug Safety and Public Health
DTG
dolutegravir
DXA
dual-energy X-ray absorptiometry
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
EFV
efavirenz
EVG
elvitegravir 
E/C/F/TDF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir disoproxil fumarate (TDF) 300 mg single tablet regimen
E/C/F/TAF
elvitegravir (EVG) 150 mg / cobicistat (COBI) 150 mg / emtricitabine (FTC) 200 mg /
tenofovir alafenamide (TAF) 10 mg single tablet regimen
ESDD
early study drug discontinuation
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FTC
emtricitabine
F/TAF
emtricitabine/tenofovir alafenamide
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate
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
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HSP
hysterosalpingogram
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor

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IMP
Investigational Medicinal Product
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
LLT
low-level term
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
Min
minute
mmHg
millimeters mercury
MVC
maraviroc
NNRTI
non-nucleoside reverse transcriptase inhibitor
N[t]RTI
nucleos(t)ide reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
NVP
nevirapine
P1NP
procollagen Type 1 N-terminal propeptide
PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term 
QD
once daily 
RAL
raltegravir
RBC
Red blood cells
RNA
ribonucleic acid
RPV
rilpivirine
RTV, /r
ritonavir
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedure
STB
Stribild®, EVG/COBI/FTC/TDF (E/C/F/TDF) STR
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV
tenofovir

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TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
VR
virologic rebound
WBC
white blood cells
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the serum, plasma concentration of drug versus time curve

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1.
INTRODUCTION
1.1.
Background
HIV-1 infection is a life-threatening and serious disease that is of major public health interest 
around the world. There are 35 million people worldwide and approximately 1.1 million people 
in the US living with HIV-1 {15971}, {19661}. Within Western and Central Europe, it is 
estimated that there are over 900,000 individuals living with HIV and 131,000 new infections 
in 2012 {35257}.
The infection, if left untreated or suboptimally treated, is characterized by deterioration in 
immune function, the subsequent occurrence of opportunistic infections and malignancies, 
ultimately resulting in death. Therapeutic strategies for the treatment of HIV-1 disease have been 
significantly advanced by the availability of highly active antiretroviral therapy (HAART); 
the introduction of HAART was associated with a dramatic decrease in acquired immune 
deficiency syndrome (AIDS)-related morbidity and mortality {27881}, {24156}, {8284}.
The primary goals of ARV therapy for HIV-1 infection are to reduce HIV-associated morbidity 
and prolong the duration and quality of life, restore and preserve immunologic function, 
maximally and durably suppress plasma HIV viral load, and prevent HIV transmission. 
The DHHS guidelines list emtricitabine/tenofovir DF (FTC/TDF) as a preferred nucleos(t)ide 
reverse transcriptase inhibitor NRTI/NtRTI backbone in combination with either 
cobicistat-boosted elvitegravir [EVG/COBI] administered as EVG/COBI/FTC/TDF, raltegravir, 
dolutegravir or darunavir/ritonavir as an initial ARV regimen {34898}. Although HAART has 
dramatically improved the prognosis of patients infected with HIV-1, eradication of the virus is 
not possible with currently available therapies. Long-term viral suppression and prevention of 
drug resistance are goals of successful therapy. In regimens of comparable efficacy, the total pill 
burden, dosing frequency, and concerns about safety and side effects are generally the most 
significant obstacles to achieving high adherence {4266}, {4256}, {34898}.
Tenofovir disoproxil fumarate (TDF) is a preferred NRTI among recommended regimens for 
treatment-naïve HIV-positive patients, but is associated with nephrotoxicity and reduced bone 
mineral density {21769}. Lifelong antiretroviral treatment and the increasing comorbidities being 
recognized and treated in HIV-positive patients creates an urgent need to improve the safety 
profile of regimens that most effectively suppress HIV replication. Tenofovir alafenamide (TAF) 
is a novel oral prodrug of tenofovir (TFV), a nucleotide analog that inhibits HIV-1 reverse 
transcription. Gilead has coformulated TAF with the integrase strand transfer inhibitor 
elvitegravir (EVG), cobicistat (COBI), and emtricitabine (FTC) into a fixed dose combination 
(FDC). Compared to TDF, the use of TAF in the E/C/F/TAF FDC is provides enhanced 
lymphatic delivery of tenofovir, resulting in higher intracellular levels of the active 
phosphorylated moiety tenofovir-diphosphate, and lower systemic circulating levels of tenofovir. 
These features translate into an improved tolerability and safety profile, especially with respect 
to renal and bone safety {34827}. 

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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 a second generation oral 
prodrug of tenofovir (TFV), a nucleotide analog that inhibits HIV-1 reverse transcription. 
Tenofovir is metabolized intracellularly to the active metabolite, tenofovir diphosphate 
(TFV-DP), a competitive inhibitor of HIV-1 reverse transcriptase (RT) that terminates the 
elongation of the viral DNA chain. 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); and GS-7340-03 as the hemifumarate (2:1). 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 and a number of ongoing studies. GS-7340-03
was also used in the Phase 2 study GS-US-292-0102 and several Phase 3 studies 
(for example: GS-US-292-0104 and GS-US-292-0111). GS-7340-03 and GS-7340-02 exist 
as the free base, TAF (GS-7340), in blood and biological fluids. 
For further information, refer to the current investigator’s brochure for E/C/F/TAF.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
TAF is metabolized to TFV, a nucleotide analog (i.e., 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 diphosphate (TFV-DP). The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{13} 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.
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, 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
TAF monofumarate (GS-7430-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006) and 
gastrointestinal systems (R990187). Single doses 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). TAF monofumarate (at 1000 mg/kg reduced 
distal transit and increased stomach weights starting 2 hours post-dosing with reversibility 

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beginning by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. 
The IC50 for the inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current 
was estimated to be greater than 10 μM.
All nonclinical pharmacokinetic experiments in this section 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).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. Peak TFV plasma concentrations occurred following 
TAF absorption, with TFV Tmax values between 0.25 to 1.7 hours in rats, dogs, and monkeys. 
TFV plasma concentrations declined with a terminal half-life of 11.2 to 16.4 hours in rats (fasted),
> 24 hours in dogs (fasted) and 8.1 to 12.5 hours in rhesus monkeys.
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in 
beagle dogs. 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, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes suggesting that TAF may be 
selectively cleaved to tenofovir in the cells of the lymphoreticular system. The primary route of 
elimination of tenofovir is renal excretion of unchanged drug based on IV studies of tenofovir. 
Following oral administration of GS-7340-02, approximately 15% of a radiolabeled dose is 
recovered in dog urine in 24 hrs. Tenofovir was the major species present in the urine (90%), 
with about 3.4% of TAF also present. Biliary excretion of tenofovir in dogs and fecal elimination 
of tenofovir in rats and dogs are negligible.
Tenofovir was the only species found in the intestinal contents and feces. In human systems, 
TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed 
oxidation (AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4 inhibition 
or induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has 
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1 
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or 
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma 
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by 
clinically relevant drug-drug interactions is very low.

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1.2.3.
Clinical Trials of E/C/F/TAF
Clinical trials using tenofovir alafenamide, coformulated into the E/C/F/TAF FDC include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI administered as E/C/F/TAF STR relative to E/C/F/TDF or TAF 
(completed)

GS-US-292-0103, a Phase 1 healthy volunteer study to evaluate the pharmacokinetics and 
relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
GS-7340 doses of 10 mg (STR) or 25 mg Single Agent (SA) (completed)

GS-US-292-0102, a Phase 2 randomized, double-blinded study of the safety and efficacy of 
E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, antiretroviral treatment-naive 
adults (completed)

GS-US-292-0104 and GS-US-292-0111, Phase 3 randomized, double-blinded study of the 
safety and efficacy of E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, 
antiretroviral treatment-naive adults (completed)

GS-US-292-0106, a Phase 2/3, open-label study of the pharmacokinetics, safety, and 
antiviral activity of the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) single tablet regimen (STR) in HIV-1 infected antiretroviral treatment-naive 
adolescents (completed)

GS-US-292-0109, a Phase 3 open-label study to evaluate switching from a TDF-containing 
combination regimen to a TAF-containing combination single tablet regimen (STR) in 
virologically-suppressed, HIV-1 positive subjects (completed)

GS-US-292-0110, a Phase 1, randomized, open-label, single dose, three-treatment, 
three-period, six-sequence crossover study of the effect of food on the TAF component of the 
E/C/F/TAF STR (completed)

GS-US-292-0112, a Phase 3 Open-label Safety Study of Elvitegravir/Cobicistat/
Emtricitabine/Tenofovir Alafenamide single-tablet Regimen in HIV-1 positive patients with 
mild to moderate renal impairment (completed)

GS-US-292-0117, a Phase 3, two-part study to evaluate the efficacy of 
Tenofovir Alafenamide versus placebo added to a failing regimen followed by treatment with 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in HIV-1 positive, 
antiretroviral treatment-experienced adults (ongoing)

GS-US-292-0119, a Phase 3 open-label study to evaluate switching from optimized stable 
antiretroviral regimens containing darunavir to Elvitegravir/Cobicistat/Emtricitabine/
Tenofovir Alafenamide (E/C/F/TAF) single tablet regimen (STR) plus darunavir (DRV) in 
treatment experienced HIV-1 positive adults (ongoing)

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Study GS-US-292-0101 was a Phase 1 study of 40 subjects evaluating the relative bioavailability 
of two different formulations of E/C/F/TAF STR, each with TAF dose of 25 mg or 40 mg, versus 
E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, and FTC were comparable 
between E/C/F/TAF vs E/C/F/TDF regardless of formulation (monolayer or bi-layer). 
In contrast, TAF exposures were ~2.2-fold higher (and corresponding tenofovir exposures 
~3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 25 mg for both 
formulations of the E/C/F/TAF, likely mediated by inhibition of Pgp-mediated intestinal 
secretion of TAF by COBI.
Study GS-US-292-0102 was a completed, randomized, active-controlled Phase 2 study, 
compares E/C/F/TAF (10 mg) versus Stribild® (STB, E/C/F/TDF) in treatment-naïve, 
HIV-1 infected subjects. At Week 48, the E/C/F/TAF demonstrated potent antiviral efficacy 
(HIV-1 RNA < 50 copies/mL) similar to STB (88.4% [99/112] vs 87.9% [51/58] using the 
snapshot algorithm); in the E/C/F/TAF group, no patient had emergent resistance to 
1 or more components of the E/C/F/TAF. Importantly, E/C/F/TAF demonstrated a potential 
benefit over E/C/F/TDF in terms of renal and bone safety: smaller median decreases in 
eGFR (mL/min) (at Week 48, E/C/F/TAF -5.5 vs E/C/F/TDF -10.0 [P < 0.001) and smaller 
median percentage decreases in BMD (at Week 48, spine E/C/F/TAF -1.00 vs E/C/F/TDF -3.37 
[P < 0.001], hip -0.62 vs -2.39 [P < 0.001]).
Study GS-US-292-0103 was a completed Phase 1 healthy volunteer study which evaluated the 
PK and relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
TAF doses of 10 (STR) or 25 mg SA. Results indicate that when dosed as the E/C/F/TAF 10 mg 
STR, TAF and TFV exposures were comparable to those observed with TAF 25 mg dosed alone. 
Exposures of EVG, COBI, and FTC were also comparable between the STR and individually 
dosed formulations.
In two controlled, double-blind phase 3 studies (GS-US-292-0104 and GS-US-292-0111), 
treatment-naive HIV-infected patients were recruited with an estimated creatinine clearance of 
50 mL per min or higher from 178 outpatient centers in 16 countries. Patients were randomly 
assigned (1:1) to receive E/C/F/TAF or E/C/F/TDF with matching placebo. Randomization was 
done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 
RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those 
assessing outcomes were masked to treatment group. All participants who received one dose of 
study drug were included in the primary intention-to-treat efficacy and safety analyses. The main 
outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at 
Week 48 as defined by the US Food and Drug Administration (FDA) snapshot algorithm 
(pre-specified noninferiority margin of 12%) and pre-specified renal and bone endpoints at 
48 weeks. There were 1733 patients who received treatment (866 given E/C/F/TAF and 
867 given E/C/F/TDF). E/C/F/TAF was non-inferior to E/C/F/TDF, with 800 (92%) of 
866 patients in the TAF group and 784 (90%) of 867 patients in the TDF group having plasma 
HIV-1 RNA less than 50 copies per mL (adjusted difference 2.0%, 95% CI -0.7 to 4.7). 
Patients given E/C/F/TAF had significantly smaller mean serum creatinine increases than those 
given E/C/F/TDF (0.08 vs 0.12 mg/dL; p < 0.0001), significantly less proteinuria 
(median % change -3 vs 20; p < 0.0001), and a significantly smaller decrease in 

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bone mineral density at spine (mean % change –1.30 vs –2.86; p < 0.0001) and 
hip (-0.66 vs -2.95; p < 0.0001) at 48 weeks. Interpretation through 48 weeks, more than 
90% of patients given E/C/F/TAF or E/C/F/TDF had virologic success. Renal and bone effects 
were significantly reduced in patients given E/C/F/TAF.
1.3.
Rationale for This Study
With the aging of the HIV-infected population such that half of the population is now over the 
age of 50 years, there is a need for efficacy and safety data in this population. This study seeks to 
address this gap by enrolling subjects 60 years or older in order to generate data on the efficacy 
and safety of E/C/F/TAF in this population.
1.4.
Risk/Benefit Assessment
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. 
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 of E/C/F/TAF relative to unchanged current antiretroviral therapy (ART)
by assessing spine and hip bone mineral density (BMD) measured at Week 48 in 
virologically-suppressed, HIV-1 infected subjects aged ≥ 60 years
The secondary objectives of this study are:

To evaluate spine and hip BMD at Week 24

To evaluate maintenance of HIV-1 RNA suppression < 50 copies/mL between regimens at 
Weeks 24 and 48

To evaluate the safety and tolerability of the two treatment groups through Week 48

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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:

Percent change from Baseline to Week 48 in spine and hip BMD
The secondary endpoints of this study are:

Percent change from Baseline to Week 24 in spine and hip BMD

Proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by 
the Food and Drug Administration (FDA) snapshot algorithm

Change in CD4+ cell count from baseline at Weeks 24 and 48
3.2.
Study Design
This protocol describes a randomized, open-label, multicenter, active-controlled study to 
evaluate switching from TDF and FTC or 3TC-containing ‘backbone’ (maximum of 2 NRTIs) 
regimen plus a third agent to E/C/F/TAF FDC in virologically-suppressed, HIV-1 infected 
subjects aged ≥ 60 years. Subjects with Hepatitis B co-infection will not be excluded.
3.3.
Study Treatments
Subjects will be randomized in a 2:1 ratio to one of the following two treatment groups:

Treatment Group 1: FDC of elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg /
tenofovir alafenamide 10 mg (E/C/F/TAF) daily (n = 100)

Treatment Group 2: Remain on current TDF and FTC or 3TC-containing ‘backbone’
(maximum of 2 NRTIs) regimen plus continuing third agent (n = 50)
Randomization will be stratified based on a bivariate cut-point of the screening spine and hip 
BMD T-score < -1.00 or ≥ -1.00.
3.4.
Duration of Treatment
The randomized treatment duration is 48 weeks. After screening, eligible subjects will be 
randomized to Treatment Group 1 or 2 and treated for 48 weeks. Following the screening and 
Day 1 visits, subjects will return for study visits at Weeks 4, 8, 12, 24, 36, and 48. 
3.5.
End of Study
End of study is defined as completion of the 48 weeks of treatment and the 30 Day Follow-Up visit.

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3.6. 
Post Study Care 
Final 
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After a subject has completedlte1minated their pruiicipation in the study, long-te1m care for the 
subject will remain the responsibility of their primruy treating physician. 
3.7. 
Source Data 
Gilead will provide source document worksheets for all study visits. 
3.8. 
Samples for Optional Exploratory Assessments 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 150 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 study procedures
2) Age ≥ 60 years
3) Currently receiving a TDF and FTC or 3TC-containing ‘backbone’ (maximum 2 NRTIs)
regimen plus a third agent for ≥ 6 consecutive months prior to screening visit. Subject must 
be on first or second ART regimen. Refer to Table 4-1 for allowed third agents of the current 
regimen.
4) Documented plasma HIV-1 RNA levels < 50 copies/mL for ≥ 6 months preceding the 
screening visit (measured at least twice using the same assay). In the preceding 6 months 
prior to screening, one episode of “blip” (HIV-1 RNA > 50 and < 400 copies/mL) is 
acceptable, only if HIV-1 RNA is < 50 copies/mL immediately before and after the “blip”.
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) Plasma HIV-1 RNA level < 50 copies/mL at screening visit
6) Adequate renal function:
Estimated glomerular filtration rate ≥ 30 mL/min according to the Cockcroft-Gault formula
(eGFRCG) and are on ARVs that are appropriately dose adjusted for renal function 
per package insert {2202}:
Male: 
(140 – age in years) × (wt in kg) = CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) × 0.85 = CLcr (mL/min)
72 × (serum creatinine in mg/dL)

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7) Documented historical genotype prior to starting initial ART showing no known resistance to 
TDF or FTC, including, but not limited to the presence of reverse transcriptase resistance 
mutations K65R, M184V/I, or thymidine analog-associated mutations (TAMs) that include 
M41L, L210W, D67N, K70R, T215Y/F, K219Q/E/N/R. If historical genotype is not 
available, subject will have proviral genotype analysis for archived resistance prior to Day 1.
8) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Total bilirubin ≤ 1.5 mg/dL or normal direct bilirubin (subjects with documented 
Gilbert’s syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin 
up to 5 × ULN)
11) Adequate hematologic function

Absolute neutrophil count ≥1,000/mm3

Platelets ≥50,000/mm3

Hemoglobin ≥ 8.5 g/dL
12) Study performed DXA scan and T-score received prior to Day 1
13) Male subjects must agree to utilize a highly effective method of contraception (as defined 
in Appendix 5) during heterosexual intercourse or be non-heterosexually active, or practice 
sexual abstinence, and agree to refrain from sperm donation from first dose throughout the 
study period and for 90 days following the last dose of study drug.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) 
(for any length of time) if the current regimen contains a PI/r
2) Subjects will have no evidence of previous virologic failure on a PI/r or INSTI-based 
regimen (with or without resistance to either class of ARV).
3) A new AIDS-defining condition diagnosed within the 30 days prior to screening 
(except CD4+ cell count and/or percentage criteria) (refer to Appendix 6)
4) Hepatitis C virus that would require therapy during the study
5) Subjects with clinical evidence of decompensated cirrhosis (ascites, encephalopathy, 
variceal bleeding)

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6) Women 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. 

Permanent sterilization includes hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy in a female subject of any age.
7) Subjects receiving ongoing treatment for bone disease (eg, osteoporosis), including 
bisphosphonates, denosumab, and strontium ranelate
8) Have an implanted defibrillator or pacemaker
9) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
10) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 30 days of Day 1 visit and must not be 
anticipated to require systemic therapy during the study
11) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1 Visit
12) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements
13) Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
14) Known hypersensitivity to the study drug, the metabolites, or formulation excipients
15) Subjects receiving ongoing therapy with any of the medications in Table 4-2, including drugs 
not to be used due to the potential for interaction with EVG, COBI, FTC, TAF, or 3TC 
(for EVG, COBI, FTC and 3TC refer to the individual agents’ Prescribing Information; 
for TAF refer to the E/C/F/TAF FDC Investigator’s Brochure); or subjects with any known 
allergies to the excipients of E/C/F/TAF FDC tablets.

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Table 4-1.
Allowable Antiretroviral Agents of Current Regimen
Antiretroviral Class
Agents
Boosted Protease Inhibitor (PI)
LPV/r, ATV + RTV, ATV + COBI (or ATV/COBI FDC),
DRV + RTV, DRV + COBI (or DRV/COBI FDC)
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
EFV, RPV, NVP, ETR
Integrase Strand Transfer Inhibitor (INSTI)
RAL, DTG, EVG + COBI
Table 4-2.
Disallowed Agents
Drug Class
Agents Disallowed*
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Bisphosphonates
Any agent in this class (e.g. alendronate, ibandronate, etc)
Calcium Channel Blockers
Bepridil
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
Other
probenecid, calcium > 500 mg/day, 
vitamin D3 or D2 > 800 IU/day, TNF-alpha antagonists 
(eg infliximab, etanercept, adlimumab, certolizumab, 
golimumab), teriparatide, denosumab, strontium ranelate
*
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.
Randomization, Blinding and Treatment Codes
Subjects will be randomized in a 2:1 ratio to Treatment Group 1 or Treatment Group 2.
The randomization will be stratified based on a bivariate cut-point of the screening spine and hip 
BMD T-score < -1.00 or ≥ 1.00.

Treatment Group 1: FDC of elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg /
tenofovir alafenamide 10 mg (E/C/F/TAF) QD (n = 100)

Treatment Group 2: Remain on current TDF and FTC or 3TC-containing ‘backbone’
(maximum of 2 NRTIs) regimen plus continuing third agent (n = 50)
This is an open-label study.
Subjects will be assigned a screening number at the time of consent.
Once eligibility has been confirmed, each subject will be assigned a unique subject number using 
an Interactive Web Response System (IWRS). Once a subject number has been assigned, it will 
not be reassigned to any other subject. The subject number assignment and randomization may 
be performed up to 3 days prior to the in-clinic Day 1 visit provided that all screening procedures 
have been completed and subject eligibility has been confirmed.
Randomization and Day 1 visit cannot occur until subject eligibility has been confirmed. 
IWRS will assign open-label study drug bottle numbers at each study visit for those subjects in 
Treatment Group 1. All Day 1 visit tests and procedures must be completed prior to the 
administration of the first dose of study drug. Initiation of treatment with the study drug must 
take place within 24 hours after the Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF FDC
5.2.1.
Formulation
E/C/F/TAF FDC 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). In addition to the active ingredients, the tablets contain 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.

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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 packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an induction sealed 
aluminum-faced liner.
Study drug(s) to be distributed to centers in participating countries shall be labeled to meet 
applicable requirements of the United States Food and Drug Administration (FDA), 
EU Guideline to Good Manufacturing Practice −Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.3.
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 FDC
E/C/F/TAF FDC tablets will be provided by Gilead Sciences.

Treatment Group 1: FDC of Elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg /
tenofovir alafenamide 10 mg (E/C/F/TAF) administered orally with food once daily at 
approximately the same time each day
5.4.
Prior and Concomitant Medications
The use of medication for the treatment of HIV, other than the study treatment (ie, E/C/F/TAF or 
TDF and FTC or 3TC-containing ‘backbone’ regimen plus a third agent) is prohibited. 
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 due to potential 
drug-drug interactions.

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

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

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Drug Class
Agents Disallowed
Use Discouraged and to be Used with Caution
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
Bisphosphonates
Any agent in this class 
(eg, alendronate, 
ibandronate, etc.)
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.

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Drug Class
Agents Disallowed
Use Discouraged and to be Used with Caution
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus:
Concentrations may increase with 
study drug(s). Therapeutic monitoring should 
be considered.
Inhaled Beta Agonist
Salmeterol:
Concentrations may increase with study drug. 
Coadministration of salmeterol with study drug 
may result in increased risk of cardiovascular 
adverse events associated with salmeterol, 
including QT prolongation, palpitations, and 
sinus tachycardia.
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: 
A dose decrease may be needed.
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).

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Drug Class
Agents Disallowed
Use Discouraged and to be Used with Caution
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.
Others
Probenecid, 
calcium > 500 mg/day, 
vitamin D3 or D2 > 800 IU/day,
TNF-alpha antagonists 
(eg, infliximab, etanercept, 
adlimumab, certolizumab, 
golimumab), teriparatide, 
denosumab, strontium ranelate
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Gilead Medical Monitor must be consulted prior to initiation of the new medication. In instances 
where an excluded medication is initiated prior to discussion with the Medical Monitor, the 
Investigator must notify Gilead as soon as he/she is aware of the use of the excluded medication.
Additionally, Investigators should refer to the product/package inserts of the other antiretroviral 
medications for contraindications related to their use.
5.5.
Accountability for Study Drug
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
The Investigator (or designee) will be responsible for maintaining an accurate inventory 
(on study drug accountability records) of the dates and quantities of all study drug received, 
dispensed, and returned. Each dose of the study drug administered at the study center will be 
administered by qualified study center personnel. The requirements of all applicable drug 
dispensing laws will apply to all doses of study drug dispensed by the Investigator (or designee). 

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The study drug 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.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug 

Record the date, subject number, subject initials, the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions for return. If return is not possible, the study monitor 
will evaluate each study center’s study drug disposal procedures and provide appropriate 
instruction for destruction. If the site has an appropriate standard operating procedure (SOP) for 
drug destruction as determined by Gilead Quality Assurance, 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 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 supplies and associate 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.
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate electronic Case Report Forms (eCRFs). In addition, the sponsor or 
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 the subject is eligible prior to enrollment. 
Please refer to Section 5 for details about randomization and treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 42 days before randomization (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: HIV-1 disease-related events, cigarette smoking
(current or previous smoker), diabetes, family cardiovascular history, history of fractures 
(including fragility fractures), and prior medications within 30 days of 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)

Height and weight

12-lead ECG performed supine

Urine collection for the following laboratory analyses:
Urinalysis
Urine chemistry

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
Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, and sodium 
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ cell count
Plasma HIV-1 RNA (TaqMan® v2.0)
Hepatitis B virus surface Antigen serology (HBsAg) and Hepatitis B core Antibody (HBcAb)
Hepatitis C virus (HCV Ab) serology (reflex HCV RNA is performed in subjects with 
positive HCV Ab serology)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula (eGFRCG)
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)

Whole blood sample for virology (if historical genotype is not available)

DXA Scan (spine and hip)
Once eligibility is confirmed the DXA scan will be performed on subjects prior to the 
Day 1 visit.

Review of concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 42 days after screening for randomization into the study.
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 eCRF. All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in 
medical history are to be captured on the medical history eCRF. See Section 7, Adverse Events 
and Toxicity Management for additional details.

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6.2.2. 
Day 1 Visit 
Final 
Original 
The following evaluations are to be completed at the Day 1 visit. The subject must complete all 
evaluations before being dispensed the study drug. Initiation of treatment with the study drug 
must take place within 24 hours after this visit. 
• 
Review of AEs (including any recent fractures) and changes in concomitant medications 
• 
Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator) 
• 
Vital signs measurement, including weight 
• 
Urine collection for the following laboratory analyses: 
-
Urinalysis and urine chemistry 
-
Renal safety evaluations: Fasting (no food or drink, except water, at least 8 hours prior to 
blood collection) retinol binding protein and beta-2 microglobulin 
o 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. 
PO 
• 
Blood sample collection for the following laboratory analyses: 
-
Chemistry profile (glucose will be done as part of the fasting metabolic assessments) 
-
Hematology profile 
-
CD4+ 
-
Plasma HIV-1 RNA 
-
Cystatin-C 
-
eGFRcG 
-
Testosterone level 
-
Metabolic assessments: Fasting (no food or drink, except water, at least 8 hours prior 
to blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, 
and triglycerides) 
o 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. 
CONFIDENTIAL 
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Final 
Original 
-
Serum bone safety evaluations: Fasting (no food or drink, except water, at least 8 hours 
prior to blood collection) parathyroid h01mone (PTH) and senun 25-0H Vitamin D 
o If the subject has not fasted prior to the visit, the visit may proceed, but the subject 
must retum within 72 hours in a fasted state. 
-
Platelet function and coagulation evaluations may include: soluble glycoprotein VI (sGPVI), 
P-selectin, soluble CD40 ligand, and d-dimer. 
-
Inflammation evaluations may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, 
sTNF-R1, and Lp-PLA2. 
-
Plasma storage sample for safety and/or virology testing 
_ 
PD 
• 
Questionnaires: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire. 
-
Visual Analog Scale (VAS) 
-
HIV Treatment Satisfaction Status (HIVTSQs) 
-
EQ-5D 
-
Medical Outcome Study Shott FOim-36 (SF-36) 
-
Functional Assessment of Chronic Illness Therapy- Fatigue (F ACIT -F) 
6.3. 
Randomization 
• 
Obtain subject munber and randomize the subject via the IWRS. 
• 
Treatment Group 1 will be dispensed study dmg as assigned via IWRS 
• 
Treatment Group 2 will continue with cunent ARV regimen. Investigators must provide a 
prescription to the subjects in Treatment Group 2. Those subjects m·e responsible for 
obtaining their ART prior to or dming the study visit 
• 
Subjects must initiate dosing of study dmg or cunent regimen within 24 hours after the 
Day 1 visit. 
• 
Subjects should also be cmmseled regm·ding the importance of adherence and taking their 
study dmg once daily with food at approximately the same time each day. 
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6.4. 
Treatment Assessments 
6.4.1. 
Treatment Visits (Weeks 4-48) 
Final 
Original 
The following assessments are to be completed at the end of Weeks 4, 8, 12, 24, 36, and 48 
unless otherwise specified. 
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within± 2 days ofthe visit date through Week 12 and completed within± 6 days of 
the visit date for Weeks 24 and 36. The visit window at Week 48 will be± 6 weeks ofthe visit 
date which coincides with the Week 48 statistical analysis window for HIV RNA. Unless 
notified by Gilead, the Week 48 visit should be completed within± 6 days ofthe visit date. 
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study drug. 
• 
Review of AEs (including any recent fractures) and changes in concomitant medications 
• 
Complete physical examination (Weeks 24 and 48) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator) 
• 
Symptom-directed physical examination, as needed (Weeks 4, 8, 12, 36) 
• 
Vital signs measurement, including weight 
• 
12-lead ECG (Week 48 only) 
• 
Urine collection for the following laboratory analyses: 
-
Urinalysis and urine chemistry 
-
Renal safety evaluations: Fasting (no food or drink, except water, at least 8 hours prior to 
blood collection) retinol binding protein and beta-2 microglobulin (Weeks 4, 12,24 and 48) 
_
. PO 
• 
Blood sample collection for the following laboratory analyses: 
-
Chemistry profile (glucose will be done as part of the fasting metabolic assessments at 
Weeks 24 and 48) 
-
Hematology profile 
-
CD4+ 
-
Plasma HIV-1 RNA 
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-
eGFRcG 
-
Testosterone level 
Final 
Original 
-
Metabolic assessments: Fasting (no food or drink, except water, at least 8 hours prior 
to blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, 
and triglycerides) (Weeks 24 and 48) 
-
Semm bone safety evaluations: Fasting (no food or drink, except water, at least 8 hours 
prior to blood collection) parathyroid hmmone (PTH) and semm 25-0H Vitamin D 
(Weeks 4, 12, 24, and 48) 
-
Platelet and coagulation ftmction evaluations may include: soluble glycoprotein VI (sGPVI), 
P-selectin, soluble CD40 ligand, and d-dimer (Weeks 4, 12, 24, and 48). 
-
Inflammation evaluations may indude: cystatin-C, IL 6, hs CRP, sCD14, sCD163, 
sTNF-Rl, and Lp-PLA2 (Weeks 4, 12, 24, and 48). 
-
Plasma storage sample for safety and/or virology testing 
• 
DXA scans for spine and hip may be perfonned ~ 10 days before study visit 
(Weeks 24 and 48). 
• 
Subjects who meet the criteria for virologic rebmmd should be managed according to 
Section 6.11, Virologic Failure. 
• 
HIV-1 gene/phenotype resistance testing for subjects with unconfitmed virologic rebound 
with HIV-1 RNA value:::: 50 copies/mL (Week 48 only) 
• 
Questiom1aires: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire. 
-
Visual Analog Scale (VAS) 
-
HIV Treatment Satisfaction Change (HIVTSQc) (Weeks 4, 24, and 48) 
-
EQ-5D (Weeks 24 and 48) 
-
SF-36 (Weeks 24 and 48) 
-
FACIT-F (Weeks 24 and 48) 
• 
Document study dmg dispensation (Weeks 4, 8, 12, 24, and 36) and accountability. 
CONFIDENTIAL 
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6.5. 
Post-Treatment Assessments 
6.5.1. 
Early Study Drug Discontinuation (ESDD) Visit 
Final 
Original 
If a subject discontinues study drug or their cmTent regimen prior to Week 48, the subject will be 
asked to return to the clinic within 72 hours for the ESDD visit. The subject will be asked to 
continue attending the scheduled study visits through Week 48. 
At the ESDD visit any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at this visit: 
• 
Review of AEs (including any recent fractures) and changes in concomitant medications 
• 
Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator) 
• 
Vital signs measurement, including weight 
• 
12-lead ECG 
• 
Urine collection for the following laborat01y analyses: 
-
Urinalysis and urine chemistry 
_ 
PD 
• 
Blood sample collection for the following laborat01y analyses: 
-
Chemis1ly profile 
-
Hematology profile 
-
CD4+ 
-Plasma HIV-1 RNA 
-
eGFRcG 
-
Plasma storage sample for safety and/or virology testing 
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
Questionnaire: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire.
VAS
HIVTSQc

HIV-1 geno/phenotype resistance testing for subjects with unconfirmed virologic rebound 
with HIV-1 RNA value ≥ 50 copies/mL

Drug accountability
6.5.2.
30 Day Follow-Up Visit
Subjects who complete the study through Week 48 will be required to return to the clinic 30 days
after the completion of study for the 30 Day Follow-Up visit.
Subjects who permanently discontinue study drug or their current regimen and refuse to continue 
study visits through Week 48 will be asked to return to the clinic after the completion of the 
ESDD visit for a 30 Day Follow-Up visit.
Those subjects who permanently discontinue study drug or their current regimen and 
continue in the study through at least one subsequent visit after the ESDD visit will not be 
required to complete the 30 Day Follow-Up visit.
A ± 6 day window may be used to schedule this visit. The following evaluations are to be 
completed at this visit:

Review of AEs (including any recent fractures) and changes in concomitant medications

Symptom-directed physical examination 

Vital signs measurement, including weight

Urine collection for the following laboratory analyses:
Urinalysis

Blood sample collection for the following laboratory analyses:
Chemistry profile 
Hematology profile
CD4+
Plasma HIV-1 RNA
At the 30 Day Follow-Up visit any evaluations showing abnormal results indicating that there is 
a possible or probable causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.

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6.6. 
Assessments for Premature Discontinuation from Study 
Final 
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If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study (see Section 6.7, Criteria for Discontinuation of 
Study Treatment) and continue to perf01m the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn 
from the study. 
6.7. 
Criteria for Discontinuation of Study Treatment 
Study dmg may be discontinued in the following instances: 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercunent illness, the subject 
may resume study dosing at the discretion of the investigator. 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compr01nises the 
ability to continue study-specific procedures or is considered to not be in the subject's best 
interest. 
• 
Lack of efficacy (virologic failure) 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 5 
• 
Discontinuation of the study at the request of Gilead, a regulat01y agency or an 
institutional review board or independent ethics committee (IRBIIEC) 
6.8. 
Other Evaluations 
6.8.1. 
Blood and Urine Storage 
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6.8.2.
Bone Mineral Density Evaluations
DXA scans will cover the spine and hip to measure changes in BMD. A complete description of 
the procedures performed for DXA scans will be provided in the DXA Site Study Binder.
Scans will occur at Screening, Week 24, and Week 48.
6.8.3.
Bone Safety and Inflammation
For all subjects blood will be collected for bone safety, including serum 25-OH Vitamin D, 
parathyroid hormone (PTH). Evaluations for inflammation may include: cystatin-C, IL 6, 
hs CRP, sCD14, sCD163, sTNF-R1, and Lp-PLA2. Collections will be made at Day 1, 
Weeks 4, 12, 24, and 48.
6.8.4.
Markers of Platelet Function and Coagulation
For all subjects, blood will be collected for selected evaluations of platelet function may include:
soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand, and d-dimer at Day 1, 
Weeks 4, 12, 24, and 48.
6.8.5.
Markers of Renal Tubular Function
For all subjects, urine will be collected for selected evaluations of renal tubular function may
include retinol binding protein and beta-2 microglobulin at Day 1, Weeks 4, 12, 24, and 48
6.9.
End of Study
End of study is defined as completion of the 48 weeks of treatment and the 30 Day Follow-Up visit. 
6.10.
Post Study Care
After a subject has completed/terminated their participation in the study, long-term care for the 
subject will remain the responsibility of their primary treating physician.
6.11.
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 two consecutive confirmed 
HIV-1 RNA test results of ≥50 copies/mL at a scheduled or unscheduled visit.

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6.11.1.
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 to 4 weeks after the date of the original test with HIV-1 RNA ≥50 copies/mL.
Upon confirmation of two consecutive results 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)
Investigators should discuss the management of all subjects with confirmed virologic failure with 
the Medical Monitor.
If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value is 
≥50 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 or current regimen is documented, study drug or 
current regimen should be discontinued. 
If no resistance is detected from genotype/phenotype testing, subject may remain on study drug
or current regimen and a repeat HIV-1 RNA should be repeated (2-4 weeks from the date of 
confirmed test with viral load ≥ 50 copies/mL). Investigators should carefully evaluate the 
benefits and risks of remaining on study drug or current regimen for each individual subject and 
document this assessment in the onsite medical record.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for 
virologic failure.
6.11.2.
Resistance Analysis at Subjects Last Visit
Subjects with HIV-1 RNA < 50 copies/mL could experience unconfirmed blips of HIV-1 RNA 
≥50 copies/mL at their last study visit. Such subjects will be analyzed for resistance if the 
unconfirmed rebound happens at Week 48 or at the last visit while taking study drug or current 
regimen (or within 72 hours of discontinuation of study drug or current regimen).

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Figure 6-1. 
Management of Virologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
Day ! 
' 
I 
At any visit, a rebound in HIV-1 RNA to~ 50 copies/mL 
I 
Unconfu·med 
~ 
virologic rebound: 
Return for scheduled/unscheduled mV-1 
remain on study 
RNA and potential genotype/phenotype 
drug or cwTent 
(2-4 weeks later) 
ngimen• 
~ 
I 
Confirmed virologic 
reboundb 
I 
Remain on study 
I HIV-1 genotype/phenotype• I 
... 
... 
If no reve1·se transcriptase, 
If reverse transcriptase, protease, 
protease, or integrase resistance 
or integrase resistance detected, 
detected, continue on study drug 
discontinue study drug m· current 
or current regimen. Repeat HIV-1 
regimen and construct a new 
RNAd 
ARVngimen• 
a 
If virologic rebotmd is not confumed, the subject will remain on the study drug or their cw1·ent regimen. 
b 
If virologic rebotmd is confumed, and the HIV -1 RNA is :::: 50 copies/mL, the HIV -1 genotype and phenotype 
(reverse transcriptase, protease, and, if applicable, integrase resistance) will be analyzed. 
c 
Based on the results of the genotype/phenotype assays, the subject will remain or discontinue study drug or current regimen. 
If genotyping/phenotyping assay fails, a new ARV regin1enmay be configured at the discretion of the Investigator. 
d 
If no resistanc.e detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews study drug/current regin1en 
c.ontinuation/disc.ontinuation options and discusses with Medical Monitor prior to discontinuation. 
e 
A new ARV regimen will be c.onfigtu·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 7.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be 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 (eg, 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 (eg, 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 and if the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, 
please refer to Appendix 3.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy 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 (eg, 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 (eg, 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, (eg, 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 4). 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 eCRF: 

All SAEs and adverse events related to protocol-mandated procedures
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.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, 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 within 30-days of the last dose of study drug, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of 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 guidelines. 
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 for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH:
Fax:
E-mail: 
1-650-522-5477
Safety_FC@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate 
safety reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.

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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU 
Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study 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 study drug 
given per administration or cumulatively which is above the maximum recommended dose as 
per protocol or in the product labelling (as it applies to the daily dose of the subject in question). 
In cases of a discrepancy in drug accountability, overdose will be established only when it is 
clear that the subject has taken the excess dose(s). Overdose cannot be established when the 
subject cannot account for the discrepancy except in cases in which the investigator has reason to 
suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the study drug.

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7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study 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 Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead 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 DSPH:
Fax:
E-mail: 
1-650-522-5477
Safety_FC@gilead.com
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 

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Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3, as outlined below:

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
(Appendix 4).

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat
testing within 3 calendar days of receipt of results and before study drug discontinuation, 
unless such a delay is not consistent with good medical practice.

Any questions regarding toxicity management should be directed to the 
Gilead Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue study drug at the discretion of the Investigator.
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤Grade 2. When restarting study drug following resolution of the 
adverse event, the study drug should be restarted at full dose upon discussion with the 
Medical Monitor.

If a laboratory abnormality recurs to ≥Grade 3 following rechallenge 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 but requires 
discussion with the Medical Monitor.

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7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to study drug, study drug should be 
permanently discontinued and the subject managed according to local practice. The subject 
should be followed as clinically indicated until the laboratory abnormality returns to baseline 
or is otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
algorithm for the new toxicity grade.

Study drug may be continued without dose interruption for a clinically non-significant 
Grade 4 laboratory abnormality (eg, Grade 4 CK after strenuous exercise, or triglyceride 
elevation that is nonfasting or that can be medically managed) or a clinical event considered 
unrelated to study drug requires discussion with the Medical Monitor.
7.6.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in
bone mineral density for HIV-1 infected patients, Gilead recommends that any subject who has a 
DXA scan that demonstrates a decrease from baseline of > 5% in the spine region or > 7% in the 
hip region be followed per local medical practice at the discretion of the Investigator.
7.6.5.
Management of Potential Nephrotoxicity
Estimated glomerular filtration rate, according to the Cockcroft-Gault (eGFRCG) formula for
creatinine clearance, will be followed post-baseline during the study. All subjects with estimated 
eGFRCG < 30 mL/min must have serum creatinine measured again within 3 calendar days of 
receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be 
measured and the eGFRCG by CKD-EPI (cystatin C) will be calculated and compared with the 
baseline measurement. Any subjects who have an estimated eGFRCG < 30 mL/min that also 
experience > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline or who have other 
clinical and/or laboratory evidence of acute renal failure will be discussed with the 
Medical Monitor and may discontinue from study drugs. For subjects with eGFRCG < 30 mL/min 
who are not discontinued based on toxicity management procedures above and considered to 
have stable renal function per Principal Investigator and Medical Monitor, it is not mandatory to 
repeat eGFR assessments within 3 days.
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499 × max(Scys/0.8, 1)1.328 × 0.996Age
[× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of Scys/κ or 1, 
and max (Scys/0.8,1) indicates the maximum of Scys/κ or 1. All subjects with a change from 
baseline serum creatinine of ≥0.4 mg/dL must have serum creatinine repeated, with a concurrent 
urinalysis and urine chemistry, within two weeks of receipt of results. If a subject has a 
confirmed change from baseline serum creatinine of ≥0.4 mg/dL, the Medical Monitor should 
be notified and a consultation with a nephrologist should be obtained.

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7.6.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × Day 1 
value and >10 × ULN, with or without associated symptoms
7.6.6.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT > 2 × Day 1 value and > 10 × ULN, the following 
is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after
initial laboratory results were drawn). During the visit, a clinical assessment of the subject 
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status.

If the ALT elevation is confirmed, request the central clinical laboratory to conduct reflex 
testing for plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM, and 
HCV serology.
Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and serum 
albumin. Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable Relative to Day 1 Liver Function Tests
If ALT levels are elevated (i.e., > 2 × Day 1 and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to Day 1, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or Day 1 level. During monitoring, 
if the ALT values remain persistently elevated, the Investigator should discuss with the 
Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on an HIV regimen containing commercially available HBV therapy if 
study drug is discontinued.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × Day 1 and > 10 × ULN), and total bilirubin is confirmed to 
be 2 × Day 1 value, and INR is 0.5 above Day 1, provided both are > ULN, the investigator 
should consider discontinuing study medication (upon discussion with the Gilead Medical Monitor, 
unless the safety of the patient is of immediate concern). The subject should be monitored 
weekly as long as ALT, total bilirubin, and INR values remain elevated or above Day 1 values.

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During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the Investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on an HIV regimen containing commercially available HBV therapy if 
study drug is discontinued.
7.6.6.2.
Management of Exacerbation of Hepatitis in Subjects Who Have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation > 2 × Day 1 and > 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function
(total bilirubin 2 × Day 1, INR 0.5 above Day 1, provided both are > ULN) and the subject is on 
no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject.

Check the following laboratory parameters: serum ALT and AST, bilirubin, INR, and
albumin.

If the ALT elevation is confirmed, request the clinical laboratory to conduct reflex testing for 
plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM and HCV.
If serum HBV DNA is increasing, the investigator should consider immediate initiation of 
approved therapy.

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or Day 1 up to a maximum of 6 months after the initial occurrence of the event.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the safety of E/C/F/TAF FDC relative to unchanged current anti-retroviral 
therapy (ART) by assessing spine and hip bone mineral density (BMD) measured at Week 48 
in virologically-suppressed, HIV-1 infected subjects aged ≥ 60 years
The secondary objectives of this study are as follows: 

To evaluate spine and hip BMD at Week 24

To evaluate maintenance of HIV-1 RNA suppression between regimens at Weeks 24 and 48

To evaluate the safety and tolerability of the two treatment groups through Week 48
8.1.2.
Primary Endpoint
The primary endpoints are:

Percent change from Baseline to Week 48 in spine and hip BMD
8.1.3.
Secondary Endpoint
Secondary endpoints are:

Percent change from baseline to Week 24 in spine and hip BMD

Proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as defined by 
the Food and Drug Administration (FDA) snapshot algorithm

Change from baseline in CD4+ cell count at Weeks 24 and 48

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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
Full Analysis Set (FAS)
The Full Analysis Set will include all the subjects who were randomized and received at least 
one dose of study drug. The FAS will exclude subjects with major protocol violations
[eg, not on the correct standard baseline regimen (SBR) regimen]. Subjects will be grouped 
according to the treatment to which they were randomized. The FAS analysis set is the primary 
analysis set for the HIV RNA based analyses.
8.2.1.2.
Safety
8.2.1.2.1.
Safety Analysis Set
The primary analysis set for safety analyses is defined as all subjects that are randomized in to 
the study and received at least one dose of study drug. Subjects will be grouped according to the 
treatment they actually received.
8.2.1.2.2.
Spine DXA Analysis Set
The primary analysis set for primary endpoint of spine BMD is defined as all subjects who are 
randomized and received at least one dose of study drug, and had non-missing spine BMD value 
at baseline visit and at least one post baseline visit. Subjects will be grouped according to the 
treatment they actually received.
8.2.1.2.3.
Hip DXA Analysis Set
Hip DXA Analysis Set for primary endpoint of hip BMD, is defined as all subjects who are 
randomized and received at least one dose of study drug, and had non-missing hip BMD value at 
baseline visit and at least one post baseline visit. Subjects will be grouped according to the 
treatment they actually received.
8.3.
Data Handling Conventions
In general, baseline value is defined as the last value measured on or prior to Day 1 of the 
randomized phase of the study.
If the primary endpoints of spine and hip BMD measurements at Week 48 are missing, then it
will be imputed with Week 24 measurement or the last post-baseline measurement available, 
ie, last observed carried forward (LOCF).

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8.4.
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, risk factors for 
HIV-1 infection and enrollment distribution. 
For categorical demographic and baseline characteristics, a Cochran-Mantel-Haenszel CMH test 
will be used to compare treatment groups. For continuous demographic and baseline 
characteristics, a Wilcoxon rank sum test will be used to compare treatment groups.
8.5.
Primary Analysis
8.5.1.
Spine BMD
The primary endpoints are percentage change from baseline in spine and hip BMD at Week 48. 
If the primary endpoint of spine BMD is statistically significant (α = 0.03), then the hip BMD 
will be tested using the fallback procedure, see details in Section 8.6.
For the hip BMD analysis, the analysis methods will be similar to those used for spine BMD
analysis outlined below.
The hypotheses of interest for the spine BMD will be:
H0: d = 0
Ha: d ≠0
where d is the mean percentage change from baseline in spine BMD at Week 48 for E/C/F/TAF 
group (Treatment Group 1) minus that for SBR group (Treatment Group 2).
The primary analysis of the percentage change from baseline in spine BMD at Week 48 will be 
conducted using an ANOVA model, including treatment group and baseline spine BMD T-score 
(< -1.00 vs ≥ -1.00) as a fixed effect in the model. 
8.5.2.
Secondary Analyses
Similar methods will be used at Week 24 for the BMD percentage changes in spine or hip as the 
primary analysis.
The secondary efficacy endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Week 24 and Week 48 as defined by the FDA snapshot algorithm using the full analysis set (FAS).
The two-sided exact 95% confidence interval for the difference in treatment group response rates
(E/C/F/TAF minus SBR) will be constructed using inverted two one-sided tests with the 
standardized statistic.

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Statistical Testing Procedure 
Final 
Original 
To control for Type I enor in the assessment of 2 primary efficacy endpoints, the hypothesis 
testing will be performed using the fallback procedure {22032}. 
SpineBMD: 
Is E/C/F/TAF vs SBR rum statistically different in percentage 
change from baseline in spine BMD at Week 48? (a= 0.03) 
HipBMD: 
HipBMD: 
Is E/C/F/TAF vs SBR aim 
statistically different in percentage 
change from baseline in hip BMD at 
Week 48? (a= 0.05) 
Is E/C/F/TAF vs SBR aim 
statistically different in percentage 
change from baseline in hip BMD at 
Week48?(a=0.02) 
8.7. 
Safety Analysis 
All safety analyses will be perfonned using the safety analysis set. 
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose of study dmg plus 30 days will be summarized by treatment group (according to the 
study dmg received). Data for the pretreatment period and the period post last dose plus 30 days 
will be included in data listings. 
8.7.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study drug 
administration data. Exposure data will be summarized by treatment group. 
Duration of exposure to study dmg will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of tempormy intem.tptions in study dmg 
administration, and sUIDinm·ized by treatment. Dosing infonnation for individual subjects will be 
listed. 
8. 7 .2. 
Adverse Events 
Clinical and laboratory adverse events will be coded using the Medical Dictionmy for 
Regulatmy Activities (MedDRA). System Organ Class (SOC), High-Level Group Tenn 
(HLGT), High-Level Tenn (HLT), Prefened Teim (PT), and Lower-Level Teim (LLT) will be 
attached to the clinical database. 
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Treatment-emergent adverse events are adverse events that meet one of the following criteria: 

Adverse events with onset dates on or after the first dose date of study drug and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and PT) will be provided by treatment group. Additional summaries will include 
summaries for adverse events by grade, Investigator’s assessment of relationship to study drug, 
and effect on study drug dosing.
8.7.3.
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 4).
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 by treatment group. If baseline data are missing, then any 
graded abnormality (ie, at least a Grade 1) will be considered treatment emergent. The maximum 
toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.
8.7.4.
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.
8.8.
Sample Size
In Study GS-US-292-0109 (virologically-suppressed subjects switched from E/C/F/TDF to 
E/C/F/TAF) for subjects 55 or older, the mean percent change from baseline at Week 48 in 
hip BMD was +1.21 in the TAF group and -0.35 in the TDF group. The SD was 2.93 for the 
difference between the 2 groups resulting in an effect size of 0.53. The mean percent change 
from baseline at Week 48 in spine BMD was +1.71 in the TAF group and -1.32 in the TDF 
group. The SD was 4.24 for the difference between the 2 groups resulting in an effect size of 
0.71. Given 150 subjects in the present study, there is at least 90% power to detect an effect size 
of 0.71 in spine BMD at Week 48 with a Type I error rate of α = 0.03 and a power of 
75% for hip BMD at Week 48 with α = 0.02 (in the situation that spine BMD is not 
statistically significantly different) or 85% with α = 0.05 in the situation that spine BMD is 
statistically significantly different) for an effect size of 0.53.

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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, Washington, 
Seoul, 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 subinvestigators 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 subinvestigator’s) participation in the study. The Investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
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 IEC. The Investigator will not begin any study subject activities until 
approval from the 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 IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial 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 IEC-approved consent form for documenting written 
informed consent. Each informed consent 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 IEC or local requirements.

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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, 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 or in accordance with 
local regulations. 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’s Brochure, this protocol, eCRF, 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, 
IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae, 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, ie, history, physical examination, and 
confirmation of diagnosis support inclusion and exclusion criteria

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number)

Study discussed and date of informed consent

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
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 (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. 
The Investigator must notify Gilead before destroying any clinical study records.
Should the Investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the Investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the Investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Electronic Case Report Forms (eCRFs)
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. The eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central monitoring 
of safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock, the Investigator will use her/his 
login credentials to confirm that the forms have been reviewed, and that the entries accurately 
reflect the information in the source documents. The eCRF capture the data required per the 
protocol schedule of events and procedures. System-generated or manual queries will be issued 

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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 (eg, data entry error). At the conclusion of the trial, Gilead will provide the 
site with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Study Drug Accountability and Return
The study monitor will provide instructions for return. 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 SOP for 
drug destruction as determined by Gilead Quality Assurance, 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 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 supplies and associated records at periodic intervals.
9.1.8.
Inspections
The Investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The Investigator must submit all protocol modifications to the IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.

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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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, eg, 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.
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.

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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) and IECs. In terminating the study, Gilead and the 
Investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.

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10.
REFERENCES
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
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Centers for Disease Control and Prevention. 1994 Revised Classification System 
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effectiveness of potent antiretroviral therapy in preventing AIDS and death: a 
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15971
Campsmith ML, Rhodes PH, Hall HI, Green TA. Undiagnosed HIV prevalence 
among adults and adolescents in the United States at the end of 2006. J Acquir 
Immune Defic Syndr 2010;53 (5):619-24.
19661
World Health Organization, UNAIDS, UNICEF. Global HIV/AIDS Response: 
Epidemic update and health sector progress towards universal access. Progress 
Report 2011.  
21769
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department 
of Health and Human Services. 1–239. Available at  
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 
2012 August 22.  
22032
Centers for Disease Control and Prevention (CDC). HIV/AIDS among Persons 
Aged 50 and Older.  2008:

E/C/F/TAF
Protocol GS-US-292-1826
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Gilead Sciences, Inc.
Original
CONFIDENTIAL
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24156
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. 
Changing patterns of mortality across Europe in patients infected with HIV-1. 
EuroSIDA Study Group. Lancet 1998;352 (9142):1725-30.
27881
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. 
Declining Morbidity and Mortality Among Patients With Advanced Human 
Immunodeficiency Virus Infection. N Eng J Med 1998;338 (13):853-60.
34827
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir 
alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, 
cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two 
randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015.
34898
Department for Health and Human Services (DHHS). Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Developed by 
the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A 
Working Group of the Office of AIDS Research Advisory Council (OARAC). 
Downloaded from http://aidsinfo.nih.gov/guidelines on 5/11/2015. Last Updated 
08 April, 2015.
35184
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity 
and Mortality Weekly Report (MMWR). Revised Surveillance Case Definition 
for HIV Infection - United States 2014. Centers for Disease Control and 
Prevention,  2014.
35257
The Joint United Nations Programme on HIV/AIDS (UNAIDS). Regional Fact 
Sheet 2012. North America, Western and Central Europe.  2012.

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

EIC/FrTAF 
Protocol GS-US-292- I 826 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 1. 
lnvestigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDYACKNOWLEDGEMffiNT 
A Phase 3b, Randomjzed, Open-Label Study to Evaluate Switching from a 
Tenofovir Disoproxil Fumarate (TDF) Containing Regimen to Elvitegravir/Cobicistat/ 
Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in 
Virologically-Suppressed, HIV-1 Infected Subjects Aged ?: 60 Years 
GS-US-292-1826, Original, 22 July 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
Richard Haubrich, MD 
Medical Monitor 
Signature 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct thls study as described. I will conduct tills study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. 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 
CONFlDENTIAL 
Page 7 J 
22 July 2015 

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Appendix 2.
Study Procedures Table
Study Procedure
Screeninga
Day 1b
End of Weekc
30 Day
Follow-up
Early Study Drug 
Discontinuationd
(ESDD)
4
8
12
24
36
48
Informed Consent
X
Medical History
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Complete Physical Exame
X
X
X
X
X
Symptom-Directed Physical Examf
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
Urinalysis and Urine Chemistry
X
X
X
X
X
X
X
X
Xr
X
Urine Storage Sample
X
X
X
X
X
X
X
X
Chemistry Profileg
X
X
X
X
X
X
X
X
X
X
Hematology Profileh
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count 
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAi
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologiesj
X
Cystatin-C
X
Estimated GFRCG
k
X
X
X
X
X
X
X
X
X
Whole Blood Samplel
X

E/C/F/TAF 
Protocol GS-US-292-1826 
Gilead Sciences, Inc. 
Study Procedure 
Testosterone Level 
Metabolic Assessmentsm 
Evaluations of Bone & Renal Safety, Inflammation, 
and Platelet & Coagulation Functionn 
Plasma Storage Sample
0 
~PPD 
DXA ScanP 
Questionnaires: VAS,HIVTSQs, HIVTSQc, 
EQ-5D, SF-36, andFACIT-Fq 
Randomization 
Study Drug Dispensation and Accountability 
Screeninga 
X 
a 
Evaluations to be completed within 42 days prior to Day 1 visit. 
Day lb 
4 
8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End ofWeekc 
12 
24 
36 
48 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
30Day 
Follow-up 
Final 
Original 
Early Study Drug 
Discontinuation d 
(ESDD) 
X 
X 
X' 
b 
Subjects will be dispensed study drug at the Day 1 visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit. E/C/F!r AF will be 
provided to subjects randomized to Treatment Group 1. 
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 
for Weeks 24 & 36. The Week 48 visit window is± 6 weeks of the visit date. Unless notified by Gilead, the Week 48 visit should be completed within± 6 days of the visit date. 
d 
Early Study Drug Discontinuation visit to occur within 72 hours oflast dose of study drug. Subjects will be asked to continue attending the scheduled study visits through the 
Week 48 visit even as the subject discontinues study drug. 
e 
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator). 
f 
Symptom-directed physical examination as needed at Weeks 4, 8, 12, and 36 
g 
Chemistry profile: alkaline phosphatase, AST, AL T, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, and sodium. At Day 1, Weeks 24 and 48 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry profile. 
h 
CBC with differential and platelet count 
If the HIV-1 RNA value is 2' 50 copies/mL a retest should be collected, at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening 
and Day 1 results). HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic failure with HIV-1 RNA value 2' 50 copies/mL. 
Subjects should be managed according to Figure 6-1. 
Hepatitis B virus surface Antigen (HBsAg), Hepatitis B core antibody (HBcAb), and Hepatitis C virus (HBCAb) serologies (reflex HCV RNA is performed in subjects with 
positive HCVAb serology) 
CONFIDENTIAL 
Page 73 
22 July 2015 
I 

E/C/F/TAF 
Protocol GS-US-292-1826 
Gilead Sciences, Inc. 
Final 
Original 
k 
1 
m 
n 
0 
p 
q 
r 
s 
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance 
Whole blood sample for virology analysis if historical genotype report not available. 
Metabolic Assessments: 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. 
Blood for bone safety, parathyroid (PTH) and serum OH-25 vitamin D; Inflammation may include cystatin-C, IL-6, hs-CRP, sCD 14, sCD163, sTNF-1 R, and Lp-PLA2; 
Platelet and coagulation fimction may include soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand, and d-dimer will be collected. Urine for renal safety, 
including retinol binding protein, and beta-2-rnicroglobulin, will be collected. Samples for bone and renal safety will be collected fasted. If the subject has not fasted prior to 
the visit, the visit may proceed, but the subject must return within 72 hours in a fast._ed"""st.::.Cat;.;;e_. -----------------------------. 
Plasma storage sample for safety and/or virology (Day 1, Weeks 4-48, and ESDD). PPD 
~~ 
performed on alleii.g~OJ.e subjects pnor to study randomization. Scr._e-eru_·_ng_ B_M_D_ r-es_ul_t_s_Vl_. a- T- -s-co_r_e_m_u_s_t _be_ a-vm-.-la-b-le_t_o_r_an_d_o_rrn 
__ z_e -su-b-~-ec_t_a_t_D_a_y-1-
. -----' 
At Weeks 24 and 48, DXA maybe performed ~ 10 days before study visit. 
VAS will be administered at Day 1, Week 4-48, and ESDD. EQ-5D, SF-36, and FACIT-F will be administered at Day 1, Weeks 24 and 48. HIVTSQs will be administered on 
Day 1. HIVTSQc will be administered at Weeks 4, 24, 48 and ESDD. 
Urinalysis only 
Drug accountability only; study drug will not be dispensed at this visit. 
CONFIDENTIAL 
Page 74 
22 July 2015 

E/C/F/TAF 
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Final 
Gilead Sciences, Inc. 
Original 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
Grade2 
Grade 3 
Grad£' 4 
May continue dosing at 
If conru·med and 
the disc.retion of the 
Repeat lab to confirm 
Rl'peat lab to confirm 
---+ 
possibly or probably 
Invl'stigator 
toxicity grade 
toxicity grade 
rl'lated to study drug, 
discontinue study 
drug dosing 
permanently and 
follow at periodic 
If confirmed and possibly and/or probably relatl'd to study drug: 
If confirmed and unrelated to study 
intl'rvals at least 
Wl'l'kly until a return 
1. Withhold study drug until ~ Grade 2 
drug, dosing may continue at the 
to baseline or is 
2. Restart study dmg at full dos£' 
discretion of thl' investigator 
otherwis£' explained 
~ 
If Gnde 3 or 4 recurrenC£' that is confirmed and possibly or 
If Gnde 3 or 4 recurrenc£' that is considered um·elated to study 
probably related to study drug, discontinu£' all study drug 
drug, c.ontinue all study drug at thl' sam£' dose at thl' discretion 
dosing permanently 
of the Investigator 
CONFIDENTIAL 
Page 75 
22 July 2015 

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Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral 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

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Gilead Sciences, Inc.
Original
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L

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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin 
if appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                       
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                    
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric 7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L

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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric > 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L

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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects > 70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA

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

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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 
(e.g., 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 
(e.g., malignant hypertension)
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure

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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 
(e.g., 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, e.g., 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, e.g., 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 
(e.g., pulmonary embolism, 
life-threatening thrombus) 
Vasovagal Episode 
(associated with a procedure of 
any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF

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

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

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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight 
loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated [e.g., tube feeding 
or total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., 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
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(.e.g, 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 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock

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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences 
(e.g., 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 (e.g., 
IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in 
Personality-Behavior or in 
Mood (e.g., 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 
(e.g., 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 
(e.g., status epilepticus), or 
difficult to control 
(e.g., 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 
(e.g., severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(e.g., status epilepticus), or 
difficult to control 
(e.g., 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 [e.g., 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 (e.g., 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 (e.g., 
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 
(e.g., 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 
(e..g, myxedema coma)
Lipoatrophy (e.g., 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 
(e.g., 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 5.
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. 
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
Females of childbearing potential are excluded from participation in the study; therefore no form 
of birth control will be required of any female subject enrolled into the study. During the study, 
male subjects with female partners of childbearing potential should use condoms when engaging 
in intercourse of reproductive potential. 
3) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 90 days or 12 weeks 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 and pregnancy outcome are 
outlined in Section 7.5.2.1.

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Appendix 6.
Definitions of HIV-1 Related Disease (CDC Guidelines) {35184}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†

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