Clinical trial NCT02707601
Conditions: HIV-1 Infection HCV Infection
Keywords: HIV HCV Antiretroviral therapy HCV direct acting antiviral(s) (DAA)
Sponsor: Gilead Sciences
Start date: 2016-04-01; Completion date: 2017-09-29
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate efficacy of ledipasvir/sofosbuvir (LDV/SOF) and safety and tolerability of switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or emtricitabine/rilpivirine/tenofovir alafenamide (F/R/TAF) from the current antiretroviral (ARV) therapy and in virologically-suppressed, HIV-1/HCV co-infected participants.

Detailed description:

Arms: arm 1: Part 1: Participants will switch from 2 nucleoside reverse transcriptase inhibitors (NRTI) plus a third agent to E/C/F/TAF.

Part 2: After 8 weeks of E/C/F/TAF treatment, the participants maintaining HIV-1 RNA \< 50 copies/mL will start receiving LDV/SOF for 12 weeks and continue their HIV treatment until the end of the study. arm 2: Part 1: Participants will switch from 2 NRTI plus a third agent to F/R/TAF.

Part 2: After 8 weeks of F/R/TAF treatment, the participants maintaining HIV-1 RNA \< 50 copies/mL will start receiving LDV/SOF for 12 weeks and continue their HIV treatment until the end of the study.
Interventions: intervention 1: E/C/F/TAF intervention 2: F/R/TAF intervention 3: LDV/SOF
Intervention descriptions: intervention 1: 150/150/200/10 mg fixed dose combination (FDC) tablet administered orally once daily intervention 2: 200/25/25 mg FDC tablet administered orally once daily intervention 3: 90/400 mg FDC tablet administered orally once daily

Protocol documents:
Prot_002.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Clinical Program 
Manager: 
Gilead Co-Medical 
Monitor: 
Gilead Co-Medical 
Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to Elvitegravir/Cobicistat/ 
Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) or 
Emtricitabine!Rilpivirine/T enofovir Alafenamide (F /R/T AF) prior 
to LDV/SOF HCV Treatment, the HIV/HCV Co-STARs study 
(Co-infection treatment with Single Tablet Antiviral Regimens) 
Gilead Sciences, fuc. 
333 Lakeside Drive 
Foster City, CA 94404 
123098 
2014-004545-27 
NCT02707601 
HIV -1 fufection 
GS-US-366-1992 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Mobile: 
Name: 
Telephone: 
Mobile: 
Original: 
Amendment 1: 
Amendment 2: 
PPD 
PPD 
PPD 
Richard Haubrich, MD 
PPD 
PPD 
Thai Ng~~yen-Cleru.y, MD 
PPD 
PPD 
18 December 2015 
27May2016 
29 November 2016 
CONFIDENTIALITY STATEMENT 
The infotmation contained in this docmnent, pru.iiculru.·ly unpublished data, is the propetty or 
under contl'ol of Gilead Sciences, fuc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
fustitutional Review Boru.·d or fudependent Ethics Committee. The infotmation 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 infotmation to others without written authorization 
from Gilead Sciences, fuc., except to the extent necessru.y to obtain infotmed 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........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................19
1.2.1.
General Information .............................................................................................................19
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®).................................................................................19
1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF, Odefsey®) Fixed Dose Combination ..................................................................22
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination..............................................22
1.3.1.
General Information .............................................................................................................22
1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant 
to the Proposed Study...........................................................................................................23
1.4.
Rationale for This Study ........................................................................................................................28
1.5.
Risk/Benefit Assessment for the Study..................................................................................................29
1.6.
Compliance ............................................................................................................................................29
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................31
3.1.
Endpoints ...............................................................................................................................................31
3.2.
Study Design..........................................................................................................................................31
3.3.
Study Treatments ...................................................................................................................................31
3.4.
Duration of Treatment............................................................................................................................32
3.5.
Samples for Optional Exploratory Assessments ....................................................................................33
4.
SUBJECT POPULATION..................................................................................................................................34
4.1.
Number of Subjects and Subject Selection ............................................................................................34
4.2.
Inclusion Criteria....................................................................................................................................34
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................40
5.1.
Randomization .......................................................................................................................................40
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF .....................................................40
5.2.1.
Formulation..........................................................................................................................40
5.2.2.
Packaging and Labeling .......................................................................................................41
5.2.3.
Storage and Handling...........................................................................................................42
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF...................................................42
5.4.
Prior and Concomitant Medications.......................................................................................................42
5.5.
Accountability for Investigational Medicinal Product (IMP).................................................................48
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49


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6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Day 1 Assessments...............................................................................................................51
6.3.
Randomization .......................................................................................................................................53
6.4.
Treatment Assessments..........................................................................................................................53
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20).........................................53
6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) .................................................................................................56
6.5.
Post-treatment Assessments ...................................................................................................................58
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................58
6.5.2.
30-Day Follow-Up Visit.......................................................................................................60
6.6.
Assessments for Premature Discontinuation from Study.......................................................................61
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................61
6.8.
Other Assessments .................................................................................................................................62
6.8.1.
Blood and Urine Storage......................................................................................................62
6.8.2.
Bone Safety and Inflammation.............................................................................................62
6.8.3.
Markers of Platelet Function and Coagulation.....................................................................62
6.8.4.
Markers of Renal Tubular Function .....................................................................................62
6.9.
HIV Virologic Failure............................................................................................................................62
6.9.1.
Management of HIV Virologic Rebound .............................................................................63
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit ........................................65
6.10.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................66
6.11.
End of Study...........................................................................................................................................66
6.12.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69
7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Toxicity Management ............................................................................................................................71
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................72
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................72
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.5.4.
Management of Potential Nephrotoxicity.............................................................................72
7.6.
Stopping Rules for HCV Treatment.......................................................................................................73
7.7.
Special Situations Reports......................................................................................................................74
7.7.1.
Definitions of Special Situations..........................................................................................74
7.7.2.
Instructions for Reporting Special Situations.......................................................................74
8.
STATISTICAL CONSIDERATIONS................................................................................................................76
8.1.
Analysis Objectives and Endpoints........................................................................................................76
8.1.1.
Analysis Objectives..............................................................................................................76
8.1.2.
Primary Endpoint .................................................................................................................76
8.1.3.
Secondary Endpoint .............................................................................................................76
8.1.4.
Other Endpoints of Interest ..................................................................................................77
8.2.
Analysis Conventions.............................................................................................................................77
8.2.1.
Analysis Sets ........................................................................................................................77


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8.3.
Demographic Data and Baseline Characteristics ...................................................................................77
8.4.
Efficacy Analysis ...................................................................................................................................78
8.4.1.
Primary Analysis..................................................................................................................78
8.4.2.
Secondary Analyses .............................................................................................................78
8.5.
Safety Analysis.......................................................................................................................................79
8.5.1.
Extent of Exposure...............................................................................................................79
8.5.2.
Adverse Events.....................................................................................................................79
8.5.3.
Laboratory Evaluations ........................................................................................................80
8.5.4.
Other Safety Evaluations......................................................................................................80
8.6.
Pharmacokinetic Analysis......................................................................................................................80
8.7.
Biomarker Analysis................................................................................................................................80
8.8.
Sample Size............................................................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only)..............96
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............97
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................119
Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions ...................................................122


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LIST OF IN-TEXT TABLES
Table 1-1.
Combined Analysis from Phase III ION Studies....................................................................25
Table 1-2.
Study 1: F/R/TAF and LDV/SOF...........................................................................................26
Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter................................................................27
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen .........................................................34
Table 4-2.
Disallowed Agentsa ................................................................................................................39
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF ............................................43
Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF................................................47
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................32
Figure 6-1.
HIV Virologic Rebound Schema............................................................................................65


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404
Study Title: 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for 
HIV/HCV Co-infected Subjects who Switch to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
(E/C/F/TAF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) prior to LDV/SOF HCV Treatment, the HIV/HCV 
Co-STARs study (Co-infection treatment with Single Tablet 
Antiviral Regimens)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
123098
2014-004545-27
TBD
Study Centers Planned:
Approximately 50 centers in North America
Objectives:
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the 
proportion of subjects achieving HCV RNA below the lower 
limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (sustained virologic response [SVR12]).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA 
below LLOQ 4 weeks after the last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after 
switching to E/C/F/TAF or F/R/TAF 24 weeks from the start of 
the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to 
E/C/F/TAF or F/R/TAF from the current antiretroviral (ARV)
therapy in virologically-suppressed, HIV-1/HCV co-infected 
subjects; 

To evaluate the safety and tolerability of 12 weeks of treatment 
for HCV with LDV/SOF in virologically-suppressed, 
HIV-1/HCV co-infected subjects who switched to E/C/F/TAF 
or F/R/TAF.


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Study Design:
Randomized, multicenter, open-label, 2-part study in adult male and 
female subjects with HIV who are co-infected with chronic
genotype (GT) 1 HCV infection. Subjects will have one of the 
following: 
1) no cirrhosis and no prior HCV treatment (treatment-naïve); 
2) no cirrhosis and have received HCV treatment only with 
interferon (IFN) +/- ribavirin (RBV) or IFN + RBV + an HCV 
protease inhibitor (PI) (treatment-experienced); or 
3) compensated cirrhosis and no prior HCV therapy
(treatment-naïve).
Subjects will be on stable ARV therapy for 6 months prior to 
screening and with HIV RNA < 50 copies/mL.
Part 1: Approximately 120 subjects will be randomized 1:1 to 
switch from stable ARV therapy to one of the following treatments. 
Randomization will be stratified by race (black vs. non-black).

Treatment Group 1: Switch from 2 nucleoside/nucleotide 
reverse transcriptase inhibitor (NRTI) plus a third ARV agent to 
E/C/F/TAF fixed dose combination (FDC) (n = 60) 

Treatment Group 2: Switch from 2 NRTI plus a third ARV
agent to F/R/TAF FDC (n = 60) 
All subjects will receive 8 weeks of treatment and will have an 
assessment of safety, tolerability and HIV-1 RNA values at the 
conclusion of 8 weeks. Plasma samples collected at Week 6 
(laboratory visit only) will be included in assessing virologic 
suppression of HIV-1 RNA at Week 8. Subjects who tolerate the 
switch to E/C/F/TAF FDC or F/R/TAF FDC and maintain virologic 
suppression of HIV-1 RNA < 50 copies/mL will continue to Part 2.
HIV treatment will be continued until their SVR12 assessment.
Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or 
F/R/TAF FDC treatment, subjects will continue their HIV treatment
and initiate 12 weeks of LDV/SOF HCV therapy.

LDV/SOF FDC tablet once daily for 12 weeks
After LDV/SOF therapy, subjects will continue their HIV treatment
and be followed for safety and efficacy for an additional 12 weeks 
to determine the HCV SVR12 endpoint and HIV safety and 
efficacy endpoints.
Number of Subjects 
Planned:
Approximately 120 subjects (approximately 60 subjects 
randomized to each of E/C/F/TAF FDC or F/R/TAF FDC).


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Target Population:
Chronic GT 1 HCV, HIV-coinfected adults who do not have 
cirrhosis and are HCV treatment-naïve or treatment-experienced 
with IFN +/- RBV +/− PI. Compensated cirrhotic subjects must be 
treatment-naïve. Subjects are on a stable HIV regimen with 
2 NRTI + 3rd agent with suppressed HIV RNA.
Duration of Treatment:
Part 1: Subjects will be randomized to receive E/C/F/TAF or 
F/R/TAF for 8 weeks.
Part 2: Subjects will receive 12 weeks of LDV/SOF and continue 
their randomized F/TAF-based regimen for 12 weeks after 
completion of LDV/SOF (total approximately 24 weeks in Part 2).
Diagnosis and Main 
Eligibility Criteria:
HIV/HCV co-infected adult subjects who meet the following 
criteria will be given the option to participate in the study:

Chronic GT 1, HCV infected, male and 
non-pregnant/non-lactating female subjects, without cirrhosis, 
treatment-naïve or treatment-experienced with 
IFN +/- RBV +/- HCV PI. Compensated cirrhotic subjects must 
be HCV treatment-naïve. No prior treatments with NS5A and 
NS5B or any HCV direct acting antivirals, except boceprevir, 
telaprevir and simeprevir, in combination with IFN and RBV.

Currently on an ARV regimen (2 NRTI + a third agent) without 
change for 6 months prior to screening. Documented plasma 
HIV-1 RNA levels < 50 copies/mL (or undetectable 
HIV-1 RNA level according to the local assay being used if the 
limit of detection is ≥ 50 copies/mL) for ≥6 months preceding 
the Screening visit. After reaching HIV-1 RNA < 50 copies/mL, 
single values (“blips”) of HIV-1 RNA ≥50 copies/mL followed 
by resuppression is allowed. For subjects with 3 or more prior 
ARV regimens, a regimen history should be provided for 
approval by the Sponsor. 

Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.

Have no documented resistance to any of the HIV study agents 
at any time in the past, including but not limited to the reverse 
transcriptase resistance mutations K65R, K70E, K101E/P, 
E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, 
H221Y, F227C, M230I/L, the combination of K103N+L100I, 
or 3 or more thymidine analog associated mutations (TAMs) 
that include M41L or L210W (TAMs are M41L, D67N, K70R, 
L210W, T215Y/F, K219Q/E/N/R). If a historical genotype prior 
to first ARV is not available or subject had 3 or more prior 
ARV regimens, subject will have proviral genotype analysis for 
archived resistance prior to Day 1.


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
No history of HIV virologic failure.

No evidence of Hepatitis B infection. 

Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min as 
estimated by Cockcroft-Gault formula.
Study Procedures/
Frequency:
Screening assessments will be completed within 42 days of the 
Day 1 visit.
After consent is obtained, screening assessments will include 
physical examination, medical history, historical HIV resistance test 
collection (if available; HIV DNA archive genotype if no historical 
HIV genotype available), height, weight, vital signs, 12-lead 
electrocardiogram (ECG), screening procedure related adverse 
events (AEs), concomitant medications (CM), safety laboratory 
tests (including hematology, chemistry, and coagulation), HCV and 
HIV RNA, serology (HIV, HCV, HBV), HCV genotyping, 
assessment of the absence of cirrhosis, serum β-hCG (females of 
child bearing potential only), IL28B genotyping, and urinalysis.
On treatment assessment:

Part 1: F/TAF-based ARV regimen switch: 
Day 1 and Weeks 4, 6 (lab only), and 8 

Part 2: LDV/SOF therapy and follow-up
First dose of LDV/SOF at Week 8, then Weeks 12, 16, and 20
(4, 8, and 12 weeks after HCV start) and post LDV/SOF 
follow up at 4 and 12 weeks posttreatment (SVR 4 and 12).
On treatment assessments will include AEs, CMs, study drug 
dosing adherence (including pill count), physical examination, 
weight, vital signs, safety laboratory tests, HCV and HIV RNA, 
urine pregnancy tests (females of child bearing potential only).
Fasting lipid profile measurements and fasting glucose will be 
performed at Day 1, Weeks 8, 20, and at Post-HCV Treatment 
Week 12. Lipids will include total cholesterol (TC), high density 
and low density lipoproteins (HDL, LDL), non-HDL cholesterol, 
triglycerides (TG) and cholesterol ratios.
Post treatment assessments will include AEs and CMs collected 
through 30 days after the last dose of HIV study drug, HCV and 
HIV RNA, safety laboratory tests (including hematology and 
chemistry), and urine pregnancy tests (females of childbearing 
potential only).


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Test Product, Dose, and 
Mode of Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
CONFIDENTIAL 
Final 
Amendment 2 
Plasma samples for viral HIV RNA will be collected at Day I and 
evety visit thereafter (except HCV RNA at Week 4). Stored 
samples for HCV RNA sequencing/phenotyping and HIV RNA 
genotyping/phenotyping will be collected at Day I and evety visit 
thereafter. Blood will be collected at Screening for analysis ofHIV 
proviral DNA genotype, as needed. 
Calculated creatinine clearance, hematology, senun chemistty, and 
urinalysis tests will be perf01med at all visits. 
Health Related Quality of Life (HRQoL) Surveys will be conducted 
at Day 1, Week 8, 20, and Post-HCV Treatment Week I2 visits. 
PPD 
Phatmacokinetic (PK) blood samples will be collected at specified 
time points pre- and/or postdose at post-Day I visits. 
Elvitegravir I 50 mg/cobicistat I50 mg/emtricitabine 200 mg/ 
tenofovir alafenamide 10 mg (E/C/F IT AF) FDC administered once 
daily with food. 
Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 
25 mg (F/R/TAF) FDC administered once daily with food. 
Ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) FDC 
administered once daily with or without food. 
None. 
Adverse events will be collected at all visits. Clinicallaborat01y 
tests will be perfotmed at all visits. 
The safety and tolerability of the treatment regimens will be 
assessed with adverse event and clinicallaborat01y tests including 
selected evaluations of renal function and PPD 
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Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® Ampliprep / COBAS® TaqMan®
HCV Quantitative Test, v2.0 and COBAS® TaqMan® HIV RNA 
Test, v2.0.
Primary endpoint

HCV RNA < lower limit of quantification (LLOQ) 12 weeks 
after completion of LDV/SOF treatment (SVR12)
Secondary endpoints
Efficacy:

HCV RNA < LLOQ 4 weeks after completion of LDV/SOF 
treatment (SVR4)

HIV-1 RNA ≥50 copies/mL (virologic failure) 24 weeks after 
start of the F/TAF-based regimen using FDA snapshot 
algorithm
Safety:

Grades 1 through 4 adverse events after switching to 
E/C/F/TAF or F/R/TAF throughout the study and during 
coadministration with LDV/SOF treatment.
Pharmacokinetics:
Samples collected for potential population PK assessment.
Health Related 
Questionnaires:
Health related questionnaires will be administered, including the 
Adherence Visual Analogue Scale (VAS), HIV Treatment 
Satisfaction (HIVTSQ), Medical Outcome Study Short Form-36 
(SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue 
scale (FACIT-F), chronic liver disease questionnaire (CLDQ-HCV) 
and work productivity and activity impairment questionnaire 
(WPAI).
Statistical Methods:
This is a two part, randomized (for HIV therapy) multicenter study 
to evaluate the efficacy and safety of switching to a F/TAF-based 
regimen in HCV co-infected subjects on a current suppressive ARV 
regimen.
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 
12 weeks post HCV treatment) in the HCV Full Analysis Set. The 
primary analysis will use a two-sided exact one-sample binomial 
test at the 0.05 significance level and construct an associated 
two-sided exact 95% confidence interval (CI).


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Secondary efficacy analyses will evaluate the proportion of subjects 
with HCV RNA < LLOQ at 4 weeks post coadministration of 
LDV/SOF treatment. Assessment of HIV-1 RNA ≥50 copies/mL 
(virologic failure) will be done at 24 weeks after start of the 
F/TAF-based regimen using FDA snapshot algorithm. Safety 
analyses will evaluate adverse events (clinical and laboratory) 
during switch to F/TAF-based regimen and during coadministration 
with LDV/SOF treatment. Additional safety analyses will evaluate 
the proportion of subjects who discontinued from study treatment 
(HIV or HCV) for an AE.
Additional endpoints to be studied will include the effect of therapy 
on health-related quality of life.
The assumed SVR12 rate will have at least 85% power to be greater 
than 8 percentage points from a performance goal of 88% by using 
a two-sided exact one-sample binomial test at significance level of 
0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C 
degrees Celsius
° F
degrees Fahrenheit
3TC
lamivudine
AASLD/IDSA
American Association for The Study of Liver Diseases/Infectious Diseases Society of 
America
ABC
abacavir
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT (SGPT)
alanine aminotransferase
APTT
activated partial thromboplastin time
ART
antiretroviral therapy
ARV
antiretroviral
AST (SGOT)
aspartate aminotransferase
APRI
AST: platelet ratio index
ATR
Atripla®
ATV
atazanavir
AUC
area under the concentration vs. time curve
AUCinf
area under the concentration verses time curve extrapolated to infinite time, calculated as 
AUC0-last + (Clast/z)
AUClast
area under the concentration curve verses time curve from time zero to the last 
quantifiable concentration
AZT
zidovudine
BMD
bone mineral density
Clast
last observed quantifiable plasma concentration of drug
Cmax
maximum observed plasma concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
Cx
minimum observed quantifiable plasma concentration x hours after the last dose of drug
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatinine kinase
CLcr
creatinine clearance 
CLDQ-HCV
chronic liver disease questionnaire
CM
concomitant medications
CMH
Cochran-Mantel-Haenszel
COBI
cobicistat, C
CRO
Contract Research Organization
CSR
clinical study report
DAA
direct acting antiviral(s)
DDI
drug-drug interaction


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DF
disoproxil fumarate
dL
deciliter
DNA
deoxyribonucleic acid
DP
diphosphate
DRV
darunavir
DSPH
Drug Safety and Public Health
DTG
dolutegravir, Tivicay®
ECG
electrocardiogram
eCRF
electronic case report forms(s)
EDC
electronic data capture
EFV
efavirenz, Sustiva®
eGFR
estimated glomerular filtration rate
eGFRcg
estimated glomerular filtration rate, Cockcroft-Gault
ESA
erythropoiesis-stimulating agents
eSAE
electronic serious adverse event
ESDD
Early Study Drug Discontinuation
ETR
etravirine
EVG
elvitegravir, E
EU
European Union
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya®
FACIT-F
functional assessment of chronic illness therapy-fatigue scale
FAS
full analysis set
FDA
(U.S.) Food and Drug Administration
FDC
fixed dose combination
FPV
fosamprenavir
FTC
emtricitabine, F
F/R/TAF
emtricitabine/rilpivirine/tenofovir alafenamide, Odefsey®
FTC/RPV/TDF 
emtricitabine/rilpivirine/tenofovir disoproxil fumarate, Complera®
FTC/TAF
emtricitabine/tenofovir alafenamide, Descovy®
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate, Truvada®  
g
gram(s)
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GLSM/GMR
geometric least squares mean ratio
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
genotype
h
hour(s)
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCC
Hepatocellular carcinoma


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HCV
hepatitis C virus
HDL
high density lipoprotein
HDPE
high-density polyethylene
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIVTSQc
HIV Treatment Satisfaction Questionnaire – Change version
HIVTSQs
HIV Treatment Satisfaction Questionnaire – Status version
HLGT
high-level group term
HLT
high-level term
HRQoL
Health Related Quality of Life
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IFN
interferon
IEC
Independent Ethics Committee
IMP
investigational medicinal product
INR
International Normalized Ratio
INSTI
integrase strand transfer inhibitor
IRB
Institutional Review Board
IUD
intrauterine device
IWRS
Interactive Web Response System 
kg
kilogram
kPa
kilopascal
KS
Kaposi's sarcoma
LDL
low density lipoprotein
LDV/SOF
ledipasvir/sofosbuvir, Harvoni®
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower–level term
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
min
minute
mL
milliliter
m2
square meter
mm3
cubic millimeter(s)
g
microgram
m
micrometer
ng
nanogram
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
NVP
nevirapine, Viramune®


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PEG-IFN
pegylated interferon 
P-gp
P-glycoprotein
PEP
post-exposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term
PT
prothrombin time
QA
Quality Assurance
QD
once daily
RAL
raltegravir, Isentress®
RBV
ribavirin
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
ritonavir
RPV
rilpivirine, R, Edurant®
SAE
serious adverse event
SADR
serious adverse drug reactions
SF-36
medical outcome study short form-36
sGPVI
soluble glycoprotein VI
SOC
system organ class
SOF
sofosbuvir, Sovaldi®
SOP
standard operation procedure
STB
Stribild®
STR
Single Tablet Regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax 
TAF  
tenofovir alafenamide 
TAF fumarate
tenofovir alafenamide fumarate
TAM
thymidine analog associated mutations
TDF
tenofovir disoproxil fumarate, Viread®
TFV
tenofovir
TPO
thrombopoietin 
TVD
Truvada®
ULN
upper limit of the normal range
US
United States
VAS
visual analogue scale
VR
virologic rebound
wt
Weight
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
HIV Infection
Human Immunodeficiency Virus type 1 (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 {Campsmith et al 2010, 
World Health Organization (WHO) 2011}. 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 
{The Joint United Nations Programme on HIV/AIDS (UNAIDS) 2012}.
If left untreated or suboptimally treated, HIV infection 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 {Mocroft et al 1998, Palella et al 1998, 
Sterne et al 2005}. 
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 {Department for Health and 
Human Services (DHHS) 2015}. 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 {Chesney 2000, Department for Health and Human Services (DHHS) 2015, 
Stone et al 2002}.
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 (BMD) {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. 
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 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 provides enhanced lymphatic delivery of tenofovir, resulting 


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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 {Sax et al 2015}.
HCV and HIV/HCV Co-Infection
Hepatitis C virus (HCV) infection is a global health challenge with an estimated 150 million 
individuals infected worldwide {Gay et al 2011}. Currently there are 6 major HCV genotypes 
recognized {Nakano et al 2012}. Genotypes 1, 2, and 3 are common throughout North America 
and Europe and when combined account for approximately 75% of the chronic HCV infections 
globally. Genotype 4, which is common in the Middle East and Africa, accounts for 
approximately 20% of the global HCV population. Genotypes 5 and 6 are the least prevalent and 
are generally found in South Africa and South East Asia, respectively {Lavanchy 2011}.
In the United States (US), approximately 2.7 million people have chronic HCV infection 
{Denniston et al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, 
although under-reporting of HCV infection on death certificates may contribute to as much as a 
5-fold underestimation of the actual number of deaths {Mahajan et al 2014}. Of the HCV related 
deaths that are reported, almost three quarters occurred in the baby-boomer generation with a 
median age of death of 57 years, which is approximately 20 years less than the average lifespan 
{Smith et al 2012}. Successful treatment of chronic HCV infection reduces the need for liver 
transplant, the incidence of hepatocellular carcinoma (HCC) and overall mortality 
{Backus et al 2011}. Thus, the public health benefit of safe and effective HCV treatment 
regimens is high. 
HIV-infected patients are frequently co-infected with HCV because of the shared routes of 
infection. HIV/HCV co-infection is estimated to occur in one quarter of HIV-infected persons in 
Europe, Australia, and the United States, {Thomas 2008}, and in a study from the Veterans 
Affairs Medical Center in Atlanta, Georgia, HCV infection occurred as many as 33% of the 
patients with HIV infection {Staples et al 1999}. The use of antiretroviral therapy (ART) has 
markedly reduced opportunistic infections and HIV-infected persons are living longer. However, 
liver disease has emerged as the main cause of morbidity and mortality in the HIV positive patient 
{Salmon-Ceron et al 2005}, and the development of end stage liver disease seems to be unrelated 
to the CD4 count and the immune virological status of the patient {Salmon-Ceron et al 2005}. In 
two meta-analyses published 8 years apart, co-infected patients were 5 to 6 times more likely to 
develop decompensated liver failure and 1.5 to 2 times more likely to develop histological 
cirrhosis {Deng et al 2009, Graham et al 2001}. In the latter analysis, the risk of death in the 
co-infected patients was nearly 4 times greater compared with that in mono-infected individuals 
{Myers et al 2008}. As might be expected, hospitalization rates due to liver disease in the 
co-infected patient have increased {Laguno et al 2004}. Furthermore, the previous gold standard 
therapy for the treatment of HCV infection, pegylated interferon alfa (PEG-IFN) plus ribavirin 
(RBV), appears to be less effective in patients with co-infection than in patients with HCV 
mono-infection {Carrat et al 2004, Torriani et al 2004}. 
The development of Sovaldi® (sofosbuvir, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated and result in higher sustained virologic response (SVR) rates than 


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prior therapies. SOF in combination with ribavirin (RBV) pegylated interferon (PEG-IFN) for 
varying durations was approved in the US and Canada in December 2013 for the treatment of 
genotype 1, 2, 3 and 4 HCV infection and was granted marketing authorization by the 
European Commission in January 2014 for the treatment of genotypes 1-6 HCV infection
{Gilead Sciences Canada Inc. 2013, Gilead Sciences Inc 2013, Gilead Sciences Limited 2014}. 
LDV/SOF is the first IFN-free regimen with high SVR rates following 8-24 weeks of treatment 
across treatment-naïve and treatment-experienced patients, including patients who failed to 
achieve SVR with PEG + RBV NS3/4A protease inhibitors, irrespective of cirrhosis 
{Gilead Sciences Inc. 2014}.
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 TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is 
metabolized intracellularly to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 
reverse transcriptase (RT) that terminates the elongation of the viral DNA chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-02 and GS-7340-03 exist as the free base, TAF (GS-7340), in blood and biological 
fluids.
For further information on the preclinical pharmacology and toxicology of TAF, refer to the 
current Investigator’s Brochure (IB).
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®)
Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, 
and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse 
transcriptase inhibitors (NRTIs), are co-formulated into a single-tablet regimen, E/C/F/TAF, or 
Genvoya®. E/C/F/TAF is indicated as a complete regimen for the treatment of HIV-1 infection in 
adults and pediatric patients 12 years of age and older who have no antiretroviral treatment 
history or to replace the current antiretroviral regimen in those who are virologically suppressed 
(HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months 
with no history of treatment failure and no known substitutions associated with resistance to the 
individual components of the regimen. E/C/F/TAF is not recommended in patients with 
estimated creatinine clearance below 30 mL per minute. The efficacy and safety of E/C/F/TAF 
continue to be evaluated in a broad clinical development program. Available data from key 
studies are described in the most current version of the E/C/F/TAF IB. The details of the key 
clinical studies are provided below.


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
Study GS-US-292-0102 is a Phase 2, randomized, double-blind, double-dummy, multicenter, 
active-controlled study which evaluated the safety and efficacy of the novel tenofovir prodrug, 
tenofovir alafenamide (TAF), as part of a single-tablet regimen for the initial treatment of HIV-1 
infection. Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 
count ≥50 cells per microliter were randomized 2:1 to receive an STR of 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 
48 weeks. Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of 
virologic suppression (< 50 HIV copies per milliliter) at Week 24 (86.6%; 89.7%) and at 
Week 48 (88.4%; 87.9%), and had similar improvements in CD4 at Week 48 (177; 204), 
respectively. Both treatments were well tolerated, and most adverse events were self-limiting and 
of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had 
smaller reductions in estimated creatinine clearance (-5.5 vs. -10.1 mL/min, p = 0.041), 
significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip 
(−0.62% vs. −2.39%, p < 0.001) and spine (-1.00% vs. -3.37%, p < 0.001). Patients on 
E/C/F/TAF had higher increases in total cholesterol, low density lipoprotein, and high-density 
lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. 
Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate 
of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced 
significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and 
bone mineral density. The efficacy data from this Phase 2 study supported the Phase 3 studies 
and provided initial evidence of durable efficacy; 87.5% of subjects who received E/C/F/TAF 
achieved and maintained HIV-1 RNA < 50 copies/mL through Week 96 (M = F). 

GS-US-292-0104 and GS-US-292-0111 are two Phase 3, randomized double-blind, 
double-dummy, multicenter, active-controlled studies which evaluated the efficacy and safety of 
two single-tablet regimens, E/C/F/TAF vs E/C/F/TDF. Key inclusion criteria were estimated 
creatinine clearance of at least 50 mL per min and genotypic sensitivity to study drugs. 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. Secondary endpoints were at Weeks 96 and 144. 1733 patients (866 E/C/F/TAF and 
867 E/C/F/TDF) were enrolled (or completed the study). E/C/F/TAF was non-inferior to 
E/C/F/TDF, with 92% of (800/866) patients in the TAF group and 90% of (784/867) 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 < 0.001), significantly less 
proteinuria (median % change –3 vs 20; p < 0.001), and a significantly smaller decrease in bone 
mineral density at spine (mean % change –1.30 vs –2.86; p < 0.001) and hip (–0.66 vs –2.95; 
p < 0.001) at 48 weeks. At 96 weeks, 86.6% in the E/C/F/TAF arm and 85.2% in the E/C/F/TDF 
arm had HIV-1 RNA < 50 c/mL (difference 1.5%; 95%CI [-1.8%, 4.8%]). With E/C/F/TAF, 
decreases in lumbar spine and hip bone mineral density and proteinuria were significantly less 
and creatinine increases were significantly smaller. These longer-term data support the use of 
E/C/F/TAF as a safe, well-tolerated and durable regimen for initial HIV-1 treatment.


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
Study GS-US-292-0109 is a Phase 3, randomized, active-controlled, multicenter, open-label, 
non-inferiority trial evaluating efficacy, safety, and tolerability of switching to E/C/F/TAF 
versus continuing a TDF-containing regimen (ie, Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF). Key inclusion criteria included virological suppression (HIV-1 RNA 
< 50 copies per mL) for at least 6 months on Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF and an estimated creatinine clearance of at least 50 mL per min. The 
primary endpoint was the proportion of patients who received at least one dose of study drug 
who had undetectable viral load (HIV-1 RNA < 50 copies per mL) at Week 48. 959 patients 
were randomly assigned to E/C/F/TAF and 477 continued Atripla, Stribild, or COBI- or 
RTV-boosted ATV with FTC/TDF. Viral suppression at Week 48 was noted in 
97% (932/959) of patients switched to E/C/F/TAF and 93% (444/477) of patients who 
continued a TDF-containing regimen (adjusted difference 4.1%, 95% CI 1.6–6.7), with 
virological failure noted in ten and six patients, respectively. The number of adverse events 
was similar between the two groups, but study drug-related adverse events were more 
common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine 
bone mineral density and glomerular filtration were each significantly improved in patients in 
the E/C/F/TAF group compared with those in the TDF-containing regimen group.

GS-US-292-0112 is a Phase 3, single-arm, open-label study which evaluated the efficacy and 
safety of E/C/F/TAF in virologically suppressed, HIV-infected subjects with estimated 
creatinine clearance of 30-69 mL/min over 144 weeks. The primary endpoint was the change 
from baseline in glomerular filtration rate estimated using various formula. A total of 
242 virologically suppressed patients enrolled and switched treatment to E/C/F/TAF. Subject 
baseline characteristics were mean age 58 years, 18% black, 39% hypertension, 
14% diabetes. Through Week 48, no significant change in estimated CrCl was observed. 
Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had 
evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had 
significant improvements in proteinuria, albuminuria, and tubular proteinuria (p < 0.001 for 
all). Hip and spine bone mineral density significantly increased from baseline to Week 48 
(mean percent change +1.47 and +2.29, respectively, p < 0.05). 92% (222 patients) 
maintained HIV-1 RNA < 50 copies/mL at Week 48. The findings of this study support the 
use of E/C/F/TAF in patients with renal impairment down to an eGFRCG of 30 mL/min.


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1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF, Odefsey®) Fixed Dose Combination
The details of the key clinical studies are provided below. Please refer to the IB for additional 
information on the F/R/TAF FDC.

GS-US-366-1159 was a randomized, open-label, single-dose, 3-way, 6-sequence, crossover 
study to determine the bioequivalence of FTC and TAF, administered as E/C/F/TAF FDC 
tablet or as F/R/TAF (Odefsey®) FDC tablet, and the bioequivalence of RPV administered as 
RPV single tablet or as F/R/TAF FDC tablet. The FTC and TAF components of the F/R/TAF
(200/25/25 mg) FDC were found to be bioequivalent to the E/C/F/TAF (150/150/200/10 mg) 
FDC. The RPV component of the F/R/TAF (200/25/25 mg) FDC was found to be 
bioequivalent to RPV 25 mg tablet (Edurant®). FTC, RPV, and TAF administered as 
F/R/TAF (200/25/25 mg) FDC, RPV (25 mg), and E/C/F/TAF (150/150/200/10 mg) FDC 
were generally safe and well-tolerated in healthy volunteers.

GS-US-366-1651 was a randomized, open-label, single-dose, 2-period, crossover, food-effect 
study. Two cohorts of subjects were enrolled to assess the effect of moderate-fat food and the 
effect of high-calorie, high-fat food, on the PK of a single-dose F/R/TAF FDC tablet. Overall 
TAF exposure (AUClast) increased by approximately 45% and 54%, FTC exposure (AUCinf) 
decreased by approximately 9% and 12%, and RPV exposure (AUCinf) increased by 
approximately 13% and 75% (moderate-fat and high-calorie, high-fat conditions, 
respectively) when the RPV/FTC/TAF FDC tablet (200/25/25 mg) was administered under 
fed compared with fasted conditions.
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination
1.3.1.
General Information
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC, or Harvoni®) combines two 
HCV specific DAA agents into a single tablet for the treatment of chronic HCV infection. 
Sofosbuvir is a nucleotide analog that is a potent and selective inhibitor of NS5B-directed HCV 
replication, irrespective of HCV genotype. Ledipasvir is a novel HCV NS5A inhibitor that has 
demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV infection. 
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF 
FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology


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1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant to 
the Proposed Study

Study GS-US-337-0102 (ION-1) was a Phase 3, multicenter, randomized, open-label study 
designed to investigate the efficacy and safety of LDV/SOF FDC + RBV for 12 and 
24 weeks. Subjects were HCV treatment-naive with chronic genotype 1 HCV infection. 
ION-1 was based on data from Phase 2 studies, which demonstrated high SVR rates in 
subjects with HCV genotype 1 infection. Subjects were randomized 1:1:1:1 to receive 
LDV/SOF once daily for 12 weeks, LDV/SOF + RBV for 12 weeks, LDV/SOF for 
24 weeks, or LDV/SOF + RBV for 24 weeks. The primary end point was SVR12.
Baseline characteristics of the 865 randomized and treated subjects included 16% with 
cirrhosis, 12% black, and 67% with HCV genotype 1a infection. The rates of SVR12 were 
99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of 
LDV/SOF; 97% (95% CI, 94 to 99) in the group that received 12 weeks of LDV/SOF plus 
ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of LDV/SOF; and 
99% (95% CI, 97 to 100) in the group that received 24 weeks of LDV/SOF plus ribavirin. No 
subject in either 12-week group discontinued LDV/SOF owing to an adverse event. The most 
common adverse events were fatigue, headache, insomnia, and nausea. The study 
demonstrated that once-daily LDV/SOF+/- RBV for 12 or 24 weeks was highly effective in 
previously untreated patients with HCV genotype 1 infection.

Study GS-US-337-0109 (ION-2) was a Phase 3, randomized, open-label study of HCV 
genotype 1 subjects with prior virologic failure of peg-interferon and ribavirin +/- an 
HCV protease inhibitor. Subjects were randomized to i) LDV/SOF for 12 weeks, 
ii) LDV/SOF + RBV for 12 weeks, iii) LDV/SOF for 24 weeks, or iv) LDV/SOF + RBV for 
24 weeks. The primary end point was SVR12. Baseline characteristics of the 440 randomized 
and treated subject included: 20% with cirrhosis and 79% with HCV genotype 1a infection. 
SVR12 rates were: 94% (95% confidence interval [CI], 87 to 97) for 12 weeks of LDV/SOF; 
96% (95% CI, 91 to 99) for 12 weeks of LDV/SOF + RBV; 99% (95% CI, 95 to 100) for 
24 weeks of LDV/SOF; and 99% (95% CI, 95 to 100) for 24 weeks of LDV/SOF + RBV. No 
patient discontinued treatment owing to an adverse event. The most common adverse events 
were fatigue, headache, and nausea. The study demonstrated that treatment with daily 
LDV/SOF resulted in high rates of SVR12 in HCV-infected subjects who had not had a 
sustained virologic response to prior interferon based treatment.


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
Study GS-US-337-0108 (ION-3) was a Phase 3, open-label study, which randomly assigned 
647 previously untreated subjects with HCV genotype 1 infection without cirrhosis to receive 
LDV/SOF +/- RBV for 8 weeks or LDV/SOF for 12 weeks. The primary end point was 
SVR12. The rate of sustained virologic response was 94% (95% confidence interval [CI], 
90 to 97) with 8 weeks of LDV/SOF, 93% (95% CI, 89 to 96) with 8 weeks of 
LDV/SOF + RBV, and 95% (95% CI, 92 to 98) with 12 weeks of LDV/SOF. As compared 
with the SVR12 rate in the group that received 8 weeks of LDV/SOF, the rate in the 12-week 
group was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that 
received 8 weeks of LDV/SOF + RBV was 1 percentage point lower (95% CI, −6 to 4) 
demonstrating noninferiority of the 8-week LDV/SOF regimen (noninferiority margin of 
12%). Adverse events were more common in the group that received ribavirin than in the 
other two groups. No patient who received 8 weeks of only LDV/SOF discontinued treatment 
owing to adverse events. Overall, previously untreated subjects treated with 8 weeks of 
LDV/SOF achieved high rates of SVR. No additional benefit was associated with the 
inclusion of ribavirin in the regimen or with extension of the duration of treatment to 
12 weeks.

GS-US-337-0115 (ION-4) was a multicenter, single-arm, open-label study that enrolled 
HIV/HCV (genotype 1 or 4) coinfected subjects to receive 12 weeks of LDV/SOF. Subjects 
were stable on antiretroviral regimens of F/TDF with EFV, RPV or RAL. The primary end 
point was SVR12. Of the 335 patients enrolled, 34% were black, 55% had been previously 
treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had SVR12 
(95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in 
patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, 
and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic 
response were similar regardless of previous treatment or the presence of cirrhosis. Of the 
13 subjects who did not have a sustained virologic response, 10 had a relapse after the end of 
treatment. No subject had confirmed HIV-1 virologic rebound. The most common adverse 
events were headache (25%), fatigue (21%), and diarrhea (11%). No subejct discontinued 
treatment because of adverse events. The study concluded that LDV/SOF for 12 weeks 
provided high rates of sustained virologic response in patients coinfected with HIV-1 and 
HCV genotype 1 or 4.
Combined Analyses of LDV/SOF Data {Bhagani et al 2015}
A combined analysis compared the safety and efficacy of the single tablet regimen of LDV/SOF 
in HCV genotype (GT) 1 patients co-infected with HIV-1 in the Phase 3 ION-4 study with HCV 
mono-infected GT1 patients in the Phase III ION 1-3 studies. 
In the ION-4 study, 327 GT1 HCV/HIV co-infected patients (126 treatment-naïve, 
non-cirrhotic, 134 treatment-experienced, non-cirrhotic, 20 treatment-naïve, cirrhotic, 
47 treatment-experienced, cirrhotic) received LDV/SOF for 12 weeks. In the ION 1-3 studies, 
538 GT1 HCV mono-infected patients (395 treatment-naïve, non-cirrhotic, 
87 treatment-experienced, non-cirrhotic, 34 treatment-naïve, cirrhotic, 22 treatment-experienced,
cirrhotic) received LDV/SOF for 12 weeks. The pooled analysis assessed safety and sustained 
virologic response at week 12 (SVR12).


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Overall, 865 patients were treated for 12 weeks. In ION 1-3, the majority of patients were male 
(329, 61%), non-black (449, 83%), and treatment-naïve (430, 80%) while 56 (10%) patients had 
cirrhosis. In ION-4, the majority of patients were male (276, 82%), non-black (220, 66%), and 
treatment-experienced (185, 55%). Sixty-seven (67, 20%) patients had cirrhosis. SVR12 and 
relapse data are reported in the table. Treatment was well tolerated in both mono-infected and 
co-infected patients. Most common adverse events (> 10% reported in any arm) were fatigue, 
headache, diarrhea, and nausea. Only two patients discontinued treatment due to an adverse 
event. The investigators concluded that the once daily, single tablet regimen of LDV/SOF for 
12 weeks provided high rates of SVR regardless of presence of HIV infection and was a safe, 
well-tolerated option for patients with both HCV mono-infection and HIV/HCV co-infection.
Table 1-1.
Combined Analysis from Phase III ION Studies
Study
ION 1
ION 2
ION 3
ION 1-3 Combined
ION 4
N (GT 1)
213
109
216
538
327
SVR12 (%)
99
94
96
97
96
Relapse rates (%)
<1
6
1
2
3
Discontinuation rates (%)
0
0
1
<1
0
LDV/SOF Drug Interactions with E/C/F/TAF and F/R/TAF {Custodio et al 2015}
Use of anti-HCV agents such as LDV, a P-glycoprotein (P-gp) and BCRP inhibitor, with HIV 
ARV such as TAF, a P-gp and BCRP substrate, may be complicated by drug-drug interactions 
(DDIs). Two Phase 1 studies evaluated DDIs between TAF-based regimens F/R/TAF or 
E/C/F/TAF and the fixed-dose combination anti-HCV regimen of LDV/SOF. In 
two multiple-dose, randomized, crossover studies, healthy volunteers received R/F/TAF 
(Study 1) or E/C/F/TAF (Study 2), alone or in combination with LDV/SOF, daily with food for 
11 [Study 1] or 10 [Study 2] days. Plasma concentrations of RPV, EVG, COBI, FTC, TAF, TFV 
(TAF metabolite), LDV, SOF, and GS-331007 (predominant circulating metabolite of SOF) 
were analyzed and PK parameters calculated via noncompartmental analysis. Geometric least 
squares mean ratio (GMR; combination vs. alone) and 90% confidence intervals (CI) for 
analytes' AUCtau, Cmax and Ctau were estimated by linear mixed effect modeling and compared to 
lack of PK alteration bounds (70-143% except RPV: 80-125%). Safety was assessed throughout 
the studies.
Forty (40) of 42 subjects (Study 1) and 30/30 subjects (Study 2) completed the study. Treatments 
were generally well tolerated.
The GMR and 90% CI for all analytes’ PK parameters are:


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Table 1-2.
Study 1: F/R/TAF and LDV/SOF
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
F/R/TAF
(Treatment B)
(N = 42)
LDV/SOF+F/R/TAF
(Treatment C)
(N = 42)
FTC
AUCtau (h*ng/mL)
10,764.1 (14.3)
10,805.1 (15.3)
100.29 (98.43,102.19)
Cmax (ng/mL)
1707.6 (20.2)
1650.3 (17.6)
97.02 (92.72,101.53)
Ctau (ng/mL)
87.9 (28.2)
88.7 (25.1)
101.59 (98.47,104.81)
RPV
AUCtau (h*ng/mL)
3040.1 (27.3)
2857.6 (25.6)
94.59 (91.20,98.10)
Cmax (ng/mL)
203.3 (25.4)
197.1 (28.3)
96.65 (91.73,101.84)
Ctau (ng/mL)
109.1 (31.6)
100.0 (26.0)
93.33 (89.38,97.45)
TAF
AUClast (h*ng/mL)
277.2 (37.5)
362.3 (34.4)
132.39 (124.99,140.22)
Cmax (ng/mL)
200.0 (43.5)
204.5 (45.7)
103.12 (93.58,113.63)
TFV
AUCtau (h*ng/mL)
268.4 (22.6)
467.2 (21.0)
174.72 (168.78,180.86)
Cmax (ng/mL)
15.8 (21.7)
25.4 (20.0)
161.50 (155.60,167.62)
Ctau (ng/mL)
9.0 (24.8)
16.7 (22.0)
184.86 (177.57,192.46)
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF
(Treatment A)
(N = 41)
LDV/SOF+F/R/TAF
(Treatment C)
(N = 42)
SOF
AUCtau (h*ng/mL)
2909.4 (32.8)
3068.9 (30.5)
104.69 (100.51,109.04)
Cmax (ng/mL)
1469.5 (35.4)
1390.6 (32.3)
95.99 (88.80,103.76)
GS-331007
AUCtau (h*ng/mL)
11,766.4 (12.8)
12,883.3 (16.1)
107.98 (106.20,109.79)
Cmax (ng/mL)
884.4 (13.7)
960.4 (14.8)
108.09 (105.05,111.20)
Ctau (ng/mL)
339.8 (16.4)
378.1 (18.9)
109.92 (107.46,112.44)
LDV
AUCtau (h*ng/mL)
11,590.4 (40.3)
11,944.8 (42.7)
101.53 (97.36, 105.88)
Cmax (ng/mL)
647.4 (35.8)
658.4 (37.7)
100.62 (96.76, 104.63)
Ctau (ng/mL)
419.7 (45.9)
434.3 (47.4)
102.40 (98.02, 106.99)


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Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
E/C/F/TAF
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
EVG
AUCtau (h*ng/mL)
26,888.6 (22.74)
29,750.7 (23.26)
110.62 (102.40, 119.50)
Cmax (ng/mL)
2184.3 (23.29)
2155.3 (27.49)
97.85 (89.57, 106.91)
Ctau (ng/mL)
513.3 (40.06)
731.3 (35.57)
145.70 (127.99, 165.86)
COBI
AUCtau (h*ng/mL)
11,354.2 (36.34)
17,046.0 (30.36)
153.17 (144.87, 161.95)
Cmax (ng/mL)
1381.4 (25.98)
1668.0 (17.14)
123.35 (115.35, 131.91)
Ctau (ng/mL)
56.1 (99.59)
175.2 (90.42)
325.08 (287.62, 367.43)
FTC
AUCtau (h*ng/mL)
12,035.7 (15.39)
11,622.9 (15.53)
96.59 (93.22, 100.08)
Cmax (ng/mL)
1777.0 (18.40)
1840.3 (22.12)
103.04 (95.93, 110.67)
Ctau (ng/mL)
103.5 (26.84)
98.5 (27.24)
95.02 (90.82, 99.42)
TAF
AUClast (h*ng/mL)
238.6 (45.87)
194.8 (29.21)
85.67 (77.63, 94.54)
Cmax (ng/mL)
165.9 (50.79)
148.2 (48.24)
90.45 (73.41, 111.45)
TFV
AUCtau (h*ng/mL)
314.8 (18.68)
396.8 (15.90)
126.61 (122.55, 130.81)
Cmax (ng/mL)
17.8 (20.43)
20.7 (16.14)
116.85 (111.71, 122.23)
Ctau (ng/mL)
11.7 (20.05)
15.5 (16.62)
132.89 (127.74, 138.25)
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF FDC
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
LDV
AUCtau (h*ng/mL)
12,657.2 (36.26)
22,939.3 (35.71)
178.99 (163.62, 195.81)
Cmax (ng/mL)
684.2 (32.25)
1136.0 (32.14)
164.74 (152.60, 177.86)
Ctau (ng/mL)
459.2 (40.34)
896.1 (37.74)
193.16 (173.91, 214.55)
SOF
AUCtau (h*ng/mL)
2336.2 (37.40)
3308.4 (24.84)
146.53 (135.44, 158.53)
Cmax (ng/mL)
1220.3 (37.87)
1573.2 (34.88)
128.48 (112.51, 146.72)
GS-331007
AUCtau (h*ng/mL)
12,611.4 (20.91)
18,739.0 (22.60)
148.15 (143.54, 152.91)
Cmax (ng/mL)
950.9 (18.74)
1228.7 (18.57)
129.36 (123.92, 135.04)
Ctau (ng/mL)
358.7 (24.66)
599.5 (27.40)
165.96 (159.61, 172.57)


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GLSM and 90% CIs for all analytes were contained within the prespecified bounds except: 
i) TFV when RPV/FTC/TAF was administered with LDV/SOF; ii) COBI, when E/C/F/TAF was 
coadministered with LDV/SOF; and iii) LDV, GS-331007 and SOF and EVG when administered 
with E/C/F/TAF.
Despite an increase in TFV exposure upon coadministration of R/F/TAF + LDV/SOF, the mean 
TFV AUCtau is ~ 5 times lower than TFV from TDF, and within the range of TFV that did not 
lead to renal AEs or bone loss (E/C/F/TAF Phase 3). There is no association between higher 
COBI exposure and incidence of AEs, renal function parameters (E/C/F/TAF Phase 2/3 data). 
Higher plasma exposures of LDV, SOF and GS-331007 in the presence of E/C/F/TAF are not 
considered to be clinically important based on the established exposure-safety analyses for 
LDV/SOF. Thus, F/R/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose 
modification.
1.4.
Rationale for This Study
Currently, LDV/SOF is approved by the US FDA for treatment of HCV genotype 1- infected 
HCV mono and HIV co-infected patients. This Phase 3 open-label study is designed to extend 
this data to examine the efficacy and safety of LDV/SOF treatment regimen for chronic genotype 
1 HCV infection in HIV-infected patients who are receiving HIV therapy with E/C/F/TAF or 
F/R/TAF. Current guidelines for treatment of HCV in HIV co-infected patients emphasize the 
added need to treat co-infected patients due to higher rates of liver disease progression even if 
the HIV infection is treated with antiretroviral agents. The complex drug interactions that can 
occur between HIV ARV and HCV DAA further the need for safe, simple regimens that cure 
HCV in HIV-infected subjects without threatening the underlying HIV suppression. Current 
IDSA/AASLD guidelines recommend that “Antiretroviral drug switches may be performed to 
allow compatibility of DAAs, with the goal of maintaining HIV suppression without 
compromising future options” {HCV Guidelines 2015}. Prior HIV treatment history, underlying 
HIV drug resistance and tolerability of regimens needs to be considered. 
LDV/SOF has been used successfully to treat HIV/HCV co-infected patients and the cure rates 
are 96%, comparable to HCV mono-infected patients {Naggie et al 2015}, which has led to a 
recent update to the LDV/SOF package insert that now includes HIV/HCV co-infection in the 
list of indications {Gilead Sciences Inc 2015}. However, few ARV regimens were evaluated in 
clinical studies of HCV treatment of HIV co-infected subjects. Only RAL, EFV and RPV were 
used in the ION-4 study with FTC/TDF as the dual NRTI component of the regimen. In the 
presence of a boosting agent, such as RTV or COBI (which increase plasma TFV 
concentrations), further increases in plasma TFV concentrations are noted when coadministered 
with LDV/SOF + TDF. Guidelines recommend avoiding RTV or COBI-boosted ARV regimens 
with TDF when treating HCV in HIV-infected patients, mainly due to lack of data. The 
availability of TAF-based regimens will obviate the problem of excessive TFV concentrations 
due to the 91% lower plasma TFV levels when TAF is used in place of TDF. The PK drug 
interaction studies (GS-US-366-1689 and Study 2) further justify the ability to use LDV/SOF in 
HIV-infected patients who are receiving TAF-based regimens (including COBI).


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Drug-drug interactions of LDV/SOF coadministered with E/C/F/TAF and F/R/TAF were 
evaluated in healthy volunteers; the studies found no significant interactions and concluded that 
LDV/SOF and TAF-regimens can be coadministered without dose modification. The duration of 
the healthy volunteer drug-interaction studies were 10 and 11 days. Although, the US package 
insert for Genvoya® (E/C/F/TAF) suggests there should be no clinically significant drug 
interaction with LDV/SOF, there is no study to date that has evaluated the safety or efficacy of 
LDV/SOF administered with E/C/F/TAF or F/R/TAF for treatment of HCV in suppressed, HIV 
co-infected population. Careful assessment of safety/tolerability of LDV/SOF with TAF 
regimens for 12 weeks is needed to ensure that the safety data, noted in healthy volunteers PK 
studies, is replicated during 12 weeks of coadministration in HIV/HCV co-infected subjects. The 
goal of this study is to evaluate E/C/F/TAF FDC or F/R/TAF FDC with LDV/SOF by 
determining the efficacy of HCV therapy (SVR 12 weeks after completion of LDV/SOF) and 
safety and tolerability of coadministration of dual STRs.
1.5.
Risk/Benefit Assessment for the Study
The risk/benefit for this study is acceptable due to the following considerations: i) treatment of 
HCV is indicated and important in all HIV co-infected patients due to accelerated progression of 
liver disease; ii) 12 weeks of LDV/SOF provides high HCV SVR rates in HIV/HCV co-infected 
subjects; iii) changing ARV regimens is an accepted strategy for management of patients prior to 
initiation of HCV therapy (AASLD/ IDSA Guidelines); iv) changing to E/C/F/TAF from other 
ART has been shown to be safe, effective and have superior treatment outcome than maintaining 
a current suppressive regimen {Mills et al 2015}; v) F/R/TAF is bioequivalent to approved HIV 
regimens and achieves plasma concentrations of FTC, RPV and TAF that have proven to be safe, 
well tolerated and effective in maintaining virologic suppression in HIV-infected patients. Thus, 
for individual subjects there is benefit to treating their HCV and for all co-infected patients, 
finding safe, tolerable, efficacious and simple regimens will be a major advance in treatment.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV 
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen;

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects;

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment)
The secondary endpoints of this study are:

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment);

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using FDA snapshot algorithm;

Grades 1 through 4 adverse events after switching to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment.
3.2.
Study Design
This protocol describes a randomized, multicenter, open-label, 2-part study to evaluate the 
efficacy, safety, and tolerability of switching to E/C/F/TAF FDC or F/R/TAF FDC HIV 
treatments and adding LDV/SOF HCV treatment for 12 weeks in adult male and female subjects 
with HIV who are co-infected with chronic GT 1 HCV infection.
3.3.
Study Treatments
Subjects will participate in 2 parts of the study. In Part 1, subjects will be randomized in a 
1:1 ratio to one of the following 2 HIV treatment groups:
Part 1: Approximately 120 subjects will be randomized 1:1 to switch from stable ARV therapy 
to one of the following treatments. Randomization will be stratified by race (black vs. non-black) 
at screening.

Treatment Group 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC 
(n = 60)

Treatment Group 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 60)
Subjects maintaining HIV-1 RNA < 50 copies/mL and tolerating E/C/F/TAF or F/R/TAF 
through Part 1 will continue to Part 2 where they will receive the HCV treatment. Subjects with 
confirmed virologic failure or who discontinue the HIV study drugs due to toxicity in Part 1 will 
be discontinued from the study.


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Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or F/RJTAF FDC treatment, subjects 
will maintain their HIV treatment and will initiate 12 weeks ofLDV/SOF HCV treatment. 
At the end of their LDV/SOF HCV treatment, subjects will continue to maintain their HIV 
treatment and be followed for safety and efficacy for an additional12 weeks to detemline the 
SVR12 endpoint and HIV safety and efficacy endpoints. 
3.4. 
Duration of Treatment 
The HIV treatment dmation is from the Day 1 visit until the last study visit at the Post-HCV 
Treatment Week 12. The HCV treatment dmation is 12 weeks. Screening assessments will be 
completed within 42 days of the Day 1 visit. 
All subjects will complete the following study visits: Screening, Day 1, Weeks 4, 6 (laborat01y 
visit only), 8 (stmi ofHCV treatment), 12, 16, and 20 (end ofHCV treatment), and post-HCV 
treatment visits 4 and 12 weeks after the last LDV/SOF dose. 
Subjects who complete the study through the last study visit at the Post-HCV Treatment 
Week 12 visit will be required to retum to the clinic 30 days after the completion of the study 
treatment for a 30-Day Follow-Up visit. 
Figure 3-1. 
Study Schema 
~~--P~a~r~t ~lb--~~~----------------P_a•_·t_2_c --------------~~ 
Screening 
-
~2days 
ptiOI' 
toDay 1 
a 
Dayl 
Treatment Groul! t•: E/C/F/TAF QD (n = 60) 
Treatment Groul! 2•: FIR/TAF QD (n=60) 
30-Day 
Follow-up 
LDV/SOFQD 
for 12 weeks 
WeekS 
Post LDV/SOF Treatment 
Follow-Up (12 week follow-up) 
Week20 
Post-HCV Treatment 
d 
Week12 
a 
Following the Day 1 visit, subjects will rehlffi for shtdy visits at Weeks 4, 6 (laboratoty visit only), 8, 12, 16, 20, and 
Post-HCV Treatment 4 and 12 weeks after the last LDV/SOF dose. 
b 
Part 1: subjects are randomized to either E/C/F/TAF FDC or FIR.ITAF PDC on Day 1 and maintain H1V treatment to the 
Week 8 visit. 
c 
Part 2: At Week 8, once HIV-1 RNA suppression(< 50 copies/mL) is confumed (based on the Week 6 HlV-1 RNA value), 
subjects will start on LDV!SOF FDC for 12 weeks (until Week 20) while maintaining their H1V treatment. At Week 20, 
LDV!SOF FDC will be discontinued while continuing H1V treatment. Subjects will continue in the shldy for another 
12 weeks to determine SVR4 ( 4 weeks post-HCV treatment) and SVR12 (12 weeks post-HCV treatment). 
d 
Subje.cts who complete the shtdy through the Post-HCV Treatment Week 12 visit will be required to rehun to the clinic 
30 days after the c.ompletion of the shtdy treatment for a 30-Day Follow-Up Visit. 
e 
At the Day 1 visit, subjects will switch to eid1er E/C/F/TAF FDC or F/RITAF FDC and continue on H1V treatment until the 
last shldy visit at the Post-HCV Treatment Week 12 visit. 
CONFIDENTIAL 
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3.5. 
Samples for Optional Exploratory Assessments 
PO 
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Amendment 2 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 120 subjects with HIV-1 who are coinfected with chronic HCV infection and 
who meet the eligibility criteria will be enrolled. In order to manage the total study enrollment, 
Gilead Sciences, Inc., at its sole discretion, may suspend screening and/or enrollment at any site 
or study-wide at any time.
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 any study procedures.
2) Age ≥ 18 years.
3) Currently on an ARV regimen (2 NRTI + a third agent, see Table 4-1) without change for 
6 months prior to screening. Documented plasma HIV-1 RNA levels < 50 copies/mL 
(or undetectable HIV-1 RNA level according to the local assay being used if the limit of 
detection is ≥ 50 copies/mL) for ≥ 6 months preceding the Screening visit. After reaching 
HIV-1 RNA < 50 copies/mL, single values (“blips”) of HIV-1 RNA ≥50 copies/mL 
followed by resuppression are allowed. For subjects with 3 or more prior ARV regimens, a 
regimen history should be provided for approval by the Sponsor. 
Note: Subjects that changed from TDF to TAF less than 6 months ago will be eligible as long 
as the TDF/ TAF change was the only change to the regimen
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen
Antiretroviral Class
Agents
Boosted PI
ATV+COBI (or ATV/COBI FDC), darunavir (DRV)+COBI (or DRV/COBI FDC), 
DRV+RTV, lopinavir (LPV)/RTV, ATV+RTV, fosamprenavir (FPV)+RTV, FPV+COBI, 
SQV+RTV, SQV+COBI, IDV+RTV, IDV+COBI, ATV (no booster)
NNRTI
EFV, etravirine (ETR), nevirapine (NVP), RPV
NRTI
FTC, TDF, TAF, abacavir (ABC), lamivudine (3TC), zidovudine (AZT)
INSTI
dolutegravir (DTG), RAL, EVG/COBI or EVG+RTV
4) No history of HIV virologic failure
5) If the current regimen is a PI/r, the previous regimen cannot contain an NNRTI or INSTI


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6) Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.
7) Have no documented resistance to any of the HIV study agents at any time in the past, 
including but not limited to the reverse transcriptase resistance mutations K65R, K70E, 
K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, 
M230I/L, the combination of K103N+L100I, or 3 or more TAMs that include M41L or 
L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). If a historical 
genotype prior to first ARV is not available or subject has 3 or more prior ARV regimens, 
subject will have proviral genotype analysis for archived resistance prior to Day 1 (all 
proviral genotype reports must be reviewed and approved by Sponsor).
8) Chronic HCV infection (≥ 6 months) documented by prior medical history.
9) HCV genotype 1 at screening as determined by the Central Laboratory. Any non-definitive 
genotype results will exclude the subject from study participation.
10) Classification as one of the following criteria:
a) Without cirrhosis and no prior HCV treatment (treatment-naïve, defined as having never 
been exposed to approved or investigational HCV-specific direct-acting antiviral agents 
or prior treatment of HCV with IFN and RBV)
b) Without cirrhosis and have received HCV treatment only with IFN +/- RBV +/- HCV PI 
(treatment-experienced, defined as prior treatment failure to a regimen containing IFN 
either with or without RBV that was completed at least 8 weeks prior to Day 1. The 
subject’s medical records must include sufficient detail of prior treatment experience for 
categorization, as either:
i)
Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
ii) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR, or
iii) HCV Treatment-Intolerant: Subjects who discontinued HCV treatment of a regimen 
containing IFN (either with or without RBV) due to toxicity
c) Compensated cirrhosis and no prior HCV treatment (treatment-naïve)
11) Cirrhosis Determination 
a) Presence of cirrhosis is defined as any one of the following:
i)
FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
screening
ii) Fibroscan with a result of > 12.5 kPa 
iii) Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score ≥5)


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b) Absence of cirrhosis is defined as any one of the following:
i)
FibroTest® score ≤ 0.48 AND APRI ≤ 1 performed during screening 
ii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
iii) Liver biopsy within 2 years of screening showing absence of cirrhosis
In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
Fibrotest®/APRI using the above criteria, a liver biopsy or fibroscan is required. Liver biopsy 
results will supersede Fibrotest®/APRI or fibroscan results and be considered definitive.
12) Liver imaging within 6 months prior to Day 1 is required in cirrhotic subjects to exclude 
hepatocellular carcinoma (HCC)
13) HCV RNA 104 IU/mL at the Screening visit
14) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
15) Adequate renal function: estimated GFR ≥ 30 mL/min according to the Cockcroft-Gault 
formula (eGFRCG) for creatinine clearance {Cockcroft et al 1976}:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) × 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
16) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
17) Total bilirubin ≤ 1.5 mg/dL, and direct bilirubin ≤ 1.5 × ULN (subjects with documented 
Gilbert’s syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin 
up to 5 × ULN as long as direct bilirubin is ≤ 1.5 × ULN.)
18) Adequate hematologic function:

Absolute neutrophil count ≥1,000/mm3

Platelets ≥50,000/mm3

Hemoglobin ≥ 8.5 g/dL
19) Albumin ≥3.0 g/dL
20) INR ≤ 1.5 × ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR


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21) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant or nursing
b) Of non-childbearing potential (ie, women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
≥54 years of age with cessation [for 12 months] of previously occurring menses), or
c) Of childbearing potential and agrees to utilize protocol-specified contraceptive methods 
or be non-heterosexually active or practice sexual abstinence from screening throughout 
the duration of study treatment and for 30 days following the last study drug dose 
(see Appendix 5 for definitions and protocol-acceptable contraceptive methods)
22) Male subjects must agree to utilize a protocol-approved method of contraception (as defined 
in Appendix 5) during heterosexual intercourse or be non-heterosexually active, or practice 
sexual abstinence from first dose throughout the study period and for 30 days following the 
last study drug dose.
23) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days 
after the last study drug dose.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) A new AIDS-defining condition diagnosed within the 30 days prior to the Screening visit
(except CD4+ cell count and/or percentage criteria) (refer to Appendix 6)
2) Prior HCV treatments with NS5A and NS5B or any HCV directly acting antivirals except 
boceprevir, telaprevir and simeprevir in combination with IFN +/- RBV.
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
4) History or current decompensation of liver disease; varices at low risk of bleeding are 
allowed.
5) Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B virus (HBV) DNA
6) Chronic use of systemically administered immunosuppressive agents (eg, prednisone 
equivalent > 10 mg/day).
7) Females who are breastfeeding
8) Positive serum pregnancy test 
9) Have an implanted defibrillator or pacemaker


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10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 42 days of Day 1visit and must not be 
anticipated to require systemic therapy during the study.
12) Active, serious infections (other than HIV-1 and HCV infections) requiring parenteral 
antibiotic or antifungal therapy within 42 days prior to Day 1
13) Gastrointestinal disorder or post-operative condition that could interfere with the absorption 
of the study drugs
14) Solid organ transplantation
15) Significant pulmonary disease or significant cardiac disease
16) 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
17) Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
18) Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
19) 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 HIV study drugs (COBI, EVG, FTC, 
RPV, or TAF. For COBI, EVG, FTC, or RPV, refer to the individual agents’ Prescribing 
Information; for TAF, refer to the E/C/F/TAF FDC or F/R/TAF FDC Investigator’s 
Brochures) or HCV study drugs (LDV or SOF); or subjects with any known allergies to the 
excipients of E/C/F/TAF, F/R/TAF, or LDV/SOF tablets.


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Table 4-2.
Disallowed Agentsa
Drug Class
Agents Disallowedb
Acid Reducing Agents
Proton pump inhibitors, such as Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, Rabeprazole
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Antiarrythmics
Amiodaroned, Quinadine
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifampin, Rifapentine, Rifabutin
Calcium Channel Blockers
Bepridil
Corticosteroids: Systemic
Dexamethasone (more than a single dose)
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplementsc
St. John’s Wort, Echinacea, Milk thistle (ie, silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin, Rosuvastatine
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a
Disallowed agents are inclusive of all HIV and HCV study drugs (E/C/F/TAF, F/R/TAF, and LDV/SOF).
b
Administration of any of the following medications must be discontinued at least 42 days prior to the Day 1 visit and for the 
duration of the study, with the exception of amiodarone (see footnote d).
c
May result in a decrease in the concentrations of all HIV and HCV study drugs.
d
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to the Day 1 visit and for the duration of the study.
e
Use with LDV/SOF may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
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. Once a subject number has 
been assigned to a subject, it will not be reassigned to any other subject. Prior to or during the 
Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web 
Response System (IWRS). The subject number assignment and randomization may be performed 
up to 7 days prior to the in-clinic Day 1 visit provided that all screening procedures have been 
completed and subject eligibility has been confirmed.
Subjects will be randomized in a 1:1 ratio to one of the following two treatment arms: 
Treatment Arm 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC (n = 60)
Treatment Arm 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 60)
Randomization will be stratified by race (black vs. non-black).
The IWRS will assign study drug bottle numbers to be dispensed to the subject at each study 
visit, for all HIV and HCV study drugs. All Day 1 assessments and procedures must be 
completed prior to the administration of the first dose of HIV study drug. Initiation of 
treatment with the HIV study drug must take place within 24 hours after the Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF
5.2.1.
Formulation
5.2.1.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets debossed with “GSI” on one 
side of the tablet and “510” on the other side. Each E/C/F/TAF tablet contains 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.
5.2.1.2.
F/R/TAF, Odefsey®
F/R/TAF tablets are capsule-shaped, film-coated gray tablets debossed with “GSI” on one side 
and “255” on the other side. Each F/R/TAF tablet contains 200 mg of FTC, 25 mg of RPV 
(as 27.5 mg RPV hydrochloride), and 25 mg of TAF (as 28 mg of TAF fumarate). 


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In addition to the active ingredients, the tablets contain lactose monohydrate, microcrystalline 
cellulose, polysorbate, povidone, croscarmellose sodium and magnesium stearate. The tablet 
cores are film-coated with polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
black iron oxide.
5.2.1.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are orange, diamond-shaped, film-coated tablets debossed with “GSI” on 
one side and “7985” on the other side. Each LDV/SOF FDC tablet contains 90 mg of LDV and 
400 mg of SOF.
In addition to the active ingredients, the tablets contain lactose monohydrate, copovidone, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and FD&C yellow # 6 /sunset 
yellow FCF aluminium lake.
5.2.2.
Packaging and Labeling
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA) and/or other local regulations.
5.2.2.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Genvoya® may 
also be used for the study.
5.2.2.2.
F/R/TAF, Odefsey®
F/R/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Odefsey® may 
also be used for the study.
5.2.2.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 28 or 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Harvoni® may 
also be used for the study.


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5.2.3.
Storage and Handling
E/C/F/TAF, F/R/TAF, and LDV/SOF 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 drugs 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 by avoiding direct eye contact or exposure when 
handling.
Commercial product of Genvoya®, Odefsey®, and Harvoni® may be used for the study. Further 
information regarding storage and handling are available in the Prescribing Information for 
commercial products.
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF
E/C/F/TAF FDC, F/R/TAF FDC, and LDV/SOF FDC tablets will be provided by 
Gilead Sciences.
The two HIV study treatments will be administered orally, once daily with food at approximately 
the same time each day:

Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg 
(E/C/F/TAF) FDC

Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg (F/R/TAF) FDC
HCV study treatment (ledipasvir 90 mg/sofosbuvir 400 mg [LDV/SOF] FDC) is to be 
administered orally, once daily with or without food at approximately the same time each day.
For a missed dose of E/C/F/TAF FDC, F/R/TAF FDC, and/or LDV/SOF FDC tablet, subjects 
should be instructed to take the missed dose of study drug as soon as possible during the same 
day. Subjects should be cautioned never to double the next dose with a missed dose of study drug 
under any circumstances.
5.4.
Prior and Concomitant Medications
The use of medications for the treatment of HIV and HCV, other than the study treatments 
(ie, E/C/F/TAF, F/R/TAF, or LDV/SOF), is prohibited.
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.


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Concomitant medications taken within 30 days prior to the Screening visit and up to and 
including 30 days after the last dose of study drug need to be recorded in the source documents 
and electronic case report form(s) (eCRFs).
Medications listed in Table 5-1 (E/C/F/TAF + LDV/SOF) and Table 5-2 (F/R/TAF + LDV/SOF) 
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.
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agents
Antacidsa
Elvitegravir plasma concentrations are lower with 
antacids due to local complexation in the GI tract and 
not to changes in gastric pH. It is recommended to 
separate study drug and antacid administration by at 
least 2 hours. 
Proton-Pump Inhibitors, H2-Receptor Antagonists, 
Antacids
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: Concentrations may 
increase with study drug(s); clinical monitoring 
is recommended.
Antiarrhythmics
Amiodaronec, Quinadine
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.
Antibacterials
Concentrations of clarithromycin and/or cobicistat 
may be altered when clarithromycin is coadministered 
with study drug(s). 
Patients with CLcr greater than or equal to 60 mL/min: 
No dose adjustment of clarithromycin is required. 
Patients with CLcr between 30 mL/min and 
60 mL/min: The dose of clarithromycin should be 
reduced by 50%. 
Concentrations of telithromycin and/or cobicistat may 
be increased when telithromycis in coadministered 
with study drug. Clinical monitoring is recommended 
upon coadministration with study drug. 
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR (International 
Normalized Ratio) monitoring is recommended.
Anticonvulsantsb
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 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
Dose reductions of colchicine may be required. Study 
drug(s) should not be coadministered with colchicine 
in patients with renal or hepatic impairment.
Antihistamines
Concentrations of astemizole and terfenadine may be 
increased when coadministered with cobicistat. 
Clinical monitoring is recommended when these 
agents are coadministered with study drug(s).
Antimycobacterialsb
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol: Clinical and ECG monitoring of 
subjects is recommended. A dose decrease may be 
needed.
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
Cardiac Medications
Digoxind
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.


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Drug Class
Agents Disallowed
Use With Caution
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 
Supplementsb
St. John’s Wort, 
Echinacea, Milk thistle 
(ie, silymarin), 
Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin, 
Rosuvastatine
Atorvastatin: Concentrations may increase with study 
drug(s). Start with the lowest dose; gradual increase in 
dose may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s). 
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: A dose 
decrease may be needed.


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Drug Class
Agents Disallowed
Use With Caution
Opiates
Methadone: Methadone exposures are unaffected 
upon coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required upon 
coadministration with study drug(s).
Meperidine (Pethidine): Dosage increase and 
long-term use are not recommended due to increased 
levels of metabolite normeperidine, which has 
analgesic and CNS stimulant (eg, seizures) activities.
Buprenorphine: Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and cobicistat, 
with no effect on opioid pharmacodynimcs. 
The concentration changes are not considered 
clinically relevant and no dose adjustment of 
buprenorphine/naloxone is required upon 
coadministration with study drug(s).
Phosphodiesterase-5 
Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil: Caution should be exercised, including 
consideration of dose reduction, when coadministered 
for treatment of pulmonary arterial hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil: It is recommended 
that a single dose of Sildenafil no more than 25 mg in 
48 hours, Vardenafil no more than 2.5 mg in 72 hours, 
or Tadalafil no more than 10 mg in 72 hours be 
coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem: A dose decrease may be 
needed for these drugs. Clinical monitoring 
is recommended.
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to
famotidine 40 mg twice daily. Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of E/C/F/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when coadministered with E/C/F/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis


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Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agentsa
Proton pump inhibitors, 
such as Esomeprazole, 
Lansoprazole, Omeprazole, 
Pantoprazole, Rabeprazole
H2-Receptor Antagonists, Antacids
Cimetidine, Famotidine, Nizatidine, Ranitidine
Coadministration of H2-receptor antagonists (H2RA) 
may cause significant decreases in RPV plasma 
concentrations (increase in gastric pH). H2RAs should 
only be administered at least 12 hours before or at 
least 4 hours after F/R/TAF
Alkaline antacids: antacids 
(eg, aluminum or 
magnesium hydroxide, 
calcium carbonate)
Antacids should be used with caution as 
coadministration may cause significant decreases in 
RPV plasma concentrations (increase in gastric pH). 
Antacids should only be administered either at least 
2 hours before or at least 4 hours after F/R/TAF.
Antiarrhythmics
Amiodaronec, Quinidine
Anticonvulsantsb
Carbamazepine, 
Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Fluconazole, Itraconazole, Ketoconazole, Posaconazole, 
Voriconazole: may increase concentration of RPV.
Antimycobacterialsb
Rifapentine, Rifabutin, 
Rifampin
Cardiac Medications
Digoxind
Corticosteroids: Systemic
Dexamethasone (more than 
a single dose)
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea, 
Milk thistle (ie, silymarin), 
Chinese herb Sho-Saiko-To 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorse
Rosuvastatin
Narcotic analgesics
Methadone
Clinical monitoring is recommended as methadone 
maintenance therapy may need to be adjusted in some 
patients upon coadministration with RPV
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily. Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of F/R/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when co-administered with F/R/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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5.5.
Accountability for Investigational Medicinal Product (IMP)
The investigator is responsible for ensuring adequate accountability of all used and unused IMP. 
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
IMP accountability records will be provided by Gilead Sciences (or equivalent documentation 
maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify Gilead or 
contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment. Please refer to Section 5.1 for details about randomization and treatment 
assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 42 days prior to the Day 1 visit to determine eligibility for 
participation in the study. The following assessments will be completed and documented at 
screening:

Obtain written informed consent

Determine eligibility including cirrhosis determination (see Section 4.2 for details)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging (CT or 
Ultrasound) should be performed within 6 months prior to Day 1 to exclude the presence 
of hepatocellular carcinoma 

Obtain medical history, including: 
History of HIV-1 disease-related events and prior medications within 30 days of the 
Screening visit. For subjects with 3 or more prior ARV regimens, a regimen history 
should be provided for approval by the Sponsor.
Collection of historical HIV genotype, if available. If a historical genotype prior to first 
ARV is not available or subject had 3 or more prior ARV regimens, subject will have 
proviral genotype analysis for archived resistance prior to Day 1 (all proviral genotype 
reports must be reviewed and approved by Sponsor).


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If HCV treatment-experienced, record the duration of the prior treatment and the type of 
IFN +/- RBV + HCV PI administered. Record whether the subject had a Non-Response 
or Relapse/Breakthrough during prior treatment or was Treatment Intolerant.
■
Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. 
■
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment, but did not achieve SVR
■
Treatment Intolerant: Subject discontinued HCV treatment of a regimen containing 
IFN either with or without RBV due to toxicity

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Obtain 12-lead ECG (performed supine)

Obtain height and weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry

Obtain blood samples for the following laboratory analyses:
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid.
Hematology profile: complete blood count (CBC) with differential and platelet count
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), 
and activated partial thromboplastin time (APTT)
CD4+ cell count 
Plasma HIV-1 RNA (COBAS® TaqMan® HIV RNA Test, v2.0) 
Whole blood sample for HIV proviral genotype analysis of archived resistance (if a 
historical genotype prior to first ARV is not available or subject had 3 or more prior ARV
regimens)
Plasma HCV RNA (COBAS® TaqMan® HCV Quantitative Test, v2.0)


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HCV genotype and subtype, and IL28B genotype testing 
Serology for:
■
HIV antibody 
■
HBV core antibody (HBcAb), surface antibody (HBsAb), surface antigen (HBsAg), 
e-antibody (HBeAg), e-antibody (HBeAb), and HBV DNA
■
HCV antibody

Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula 
(see Section 4.2 for details)

Obtain details of adverse events related to screening procedures

Review concomitant medications
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 42 days after the Screening visit for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events (AE) 
related to protocol-mandated procedures on the adverse events electronic case report form 
(eCRF). All other untoward medical occurrences observed until dosing of study drugs, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF. 
See Section 7, Adverse Events and Toxicity Management, for additional details.
6.2.2.
Day 1 Assessments
The following assessments are to be completed at the Day 1 visit. The Investigator must have 
received the results from the screening assessments before proceeding with the visit. Subjects 
must complete all Day 1 procedures before being dispensed the study drugs. Initiation of 
treatment with HIV study drugs must take place within 24 hours after the Day 1 visit.

Review AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive at Day 1, study drugs will not be dispensed. The positive result will be 
confirmed with a serum pregnancy test. If the serum pregnancy test is positive, the 
subject will not be able to participate.


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Renal tubular function assessments (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection): retinol binding protein, beta-2 microglobulin, 
urine albumin, and urine protein 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratmy analyses: 
-
Chemistty profile 
-
Hematology profile 
-
Coagulation assessments 
-
Metabolic assessments (collected fasted, 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 ). 
• 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 to draw blood for the metabolic 
assessments. 
-
CD4+ cell count 
-Plasma HIV-1 RNA 
-
Plasma HCV RNA 
-
Sennn bone safety assessments: (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection) parathyroid hmmone (PTH) and sennn 25-0H 
VitaminD 
• 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 to draw blood for these assessments. 
-
Platelet and coagulation function assessments may include: Soluble glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and D-dimer 
-
Inflammation assessments may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, 
sTNF-Rl, and Lp-PLA2 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Semm storage sample for possible additional clinical testing 
PD 
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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula 
(see Section 4.2 for details)

Complete questionnaires: subject is to read questionnaire by her/himself and write/mark 
answers directly onto the questionnaires.
Adherence for HIV (VAS)
HIV Treatment Satisfaction Questionnaire – Status version (HIVTSQs)
Medical Outcomes Short Form-36 (SF-36)
Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F)
Chronic Liver Disease Questionnaire (CLDQ-HCV)
Work Productivity and Activity Impairment Questionnaire: Hepatitis C, v2.0 
(WPAI: Hepatitis C)
6.3.
Randomization

Obtain subject number and randomize the subject via the IWRS. The subject number 
assignment and randomization may be performed up to 7 days prior to the in-clinic Day 1 
visit provided that all screening procedures have been completed and subject eligibility has 
been confirmed.

Dispense HIV study drugs. Subjects should initiate dosing of HIV study drugs after Day 1 
visit assessments. Initiation of treatment with the study drugs must take place within 24 hours 
after the Day 1 visit.
Subjects should also be counseled regarding the importance of adherence and taking their 
study drug daily with food at approximately the same time each day.
6.4.
Treatment Assessments
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20)
The following assessments are to be completed at the end of Weeks 4, 8, 12, 16, and 20, unless 
otherwise specified. The Week 6 visit is a laboratory visit only – please see Section 6.4.1.1 for 
details.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specified visit date based on the Day 1 visit through 
Week 20. 

Review AEs and changes in concomitant medications

Perform symptom-directed physical examination as needed 


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Obtain vital signs, including weight 
• 
Obtain urine samples for the following laboratmy analyses: 
-
Urinalysis and urine chemistly 
Final 
Amendment 2 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a serum test. If the sennn test is positive, the subject will be 
discontinued. 
-
Renal tubular function assessments (Weeks 4, 8, 12, and 20 only) 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratmy analyses: 
-
Chemistly profile 
-
Hematology profile 
-
Coagulation assessments 
-
Metabolic assessments (Weeks 8 and 20 only) 
-
CD4+ cell count 
-Plasma HIV-1 RNA 
-
Plasma HCV RNA (Weeks 8, 12, 16, and 20 only) 
-
Samples for population PK (Weeks 4, 8, 12, 16, and 20) 
• 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior 
to observed study dm g dosing; 2) the postdose sample should be drawn between 
15 mins and 4 hours postdose. 
-
Semm bone safety assessments (Weeks 4, 8, 12, and 20 only) 
-
Platelet and coagulation function assessments (Weeks 4, 8, 12, and 20 only) 
-
Inflammation assessments (Weeks 4, 8, 12, and 20 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Semm storage sample for possible additional clinical testing 
PO 
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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula 
(see Section 4.2 for details)

Complete questionnaires (Weeks 8 and 20 only): subject is to read questionnaire by 
her/himself and write/mark answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version 
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

Subjects who meet the criteria for virologic rebound should be managed according to 
Management of HIV Virologic Failure (Section 6.9)

Document study drugs dispensation and accountability for all study drugs dispensed. Counsel 
all subjects regarding the importance of adherence and maintaining consistency to study drug 
administration.
HIV study drugs are dispensed at every visit (with the exception of Week 6 
laboratory visit).
HCV treatment will commence at Week 8, after determination of HIV suppression 
(< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability of HIV study 
drugs. Once confirmed, dispense HCV study drug (LDV/SOF) at Weeks 8, 12, and 16 
only.
6.4.1.1.
Week 6 (Laboratory Visit Only)
The Week 6 visit is a laboratory visit only, to confirm HIV suppression prior to initiation of 
HCV treatment. 
The following will be performed and documented at the Week 6 visit:

Obtain blood samples for plasma HIV-1 RNA testing

Plasma storage sample for safety and virology testing


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6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) 
The following evaluations are to be completed at the end of 4 and 12 weeks after completion of 
HCV treatment (Post-HCV Treatment Weeks 4 and 12 visits, respectively) and should be timed 
from the date of last administration of the HCV treatment. The Post-HCV Treatment Week 4 
visit is to be completed ± 2 days, and the Post-HCV Treatment Week 12 visit is to be completed 
within ± 4 days; however, unless notified by Gilead Sciences, the Post-HCV Treatment Week 4 
and 12 should be completed within 2 and 4 days of the protocol-specified visit date, respectively.
All subjects must complete the Post-HCV Treatment Weeks 4 and 12 visits. The end of study 
will occur at the Post-HCV Treatment Week 12 visit.
The following assessments are to be completed:

Review AEs and changes in concomitant medications

Complete physical examination (Post-HCV Treatment Week 12 only) (urogenital/anorectal 
exams will be performed at the discretion of the Investigator)

Perform symptom-directed physical examination as needed 

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the serum test is positive, the subject will be 
discontinued.
Renal tubular function assessments (Post-HCV Treatment Week 12 only)
Urine sample storage for possible additional clinical testing

Obtain blood samples for the following laboratory analyses:
Chemistry profile 
Hematology profile
Coagulation assessments 
Metabolic assessments (Post-HCV Treatment Week 12 only)


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CD4+ cell count 
-
Plasma HIV -1 RNA 
-Plasma HCV RNA 
-
Semm bone safety assessments (Post-HCV Treatment Week 12 only) 
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-
Platelet and coagulation function assessments (Post-HCV Treatment Week 12 only) 
-
Inflammation assessments (Post-HCV Treatment Week 12 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Semm storage sample for possible additional clinical testing 
-r_Po __ _ 
• 
Obtain estimated glomemlar filtration rate according to the Cockcroft-Gault f01mula 
(see Section 4.2 for details) 
• 
Complete questiollllaires (Post-HCV Treatment Week 12 only): subject is to read 
questiollllaire by her/himself and write/mark answers directly onto the questiollllaires. 
-
VAS for HIV adherence 
-
HIVTSQc - Change version 
-
SF-36 
-
FACIT-F 
-
CLDQ-HCV 
-
WP AI: Hepatitis C 
• 
Subjects who meet the criteria for virologic rebOlmd should be managed according to 
Management of HIV Virologic Failure (Section 6.9) 
• 
Document study chugs dispensation and accmmtability for all HIV study drugs dispensed. 
Counsel all subjects regarding the importance of adherence and maintaining consistency to 
HIV study chug achninistration. 
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6.5.
Post-treatment Assessments
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit
Early study drug discontinuation during Part 1 (Day 1 through Week 8):
If the subject discontinues HIV study drug dosing in Part 1, the subject will be discontinued from 
the study and will not continue to Part 2 of the study. The subject will be asked to return to the 
clinic within 72 hours of stopping HIV study drugs for the ESDD visit, followed by the 30-Day 
Follow-Up visit. 
Early study drug discontinuation during Part 2 (after initiation of HCV treatment):
If the subject discontinues HCV study drug dosing only prior to completing the 12-week HCV 
treatment, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HCV study drug for the ESDD 
visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.

Continue to receive HIV study drugs (see ESDD procedures below).
If the subject discontinues HIV study drug dosing only, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HIV study drugs for the ESDD 
visit. 

HIV regimen may be changed, after discussion with the Medical Monitor. The new HIV 
regimen should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be 
continued unless an HIV regimen cannot be constructed that would allow coadministration 
with the new HIV regimen. 

Remain in the study to complete the 12-week HCV treatment (see Section 6.4.1) and 
follow-up visits 4 and 12 weeks after the last dose of LDV/SOF, as described in 
Section 6.4.2.
If the subject discontinues both HIV and HCV study drug dosing, the following will occur:

Be asked to return to the clinic within 72 hours of stopping study drugs for the ESDD visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.


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At the ESDD Visit, any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drugs, should be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at the ESDD Visit: 
• 
Review of AEs and changes in concomitant medications 
• 
Complete physical examination (mogenitallanorectal exams will be perfonned at the 
discretion of the Investigator) 
• 
Obtain vital signs, including weight 
• 
Obtain 12-lead ECG (performed supine) 
• 
Obtain mine samples for the following laboratmy analyses: 
-
Urinalysis and mine chemistiy 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a sennn test. 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratmy analyses: 
-
Chemistiy profile 
-
Hematology profile 
-
CD4+ cell count 
-
PlasmaHIV-1 RNA 
-
Plasma HCV RNA 
-
Plasma storage samples for virology, safety, and/or PK testing 
-PPD 
• 
Obtain estimated glomemlar filtration rate according to the Cockcroft-Gault formula 
(see Section 4.2 for details) 
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
Complete questionnaires: subject is to read questionnaire by her/himself and write/mark 
answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 400 copies/mL.

Perform study drug accountability:
For subjects that discontinue during Part 1 of the study, perform study drug 
accountability on HIV study drugs.
For subjects that discontinue during Part 2 of the study, perform study drug 
accountability for HIV and HCV study drugs. 
■
If the subject discontinues HCV study drug and is staying on HIV study drug, 
dispense HIV study drug until the last study visit. 
■
If the subject discontinues HIV study drug, HCV study drug will be dispensed at the 
scheduled visits as described in Section 6.4.1
6.5.2.
30-Day Follow-Up Visit
Subjects who complete the study through the Post-HCV Treatment Week 12 visit 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 HIV study drug in Part 1 of the study will be asked to 
return to the clinic after the completion of the ESDD visit for a 30-Day Follow-Up visit.
A ± 6 days window may be used to schedule this visit. The following evaluations are to be 
completed at this visit:

Review of AEs and changes in concomitant medications

Perform symptom-directed physical examination 


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
Obtain vital signs measurement, including weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. 

Obtain blood samples for the following laboratory analyses:
Chemistry profile
Hematology profile
CD4+ cell count
Plasma HIV-1 RNA
Plasma HCV RNA
At the 30-Day Follow-Up Visit, any evaluations showing abnormal results indicating that there is 
a reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.6.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (refer to Appendix 2). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study and asked to return for the 
ESDD Visit followed by the 30-Day Follow-Up Visit.
6.7.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree.

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the Investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Lack of efficacy (virologic failure)

Subject request to discontinue for any reason


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
Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.8.
Other Assessments
6.8.1.
Blood and Urine Storage
A portion of the blood drawn and urine collected at all visits (except Screening, Week 6, 30-Day 
Follow-Up, or Unscheduled) will be frozen and stored. From subjects who provide additional 
consent, a portion of the blood draw at Day 1, Weeks 4, 8, 20, Post-HCV Treatment Week 12, 
and ESDD visit will be frozen and stored. These stored samples may be used by Gilead or our 
research partners to help answer questions about the study drug, HIV-1 infection and its 
associated conditions, or clinical laboratory testing to provide additional safety data. No human 
genetic testing will be performed without express consent of the study subjects. At the 
conclusion of this study, these samples may be retained in storage for Gilead for a period of up to 
15 years.
6.8.2.
Bone Safety and Inflammation
For all subjects, blood will be collected for selected assessments of bone safety, including serum 
25-OH Vitamin D and PTH. Assessments 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, 8, 12, 20, and Post-HCV Treatment Week 12.
6.8.3.
Markers of Platelet Function and Coagulation
For all subjects, blood will be collected for selected assessments of platelet function and 
coagulation that may include: soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand 
and D-dimer. Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment 
Week 12.
6.8.4.
Markers of Renal Tubular Function
For all subjects, urine will be collected for selected assessments of renal tubular function that 
may include retinol binding protein, beta-2 microglobulin, urine albumin, and urine protein. 
Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment Week 12.
6.9.
HIV 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 at any visit has an HIV-1 RNA value 
50 copies/mL confirmed at the next scheduled or unscheduled visit (2 to 4 weeks later).


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6.9.1.
Management of HIV Virologic Rebound
The management of virologic rebound during Part 1 and Part 2 are different; subjects that have 
confirmed virologic failure during Part 1 will be discontinued from the study and not begin 
Part 2, while subjects that have virologic failure in Part 2 will be managed as described below.
Management of HIV-1 RNA ≥50 copies/mL during Part 1 (Day 1 through Week 8)

All HIV-1 RNA values ≥ 50 copies/mL should be discussed with the Medical Monitor. 

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If virologic failure is confirmed during Part 1 (regardless of detection of HIV drug 
resistance), the subject should be discontinued from HIV study drug and have the ESDD and 
30 Day Follow-Up visit.

If the viral load at the Week 6 visit is ≥ 50 copies/mL (and this is not a confirmation of 
virologic failure value), the HIV-1 RNA will be repeated at an unscheduled visit in about 
2 weeks from the Week 6 visit. This unscheduled visit for confirmation of virologic failure 
must be completed prior to the Week 8 visit (which subsequently means that the Week 8 visit 
will be delayed). The subject should not start Part 2 (nor should the subject start LDV/SOF 
therapy) until the repeat HIV-1 RNA value is available. If the repeat HIV-1 RNA confirms 
virologic rebound (≥ 50 copies/mL), then the subject will be discontinued from HIV study 
drugs as above. If the repeat HIV-1 RNA is < 50 copies/mL, then the subject may proceed to 
Part 2 and maintain the same visit schedule. Initiation of LDV/SOF therapy must occur 
within 2 to 4 weeks of the original visit window of the Week 8 visit. 


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Management of HIV-1 RNA ≥50 copies/mL during Part 2 (at or after Week 8)

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented. Assessment should include:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

All subjects with confirmed virologic failure should be discussed with the Medical Monitor.

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If genotypic/phenotypic resistance to study drug is documented, HIV study drugs 
(E/C/F/TAF or F/R/TAF) should be discontinued. 

If the HIV study drugs (E/C/F/TAF or F/R/TAF) are discontinued, a new HIV regimen 
should be constructed, after discussion with the Medical Monitor. The new HIV regimen 
should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued 
unless an HIV regimen cannot be constructed that would allow coadministration with the 
new HIV regimen.
If no resistance is detected from genotype/phenotype testing, the subject may remain on HIV 
study drugs and an HIV-1 RNA should be repeated (2 to 4 weeks after date of test with viral load 
≥50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on 
HIV study drug for each individual subject and document this assessment in the source 
documents. Investigators who opt to discontinue HIV study drugs for an individual subject must 
discuss with the Medical Monitor prior to study drug discontinuation.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
rebound.


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Figure 6-1.
HIV Virologic Rebound Schema
a
If virologic rebound is not confirmed, the subject will remain on their current HIV regimen.
b
If virologic rebound is confirmed, and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, integrase, and protease) will be analyzed.
c
Based on the results of the genotype/phenotype assays, the subject will remain on HIV study drugs or study drugs will be 
discontinued. If genotyping/phenotyping fails, a new ARV regimen may be configured at the discretion of the Investigator.
d
If no resistance detected, HIV-1 RNA will be repeated (2 to 4 weeks later). Investigator reviews HIV study drug 
continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation.
e
A new ARV regimen will be configured, after discussion with the Medical Monitor. The new HIV regimen should be 
designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued unless an HIV regimen cannot be 
constructed that would allow coadministration with the new HIV regimen.
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at the Post-HCV Treatment Week 12 visit, or last visit while receiving HIV 
study drugs (or within 72 hours of discontinuation of study treatment).


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6.10.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed > 1 log10 increase from on treatment nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the HCV on treatment phase.
All subjects who terminate LDV/SOF treatment early will complete the ESDD visit 
(see Section 6.5.1) and post-HCV treatment follow-up visits at 4 and 12 weeks after the last dose 
of LDV/SOF (see Section 6.4.2).
6.11.
End of Study
End of study is defined as completion of the Post-HCV Treatment Week 12 visit and the 30-Day 
Follow-Up visit.
6.12.
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.


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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, 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be 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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (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. 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 Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. 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 medication, 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 medication, collect all AEs, regardless of cause or relationship, 
until 30 days or 4 weeks after last administration of study IMP and report 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
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
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 unable to be accessed, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above.
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.


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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 (CFR), the EU Clinical Trials Directive (2001/20/EC) and relevant updates, 
and other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management

All clinical and clinically significant laboratory toxicities relating to HIV ARV agents will be 
managed according to uniform guidelines detailed in Appendix 3.

Management for toxicity should be differentiated between ARV and HCV medications.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose after discussion with the 
Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Medical Monitor


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7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase (CK) after 
strenuous exercise or triglyceride elevation that is nonfasting or that can be medically 
managed) or a clinical event considered unrelated to investigational medicinal product
7.5.4.
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 eGFR 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. 


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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/1.73 m2) = 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.
7.6.
Stopping Rules for HCV Treatment
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of study drug may be discontinued in the event of a clinical or laboratory event. 
There is no option for dose reduction of LDV/SOF. If LDV/SOF FDC is stopped due to toxicity, 
it must not be restarted. The ESDD visit should be completed after discontinuation of LDV/SOF. 
The Post-HCV Treatment Week 4 and Week 12 visits must also be completed. 
Subjects who meet any of the following laboratory criteria must stop HCV study treatment:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to LDV/SOF


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7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, and 
pregnancy reports regardless of an associated AE.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint associated with an adverse event is defined as complaints arising from 
potential deviations in the manufacture, packaging, or distribution of the medicinal product
associated with an adverse event, which is any untoward medical occurrence in a study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the study drug.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. The same reporting obligations shall apply to female partners of male study 
subject (ie, partner pregnancies).
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.


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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 
Sections 7.1.2 and 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 (of both female subject pregnancies and male subject’s partner 
pregnancies) 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: 
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
safety_fc@gilead.com
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV 
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects; 

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment). 
8.1.3.
Secondary Endpoint
Secondary efficacy endpoints are: 

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment).

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using FDA snapshot algorithm
Note: Most often, 24 weeks of HIV therapy will coincide with the Post-HCV Treatment Week 4 
visit
Secondary safety endpoint is:

Grades 1 through 4 adverse events after switch to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment.


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8.1.4.
Other Endpoints of Interest
No other endpoints of interest will be considered.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
HIV Full Analysis Set: The primary analysis set for HIV efficacy analysis will be the HIV full
analysis set (HIV FAS) and is defined as all subjects randomized and who received at least one 
dose of F/TAF-based regimen. 
HCV Full Analysis Set: The primary analysis set for HCV efficacy analysis will be the HCV full 
analysis set (HCV FAS) and is defined as all subjects who received at least one dose of 
LDV/SOF. 
Subjects will be grouped according to the treatment they were randomized to.
8.2.1.2.
Safety
HIV Safety Analysis Set: The primary analysis set for HIV safety analyses will be the HIV 
safety analysis set and is defined as all subjects randomized to the study and who received at 
least one dose of F/TAF-based regimen. 
HCV Safety Analysis Set: The primary analysis set for HCV safety analyses with 
coadministration with the F/TAF-based regimen in Part 2 will be the HCV safety analysis set and 
is defined as all subjects who received at least one dose of LDV/SOF.
All data collected during treatment will be included in the safety summaries. Subjects will be 
grouped according to the treatment they actually received.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who were randomized and have received at least one 
dose of either the F/TAF-based regimen (at Week 4) or coadministration of the F/TAF-based 
regimen and LDV/SOF, and for whom concentration data of any analyte of interest are available. 
The PK analysis set will be used for listing PK concentration data and summaries.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by standard descriptive methods 
using the safety analysis set. Demographic and baseline measurements will be summarized by 
treatment group (E/C/F/TAF; F/R/TAF) and overall. 
Summaries will include sex, race/ethnicity, age, height, weight and body-mass index.


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Baseline data will include a summary of risk factors for HIV-1 infection and HCV 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 the treatment groups.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
therapy). The primary analysis will be performed after all enrolled subjects have been followed 
through post-HCV treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate will be compared to the performance goal of 
88% by using two-sided exact one-sample binomial test at the 0.05 significance level. The basis 
for this benchmark includes the overall trend toward increasing SVR rates in recent years; and 
the general appeal of using a fixed clinically relevant threshold as a measure of treatment benefit 
of LDV/SOF.
The null (H0) and alternative (H1) hypotheses used to assess superiority of LDV/SOF relative to 
the performance goal of 88% are:

H0: SVR12 = 88%

H1: SVR12 ≠ 88%
The primary efficacy analysis will also include the construction of an associated two-sided exact 
95% CI.
Furthermore, SVR12 will also be summarized by the HIV treatment arms (F/TAF-based 
regimen).
8.4.2.
Secondary Analyses
The methods to assess proportion of HIV-1 RNA ≥50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using a FDA snapshot algorithm will be provided in 
detail in the Statistical Analysis Plan.
The changes from baseline in CD4+ count at Week 8 and Post-HCV Treatment Week 12 will be 
summarized using descriptive statistics.
The analysis of SVR4 will be summarized using similar methods as for the primary endpoint.


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8.5.
Safety Analysis
All safety data collected on or after the date F/TAF-based ARV regimen was first dispensed up 
to the date of last dose of study drug(s) (either F/TAF-based regimen alone or in combination 
with LDV/SOF) plus 30 days will be summarized overall, according to the study drug(s) 
received. 
Additionally, safety data collection on or after the first dose of LDV/SOF until the last dose of 
LDV/SOF plus 30 days (ie, during coadministration of HIV/HCV study drugs), will also be 
summarized.
Data for pretreatment and post-last-dose-plus-30-days will be included in data listings. 
8.5.1.
Extent of Exposure
A subject’s extent of exposure to each study drug will be generated from the corresponding study 
drug administration data. Duration of exposure to each study drug will be expressed as the 
number of weeks between the first and last dose for each study drug, inclusive, regardless of 
temporary interruptions in study drug administration. 
Dosing information for individual subjects will be listed. 
8.5.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
HIV treatment-emergent AEs are events that meet one of the following criteria up to 30 days 
after the permanent discontinuation of HIV study drug(s): 

AEs with onset dates on or after the first dose date of HIV study drug(s) and no later than 
30 days after permanent discontinuation of HIV study drug(s), or,

AEs that result in permanent study drug discontinuation of HIV study drug(s).
The number and percentage of subjects with treatment-emergent AEs (by SOC and PT) will be 
summarized as described in Section 8.5. A similar definition will be used to define HCV 
treatment-emergent AEs during coadministration of HIV/HCV study drugs. Additional 
summaries will include summaries for AEs by grade, Investigator’s assessment of relationship to 
study drug, and effect on study drug dosing.
All treatment-emergent and non-treatment emergent AEs will be included in a data listing.


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8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 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 HIV 
study drug(s) plus 30 days, will be summarized as described in Section 8.5. Similarly, 
treatment-emergent abnormalities during coadministration of HIV/HCV study drugs will also be 
summarized. 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 HIV study drug(s) or after the subject 
has been discontinued from HIV study drug(s) plus 30 days will be included in a data listing.
8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Population PK assessments may be conducted for some of the relevant analytes: TAF, TFV, 
RPV, FTC, EVG, COBI, LDV, SOF, or GS-331007. Population PK assessments will be 
summarized in a separate report.
8.7.
Biomarker Analysis
The renal, vascular and inflammatory markers (see Sections 6.8.2 – 6.8.4 for details) will be 
summarized by treatment group and visit using descriptive statistics. The difference in change 
from baseline in these biomarkers between the treatment groups (E/C/F/TAF and F/R/TAF) will 
be tested using Wilcoxon rank sum test.
8.8.
Sample Size
A sample size of 120 subjects will provide at least 85% power to detect an improvement of at 
least 8 percentage points in SVR12 rate from the performance goal of 88% by using a two-sided 
exact one-sample binomial test at significance level of 0.05.


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


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC or 
local requirements.
9.1.4.
Confidentiality
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, or laboratory. Laboratory specimens must 
be labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions NOTE: The Investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any 
interim time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 


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accurately reflect the information in the source documents. The eCRF capture the data required 
per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (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.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead Quality Assurance (QA), the site may destroy used (empty or partially empty) and unused 
IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP 
will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, 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 IRB/IEC in 
accordance with local requirements and receive documented IRB/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, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/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 CRF/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), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 87
29 November 2016
10.
REFERENCES
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Bhagani S, Sulkowski MS, Cooper C, Kwo PY, Kowdley K, Mertens M, et al. 
Ledipasvir/Sofosbuvir is Safe and Effective for the Treatment of Patients with 
Genotype 1 Chronic HCV Infection in Both HCV  Mono-and HCV/HIV Co-
infected Patients [Abstract: 386]. European AIDS Clinical Society (EACS); 2015 
21-24 October; Barcelona, Spain. 
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.
Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated 
interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic 
hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 
2004;292 (23):2839-48.
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30 
(Suppl 2):S-171-S6.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Custodio J, Doyle E, Pang PS, Das M, H. C, Ma G, et al. Lack of Drug Interactions between 
Boosted and Unboosted Tenofovir Alafenamide-based Antiretroviral Single 
Tablet Regimens (Emtricitabine/Rilpivirine/Tenofovir Alafenamide and 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) and the anti-HCV 
Single Tablet Regimen Ledipasvir/Sofosbuvir [Abstract 727]. Infectious Diseases 
Society of America (IDSA); 2015 7-11 October; San Diego, CA. 
Deng LP, Gui XE, Zhang YX, Gao SC, Yang RR. Impact of human immunodeficiency virus 
infection on the course of hepatitis C virus infection: a meta-analysis. World J 
Gastroenterol 2009;15 (8):996-1003.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.


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Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 88
29 November 2016
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.
Gay CL, Mayo AJ, Mfalila CK, Chu H, Barry AC, Kuruc JD, et al. Efficacy of NNRTI-based 
antiretroviral therapy initiated during acute HIV infection. AIDS 2011;25 (7):941-
9.
Gilead Sciences Canada Inc. SOVALDI® (Sofosbuvir) Tablets 400 mg. Product Monograph.  
Mississauga, ON. December 2013:
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised November 2015:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA October 2014:
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of Product 
Characteristics.  County Cork Ireland. January 2014.  2014:
Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human 
immunodeficiency virus infection on the course of hepatitis C virus infection: a 
meta-analysis. Clin Infect Dis 2001;33 (4):562-9.
HCV Guidelines. Recommendations for Testing, Managing, and Treating Hepatitis C.  2015.
Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, et al. 
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus 
ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004;18 (13):F27-
36.
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17 (2):107-
15.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010 [Accepted Manuscript]. Clin Infect Dis 2014.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 89
29 November 2016
Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study 
[Supplementary Webappendix]. Lancet 2015.
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.
Myers RP, Liu M, Shaheen AA. The burden of hepatitis C virus infection is growing: a Canadian 
population-based study of hospitalizations from 1994 to 2004. Can J 
Gastroenterol 2008;22 (4):381-7.
Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and 
Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med 2015:705-
13.
Nakano T, Lau GM, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus 
genotypes and subtypes based on the complete coding region. Liver Int 2012;32 
(2):339-45.
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.
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 
August 22.  2012.
Salmon-Ceron D, Lewden C, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Liver disease as 
a major cause of death among HIV infected patients: role of hepatitis C and B 
viruses and alcohol. J Hepatol 2005;42 (6):799-805.
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;385:2606-15.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.


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Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 90
29 November 2016
Smith BD, Morgan ML, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. 
Recommendations for the Identification of Chronic Hepatitis C Virus Infection 
Among Persons Born During 1945–1965. Centers for Disease Control and 
Prevention MMWR  August, 2012.
Staples CT, Jr., Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) 
Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the 
effect of coinfection on survival. Clin Infect Dis 1999;29 (1):150-4.
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to 
HAART [abstract]. . 40th Annual Meeting of the Infectious Disease Society of 
America; 2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
The Joint United Nations Programme on HIV/AIDS (UNAIDS). Regional Fact Sheet 2012. 
North America, Western and Central Europe.  2012.
Thomas DL. The challenge of hepatitis C in the HIV-infected person. Annu Rev Med 
2008;59:473-85.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. 
Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in
HIV-infected patients. N Engl J Med 2004;351 (5):438-50.
World Health Organization (WHO). World Health Organization, UNAIDS, UNICEF. Global 
HIV/AIDS Response: Epidemic update and health sector progress towards 
universal access. Progress Report 2011.  2011.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 91
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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 (HIV ARV Agents only)
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.
CDC Classification Systems, AIDS-Indicator Conditions


FTC/RPV IT AF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences, lnc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Randomized, Open-label, Controlled Study of the Efficacy, Safety and Tolerability 
of 12 Weeks of Ledipasvir/Sofosbuvir (LOY /SOF) Treatment for HJV/HCV Co-infected 
Subjects who Switch to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir A lafenamide 
(E/C/F/TAF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide (F/R/TAF) prior to 
LDV/SOF HCV Treatment, the HIV/HCV Co-STARs study (Co-infection treatment with 
Single Tablet Antiviral Regimens) 
GS-US-366-1992, Amendment 2, 29 November 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Thai Nguyen-Cieary (Printed) 
Medical Monitor 
Date 
_IPPD 
Si.,.--
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. l will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within tbe time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
tbat they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 92 
29 November 2016 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 93
29 November 2016
Appendix 2.
Study Procedures Table
Screeninga
Day 1b
End of Weekc 
Part 1
On Treatment
End of Weekc – Part 2
30-Day 
Follow-Upd
ESDDe
On Treatment
Post-HCV Treatment
4
6
8
12
16
20
4
12
Written Informed Consent
X
Medical History 
X
Liver Cirrhosis Determination
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examinationf
X
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-Lead ECG (performed supine)
X
X
Urinalysis & Urine Chemistry
X
X
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
X
Urine Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Testg
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
X
Hematology Profilei
X
X
X
X
X
X
X
X
X
X
X
Coagulation Assessmentsj
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsk
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 Proviral Genotypel
X
HIV-1 Genotype/Phenotypem
X


FTC/RPV IT AF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
PlasmaHCVRNA 
HCV Genotype & Subtype 
HCV IL28B Genotype 
HIV, HBV & HCV Serologies" 
Evaluations of Bone & Renal Safety, 
Inflammation and Platelet and Coagulation 
Function° 
Plasma Storage SampleP 
Serum Storage SampleP 
I 
IFPD I 
Estimated G FRear 
Population PK' 
Health Related Questionnaires! 
Randomization 
Study Drug Dispensation and 
Accountability" 
Screeninga 
Day 1b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Evaluations to be completed within 42 days prior to the Day 1 visit 
End ofWeekc 
Part 1 
On Treatment 
4 
6 
X 
X 
X 
X 
X 
X 
X 
X 
End ofWeekc- Part 2 
On Treatment 
Post-HCV Treatment 
8 
12 
16 
20 
4 
12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 2 
30-Day 
Follow-Upd 
ESDD• 
X 
X 
X 
X 
X 
X 
X 
X 
xv 
b 
Subjects will be dispensed HIV study drugs only at the Day 1 visit; initiation ofHIV treatment with the study drugs must take place within 24 hours after the Day 1 visit. 
c 
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are± 2 days of the protocol specified date through Post-HCV Treatment Week 4 visit, and 
± 4 days of the protocol specified date at Post-HCV Treatment Week 12. 
d 
For the purpose of scheduling a 30-Day Follow-Up Visit, a± 6 days window may be used 
e 
Early Study Drug Discontinuation visit to occur within 72 hours oflast dose of study drug. Refer to Section 6.5.1 for management of early study drug discontinuation of 
Parts 1 and 2. 
f 
Symptom-directed physical examination as needed 
g 
For females of childbearing potential only as defined by Appendix 5. Positive urine pregnancy tests will be confirmed with a serum test. 
h 
Chemistry profile: alkaline phosphatase, AST, AL T, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid. At visits in which metabolic assessments are to be performed, analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry profile 
CBC with differential and platelet count 
CONFIDENTIAL 
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29November 2016 


FTC/RPV IT AF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
Final 
Amendment 2 
J 
k 
m 
n 
0 
p 
q 
r 
s 
u 
v 
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) 
Metabolic assessments (collected fasted, 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) 
If a historical genotype report prior to first AR Vis not available, or subject has 3 or more prior ARV regimens, whole blood sample for proviral genotype analysis of archived 
resistance 
HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic rebound with HIV-1 RNA value 2: 400 copies/mL 
Serology testing includes HIV and HCV antibody, and HBV core antibody(HBcAb), surface antibody(HBsAb), surface antigen (HBsAg), e-antibody (HBeAg), e-antibody 
(HBeAb), andHBVDNA. 
Blood for bone safety, parathyroid (PTH) and serum OH-25 vitamin D; Inflammation may include cystatin-C, IL-6, hs-CRP, sCD14, sCD163, sTNF -1 R, and L p-PLA2; 
Platelet and coagulation function 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, beta-2-microglobulin, urine albumin, and urine protein will be collected. Samples 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 fasted state. 
Plasma storage samples for safety, virology, and/or PK testing. Serum storage samples for possible additional clinical testing. 
PPD 
'Esnmatea GFR according to the C0cKcroU-tiaiilt formillator creatmme clearance (see Secb.on 4.2 lor Cletmls 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior to observed study drug dosing; 2) the postdose sample should be drawn between 
15 mins and 4 hours postdose 
Health related questionnaires: adherence for HIV (VAS), HIVTSQs- Status version (at Day 1 only), HIVTSQc -Change version (at all other visits), SF-36, FA CIT -F, 
CLDQ-HCV, and WPAI: Hepatitis C. 
Part 1: HIV study drugs are dispensed after all Day 1 assessments are completed and randomization occurred, and through the duration of the study. 
Part 2: After determination ofHIV suppression(< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability of HIV study drugs, LDV/SOF will be dispensed at 
Weeks 8, 12, and 16 only. 
Post-HCV Treatment Week 12: drug accountability only; study drug will not be dispensed at this visit. 
If subjects discontinue during Part 1, only drug accountability will be performed; study drug will not be dispensed at this visit. In Part 2, if subject discontinues LDV/SOF but 
still continues with HIV study drug, HIV study drug will be dispensed until the last study visit. If subject discontinues HIV study drug but still continues with LDV/SOF, 
LDV/SOF will be dispensed. If subject discontinues both HIV and HCV study drugs, only drug accountability will be performed; no dispensation will occur at this visit. 
CONFIDENTIAL 
Page 95 
29November 2016 


FTCIRPV/TAF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only) 
Grade 1 
L_ ______ 
G_r_a_d_e_2 ______ _JI 
Ll _______ 
G_r_a_d_e_3 ______ _JI 
Ll ----------G--r-a-de--4----------~ 
May continue 
Repeat lab to 
dosing at the 
confirm toxicit) 
discretion of the 
grade 
investigator 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
1. Withhold investigational medicinal products until ~Grade 2 
2. Restart all investigational medicinal products at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently 
Repeat lab to 
confirm toxicity 
grade 
1 
1 
Ifc 
unrelated to 
inve 
edicinal products, 
dos 
onfirmed and 
stigational m 
mg may conti 
retion of the 
nue at the 
disc 
investi~ator 
If confirmed and 
possibly or probably 
____. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 
CONFIDENTIAL 
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FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 97
29 November 2016
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 98
29 November 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized 
Ratio of prothrombin time 
(INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time 
(APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 99
29 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 100
29 November 2016
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
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 101
29 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 102
29 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 103
29 November 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 104
29 November 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 105
29 November 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-urgent 
medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant 
acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening 
consequences (eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences (eg, malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences (eg, 
tamponade) OR Urgent 
intervention indicated


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 106
29 November 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV block 
OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, 
pulmonary embolism, life-
threatening thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 107
29 November 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced 
to 70% to 80%
FEV1 or peak flow 50% to 
69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak 
flow 25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social 
& functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse 
oximetry 90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in 
affected eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing 
greater than minimal 
interference with usual social 
& functional activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in 
affected eye(s)


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 108
29 November 2016
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by study 
participant or  caregiver (for 
disabled adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited number of 
bullae OR Superficial 
ulcerations of mucous 
membrane limited to one site
Extensive or generalized 
bullous lesions OR Stevens-
Johnson syndrome OR 
Ulceration of mucous 
membrane involving two or 
more distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or minimal 
interference with usual social 
& functional activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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29 November 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight 
loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated [eg, 
tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(eg, diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences (eg, sepsis or 
perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention
indicated
Life-threatening reduction in 
oral intake


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Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 110
29 November 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–
48 hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability 
to perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences 
(eg, hypotensive shock)


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


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


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Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 113
29 November 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase from 
Previous Level of Control to 
Any of These Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5–20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated with 
a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


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


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


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


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


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Amendment 2
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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. 
Women who are not post-menopausal or permanently sterile in accordance with these definitions 
will be considered of childbearing potential.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of E/C/F/TAF have demonstrated that 
E/C/F/TAF reduces the exposure of ethinyl estradiol in hormonal contraceptives. No clinically 
significant interactions between the components of F/R/TAF and LDV/SOF and hormonal 
contraception are known. Female subjects who choose hormonal contraception will be required 
to select a second backup method as defined below. 
Non-clinical toxicity studies of LDF/SOF, F/R/TAF, and E/C/F/TAF have demonstrated no 
adverse effect on fertility or embryo-fetal development. However, there is insufficient clinical 
data available on use of these products in pregnant women. Please refer to the latest version of 
the IB (F/R/TAF) and package inserts (E/C/F/TAF and LDV/SOF) for additional information.
b. Contraceptive Methods allowed for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. Women must also not rely solely on hormone-containing 
contraceptives (except for intrauterine devices [IUDs] that may release hormones) as a form of 
birth control during the study. Women may continue oral, injectable, transdermal, or other 
hormonally based contraceptives that are designed to inhibit ovulation, if desired, but these will 


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Amendment 2
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not be acceptable as a sole form of contraception; an additional form of acceptable effective 
contraception (methods below) must be chosen even if hormonal ovulation-inhibiting 
contraception is continued. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Day 1 visit prior to randomization. At minimum, a pregnancy test 
will be performed at the end of relevant systemic exposure. In the event of a delayed menstrual 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy. This is even true for women of childbearing potential with infrequent or irregular 
periods.
Women of child bearing potential in this study must agree to use the following forms of 
contraception from Screening until 30 days after the last dose of study drug.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of < 1% per year. Hormonal IUDs meeting 
this criterion are acceptable as a sole method.
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Combined barrier methods: 
■
Diaphragm with spermicide and a male condom without spermicide
Or 
■
Cervical cap with spermicide and male condom without spermicide 

Women who choose to continue on their hormonal contraceptive method (eg, combined oral 
contraceptives, injectable, transdermal, and intravaginal contraceptives) are asked to also 
choose one of the above methods to supplement the hormonally based method given the 
effect of E/C/F/TAF on ethinyl estradiol. These women may, however, use their hormonal 
contraceptive method and choose a single barrier method to supplement their hormonal 
contraceptive method (preferably the male condom). 
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.


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Amendment 2
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3) Contraception Requirements for Male Subjects
During the study and for 30 days after the last dose of study drug, male subjects with female 
partners of childbearing potential should use condoms without spermicide when engaging in 
intercourse of reproductive potential.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Male subjects should 
also notify the investigator if their female partner becomes pregnant during the study or within 
30 days of last dose of study drugs. Instructions for reporting pregnancy and pregnancy outcome 
are outlined in Section 7.7.2.1.


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Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions

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)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month 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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 123
29 November 2016

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome attributed to HIV Infection
CDC Revised Surveillance Case Definition for HIV Infection – 2014 {Selik et al 2014}

SAP_003.pdf: 


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Prot_001.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F IT AF) or Emtricitabine!Rilpivirine/T enofovir Alafenamide 
(F/R/TAF) prior to LDV/SOF HCV Treatment, the HIV/HCV 
Co-STARs study (Co-infection treatment with Single Tablet Antiviral 
Regimens) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
123098 
2014-004545-27 
NCT02707601 
HIV -1 Infection 
GS-US-366-1992 
Gilead Clinical 
Name: 
PPD 
PPU 
PPD 
Program Manager: 
Telephone: 
Fax: 
Gilead Co-Medical 
Name: 
Monitor: 
Telephone: 
Mobile: 
Gilead Co-Medical 
Name: 
Monitor: 
Telephone: 
Mobile: 
Protocol Version/Date: 
Original: 
Amendment 1: 
Richard Haubrich, MD 
PPD 
PPD 
Thai N~yen-Clemy, MD 
PPD 
PPD 
18 December 2015 
27May2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, patiiculm·ly 1mpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the inf01mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 2
27 May 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................19
1.2.1.
General Information .............................................................................................................19
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®).................................................................................19
1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF, Odefsey®) Fixed Dose Combination ..................................................................21
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination..............................................22
1.3.1.
General Information .............................................................................................................22
1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant 
to the Proposed Study...........................................................................................................22
1.4.
Rationale for This Study ........................................................................................................................27
1.5.
Risk/Benefit Assessment for the Study..................................................................................................28
1.6.
Compliance ............................................................................................................................................29
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................31
3.1.
Endpoints ...............................................................................................................................................31
3.2.
Study Design..........................................................................................................................................31
3.3.
Study Treatments ...................................................................................................................................31
3.4.
Duration of Treatment............................................................................................................................32
3.5.
Samples for Optional Exploratory Assessments ....................................................................................33
4.
SUBJECT POPULATION..................................................................................................................................34
4.1.
Number of Subjects and Subject Selection ............................................................................................34
4.2.
Inclusion Criteria....................................................................................................................................34
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................40
5.1.
Randomization .......................................................................................................................................40
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF .....................................................40
5.2.1.
Formulation..........................................................................................................................40
5.2.2.
Packaging and Labeling .......................................................................................................41
5.2.3.
Storage and Handling...........................................................................................................42
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF...................................................42
5.4.
Prior and Concomitant Medications.......................................................................................................42
5.5.
Accountability for Investigational Medicinal Product (IMP).................................................................48
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 3
27 May 2016
6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Day 1 Assessments...............................................................................................................51
6.3.
Randomization .......................................................................................................................................53
6.4.
Treatment Assessments..........................................................................................................................53
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20).........................................53
6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) .................................................................................................56
6.5.
Post-treatment Assessments ...................................................................................................................58
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................58
6.5.2.
30-Day Follow-Up Visit.......................................................................................................60
6.6.
Assessments for Premature Discontinuation from Study.......................................................................61
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................61
6.8.
Other Assessments .................................................................................................................................62
6.8.1.
Blood and Urine Storage......................................................................................................62
6.8.2.
Bone Safety and Inflammation.............................................................................................62
6.8.3.
Markers of Platelet Function and Coagulation.....................................................................62
6.8.4.
Markers of Renal Tubular Function .....................................................................................62
6.9.
HIV Virologic Failure............................................................................................................................63
6.9.1.
Management of HIV Virologic Rebound .............................................................................63
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit ........................................65
6.10.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................66
6.11.
End of Study...........................................................................................................................................66
6.12.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69
7.4.
Gilead Reporting Requirements.............................................................................................................70
7.5.
Toxicity Management ............................................................................................................................71
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................71
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................72
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.5.4.
Management of Potential Nephrotoxicity.............................................................................72
7.6.
Stopping Rules for HCV Treatment.......................................................................................................73
7.7.
Special Situations Reports......................................................................................................................73
7.7.1.
Definitions of Special Situations..........................................................................................73
7.7.2.
Instructions for Reporting Special Situations.......................................................................74
8.
STATISTICAL CONSIDERATIONS................................................................................................................76
8.1.
Analysis Objectives and Endpoints........................................................................................................76
8.1.1.
Analysis Objectives..............................................................................................................76
8.1.2.
Primary Endpoint .................................................................................................................76
8.1.3.
Secondary Endpoint .............................................................................................................76
8.1.4.
Other Endpoints of Interest ..................................................................................................77
8.2.
Analysis Conventions.............................................................................................................................77
8.2.1.
Analysis Sets ........................................................................................................................77


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 4
27 May 2016
8.3.
Demographic Data and Baseline Characteristics ...................................................................................77
8.4.
Efficacy Analysis ...................................................................................................................................78
8.4.1.
Primary Analysis..................................................................................................................78
8.4.2.
Secondary Analyses .............................................................................................................78
8.5.
Safety Analysis.......................................................................................................................................79
8.5.1.
Extent of Exposure...............................................................................................................79
8.5.2.
Adverse Events.....................................................................................................................79
8.5.3.
Laboratory Evaluations ........................................................................................................80
8.5.4.
Other Safety Evaluations......................................................................................................80
8.6.
Pharmacokinetic Analysis......................................................................................................................80
8.7.
Biomarker Analysis................................................................................................................................80
8.8.
Sample Size............................................................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only)..............96
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............97
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120
Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions ...................................................123


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 5
27 May 2016
LIST OF IN-TEXT TABLES
Table 1-1.
Combined Analysis from Phase III ION Studies....................................................................24
Table 1-2.
Study 1: F/R/TAF and LDV/SOF...........................................................................................25
Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter................................................................26
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen .........................................................34
Table 4-2.
Disallowed Agentsa ................................................................................................................38
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF ............................................43
Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF................................................47
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................32
Figure 6-1.
HIV Virologic Rebound Schema............................................................................................65


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 6
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404
Study Title: 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to  
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) prior to LDV/SOF HCV Treatment, the HIV/HCV 
Co-STARs study (Co-infection treatment with Single Tablet Antiviral 
Regimens)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
123098
2014-004545-27
TBD
Study Centers 
Planned:
Approximately 50 centers in North America
Objectives:
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the proportion 
of subjects achieving HCV RNA below the lower limit of 
quantification (LLOQ) 12 weeks after the last dose of LDV/SOF 
(sustained virologic response [SVR12]).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA 
below LLOQ 4 weeks after the last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after 
switching to E/C/F/TAF or F/R/TAF 24 weeks from the start of 
the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to E/C/F/TAF 
or F/R/TAF from the current antiretroviral (ARV) therapy in 
virologically-suppressed, HIV-1/HCV co-infected subjects; 

To evaluate the safety and tolerability of 12 weeks of treatment 
for HCV with LDV/SOF in virologically-suppressed, HIV-1/HCV 
co-infected subjects who switched to E/C/F/TAF or F/R/TAF.


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Amendment 1
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Study Design:
Randomized, multicenter, open-label, 2-part study in adult male and 
female subjects with HIV who are co-infected with chronic genotype 
(GT) 1 HCV infection.  Subjects will have one of the following: 
1) no cirrhosis and no prior HCV treatment (treatment-naïve); 
2) no cirrhosis and have received HCV treatment only with 
interferon (IFN) +/- ribavirin (RBV) or IFN + RBV + an HCV 
protease inhibitor (PI) (treatment-experienced); or 
3) compensated cirrhosis and no prior HCV therapy
(treatment-naïve).  
Subjects will be on stable ARV therapy for 6 months prior to 
screening and with HIV RNA < 50 copies/mL.
Part 1: Approximately 240 subjects will be randomized 1:1 to switch 
from stable ARV therapy to one of the following treatments.  
Randomization will be stratified by race (black vs. non-black).

Treatment Group 1: Switch from 2 nucleoside/nucleotide 
reverse transcriptase inhibitor (NRTI) plus a third ARV agent to 
E/C/F/TAF fixed dose combination (FDC) (n = 120) 

Treatment Group 2: Switch from 2 NRTI plus a third ARV
agent to F/R/TAF FDC (n = 120) 
All subjects will receive 8 weeks of treatment and will have an 
assessment of safety, tolerability and HIV-1 RNA values at the 
conclusion of 8 weeks. Plasma samples collected at Week 6 
(laboratory visit only) will be included in assessing virologic 
suppression of HIV-1 RNA at Week 8. Subjects who tolerate the 
switch to E/C/F/TAF FDC or F/R/TAF FDC and maintain virologic 
suppression of HIV-1 RNA < 50 copies/mL will continue to 
Part 2. HIV treatment will be continued until their SVR12 
assessment.
Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or 
F/R/TAF FDC treatment, subjects will continue their HIV treatment
and initiate 12 weeks of LDV/SOF HCV therapy.  

LDV/SOF FDC tablet once daily for 12 weeks
After LDV/SOF therapy, subjects will continue their HIV treatment
and be followed for safety and efficacy for an additional 12 weeks to 
determine the HCV SVR12 endpoint and HIV safety and efficacy 
endpoints.


FTC/RPV/TAF
Protocol GS-US-366-1992
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Amendment 1
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Number of Subjects 
Planned:
240 subjects (approximately 120 subjects randomized to each of 
E/C/F/TAF FDC or F/R/TAF FDC).
Target Population:
Chronic GT 1 HCV, HIV-coinfected adults who do not have cirrhosis 
and are HCV treatment-naïve or treatment-experienced with 
IFN +/- RBV +/- PI.  Compensated cirrhotic subjects must be 
treatment-naïve. Subjects are on a stable HIV regimen with 2 NRTI 
+ 3rd agent with suppressed HIV RNA.
Duration of 
Treatment:
Part 1: Subjects will be randomized to receive E/C/F/TAF or 
F/R/TAF for 8 weeks.  
Part 2: Subjects will receive 12 weeks of LDV/SOF and continue 
their randomized F/TAF-based regimen for 12 weeks after 
completion of LDV/SOF (total approximately 24 weeks in Part 2).
Diagnosis and Main 
Eligibility Criteria:
HIV/HCV co-infected adult subjects who meet the following criteria 
will be given the option to participate in the study:

Chronic GT 1, HCV infected, male and non-
pregnant/non-lactating female subjects, without cirrhosis, 
treatment-naïve or treatment-experienced with 
IFN +/- RBV +/- HCV PI.  Compensated cirrhotic subjects must 
be HCV treatment-naïve. No prior treatments with NS5A and 
NS5B or any HCV direct acting antivirals, except boceprevir, 
telaprevir and simeprevir, in combination with IFN and RBV.

Currently on an ARV regimen (2 NRTI + a third agent) without 
change for 6 months prior to screening. Documented plasma 
HIV-1 RNA levels < 50 copies/mL (or undetectable HIV-1 RNA 
level according to the local assay being used if the limit of 
detection is ≥ 50 copies/mL) for ≥6 months preceding the 
Screening visit. After reaching HIV-1 RNA < 50 copies/mL, 
single values (“blips”) of HIV-1 RNA ≥50 copies/mL followed 
by resuppression is allowed. For subjects with 3 or more prior 
ARV regimens, a regimen history should be provided for approval
by the Sponsor. 

Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.


FTC/RPV/TAF
Protocol GS-US-366-1992
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Amendment 1
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
Have no documented resistance to any of the HIV study agents at 
any time in the past, including but not limited to the reverse 
transcriptase resistance mutations K65R, K70E, K101E/P, 
E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, 
F227C, M230I/L, the combination of K103N+L100I, or 3 or more 
thymidine analog associated mutations (TAMs) that include 
M41L or L210W (TAMs are M41L, D67N, K70R, L210W, 
T215Y/F, K219Q/E/N/R). If a historical genotype prior to first 
ARV is not available or subject had 3 or more prior ARV 
regimens, subject will have proviral genotype analysis for 
archived resistance prior to Day 1.

No history of HIV virologic failure.

No evidence of Hepatitis B infection. 

Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min as 
estimated by Cockcroft-Gault formula.
Study Procedures/
Frequency:
Screening assessments will be completed within 42 days of the Day 1 
visit.
After consent is obtained, screening assessments will include physical 
examination, medical history, historical HIV resistance test collection 
(if available; HIV DNA archive genotype if no historical HIV 
genotype available), height, weight, vital signs, 12-lead 
electrocardiogram (ECG), screening procedure related adverse events 
(AEs), concomitant medications (CM), safety laboratory tests 
(including hematology, chemistry, and coagulation), HCV and HIV 
RNA, serology (HIV, HCV, HBV), HCV genotyping, assessment of 
the absence of cirrhosis, serum β-hCG (females of child bearing 
potential only), IL28B genotyping, and urinalysis.
On treatment assessment:

Part 1: F/TAF-based ARV regimen switch: 
Day 1 and Weeks 4, 6 (lab only), and 8 

Part 2: LDV/SOF therapy and follow-up
First dose of LDV/SOF at Week 8, then Weeks 12, 16, and 
20 (4, 8, and 12 weeks after HCV start) and post LDV/SOF 
follow up at 4 and 12 weeks posttreatment (SVR 4 and 12).
On treatment assessments will include AEs, CMs, study drug dosing 
adherence (including pill count), physical examination, weight, vital 
signs, safety laboratory tests, HCV and HIV RNA, urine pregnancy 
tests (females of child bearing potential only).


FTC/RPV/TAF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Amendment 1 
Fasting lipid profile measurements and fasting glucose will be 
performed at Day 1, Weeks 8, 20, and at Post-HCV Treatment 
Week 12. Lipids will include total cholesterol (TC), high density and 
low density lipoproteins (HDL, LDL), non-HDL cholesterol, 
triglycerides (TG) and cholesterol ratios. 
Post treatment assessments will include AEs and CMs collected 
through 30 days after the last dose ofHIV study drug, HCV and HIV 
RNA, safety laborat01y tests (including hematology and chemistry), 
and urine pregnancy tests (females of childbearing potential only). 
Plasma samples for viral HIV RNA will be collected at Day 1 and 
every visit thereafter (except HCV RNA at Week 4). Stored samples 
for HCV RNA sequencing/phenotyping and HIV RNA 
genotyping/phenotyping will be collected at Day 1 and eve1y visit 
thereafter. Blood will be collected at Screening for analysis ofHIV 
proviral DNA genotype, as needed. 
Calculated creatinine clea!'ance, hematology, semm chemistiy, and 
minalysis tests will be perf01med at all visits. 
Health Related Quality of Life (HRQoL) Surveys will be conducted 
at Day 1, Week 8, 20, and Post-HCV Treatment Week 12 visits. 
PO 
Pha1macokinetic (PK) blood samples will be collected at specified 
time points pre- and/or postdose at post-Day 1 visits. 
Elvitegravir 150 mg/cobicistat 150 mg/emtJ.'icitabine 200 mg/ 
tenofovir alafenamide 10 mg (EICIFITAF) FDC administered once 
daily with food. 
EmtJ.·icitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg 
(FIRITAF) FDC administered once daily with food. 
Ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) FDC administered 
once daily with or without food. 
None. 
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FTC/RPV IT AF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Pharmacokinetics: 
Health Related 
Questionnaires: 
CONFIDENTIAL 
Final 
Amendment 1 
Adverse events will be collected at all visits. Clinical laboratory tests 
will be performed at all visits. 
The safety and tolerability of the treatment regimens will be assessed 
with adverse event and clinicallaborato!)' tests including selected 
evaluations of renal function and PPD 
~------------------~ 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
performed using COBAS® Ampliprep I COBAS® TaqMan® HCV 
Quantitative Test, v2.0 and COBAS® TaqMan® HIV RNA Test, v2.0. 
Primary endpoint 
• 
HCV RNA < lower limit of quantification (LLOQ) 12 weeks after 
completion of LDV /SOF treatment (SVR12) 
Secondary endpoints 
Efficacy: 
• 
HCV RNA < LLOQ 4 weeks after completion ofLDV/SOF 
treatment (SVR4) 
• 
HIV -1 RNA ::.: 50 copies/mL (virologic failure) 24 weeks after 
start ofthe F/TAF-based regimen using modified FDA snapshot 
algorithm 
Safety: 
• 
Grades 1 through 4 adverse events after switching to E/C/F/TAF 
or F/R/TAF throughout the study and during coadministration 
with LDV /SOF treatment. 
Samples collected for potential population PK assessment. 
Health related questionnaires will be administered, including the 
Adherence Visual Analogue Scale (VAS), HIV Treatment 
Satisfaction (HIVTSQ), Medical Outcome Study Short Form-36 
(SF -36), Functional Assessment of Chronic Illness Therapy-Fatigue 
scale (FACIT-F), chronic liver disease questionnaire (CLDQ-HCV) 
and work productivity and activity impairment questionnaire (WP AI). 
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Amendment 1
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Statistical Methods:
This is a two part, randomized (for HIV therapy) multicenter study to 
evaluate the efficacy and safety of switching to a F/TAF-based 
regimen in HCV co-infected subjects on a current suppressive ARV 
regimen.  
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 
12 weeks post HCV treatment) in the HCV Full Analysis Set. The 
primary analysis will use a two-sided exact one-sample binomial test 
at the 0.05 significance level and construct an associated two-sided 
exact 95% confidence interval (CI).   
Secondary efficacy analyses will evaluate the proportion of subjects 
with HCV RNA < LLOQ at 4 weeks post coadministration of 
LDV/SOF treatment.  Assessment of HIV-1 RNA ≥50 copies/mL 
(virologic failure) will be done at 24 weeks after start of the 
F/TAF-based regimen using modified FDA snapshot algorithm. 
Safety analyses will evaluate adverse events (clinical and laboratory) 
during switch to F/TAF-based regimen and during coadministration 
with LDV/SOF treatment. Additional safety analyses will evaluate 
the proportion of subjects who discontinued from study treatment 
(HIV or HCV) for an AE.
Additional endpoints to be studied will include the effect of therapy 
on health-related quality of life.
Assuming that at least 94% of subjects achieve HCV SVR12, the 
95% CI around the SVR12 rate will be ± 3.2% using exact methods.
The assumed SVR12 rate will have at least 85% power to be greater 
than 6 percentage points from a performance goal of 88% by using a 
two-sided exact one-sample binomial test at significance level of 
0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
3TC
lamivudine
AASLD/IDSA
American Association for The Study of Liver Diseases/Infectious Diseases Society of 
America
ABC
abacavir
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT (SGPT)
alanine aminotransferase
APTT
activated partial thromboplastin time
ART
antiretroviral therapy
ARV
antiretroviral
AST (SGOT)
aspartate aminotransferase
APRI
AST: platelet ratio index
ATR
Atripla®
ATV
atazanavir
AUC
area under the concentration vs. time curve
AUCinf
area under the concentration verses time curve extrapolated to infinite time, calculated as 
AUC0-last + (Clast/z)
AUClast
area under the concentration curve verses time curve from time zero to the last 
quantifiable concentration
AZT
zidovudine
BMD
bone mineral density
Clast
last observed quantifiable plasma concentration of drug
Cmax
maximum observed plasma concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
Cx
minimum observed quantifiable plasma concentration x hours after the last dose of drug
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatinine kinase
CLcr
creatinine clearance 
CLDQ-HCV
chronic liver disease questionnaire
CM
concomitant medications
CMH
Cochran-Mantel-Haenszel
COBI
cobicistat, C
CRO
Contract Research Organization
CSR
clinical study report
DAA
direct acting antiviral(s)
DDI
drug-drug interaction


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DF
disoproxil fumarate
dL
deciliter
DNA
deoxyribonucleic acid
DP
diphosphate
DRV
darunavir
DSPH
Drug Safety and Public Health
DTG
dolutegravir, Tivicay®
ECG
electrocardiogram
eCRF
electronic case report forms(s)
EDC
electronic data capture
EFV
efavirenz, Sustiva®
eGFR
estimated glomerular filtration rate
eGFRcg
estimated glomerular filtration rate, Cockcroft-Gault
ESA
erythropoiesis-stimulating agents
eSAE
electronic serious adverse event
ESDD
Early Study Drug Discontinuation
ETR
etravirine
EVG
elvitegravir, E
EU
European Union
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya®
FACIT-F
functional assessment of chronic illness therapy-fatigue scale
FAS
full analysis set
FDA
(U.S.) Food and Drug Administration
FDC
fixed dose combination
FPV
fosamprenavir
FTC
emtricitabine, F
F/R/TAF
emtricitabine/rilpivirine/tenofovir alafenamide, Odefsey®  
FTC/RPV/TDF 
emtricitabine/rilpivirine/tenofovir disoproxil fumarate, Complera®  
FTC/TAF
emtricitabine/tenofovir alafenamide, Descovy®
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate, Truvada®  
g
gram(s)
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GLSM/GMR
geometric least squares mean ratio
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
genotype
h
hour(s)
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen


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HCC
Hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high density lipoprotein
HDPE
high-density polyethylene
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIVTSQc
HIV Treatment Satisfaction Questionnaire – Change version
HIVTSQs
HIV Treatment Satisfaction Questionnaire – Status version
HLGT
high-level group term
HLT
high-level term
HRQoL
Health Related Quality of Life
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IFN
interferon
IEC
Independent Ethics Committee
IMP
investigational medicinal product
INR
International Normalized Ratio
INSTI
integrase strand transfer inhibitor
IRB
Institutional Review Board
IUD
intrauterine device
IWRS
Interactive Web Response System 
kg
kilogram
kPa
kilopascal
KS
Kaposi's sarcoma
LDL
low density lipoprotein
LDV/SOF
ledipasvir/sofosbuvir, Harvoni®
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower–level term
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
min
minute
mL
milliliter
m2
square meter
mm3
cubic millimeter(s)
g
microgram
m
micrometer
ng
nanogram
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor


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NVP
nevirapine, Viramune®
PEG-IFN
pegylated interferon 
P-gp
P-glycoprotein
PEP
post-exposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term
PT
prothrombin time
QA
Quality Assurance
QD
once daily
RAL
raltegravir, Isentress®
RBV
ribavirin
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
ritonavir
RPV
rilpivirine, R, Edurant®
SAE
serious adverse event
SADR
serious adverse drug reactions
SF-36
medical outcome study short form-36
sGPVI
soluble glycoprotein VI
SOC
system organ class
SOF
sofosbuvir, Sovaldi®
SOP
standard operation procedure
STB
Stribild®
STR
Single Tablet Regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax 
TAF  
tenofovir alafenamide 
TAF fumarate
tenofovir alafenamide fumarate
TAM
thymidine analog associated mutations
TDF
tenofovir disoproxil fumarate, Viread®
TFV
tenofovir
TPO
thrombopoietin 
TVD
Truvada®
ULN
upper limit of the normal range
US
United States
VAS
visual analogue scale
VR
virologic rebound
wt
Weight
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
HIV Infection
Human Immunodeficiency Virus type 1 (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 {Campsmith et al 
2010}, {World Health Organization (WHO) 2011}. 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 {The Joint United Nations Programme on HIV/AIDS (UNAIDS) 2012}.
If left untreated or suboptimally treated, HIV infection 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 {Palella et al 1998}, {Mocroft et al 
1998}, {Sterne et al 2005}. 
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 {Department for Health and 
Human Services (DHHS) 2015}. 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 {Stone VE 2002}, {Chesney 2000}, {Department for Health and Human 
Services (DHHS) 2015}.
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 (BMD) {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. 
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 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 


FTC/RPV/TAF
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use of TAF in the E/C/F/TAF FDC 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 {Sax et al 2015}.
HCV and HIV/HCV Co-Infection
Hepatitis C virus (HCV) infection is a global health challenge with an estimated 150 million 
individuals infected worldwide {Gay et al 2011}. Currently there are 6 major HCV genotypes 
recognized {Nakano et al 2012}. Genotypes 1, 2, and 3 are common throughout North America 
and Europe and when combined account for approximately 75% of the chronic HCV infections 
globally. Genotype 4, which is common in the Middle East and Africa, accounts for 
approximately 20% of the global HCV population. Genotypes 5 and 6 are the least prevalent and 
are generally found in South Africa and South East Asia, respectively {Lavanchy 2011}.
In the United States (US), approximately 2.7 million people have chronic HCV infection 
{Denniston et al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, 
although under-reporting of HCV infection on death certificates may contribute to as much as a 
5-fold underestimation of the actual number of deaths {Mahajan et al 2014}. Of the HCV related 
deaths that are reported, almost three quarters occurred in the baby-boomer generation with a 
median age of death of 57 years, which is approximately 20 years less than the average lifespan 
{Smith et al 2012}. Successful treatment of chronic HCV infection reduces the need for liver 
transplant, the incidence of hepatocellular carcinoma (HCC) and overall mortality {Backus et al 
2011}. Thus, the public health benefit of safe and effective HCV treatment regimens is high. 
HIV-infected patients are frequently co-infected with HCV because of the shared routes of 
infection. HIV/HCV co-infection is estimated to occur in one quarter of HIV-infected persons in 
Europe, Australia, and the United States, {Thomas 2008}, and in a study from the Veterans 
Affairs Medical Center in Atlanta, Georgia, HCV infection occurred as many as 33% of the 
patients with HIV infection {Staples et al 1999}. The use of antiretroviral therapy (ART) has 
markedly reduced opportunistic infections and HIV-infected persons are living longer.  
However, liver disease has emerged as the main cause of morbidity and mortality in the HIV 
positive patient {Salmon-Ceron et al 2005}, and the development of end stage liver disease 
seems to be unrelated to the CD4 count and the immune virological status of the patient 
{Salmon-Ceron et al 2005}. In two meta-analyses published 8 years apart, co-infected patients 
were 5 to 6 times more likely to develop decompensated liver failure and 1.5 to 2 times more 
likely to develop histological cirrhosis {Graham et al 2001}, {Deng et al 2009}. In the latter 
analysis, the risk of death in the co-infected patients was nearly 4 times greater compared with 
that in mono-infected individuals {Myers et al 2008}. As might be expected, hospitalization rates 
due to liver disease in the co-infected patient have increased {Laguno et al 2004}. Furthermore, 
the previous gold standard therapy for the treatment of HCV infection, pegylated nterferon alfa 
(PEG-IFN) plus ribavirin (RBV), appears to be less effective in patients with co-infection than in 
patients with HCV mono-infection {Torriani et al 2004}, {Carrat et al 2004}. 


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The development of Sovaldi® (sofosbuvir, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated and result in higher sustained virologic response (SVR) rates than 
prior therapies. SOF in combination with ribavirin (RBV) pegylated interferon (PEG-IFN) for 
varying durations was approved in the US and Canada in December 2013 for the treatment of 
genotype 1, 2, 3 and 4 HCV infection and was granted marketing authorization by the European 
Commission in January 2014 for the treatment of genotypes 1-6 HCV infection {Gilead Sciences 
Inc 2013}, {Gilead Sciences Canada Inc. 2013}, {Gilead Sciences Limited 2014}. LDV/SOF is the first 
IFN-free regimen with high SVR rates following 8-24 weeks of treatment across treatment-naïve 
and treatment-experienced patients, including patients who failed to achieve SVR with PEG + 
RBV NS3/4A protease inhibitors, irrespective of cirrhosis {Gilead Sciences Inc. 2014}.
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 TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is 
metabolized intracellularly to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 
reverse transcriptase (RT) that terminates the elongation of the viral DNA chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-02 and GS-7340-03 exist as the free base, TAF (GS-7340), in blood and biological 
fluids.
For further information on the preclinical pharmacology and toxicology of TAF, refer to the 
current Investigator’s Brochure (IB).
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®)
Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, 
and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse 
transcriptase inhibitors (NRTIs) are co-formulated into a single-tablet regimen, E/C/F/TAF, or 
Genvoya®. E/C/F/TAF is indicated as a complete regimen for the treatment of HIV-1 infection in 
adults and pediatric patients 12 years of age and older who have no antiretroviral treatment 
history or to replace the current antiretroviral regimen in those who are virologically suppressed 
(HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months 
with no history of treatment failure and no known substitutions associated with resistance to the 
individual components of the regimen.  E/C/F/TAF is not recommended in patients with 
estimated creatinine clearance below 30 mL per minute. The efficacy and safety of E/C/F/TAF 
continue to be evaluated in a broad clinical development program. Available data from key 
studies are described in the most current version of the E/C/F/TAF IB. The details of the key 
clinical studies are provided below.


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
Study GS-US-292-0102 is a Phase 2, randomized, double-blind, double-dummy, multicenter, 
active-controlled study which evaluated the safety and efficacy of the novel tenofovir 
prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen for the initial 
treatment of HIV-1 infection. Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per 
milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR 
of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo 
for 48 weeks. Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates 
of virologic suppression (< 50 HIV copies per milliliter) at Week 24 (86.6%; 89.7%) and at 
Week 48 (88.4%; 87.9%), and had similar improvements in CD4 at Week 48 (177; 204), 
respectively. Both treatments were well tolerated, and most adverse events were self-limiting 
and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on 
E/C/F/TAF had smaller reductions in estimated creatinine clearance (-5.5 vs. -10.1 mL/min, 
p = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral 
density for hip (-0.62% vs. -2.39%, p < 0.001) and spine (-1.00% vs. -3.37%, p < 0.001). 
Patients on E/C/F/TAF had higher increases in total cholesterol, low density lipoprotein, and 
high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was 
unchanged for both. Treatment-naive patients given the STR that contained either TAF or 
TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients 
on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, 
renal tubular proteinuria, and bone mineral density.  The efficacy data from this Phase 2 
study supported the Phase 3 studies and provided initial evidence of durable efficacy; 87.5% 
of subjects who received E/C/F/TAF achieved and maintained HIV-1 RNA < 50 copies/mL 
through Week 96 (M = F). 

GS-US-292-0104 and GS-US-292-0111 are two Phase 3, randomized double-blind, 
double-dummy, multicenter, active-controlled studies which evaluated the efficacy and 
safety of two single-tablet regimens, E/C/F/TAF vs E/C/F/TDF. Key inclusion criteria were 
estimated creatinine clearance of at least 50 mL per min and genotypic sensitivity to study 
drugs. 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. Secondary endpoints were at Weeks 96 and 144.  1733 patients 
(866 E/C/F/TAF and 867 E/C/F/TDF) were enrolled (or completed the study). E/C/F/TAF 
was non-inferior to E/C/F/TDF, with 92% of (800/866) patients in the TAF group and 90% 
of (784/867) 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 < 0.001), significantly less proteinuria (median % change –3 vs 20; p < 0.001), 
and a significantly smaller decrease in bone mineral density at spine (mean % change –1.30 
vs –2.86; p < 0.001) and hip (–0.66 vs –2.95; p < 0.001) at 48 weeks. At 96 weeks, 86.6% in 
the E/C/F/TAF arm and 85.2% in the E/C/F/TDF arm had HIV-1 RNA < 50 c/mL (difference 
1.5%; 95%CI [-1.8%, 4.8%]). With E/C/F/TAF, decreases in lumbar spine and hip bone 
mineral density and proteinuria were significantly less and creatinine increases were 
significantly smaller. These longer-term data support the use of E/C/F/TAF as a safe, 
well-tolerated and durable regimen for initial HIV-1 treatment.


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Study GS-US-292-0109 is a Phase 3, randomized, active-controlled, multicenter, open-label, 
non-inferiority trial evaluating efficacy, safety, and tolerability of switching to E/C/F/TAF 
versus continuing a TDF-containing regimen (ie, Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF). Key inclusion criteria included virological suppression (HIV-1 RNA 
< 50 copies per mL) for at least 6 months on Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF and an estimated creatinine clearance of at least 50 mL per min. The 
primary endpoint was the proportion of patients who received at least one dose of study drug 
who had undetectable viral load (HIV-1 RNA < 50 copies per mL) at Week 48.  959 patients 
were randomly assigned to E/C/F/TAF and 477 continued Atripla, Stribild, or COBI- or 
RTV-boosted ATV with FTC/TDF. Viral suppression at Week 48 was noted in 97% 
(932/959) of patients switched to E/C/F/TAF and 93% (444/477) of patients who continued a 
TDF-containing regimen (adjusted difference 4.1%, 95% CI 1.6–6.7), with virological failure 
noted in ten and six patients, respectively. The number of adverse events was similar between 
the two groups, but study drug-related adverse events were more common in the tenofovir 
alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density 
and glomerular filtration were each significantly improved in patients in the E/C/F/TAF 
group compared with those in the TDF-containing regimen group.

GS-US-292-0112 is a Phase 3, single-arm, open-label study which evaluated the efficacy and 
safety of E/C/F/TAF in virologically suppressed, HIV-infected subjects with estimated 
creatinine clearance of 30-69 mL/min over 144 weeks. The primary endpoint was the change 
from baseline in glomerular filtration rate estimated using various formula. A total of 
242 virologically suppressed patients enrolled and switched treatment to E/C/F/TAF.  Subject 
baseline characteristics were mean age 58 years, 18% black, 39% hypertension, 14% 
diabetes. Through Week 48, no significant change in estimated CrCl was observed. Two 
patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had 
evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had 
significant improvements in proteinuria, albuminuria, and tubular proteinuria (p < 0.001 for 
all). Hip and spine bone mineral density significantly increased from baseline to Week 48 
(mean percent change +1.47 and +2.29, respectively, p < 0.05). 92% (222 patients) 
maintained HIV-1 RNA < 50 copies/mL at Week 48. The findings of this study support the 
use of E/C/F/TAF in patients with renal impairment down to an eGFRCG of 30 mL/min.
1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF, Odefsey®) Fixed Dose Combination
The details of the key clinical studies are provided below. Please refer to the IB for additional 
information on the F/R/TAF FDC.

GS-US-366-1159 was a randomized, open-label, single-dose, 3-way, 6-sequence, crossover 
study to determine the bioequivalence of FTC and TAF, administered as E/C/F/TAF FDC 
tablet or as F/R/TAF (Odefsey®) FDC tablet, and the bioequivalence of RPV administered as 
RPV single tablet or as F/R/TAF FDC tablet. The FTC and TAF components of the F/R/TAF
(200/25/25 mg) FDC were found to be bioequivalent to the E/C/F/TAF (150/150/200/10 mg) 
FDC. The RPV component of the F/R/TAF (200/25/25 mg) FDC was found to be 


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bioequivalent to RPV 25 mg tablet (Edurant®). FTC, RPV, and TAF administered as 
F/R/TAF (200/25/25 mg) FDC, RPV (25 mg), and E/C/F/TAF (150/150/200/10 mg) FDC 
were generally safe and well-tolerated in healthy volunteers.

GS-US-366-1651 was a randomized, open-label, single-dose, 2-period, crossover, food-effect 
study. Two cohorts of subjects were enrolled to assess the effect of moderate-fat food and the 
effect of high-calorie, high-fat food, on the PK of a single-dose F/R/TAF FDC tablet.  
Overall TAF exposure (AUClast) increased by approximately 45% and 54%, FTC exposure 
(AUCinf) decreased by approximately 9% and 12%, and RPV exposure (AUCinf) increased by 
approximately 13% and 75% (moderate-fat and high-calorie, high-fat conditions, 
respectively) when the RPV/FTC/TAF FDC tablet (200/25/25 mg) was administered under 
fed compared with fasted conditions.
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination
1.3.1.
General Information
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC, or Harvoni®) combines two 
HCV specific DAA agents into a single tablet for the treatment of chronic HCV infection. 
Sofosbuvir is a nucleotide analog that is a potent and selective inhibitor of NS5B-directed HCV 
replication, irrespective of HCV genotype. Ledipasvir is a novel HCV NS5A inhibitor that has 
demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV infection. 
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF 
FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology
1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant to 
the Proposed Study 

Study GS-US-337-0102 (ION-1) was a Phase 3, multicenter, randomized, open-label study 
designed to investigate the efficacy and safety of LDV/SOF FDC + RBV for 12 and 
24 weeks.  Subjects were HCV treatment-naive with chronic genotype 1 HCV infection. 
ION-1 was based on data from Phase 2 studies, which demonstrated high SVR rates in 
subjects with HCV genotype 1 infection. Subjects were randomized 1:1:1:1 to receive 
LDV/SOF once daily for 12 weeks, LDV/SOF + RBV for 12 weeks, LDV/SOF for 
24 weeks, or LDV/SOF + RBV for 24 weeks. The primary end point was SVR12.
Baseline characteristics of the 865 randomized and treated subjects included 16% with 
cirrhosis, 12% black, and 67% with HCV genotype 1a infection. The rates of SVR12 were 
99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of 


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LDV/SOF; 97% (95% CI, 94 to 99) in the group that received 12 weeks of LDV/SOF plus 
ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of LDV/SOF; and 
99% (95% CI, 97 to 100) in the group that received 24 weeks of LDV/SOF plus ribavirin. No 
subject in either 12-week group discontinued LDV/SOF owing to an adverse event. The most 
common adverse events were fatigue, headache, insomnia, and nausea. The study 
demonstrated that once-daily LDV/SOF+/- RBV for 12 or 24 weeks was highly effective in 
previously untreated patients with HCV genotype 1 infection.

Study GS-US-337-0109 (ION-2) was a Phase 3, randomized, open-label study of HCV 
genotype 1 subjects with prior virologic failure of peg-interferon and ribavirin +/- an HCV 
protease inhibitor. Subjects were randomized to i) LDV/SOF for 12 weeks, ii) LDV/SOF + 
RBV for 12 weeks, iii) LDV/SOF for 24 weeks, or iv) LDV/SOF + RBV for 24 weeks. The 
primary end point was SVR12. Baseline characteristics of the 440 randomized and treated 
subject included: 20% with cirrhosis and 79% with HCV genotype 1a infection. SVR12 rates 
were: 94% (95% confidence interval [CI], 87 to 97) for 12 weeks of LDV/SOF; 96% (95% 
CI, 91 to 99) for 12 weeks of LDV/SOF + RBV; 99% (95% CI, 95 to 100) for 24 weeks of 
LDV/SOF; and 99% (95% CI, 95 to 100) for 24 weeks of LDV/SOF + RBV. No patient 
discontinued treatment owing to an adverse event. The most common adverse events were 
fatigue, headache, and nausea.  The study demonstrated that treatment with daily LDV/SOF 
resulted in high rates of SVR12 in HCV-infected subjects who had not had a sustained 
virologic response to prior interferon based treatment.

Study GS-US-337-0108 (ION-3) was a Phase 3, open-label study, which randomly assigned 
647 previously untreated subjects with HCV genotype 1 infection without cirrhosis to receive 
LDV/SOF +/- RBV for 8 weeks or LDV/SOF for 12 weeks. The primary end point was 
SVR12. The rate of sustained virologic response was 94% (95% confidence interval [CI], 
90 to 97) with 8 weeks of LDV/SOF, 93% (95% CI, 89 to 96) with 8 weeks of LDV/SOF + 
RBV, and 95% (95% CI, 92 to 98) with 12 weeks of LDV/SOF. As compared with the 
SVR12 rate in the group that received 8 weeks of LDV/SOF, the rate in the 12-week group 
was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that received 
8 weeks of LDV/SOF + RBV was 1 percentage point lower (95% CI, −6 to 4) demonstrating 
noninferiority of the 8-week LDV/SOF regimen (noninferiority margin of 12%). Adverse 
events were more common in the group that received ribavirin than in the other two groups. 
No patient who received 8 weeks of only LDV/SOF discontinued treatment owing to adverse 
events.  Overall, previously untreated subjects treated with 8 weeks of LDV/SOF achieved 
high rates of SVR. No additional benefit was associated with the inclusion of ribavirin in the 
regimen or with extension of the duration of treatment to 12 weeks.

GS-US-337-0115 (ION-4) was a multicenter, single-arm, open-label study that enrolled 
HIV/HCV (genotype 1 or 4) coinfected subjects to receive 12 weeks of LDV/SOF. Subjects 
were stable on antiretroviral regimens of F/TDF with EFV, RPV or RAL. The primary end 
point was SVR12. Of the 335 patients enrolled, 34% were black, 55% had been previously 
treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had SVR12 (95% 
confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with 
HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% 


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CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were 
similar regardless of previous treatment or the presence of cirrhosis. Of the 13 subjects who 
did not have a sustained virologic response, 10 had a relapse after the end of treatment. No 
subject had confirmed HIV-1 virologic rebound. The most common adverse events were 
headache (25%), fatigue (21%), and diarrhea (11%). No subejct discontinued treatment 
because of adverse events.  The study concluded that LDV/SOF for 12 weeks provided high 
rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 
or 4.
Combined Analyses of LDV/SOF Data {Bhagani et al 2015}
A combined analysis compared the safety and efficacy of the single tablet regimen of LDV/SOF 
in HCV genotype (GT) 1 patients co-infected with HIV-1 in the Phase 3 ION-4 study with HCV 
mono-infected GT1 patients in the Phase III ION 1-3 studies. 
In the ION-4 study, 327 GT1 HCV/HIV co-infected patients (126 treatment-naïve, non-cirrhotic, 
134 treatment-experienced, non-cirrhotic, 20 treatment-naïve, cirrhotic, 
47 treatment-experienced, cirrhotic) received LDV/SOF for 12 weeks. In the ION 1-3 studies, 
538 GT1 HCV mono-infected patients (395 treatment-naïve, non-cirrhotic, 
87 treatment-experienced, non-cirrhotic, 34 treatment-naïve, cirrhotic, 22 treatment-experienced,
cirrhotic) received LDV/SOF for 12 weeks. The pooled analysis assessed safety and sustained 
virologic response at week 12 (SVR12).
Overall, 865 patients were treated for 12 weeks. In ION 1-3, the majority of patients were male 
(329, 61%), non-black (449, 83%), and treatment-naïve (430, 80%) while 56 (10%) patients had 
cirrhosis. In ION-4, the majority of patients were male (276, 82%), non-black (220, 66%), and 
treatment-experienced (185, 55%). Sixty-seven (67, 20%) patients had cirrhosis. SVR12 and 
relapse data are reported in the table. Treatment was well tolerated in both mono-infected and 
co-infected patients. Most common adverse events (> 10% reported in any arm) were fatigue, 
headache, diarrhea, and nausea. Only two patients discontinued treatment due to an adverse 
event.  The investigators concluded that the once daily, single tablet regimen of LDV/SOF for 
12 weeks provided high rates of SVR regardless of presence of HIV infection and was a safe, 
well-tolerated option for patients with both HCV mono-infection and HIV/HCV co-infection.
Table 1-1.
Combined Analysis from Phase III ION Studies
Study
ION 1
ION 2
ION 3
ION 1-3 Combined
ION 4
N (GT 1)
213
109
216
538
327
SVR12 (%)
99
94
96
97
96
Relapse rates (%)
<1
6
1
2
3
Discontinuation rates (%)
0
0
1
<1
0


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LDV/SOF Drug Interactions with E/C/F/TAF and F/R/TAF {Custodio et al 2015}
Use of anti-HCV agents such as LDV, a P-glycoprotein (P-gp) and BCRP inhibitor, with HIV 
ARV such as TAF, a P-gp and BCRP substrate, may be complicated by drug-drug interactions 
(DDIs). Two Phase 1 studies evaluated DDIs between TAF-based regimens F/R/TAF or 
E/C/F/TAF and the fixed-dose combination anti-HCV regimen of LDV/SOF. In two 
multiple-dose, randomized, crossover studies, healthy volunteers received R/F/TAF (Study 1) or 
E/C/F/TAF (Study 2), alone or in combination with LDV/SOF, daily with food for 11 [Study 1] 
or 10 [Study 2] days. Plasma concentrations of RPV, EVG, COBI, FTC, TAF, TFV (TAF 
metabolite), LDV, SOF, and GS-331007 (predominant circulating metabolite of SOF) were 
analyzed and PK parameters calculated via noncompartmental analysis. Geometric least squares 
mean ratio (GMR; combination vs. alone) and 90% confidence intervals (CI) for analytes' 
AUCtau, Cmax and Ctau were estimated by linear mixed effect modeling and compared to lack of 
PK alteration bounds (70-143% except RPV: 80-125%). Safety was assessed throughout the 
studies.
Forty (40) of 42 subjects (Study 1) and 30/30 subjects (Study 2) completed the study. Treatments 
were generally well tolerated.
The GMR and 90% CI for all analytes’ PK parameters are:
Table 1-2.
Study 1: F/R/TAF and LDV/SOF
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
F/R/TAF
(Treatment B)
(N = 42)
LDV/SOF+F/R/TAF
(Treatment C)
(N = 42)
FTC
AUCtau (h*ng/mL)
10,764.1 (14.3)
10,805.1 (15.3)
100.29 (98.43,102.19)
Cmax (ng/mL)
1707.6 (20.2)
1650.3 (17.6)
97.02 (92.72,101.53)
Ctau (ng/mL)
87.9 (28.2)
88.7 (25.1)
101.59 (98.47,104.81)
RPV
AUCtau (h*ng/mL)
3040.1 (27.3) 
2857.6 (25.6)
94.59 (91.20,98.10)
Cmax (ng/mL)
203.3 (25.4) 
197.1 (28.3)
96.65 (91.73,101.84)
Ctau (ng/mL)
109.1 (31.6) 
100.0 (26.0)
93.33 (89.38,97.45)
TAF
AUClast (h*ng/mL)
277.2 (37.5) 
362.3 (34.4)
132.39 (124.99,140.22)
Cmax (ng/mL)
200.0 (43.5) 
204.5 (45.7)
103.12 (93.58,113.63)
TFV
AUCtau (h*ng/mL)
268.4 (22.6) 
467.2 (21.0)
174.72 (168.78,180.86)
Cmax (ng/mL)
15.8 (21.7) 
25.4 (20.0)
161.50 (155.60,167.62)
Ctau (ng/mL)
9.0 (24.8) 
16.7 (22.0)
184.86 (177.57,192.46)


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PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF
(Treatment A)
(N = 41)
LDV/SOF+F/R/TAF
(Treatment C)
(N = 42)
SOF
AUCtau (h*ng/mL)
2909.4 (32.8)
3068.9 (30.5)
104.69 (100.51,109.04)
Cmax (ng/mL)
1469.5 (35.4) 
1390.6 (32.3)
95.99 (88.80,103.76)
GS-331007
AUCtau (h*ng/mL)
11,766.4 (12.8) 
12,883.3 (16.1)
107.98 (106.20,109.79)
Cmax (ng/mL)
884.4 (13.7) 
960.4 (14.8)
108.09 (105.05,111.20)
Ctau (ng/mL)
339.8 (16.4) 
378.1 (18.9)
109.92 (107.46,112.44)
LDV
AUCtau (h*ng/mL)
11,590.4 (40.3)
11,944.8 (42.7)
101.53 (97.36, 105.88)
Cmax (ng/mL)
647.4 (35.8) 
658.4 (37.7)
100.62 (96.76, 104.63)
Ctau (ng/mL)
419.7 (45.9) 
434.3 (47.4)
102.40 (98.02, 106.99)
Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
E/C/F/TAF
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
EVG
AUCtau (h*ng/mL)
26,888.6 (22.74)
29,750.7 (23.26)
110.62 (102.40, 119.50)
Cmax (ng/mL)
2184.3 (23.29)
2155.3 (27.49)
97.85 (89.57, 106.91)
Ctau (ng/mL)
513.3 (40.06)
731.3 (35.57)
145.70 (127.99, 165.86)
COBI
AUCtau (h*ng/mL)
11,354.2 (36.34)
17,046.0 (30.36)
153.17 (144.87, 161.95)
Cmax (ng/mL)
1381.4 (25.98)
1668.0 (17.14)
123.35 (115.35, 131.91)
Ctau (ng/mL)
56.1 (99.59)
175.2 (90.42)
325.08 (287.62, 367.43)
FTC
AUCtau (h*ng/mL)
12,035.7 (15.39)
11,622.9 (15.53)
96.59 (93.22, 100.08)
Cmax (ng/mL)
1777.0 (18.40)
1840.3 (22.12)
103.04 (95.93, 110.67)
Ctau (ng/mL)
103.5 (26.84)
98.5 (27.24)
95.02 (90.82, 99.42)
TAF
AUClast (h*ng/mL)
238.6 (45.87)
194.8 (29.21)
85.67 (77.63, 94.54)
Cmax (ng/mL)
165.9 (50.79)
148.2 (48.24)
90.45 (73.41, 111.45)
TFV
AUCtau (h*ng/mL)
314.8 (18.68)
396.8 (15.90)
126.61 (122.55, 130.81)
Cmax (ng/mL)
17.8 (20.43)
20.7 (16.14)
116.85 (111.71, 122.23)
Ctau (ng/mL)
11.7 (20.05)
15.5 (16.62)
132.89 (127.74, 138.25)


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PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF FDC
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
LDV
AUCtau (h*ng/mL)
12,657.2 (36.26)
22,939.3 (35.71)
178.99 (163.62, 195.81)
Cmax (ng/mL)
684.2 (32.25)
1136.0 (32.14)
164.74 (152.60, 177.86)
Ctau (ng/mL)
459.2 (40.34)
896.1 (37.74)
193.16 (173.91, 214.55)
SOF
AUCtau (h*ng/mL)
2336.2 (37.40)
3308.4 (24.84)
146.53 (135.44, 158.53)
Cmax (ng/mL)
1220.3 (37.87)
1573.2 (34.88)
128.48 (112.51, 146.72)
GS-331007
AUCtau (h*ng/mL)
12,611.4 (20.91)
18,739.0 (22.60)
148.15 (143.54, 152.91)
Cmax (ng/mL)
950.9 (18.74)
1228.7 (18.57)
129.36 (123.92, 135.04)
Ctau (ng/mL)
358.7 (24.66)
599.5 (27.40)
165.96 (159.61, 172.57)
GLSM and 90% CIs for all analytes were contained within the prespecified bounds except: 
i) TFV when RPV/FTC/TAF was administered with LDV/SOF; ii) COBI, when E/C/F/TAF was 
coadministered with LDV/SOF; and iii) LDV, GS-331007 and SOF and EVG when administered 
with E/C/F/TAF.
Despite an increase in TFV exposure upon coadministration of R/F/TAF + LDV/SOF, the mean 
TFV AUCtau is ~ 5 times lower than TFV from TDF, and within the range of TFV that did not 
lead to renal AEs or bone loss (E/C/F/TAF Phase 3). There is no association between higher 
COBI exposure and incidence of AEs, renal function parameters (E/C/F/TAF Phase 2/3 data). 
Higher plasma exposures of LDV, SOF and GS-331007 in the presence of E/C/F/TAF are not 
considered to be clinically important based on the established exposure-safety analyses for 
LDV/SOF. Thus, F/R/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose 
modification.
1.4.
Rationale for This Study
Currently, LDV/SOF is approved by the US FDA for treatment of HCV genotype 1- infected 
HCV mono and HIV co-infected patients. This Phase 3 open-label study is designed to extend 
this data to examine the efficacy and safety of LDV/SOF treatment regimen for chronic genotype 
1 HCV infection in HIV-infected patients who are receiving HIV therapy with E/C/F/TAF or 
F/R/TAF. Current guidelines for treatment of HCV in HIV co-infected patients emphasize the 
added need to treat co-infected patients due to higher rates of liver disease progression even if 
the HIV infection is treated with antiretroviral agents. The complex drug interactions that can 
occur between HIV ARV and HCV DAA further the need for safe, simple regimens that cure 
HCV in HIV-infected subjects without threatening the underlying HIV suppression. Current 


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IDSA/AASLD guidelines recommend that “Antiretroviral drug switches may be performed to 
allow compatibility of DAAs, with the goal of maintaining HIV suppression without 
compromising future options.” {HCV Guidelines 2015} Prior HIV treatment history, underlying 
HIV drug resistance and tolerability of regimens needs to be considered. 
LDV/SOF has been used successfully to treat HIV/HCV co-infected patients and the cure rates 
are 96%, comparable to HCV mono-infected patients {Naggie et al 2015}, which has led to a 
recent update to the LDV/SOF package insert that now includes HIV/HCV co-infection in the 
list of indications {Gilead Sciences Inc 2015}. However, few ARV regimens were evaluated in 
clinical studies of HCV treatment of HIV co-infected subjects.  Only RAL, EFV and RPV were 
used in the ION-4 study with FTC/TDF as the dual NRTI component of the regimen. In the 
presence of a boosting agent, such as RTV or COBI (which increase plasma TFV 
concentrations), further increases in plasma TFV concentrations are noted when coadministered 
with LDV/SOF + TDF.  Guidelines recommend avoiding RTV or COBI-boosted ARV regimens 
with TDF when treating HCV in HIV-infected patients, mainly due to lack of data.  The 
availability of TAF-based regimens will obviate the problem of excessive TFV concentrations 
due to the 91% lower plasma TFV levels when TAF is used in place of TDF.  The PK drug 
interaction studies (GS-US-366-1689 and Study 2) further justify the ability to use LDV/SOF in 
HIV-infected patients who are receiving TAF-based regimens (including COBI).
Drug-drug interactions of LDV/SOF coadministered with E/C/F/TAF and F/R/TAF were 
evaluated in healthy volunteers; the studies found no significant interactions and concluded that 
LDV/SOF and TAF-regimens can be coadministered without dose modification. The duration of 
the healthy volunteer drug-interaction studies were 10 and 11 days. Although, the US package 
insert for Genvoya® (E/C/F/TAF) suggests there should be no clinically significant drug 
interaction with LDV/SOF, there is no study to date that has evaluated the safety or efficacy of 
LDV/SOF administered with E/C/F/TAF or F/R/TAF for treatment of HCV in suppressed, HIV 
co-infected population. Careful assessment of safety/tolerability of LDV/SOF with TAF 
regimens for 12 weeks is needed to ensure that the safety data, noted in healthy volunteers PK 
studies, is replicated during 12 weeks of coadministration in HIV/HCV co-infected subjects. The 
goal of this study is to evaluate E/C/F/TAF FDC or F/R/TAF FDC with LDV/SOF by 
determining the efficacy of HCV therapy (SVR 12 weeks after completion of LDV/SOF) and 
safety and tolerability of coadministration of dual STRs.
1.5.
Risk/Benefit Assessment for the Study
The risk/benefit for this study is acceptable due to the following considerations: i) treatment of 
HCV is indicated and important in all HIV co-infected patients due to accelerated progression of 
liver disease; ii) 12 weeks of LDV/SOF provides high HCV SVR rates in HIV/HCV co-infected 
subjects; iii) changing ARV regimens is an accepted strategy for management of patients prior to 
initiation of HCV therapy (AASLD/ IDSA Guidelines); iv) changing to E/C/F/TAF from other 
ART has been shown to be safe, effective and have superior treatment outcome than maintaining 
a current suppressive regimen {Mills et al 2015}; v) F/R/TAF is bioequivalent to approved HIV 
regimens and achieves plasma concentrations of FTC, RPV and TAF that have proven to be safe, 
well tolerated and effective in maintaining virologic suppression in HIV-infected patients. Thus, 
for individual subjects there is benefit to treating their HCV and for all co-infected patients, 
finding safe, tolerable, efficacious and simple regimens will be a major advance in treatment.


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1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV 
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen;

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects;

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment)
The secondary endpoints of this study are:

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment);

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using modified FDA snapshot algorithm;

Grades 1 through 4 adverse events after switching to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment.
3.2.
Study Design
This protocol describes a randomized, multicenter, open-label, 2-part study to evaluate the 
efficacy, safety, and tolerability of switching to E/C/F/TAF FDC or F/R/TAF FDC HIV 
treatments and adding LDV/SOF HCV treatment for 12 weeks in adult male and female subjects 
with HIV who are co-infected with chronic GT 1 HCV infection.
3.3.
Study Treatments
Subjects will participate in 2 parts of the study. In Part 1, subjects will be randomized in a 
1:1 ratio to one of the following 2 HIV treatment groups:
Part 1: Approximately 240 subjects will be randomized 1:1 to switch from stable ARV therapy 
to one of the following treatments.  Randomization will be stratified by race (black vs. 
non-black) at screening.

Treatment Group 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC 
(n = 120)

Treatment Group 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC 
(n = 120)
Subjects maintaining HIV-1 RNA < 50 copies/mL and tolerating E/C/F/TAF or F/R/TAF 
through Part 1 will continue to Part 2 where they will receive the HCV treatment.  Subjects with 
confirmed virologic failure or who discontinue the HIV study drugs due to toxicity in Part 1 will 
be discontinued from the study.


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Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or F/R/TAF FDC treatment, subjects 
will maintain their HIV treatment and will initiate 12 weeks of LDV/SOF HCV treatment.  
At the end of their LDV/SOF HCV treatment, subjects will continue to maintain their HIV 
treatment and be followed for safety and efficacy for an additional 12 weeks to determine the 
SVR12 endpoint and HIV safety and efficacy endpoints.
3.4.
Duration of Treatment
The HIV treatment duration is from the Day 1 visit until the last study visit at the Post-HCV 
Treatment Week 12. The HCV treatment duration is 12 weeks. Screening assessments will be 
completed within 42 days of the Day 1 visit.
All subjects will complete the following study visits: Screening, Day 1, Weeks 4, 6 (laboratory 
visit only), 8 (start of HCV treatment), 12, 16, and 20 (end of HCV treatment), and post-HCV 
treatment visits 4 and 12 weeks after the last LDV/SOF dose. 
Subjects who complete the study through the last study visit at the Post-HCV Treatment
Week 12 visit will be required to return to the clinic 30 days after the completion of the study 
treatment for a 30-Day Follow-Up visit.
Figure 3-1.
Study Schema
a
Following the Day 1 visit, subjects will return for study visits at Weeks 4, 6 (laboratory visit only), 8, 12, 16, 20, and 
Post-HCV Treatment 4 and 12 weeks after the last LDV/SOF dose.
b
Part 1: subjects are randomized to either E/C/F/TAF FDC or F/R/TAF FDC on Day 1 and maintain HIV treatment to the 
Week 8 visit.
c
Part 2: At Week 8, once HIV-1 RNA suppression (< 50 copies/mL) is confirmed (based on the Week 6 HIV-1 RNA value), 
subjects will start on LDV/SOF FDC for 12 weeks (until Week 20) while maintaining their HIV treatment. At Week 20, 
LDV/SOF FDC will be discontinued while continuing HIV treatment. Subjects will continue in the study for another 
12 weeks to determine SVR4 (4 weeks post-HCV treatment) and SVR12 (12 weeks post-HCV treatment).
d
Subjects who complete the study through the Post-HCV Treatment Week 12 visit will be required to return to the clinic 
30 days after the completion of the study treatment for a 30-Day Follow-Up Visit. 
e
At the Day 1 visit, subjects will switch to either E/C/F/TAF FDC or F/R/TAF FDC and continue on HIV treatment until the 
last study visit at the Post-HCV Treatment Week 12 visit.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 240 subjects with HIV-1 who are coinfected with chronic HCV infection and 
who meet the eligibility criteria will be enrolled. In order to manage the total study enrollment, 
Gilead Sciences, Inc., at its sole discretion, may suspend screening and/or enrollment at any site 
or study-wide at any time.
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 any study procedures.
2) Age ≥ 18 years.
3) Currently on an ARV regimen (2 NRTI + a third agent, see Table 4-1) without change for 
6 months prior to screening. Documented plasma HIV-1 RNA levels < 50 copies/mL (or 
undetectable HIV-1 RNA level according to the local assay being used if the limit of 
detection is ≥50 copies/mL) for ≥ 6 months preceding the Screening visit. After reaching 
HIV-1 RNA < 50 copies/mL, single values (“blips”) of HIV-1 RNA ≥50 copies/mL 
followed by resuppression are allowed. For subjects with 3 or more prior ARV regimens, a 
regimen history should be provided for approval by the Sponsor. 
Note: Subjects that changed from TDF to TAF less than 6 months ago will be eligible as long 
as the TDF/ TAF change was the only change to the regimen
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen
Antiretroviral Class
Agents
Boosted PI
ATV+COBI (or ATV/COBI FDC), darunavir (DRV)+COBI (or DRV/COBI FDC), 
DRV+RTV, lopinavir (LPV)/RTV, ATV+RTV, fosamprenavir (FPV)+RTV, 
FPV+COBI, SQV+RTV, SQV+COBI, IDV+RTV, IDV+COBI, ATV (no booster)
NNRTI
EFV, etravirine (ETR), nevirapine (NVP), RPV
NRTI
FTC, TDF, TAF, abacavir (ABC), lamivudine (3TC), zidovudine (AZT)
INSTI
dolutegravir (DTG), RAL, EVG/COBI or EVG+RTV
4) No history of HIV virologic failure
5) If the current regimen is a PI/r, the previous regimen cannot contain an NNRTI or INSTI
6) Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.


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7) Have no documented resistance to any of the HIV study agents at any time in the past, 
including but not limited to the reverse transcriptase resistance mutations K65R, K70E, 
K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, 
M230I/L, the combination of K103N+L100I, or 3 or more TAMs that include M41L or 
L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). If a historical 
genotype prior to first ARV is not available or subject has 3 or more prior ARV regimens, 
subject will have proviral genotype analysis for archived resistance prior to Day 1 (all 
proviral genotype reports must be reviewed and approved by Sponsor).
8) Chronic HCV infection (≥ 6 months) documented by prior medical history.
9) HCV genotype 1 at screening as determined by the Central Laboratory. Any non-definitive 
genotype results will exclude the subject from study participation.
10) Classification as one of the following criteria:
a) Without cirrhosis and no prior HCV treatment (treatment-naïve, defined as having never 
been exposed to approved or investigational HCV-specific direct-acting antiviral agents 
or prior treatment of HCV with IFN and RBV)
b) Without cirrhosis and have received HCV treatment only with IFN +/- RBV +/- HCV PI 
(treatment-experienced, defined as prior treatment failure to a regimen containing IFN 
either with or without RBV that was completed at least 8 weeks prior to Day 1. The 
subject’s medical records must include sufficient detail of prior treatment experience for 
categorization, as either:
i.
Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
ii.
Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR, or
iii.
HCV Treatment-Intolerant: Subjects who discontinued HCV treatment of a regimen 
containing IFN (either with or without RBV) due to toxicity  
c) Compensated cirrhosis and no prior HCV treatment (treatment-naïve)
11) Cirrhosis Determination 
a) Presence of cirrhosis is defined as any one of the following:
i.
FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
screening
ii.
Fibroscan with a result of > 12.5 kPa 
iii.
Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score ≥5)
b) Absence of cirrhosis is defined as any one of the following:
i.
FibroTest® score ≤ 0.48 AND APRI ≤ 1 performed during screening 


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ii.
Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
iii.
Liver biopsy within 2 years of screening showing absence of cirrhosis
In the absence of a definitive diagnosis of presence or absence of cirrhosis by Fibrotest®
/APRI using the above criteria, a liver biopsy or fibroscan is required. Liver biopsy results 
will supersede Fibrotest® /APRI or fibroscan results and be considered definitive.
12) Liver imaging within 6 months of Day 1 is required in cirrhotic subjects only to exclude 
hepatocellular carcinoma (HCC)
13) HCV RNA 104 IU/mL at the Screening visit
14) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
15) Adequate renal function: estimated GFR ≥ 30 mL/min according to the Cockcroft-Gault 
formula (eGFRCG) for creatinine clearance {Cockcroft et al 1976}:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) × 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
16) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
17) Total bilirubin ≤ 1.5 mg/dL, and direct bilirubin ≤ 1.5 x ULN (subjects with documented 
Gilbert’s syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin 
up to 5 × ULN as long as direct bilirubin is ≤ 1.5 x ULN.)
18) Adequate hematologic function:

Absolute neutrophil count ≥1,000/mm3

Platelets ≥50,000/mm3

Hemoglobin ≥ 8.5 g/dL
19) Albumin 3.0 g/dL
20) INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
21)
A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant or nursing


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b) Of non-childbearing potential (ie, women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
≥54 years of age with cessation [for 12 months] of previously occurring menses), or
c) Of childbearing potential and agrees to utilize protocol-specified contraceptive methods 
or be non-heterosexually active or practice sexual abstinence from screening throughout 
the duration of study treatment and for 30 days following the last study drug dose (see 
Appendix 5 for definitions and protocol-acceptable contraceptive methods)
22)
Male subjects must agree to utilize a protocol-approved method of contraception (as 
defined in Appendix 5) during heterosexual intercourse or be non-heterosexually active, or 
practice sexual abstinence from first dose throughout the study period and for 30 days 
following the last study drug dose.
23)
Male subjects must agree to refrain from sperm donation from first dose until at least 
30 days after the last study drug dose.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) A new AIDS-defining condition diagnosed within the 30 days prior to the Screening visit
(except CD4+ cell count and/or percentage criteria) (refer to Appendix 6)
2) Prior HCV treatments with NS5A and NS5B or any HCV directly acting antivirals except 
boceprevir, telaprevir and simeprevir in combination with IFN +/- RBV.
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
4) History or current decompensation of liver disease; varices at low risk of bleeding are 
allowed.
5) Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B virus (HBV) DNA
6) Chronic use of systemically administered immunosuppressive agents (eg, prednisone 
equivalent > 10 mg/day).
7) Females who are breastfeeding
8) Positive serum pregnancy test 
9) Have an implanted defibrillator or pacemaker
10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance


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11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 42 days of Day 1visit and must not be 
anticipated to require systemic therapy during the study.
12) Active, serious infections (other than HIV-1 and HCV infections) requiring parenteral 
antibiotic or antifungal therapy within 42 days prior to Day 1
13) Gastrointestinal disorder or post-operative condition that could interfere with the absorption 
of the study drugs
14) Solid organ transplantation
15) Significant pulmonary disease or significant cardiac disease
16) 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
17) Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
18) Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
19) 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 HIV study drugs (COBI, EVG, FTC, 
RPV, or TAF. For COBI, EVG, FTC, or RPV, refer to the individual agents’ Prescribing 
Information; for TAF, refer to the E/C/F/TAF FDC or F/R/TAF FDC Investigator’s 
Brochures) or HCV study drugs (LDV or SOF); or subjects with any known allergies to the 
excipients of E/C/F/TAF, F/R/TAF, or LDV/SOF tablets.
Table 4-2.
Disallowed Agentsa
Drug Class
Agents Disallowedb
Acid Reducing Agents
Proton pump inhibitors, such as Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, Rabeprazole
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Antiarrythmics
Amiodaroned, Quinadine
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifampin, Rifapentine, Rifabutin
Calcium Channel Blockers
Bepridil
Corticosteroids: Systemic
Dexamethasone (more than a single dose)


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Drug Class
Agents Disallowedb
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplementsc
St. John’s Wort, Echinacea, Milk thistle (ie, silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin, Rosuvastatine
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a.
Disallowed agents are inclusive of all HIV and HCV study drugs (E/C/F/TAF, F/R/TAF, and LDV/SOF).
b.
Administration of any of the following medications must be discontinued at least 42 days prior to the Day 1 visit and for the 
duration of the study, with the exception of amiodarone (see footnote d).
c.
May result in a decrease in the concentrations of all HIV and HCV study drugs.
d.
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to the Day 1 visit and for the duration of the study.
e.
Use with LDV/SOF may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
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. Once a subject number has 
been assigned to a subject, it will not be reassigned to any other subject. Prior to or during the 
Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web 
Response System (IWRS). The subject number assignment and randomization may be performed 
up to 7 days prior to the in-clinic Day 1 visit provided that all screening procedures have been 
completed and subject eligibility has been confirmed.
Subjects will be randomized in a 1:1 ratio to one of the following two treatment arms: 
Treatment Arm 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC (n = 120)
Treatment Arm 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 120)
Randomization will be stratified by race (black vs. non-black).
The IWRS will assign study drug bottle numbers to be dispensed to the subject at each study 
visit, for all HIV and HCV study drugs. All Day 1 assessments and procedures must be 
completed prior to the administration of the first dose of HIV study drug. Initiation of 
treatment with the HIV study drug must take place within 24 hours after the Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF
5.2.1.
Formulation
5.2.1.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets debossed with “GSI” on one 
side of the tablet and “510” on the other side. Each E/C/F/TAF tablet contains 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.
5.2.1.2.
F/R/TAF, Odefsey®
F/R/TAF tablets are capsule-shaped, film-coated gray tablets debossed with “GSI” on one side 
and “255” on the other side. Each F/R/TAF tablet contains 200 mg of FTC, 25 mg of RPV (as 
27.5 mg RPV hydrochloride), and 25 mg of TAF (as 28 mg of TAF fumarate). 


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In addition to the active ingredients, the tablets contain lactose monohydrate, microcrystalline 
cellulose, polysorbate, povidone, croscarmellose sodium and magnesium stearate. The tablet 
cores are film-coated with polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
black iron oxide.
5.2.1.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are orange, diamond-shaped, film-coated tablets debossed with “GSI” on one 
side and “7985” on the other side. Each LDV/SOF FDC tablet contains 90 mg of LDV and 
400 mg of SOF.
In addition to the active ingredients, the tablets contain lactose monohydrate, copovidone, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and FD&C yellow # 6 /sunset 
yellow FCF aluminium lake.
5.2.2.
Packaging and Labeling
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA) and/or other local regulations.
5.2.2.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles.  Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Genvoya® may 
also be used for the study.
5.2.2.2.
F/R/TAF, Odefsey®
F/R/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles.  Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Odefsey® may 
also be used for the study.
5.2.2.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 28 or 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Harvoni® may 
also be used for the study.


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5.2.3.
Storage and Handling
E/C/F/TAF, F/R/TAF, and LDV/SOF 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 drugs 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 by avoiding direct eye contact or exposure when 
handling.
Commercial product of Genvoya®, Odefsey®, and Harvoni® may be used for the study. Further 
information regarding storage and handling are available in the Prescribing Information for 
commercial products.
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF
E/C/F/TAF FDC, F/R/TAF FDC, and LDV/SOF FDC tablets will be provided by 
Gilead Sciences.
The two HIV study treatments will be administered orally, once daily with food at approximately 
the same time each day:

Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg 
(E/C/F/TAF) FDC

Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg (F/R/TAF) FDC
HCV study treatment (ledipasvir 90 mg/sofosbuvir 400 mg [LDV/SOF] FDC) is to be 
administered orally, once daily with or without food at approximately the same time each day.
For a missed dose of E/C/F/TAF FDC, F/R/TAF FDC, and/or LDV/SOF FDC tablet, subjects 
should be instructed to take the missed dose of study drug as soon as possible during the same 
day.  Subjects should be cautioned never to double the next dose with a missed dose of study 
drug under any circumstances.
5.4.
Prior and Concomitant Medications
The use of medications for the treatment of HIV and HCV, other than the study treatments 
(ie, E/C/F/TAF, F/R/TAF, or LDV/SOF), is prohibited.
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.


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Amendment 1
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Concomitant medications taken within 30 days prior to the Screening visit and up to and 
including 30 days after the last dose of study drug need to be recorded in the source documents 
and electronic case report form(s) (eCRFs).
Medications listed in Table 5-1 (E/C/F/TAF + LDV/SOF) and Table 5-2 (F/R/TAF + LDV/SOF) 
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.
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agents
Antacidsa
Elvitegravir plasma concentrations are lower with 
antacids due to local complexation in the GI tract 
and not to changes in gastric pH. It is recommended 
to separate study drug and antacid administration by 
at least 2 hours. 
Proton- Pump Inhibitors, H2-Receptor Antagonists, 
Antacids
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antiarrhythmics
Amiodaronec, Quinadine
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.
Antibacterials
Concentrations of clarithromycin and/or cobicistat 
may be altered when clarithromycin is 
coadministered with study drug(s). 
Patients with CLcr greater than or equal to 
60 mL/min: 
No dose adjustment of clarithromycin is required. 
Patients with CLcr between 30 mL/min and 
60 mL/min: 
The dose of clarithromycin should be reduced by 
50%. 
Concentrations of telithromycin and/or cobicistat 
may be increased when telithromycis in 
coadministered with study drug. Clinical monitoring 
is recommended upon coadministration with study 
drug. 
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR 
(International Normalized Ratio) monitoring 
is recommended.


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Drug Class
Agents Disallowed
Use With Caution
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics:
Concentrations may increase or decrease with study 
drug(s). Concentration monitoring is recommended 
to ensure adequate clinical response.
Trazodone:
Concomitant use with CYP3A inhibitors results in 
increased concentrations and adverse events; dose 
reduction should be considered.
Antifungals
Ketoconazole and Itraconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Daily dose of 
ketoconazole and itraconazole should be restricted 
to 200 mg. Subjects receiving ketoconazole or 
itraconazole should be monitored for adequate 
clinical response.
Voriconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Clinical monitoring may 
be needed.
Antigout
Dose reductions of colchicine may be required. 
Study drug(s) should not be coadministered with 
colchicine in patients with renal or hepatic 
impairment.
Antihistamines
Concentrations of astemizole and terfenadine may 
be increased when coadministered with cobicistat. 
Clinical monitoring is recommended when these 
agents are coadministered with study drug(s).
Antimycobacterialsb
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
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
Cardiac Medications
Digoxind


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Drug Class
Agents Disallowed
Use With Caution
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 Supplementsb
St. John’s Wort, 
Echinacea, Milk thistle 
(ie, silymarin), Chinese 
herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin, 
Rosuvastatine
Atorvastatin:
Concentrations may increase with study drug(s). 
Start with the lowest dose; gradual increase in dose 
may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s). 
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: 
A dose decrease may be needed.


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Drug Class
Agents Disallowed
Use With Caution
Opiates
Methadone:
Methadone exposures are unaffected upon 
coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required upon 
coadministration with study drug(s).
Meperidine (Pethidine):
Dosage increase and long-term use are not 
recommended due to increased levels of metabolite 
normeperidine, which has analgesic and 
CNS stimulant (eg, seizures) activities.
Buprenorphine:
Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and cobicistat, 
with no effect on opioid pharmacodynimcs.
The concentration changes are not considered 
clinically relevant and no dose adjustment of 
buprenorphine/naloxone is required upon 
coadministration with study drug(s).
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil:
Caution should be exercised, including 
consideration of dose reduction, when 
coadministered for treatment of pulmonary arterial 
hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil:
It is recommended that a single dose of Sildenafil 
no more than 25 mg in 48 hours, Vardenafil no 
more than 2.5 mg in 72 hours, or Tadalafil no more 
than 10 mg in 72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem:
A dose decrease may be needed for these drugs. 
Clinical monitoring is recommended.
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of E/C/F/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when coadministered with E/C/F/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis


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Amendment 1
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Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agentsa
Proton pump inhibitors, such as 
Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, 
Rabeprazole
H2-Receptor Antagonists, Antacids
Cimetidine, Famotidine, Nizatidine, 
Ranitidine
Coadministration of H2-receptor antagonists 
(H2RA) may cause significant decreases in 
RPV plasma concentrations (increase in 
gastric pH). H2RAs should only be 
administered at least 12 hours before or at 
least 4 hours after F/R/TAF
Alkaline antacids: antacids (eg, 
aluminum or magnesium 
hydroxide, calcium carbonate)
Antacids should be used with caution as 
coadministration may cause significant 
decreases in RPV plasma concentrations 
(increase in gastric pH). Antacids should 
only be administered either at least 2 hours 
before or at least 4 hours after F/R/TAF.
Antiarrhythmics
Amiodaronec, Quinidine
Anticonvulsantsb
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Fluconazole, Itraconazole, Ketoconazole, 
Posaconazole, Voriconazole: may increase 
concentration of RPV.
Antimycobacterialsb
Rifapentine, Rifabutin, Rifampin
Cardiac Medications
Digoxind
Corticosteroids: Systemic
Dexamethasone (more than a 
single dose)
Herbal/Natural Supplementsb
St. John’s Wort, Echinacea, Milk 
thistle (ie, silymarin), Chinese 
herb Sho-Saiko-To (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorse
Rosuvastatin
Narcotic analgesics
Methadone
Clinical monitoring is recommended as 
methadone maintenance therapy may need 
to be adjusted in some patients upon 
coadministration with RPV
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of F/R/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when co-administered with F/R/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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Amendment 1
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5.5.
Accountability for Investigational Medicinal Product (IMP)
The investigator is responsible for ensuring adequate accountability of all used and unused IMP. 
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
IMP accountability records will be provided by Gilead Sciences (or equivalent documentation 
maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify Gilead or 
contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment. Please refer to Section 5.1 for details about randomization and treatment 
assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 42 days prior to the Day 1 visit to determine eligibility for 
participation in the study. The following assessments will be completed and documented at 
screening:

Obtain written informed consent

Determine eligibility including cirrhosis determination (see Section 4.2 for details)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging (CT or 
Ultrasound) should be performed within 6 months of Day 1 to exclude the presence of
hepatocellular carcinoma 

Obtain medical history, including: 
History of HIV-1 disease-related events and prior medications within 30 days of the 
Screening visit. For subjects with 3 or more prior ARV regimens, a regimen history 
should be provided for approval by the Sponsor.
Collection of historical HIV genotype, if available. If a historical genotype prior to first 
ARV is not available or subject had 3 or more prior ARV regimens, subject will have 
proviral genotype analysis for archived resistance prior to Day 1 (all proviral genotype 
reports must be reviewed and approved by Sponsor).
If HCV treatment-experienced, record the duration of the prior treatment and the type of 
IFN +/- RBV + HCV PI administered. Record whether the subject had a Non-Response 
or Relapse/Breakthrough during prior treatment or was Treatment Intolerant.
■
Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. 


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■
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment, but did not achieve SVR
■
Treatment Intolerant: Subject discontinued HCV treatment of a regimen containing 
IFN either with or without RBV due to toxicity

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Obtain 12-lead ECG (performed supine)

Obtain height and weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry

Obtain blood samples for the following laboratory analyses:
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid.  
Hematology profile: complete blood count (CBC) with differential and platelet count
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), 
and activated partial thromboplastin time (APTT)
CD4+ cell count 
Plasma HIV-1 RNA (COBAS® TaqMan® HIV RNA Test, v2.0) 
Whole blood sample for HIV proviral genotype analysis of archived resistance (if a 
historical genotype prior to first ARV is not available or subject had 3 or more prior ARV
regimens)
Plasma HCV RNA (COBAS® TaqMan® HCV Quantitative Test, v2.0)
HCV genotype and subtype, and IL28B genotype testing 


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Serology for:
■
HIV antibody 
■
HBV core antibody (HBcAb), surface antibody (HBsAb), surface antigen (HBsAg), 
e-antibody (HBeAg), e-antibody (HBeAb), and HBV DNA
■
HCV antibody

Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula (see 
Section 4.2 for details)

Obtain details of adverse events related to screening procedures

Review concomitant medications
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 42 days after the Screening visit for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events (AE) 
related to protocol-mandated procedures on the adverse events electronic case report form 
(eCRF).  All other untoward medical occurrences observed until dosing of study drugs, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  See 
Section 7, Adverse Events and Toxicity Management, for additional details.
6.2.2.
Day 1 Assessments
The following assessments are to be completed at the Day 1 visit. The Investigator must have 
received the results from the screening assessments before proceeding with the visit. Subjects 
must complete all Day 1 procedures before being dispensed the study drugs.  Initiation of 
treatment with HIV study drugs must take place within 24 hours after the Day 1 visit.

Review AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive at Day 1, study drugs will not be dispensed. The positive result will be 
confirmed with a serum pregnancy test. If the serum pregnancy test is positive, the 
subject will not be able to participate.  


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Renal tubular function assessments (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection): retinol binding protein, beta-2 microglobulin, 
urine albumin, and urine protein 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratmy analyses: 
-
Chemistty profile 
-
Hematology profile 
-
Coagulation assessments 
-
Metabolic assessments (collected fasted, 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 ). 
• 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 to draw blood for the metabolic 
assessments. 
-
CD4+ cell count 
-Plasma HIV-1 RNA 
-
Plasma HCV RNA 
-
Sennn bone safety assessments: (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection) parathyroid hmmone (PTH) and sennn 25-0H 
VitaminD 
• 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 to draw blood for these assessments. 
-
Platelet and coagulation :fi.mction assessments may include: Soluble glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and D-dimer 
-
Inflammation assessments may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, 
sTNF-Rl, and Lp-PLA2 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Semm storage sample for possible additional clinical testing 
PD 
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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula (see 
Section 4.2 for details)

Complete questionnaires: subject is to read questionnaire by her/himself and write/mark
answers directly onto the questionnaires.
Adherence for HIV (VAS)
HIV Treatment Satisfaction Questionnaire – Status version (HIVTSQs)
Medical Outcomes Short Form-36 (SF-36)
Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F)
Chronic Liver Disease Questionnaire (CLDQ-HCV)
Work Productivity and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: 
Hepatitis C)
6.3.
Randomization

Obtain subject number and randomize the subject via the IWRS. The subject number 
assignment and randomization may be performed up to 7 days prior to the in-clinic Day 1 
visit provided that all screening procedures have been completed and subject eligibility has 
been confirmed.

Dispense HIV study drugs. Subjects should initiate dosing of HIV study drugs after Day 1 
visit assessments. Initiation of treatment with the study drugs must take place within 24 hours 
after the Day 1 visit.
Subjects should also be counseled regarding the importance of adherence and taking their 
study drug daily with food at approximately the same time each day.
6.4.
Treatment Assessments
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20)
The following assessments are to be completed at the end of Weeks 4, 8, 12, 16, and 20, unless 
otherwise specified. The Week 6 visit is a laboratory visit only – please see Section 6.4.1.1 for 
details.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specified visit date based on the Day 1 visit through 
Week 20. 

Review AEs and changes in concomitant medications

Perform symptom-directed physical examination as needed 


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• 
Obtain vital signs, including weight 
• 
Obtain urine samples for the following laboratmy analyses: 
-
Urinalysis and urine chemistly 
Final 
Amendment 1 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a serum test. If the sennn test is positive, the subject will be 
discontinued. 
-
Renal tubular function assessments (Weeks 4, 8, 12, and 20 only) 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratmy analyses: 
-
Chemistly profile 
-
Hematology profile 
-
Coagulation assessments 
-
Metabolic assessments (Weeks 8 and 20 only) 
-
CD4+ cell count 
-Plasma HIV-1 RNA 
-
Plasma HCV RNA (Weeks 8, 12, 16, and 20 only) 
-
Samples for population PK (Weeks 4, 8, 12, 16, and 20) 
• 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior 
to observed study dmg dosing; 2) the postdose sample should be drawn between 
15 mins and 4 hours postdose. 
-
Semm bone safety assessments (Weeks 4, 8, 12, and 20 only) 
-
Platelet and coagulation :fi.mction assessments (Weeks 4, 8, 12, and 20 only) 
-
Inflammation assessments (Weeks 4, 8, 12, and 20 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Semm storage sample for possible additional clinical testing 
PO 
) 
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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula (see 
Section 4.2 for details)

Complete questionnaires (Weeks 8 and 20 only): subject is to read questionnaire by 
her/himself and write/mark answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version 
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

Subjects who meet the criteria for virologic rebound should be managed according to 
Management of HIV Virologic Failure (Section 6.9)

Document study drugs dispensation and accountability for all study drugs dispensed. Counsel 
all subjects regarding the importance of adherence and maintaining consistency to study drug 
administration.
HIV study drugs are dispensed at every visit (with the exception of Week 6 
laboratory visit).
HCV treatment will commence at Week 8, after determination of HIV suppression 
(< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability of HIV study 
drugs. Once confirmed, dispense HCV study drug (LDV/SOF) at Weeks 8, 12, and 16 
only.
6.4.1.1.
Week 6 (Laboratory Visit Only)
The Week 6 visit is a laboratory visit only, to confirm HIV suppression prior to initiation of 
HCV treatment. 
The following will be performed and documented at the Week 6 visit:

Obtain blood samples for plasma HIV-1 RNA testing

Plasma storage sample for safety and virology testing


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6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) 
The following evaluations are to be completed at the end of 4 and 12 weeks after completion of 
HCV treatment (Post-HCV Treatment Weeks 4 and 12 visits, respectively) and should be timed 
from the date of last administration of the HCV treatment. The Post-HCV Treatment Week 4 
visit is to be completed ± 2 days, and the Post-HCV Treatment Week 12 visit is to be completed 
within ± 4 days; however, unless notified by Gilead Sciences, the Post-HCV Treatment Week 12 
should be completed within 4 days of the protocol-specified visit date.
All subjects must complete the Post-HCV Treatment Weeks 4 and 12 visits. The end of study 
will occur at the Post-HCV Treatment Week 12 visit.
The following assessments are to be completed:

Review AEs and changes in concomitant medications

Complete physical examination (Post-HCV Treatment Week 12 only) (urogenital/anorectal 
exams will be performed at the discretion of the Investigator)

Perform symptom-directed physical examination as needed 

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the serum test is positive, the subject will be 
discontinued.
Renal tubular function assessments (Post-HCV Treatment Week 12 only)
Urine sample storage for possible additional clinical testing

Obtain blood samples for the following laboratory analyses:
Chemistry profile 
Hematology profile
Coagulation assessments 
Metabolic assessments (Post-HCV Treatment Week 12 only)
CD4+ cell count


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Plasma HIV -1 RNA 
-
Plasma HCV RNA 
-
Semm bone safety assessments (Post-HCV Treatment Week 12 only) 
Final 
Amendment 1 
-
Platelet and coagulation function assessments (Post-HCV Treatment Week 12 only) 
-Inflammation assessments (Post-HCV Treatment Week 12 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Sennn storage sample for possible additional clinical testing 
-PPD 
• 
Obtain estimated glomemlar filtration rate according to the Cockcroft-Gault f01mula (see 
Section 4.2 for details) 
• 
Complete questionnaires (Post-HCV Treatment Week 12 only): subject is to read 
questionnaire by her/himself and write/mark answers directly onto the questionnaires. 
-
VAS for HIV adherence 
-
HIVTSQc - Change version 
-
SF-36 
-
FACIT-F 
-
CLDQ-HCV 
-
WP AI: Hepatitis C 
• 
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of HIV Virologic Failure (Section 6.9) 
• 
Document study chugs dispensation and accmmtability for all HIV study drugs dispensed. 
Counsel all subjects regarding the importance of adherence and maintaining consistency to 
HIV study chug achninistration. 
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6.5.
Post-treatment Assessments
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit
Early study drug discontinuation during Part 1 (Day 1 through Week 8):
If the subject discontinues HIV study drug dosing in Part 1, the subject will be discontinued from 
the study and will not continue to Part 2 of the study. The subject will be asked to return to the 
clinic within 72 hours of stopping HIV study drugs for the ESDD visit, followed by the 30-Day 
Follow-Up visit. 
Early study drug discontinuation during Part 2 (after initiation of HCV treatment):
If the subject discontinues HCV study drug dosing only prior to completing the 12-week HCV 
treatment, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HCV study drug for the ESDD 
visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.

Continue to receive HIV study drugs (see ESDD procedures below).
If the subject discontinues HIV study drug dosing only, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HIV study drugs for the ESDD 
visit. 

HIV regimen may be changed, after discussion with the Medical Monitor. The new HIV 
regimen should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be 
continued unless an HIV regimen cannot be constructed that would allow coadministration 
with the new HIV regimen. 

Remain in the study to complete the 12-week HCV treatment (see Section 6.4.1) and follow-
up visits 4 and 12 weeks after the last dose of LDV/SOF, as described in Section 6.4.2.
If the subject discontinues both HIV and HCV study drug dosing, the following will occur:

Be asked to return to the clinic within 72 hours of stopping study drugs for the ESDD visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.


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Amendment 1 
At the ESDD Visit, any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drugs, should be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at the ESDD Visit: 
• 
Review of AEs and changes in concomitant medications 
• 
Complete physical examination (urogenitaVanorectal exams will be perf01med at the 
discretion of the Investigator) 
• 
Obtain vital signs, including weight 
• 
Obtain 12-lead ECG (perfom1ed supine) 
• 
Obtain urine samples for the following laboratory analyses: 
-
Urinalysis and urine chemistry 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a se1um test. 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratory analyses: 
-
Chemistly profile 
-
Hematology profile 
-
CD4+ cell count 
-
PlasmaHIV-1 RNA 
-
Plasma HCV RNA 
-
Plasma storage samples for virology, safety, and/or PK testing 
PD 
• 
Obtain estimated glomemlar filtration rate according to the Cockcroft-Gault f01mula (see 
Section 4.2 for details) 
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
Complete questionnaires: subject is to read questionnaire by her/himself and write/mark 
answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 400 copies/mL.

Perform study drug accountability:
For subjects that discontinue during Part 1 of the study, perform study drug 
accountability on HIV study drugs.
For subjects that discontinue during Part 2 of the study, perform study drug 
accountability for HIV and HCV study drugs. 
■
If the subject discontinues HCV study drug and is staying on HIV study drug, 
dispense HIV study drug until the last study visit. 
■
If the subject discontinues HIV study drug, HCV study drug will be dispensed at the 
scheduled visits as described in Section 6.4.1
6.5.2.
30-Day Follow-Up Visit
Subjects who complete the study through the Post-HCV Treatment Week 12 visit 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 HIV study drug in Part 1 of the study will be asked to 
return to the clinic after the completion of the ESDD visit for a 30-Day Follow-Up visit.
A ± 6 days window may be used to schedule this visit. The following evaluations are to be 
completed at this visit:

Review of AEs and changes in concomitant medications

Perform symptom-directed physical examination 


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
Obtain vital signs measurement, including weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. 

Obtain blood samples for the following laboratory analyses:
Chemistry profile
Hematology profile
CD4+ cell count
Plasma HIV-1 RNA
Plasma HCV RNA
At the 30-Day Follow-Up Visit, any evaluations showing abnormal results indicating that there is 
a reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.6.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (refer to Appendix 2). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study and asked to return for the 
ESDD Visit followed by the 30-Day Follow-Up Visit.
6.7.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree.

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the Investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Lack of efficacy (virologic failure)


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
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 Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.8.
Other Assessments
6.8.1.
Blood and Urine Storage
A portion of the blood drawn and urine collected at all visits (except Screening, Week 6, 30-Day 
Follow-Up, or Unscheduled) will be frozen and stored. From subjects who provide additional 
consent, a portion of the blood draw at Day 1, Weeks 4, 8, 20, Post-HCV Treatment Week 12, 
and ESDD visit will be frozen and stored. These stored samples may be used by Gilead or our 
research partners to help answer questions about the study drug, HIV-1 infection and its 
associated conditions, or clinical laboratory testing to provide additional safety data. No human 
genetic testing will be performed without express consent of the study subjects. At the 
conclusion of this study, these samples may be retained in storage for Gilead for a period of up to 
15 years.
6.8.2.
Bone Safety and Inflammation
For all subjects, blood will be collected for selected assessments of bone safety, including serum 
25-OH Vitamin D and PTH. Assessments 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, 8, 
12, 20, and Post-HCV Treatment Week 12.
6.8.3.
Markers of Platelet Function and Coagulation
For all subjects, blood will be collected for selected assessments of platelet function and 
coagulation that may include: soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand 
and D-dimer. Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment 
Week 12.
6.8.4.
Markers of Renal Tubular Function
For all subjects, urine will be collected for selected assessments of renal tubular function that 
may include retinol binding protein, beta-2 microglobulin, urine albumin, and urine protein. 
Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment Week 12.


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6.9.
HIV 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 at any visit has an HIV-1 RNA value 
50 copies/mL confirmed at the next scheduled or unscheduled visit (2 to 4 weeks later).
6.9.1.
Management of HIV Virologic Rebound
The management of virologic rebound during Part 1 and Part 2 are different; subjects that have 
confirmed virologic failure during Part 1 will be discontinued from the study and not begin 
Part 2, while subjects that have virologic failure in Part 2 will be managed as described below.
Management of HIV-1 RNA ≥50 copies/mL during Part 1 (Day 1 through Week 8)

All HIV-1 RNA values ≥ 50 copies/mL should be discussed with the Medical Monitor. 

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If virologic failure is confirmed during Part 1 (regardless of detection of HIV drug 
resistance), the subject should be discontinued from HIV study drug and have the ESDD and 
30 Day Follow-Up visit.

If the viral load at the Week 6 visit is ≥ 50 copies/mL (and this is not a confirmation of 
virologic failure value), the HIV-1 RNA will be repeated at an unscheduled visit in about 
2 weeks from the Week 6 visit. This unscheduled visit for confirmation of virologic failure 
must be completed prior to the Week 8 visit (which subsequently means that the Week 8 visit 
will be delayed).  The subject should not start Part 2 (nor should the subject start LDV/SOF 
therapy) until the repeat HIV-1 RNA value is available.  If the repeat HIV-1 RNA confirms 
virologic rebound (≥ 50 copies/mL), then the subject will be discontinued from HIV study 
drugs as above.  If the repeat HIV-1 RNA is < 50 copies/mL, then the subject may proceed to 
Part 2 and maintain the same visit schedule. Initiation of LDV/SOF therapy must occur 
within 2 to 4 weeks of the original visit window of the Week 8 visit. 


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Management of HIV-1 RNA ≥50 copies/mL during Part 2 (at or after Week 8)

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented. Assessment should include:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

All subjects with confirmed virologic failure should be discussed with the Medical Monitor.

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If genotypic/phenotypic resistance to study drug is documented, HIV study drugs 
(E/C/F/TAF or F/R/TAF) should be discontinued. 

If the HIV study drugs (E/C/F/TAF or F/R/TAF) are discontinued, a new HIV regimen 
should be constructed, after discussion with the Medical Monitor. The new HIV regimen 
should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued 
unless an HIV regimen cannot be constructed that would allow coadministration with the 
new HIV regimen.
If no resistance is detected from genotype/phenotype testing, the subject may remain on HIV 
study drugs and an HIV-1 RNA should be repeated (2 to 4 weeks after date of test with viral load 
≥50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on 
HIV study drug for each individual subject and document this assessment in the source 
documents. Investigators who opt to discontinue HIV study drugs for an individual subject must 
discuss with the Medical Monitor prior to study drug discontinuation.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
rebound.


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Figure 6-1.
HIV Virologic Rebound Schema
a.
If virologic rebound is not confirmed, the subject will remain on their current HIV regimen.
b.
If virologic rebound is confirmed, and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, integrase, and protease) will be analyzed.
c.
Based on the results of the genotype/phenotype assays, the subject will remain on HIV study drugs or study drugs will be 
discontinued. If genotyping/phenotyping fails, a new ARV regimen may be configured at the discretion of the Investigator.
d.
If no resistance detected, HIV-1 RNA will be repeated (2 to 4 weeks later). Investigator reviews HIV study drug 
continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation.
e.
A new ARV regimen will be configured, after discussion with the Medical Monitor.  The new HIV regimen should be 
designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued unless an HIV regimen cannot be 
constructed that would allow coadministration with the new HIV regimen.
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at the Post-HCV Treatment Week 12 visit, or last visit while receiving HIV 
study drugs (or within 72 hours of discontinuation of study treatment).


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6.10.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed > 1 log10 increase from on treatment nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the HCV on treatment phase.  
All subjects who terminate LDV/SOF treatment early will complete the ESDD visit (see 
Section 6.5.1) and post-HCV treatment follow-up visits at 4 and 12 weeks after the last dose of 
LDV/SOF (see Section 6.4.2).
6.11.
End of Study
End of study is defined as completion of the Post-HCV Treatment Week 12 visit and the 30-Day 
Follow-Up visit.
6.12.
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.


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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, 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be 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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (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. 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 Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. 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 medication, 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 medication, collect all AEs, regardless of cause or relationship, 
until 30 days or 4 weeks after last administration of study IMP and report 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 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
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 unable to be accessed, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above.
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations (CFR), 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 


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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management 

All clinical and clinically significant laboratory toxicities relating to HIV ARV agents will be 
managed according to uniform guidelines detailed in Appendix 3.

Management for toxicity should be differentiated between ARV and HCV medications.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose after discussion with the 
Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Medical Monitor
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.


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7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.

If a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase (CK) after 
strenuous exercise or triglyceride elevation that is nonfasting or that can be medically 
managed) or a clinical event considered unrelated to investigational medicinal product
7.5.4.
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 eGFR 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.


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CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73 m2) = 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.
7.6.
Stopping Rules for HCV Treatment
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of study drug may be discontinued in the event of a clinical or laboratory event. 
There is no option for dose reduction of LDV/SOF. If LDV/SOF FDC is stopped due to toxicity, 
it must not be restarted. The ESDD visit should be completed after discontinuation of LDV/SOF. 
The Post-HCV Treatment Week 4 and Week 12 visits must also be completed. 
Subjects who meet any of the following laboratory criteria must stop HCV study treatment:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to LDV/SOF
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, and 
pregnancy reports regardless of an associated AE.  


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint associated with an adverse event is defined as complaints arising from 
potential deviations in the manufacture, packaging, or distribution of the medicinal product
associated with an adverse event, which is any untoward medical occurrence in a study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the study drug.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.  
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. The same reporting obligations shall apply to female partners of male study 
subject (ie, partner pregnancies).
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.


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A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.2 and 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 (of both female subject pregnancies and male subject’s partner 
pregnancies) 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: 
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
safety_fc@gilead.com
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV 
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are: 

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4); 

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects; 

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment). 
8.1.3.
Secondary Endpoint
Secondary efficacy endpoints are: 

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment).

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using modified FDA snapshot algorithm
Note: Most often, 24 weeks of HIV therapy will coincide with the Post-HCV Treatment Week 4 
visit
Secondary safety endpoint is:

Grades 1 through 4 adverse events after switch to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment.


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8.1.4.
Other Endpoints of Interest
No other endpoints of interest will be considered.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
HIV Full Analysis Set: The primary analysis set for HIV efficacy analysis will be the HIV full
analysis set (HIV FAS) and is defined as all subjects randomized and who received at least one 
dose of F/TAF-based regimen. 
HCV Full Analysis Set: The primary analysis set for HCV efficacy analysis will be the HCV full 
analysis set (HCV FAS) and is defined as all subjects who received at least one dose of 
LDV/SOF. 
Subjects will be grouped according to the treatment they were randomized to.
8.2.1.2.
Safety
HIV Safety Analysis Set: The primary analysis set for HIV safety analyses will be the HIV 
safety analysis set and is defined as all subjects randomized to the study and who received at 
least one dose of F/TAF-based regimen. 
HCV Safety Analysis Set: The primary analysis set for HCV safety analyses with 
coadministration with the F/TAF-based regimen in Part 2 will be the HCV safety analysis set and 
is defined as all subjects who received at least one dose of LDV/SOF.
All data collected during treatment will be included in the safety summaries. Subjects will be 
grouped according to the treatment they actually received.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who were randomized and have received at least one 
dose of either the F/TAF-based regimen (at Week 4) or coadministration of the F/TAF-based 
regimen and LDV/SOF, and for whom concentration data of any analyte of interest are available. 
The PK analysis set will be used for listing PK concentration data and summaries.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by standard descriptive methods 
using the safety analysis set. Demographic and baseline measurements will be summarized by 
treatment group (E/C/F/TAF; F/R/TAF) and overall. 
Summaries will include sex, race/ethnicity, age, height, weight and body-mass index.


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Baseline data will include a summary of risk factors for HIV-1 infection and HCV 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 the treatment groups.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
therapy). The primary analysis will be performed after all enrolled subjects have been followed 
through post-HCV treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate will be compared to the performance goal of 
88% by using two-sided exact one-sample binomial test at the 0.05 significance level. The basis 
for this benchmark includes the overall trend toward increasing SVR rates in recent years; and 
the general appeal of using a fixed clinically relevant threshold as a measure of treatment benefit 
of LDV/SOF.
The null (H0) and alternative (H1) hypotheses used to assess superiority of LDV/SOF relative to 
the performance goal of 88% are:

H0: SVR12 = 88%

H1: SVR12 ≠ 88%
The primary efficacy analysis will also include the construction of an associated two-sided exact 
95% CI.
Furthermore, SVR12 will also be summarized by the HIV treatment arms (F/TAF-based 
regimen).
8.4.2.
Secondary Analyses
The methods to assess proportion of HIV-1 RNA ≥50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using a modified FDA snapshot algorithm will be 
provided in detail in the Statistical Analysis Plan.
The changes from baseline in CD4+ count at Week 8 and Post-HCV Treatment Week 12 will be 
summarized using descriptive statistics.
The analysis of SVR4 will be summarized using similar methods as for the primary endpoint.


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8.5.
Safety Analysis
All safety data collected on or after the date F/TAF-based ARV regimen was first dispensed up 
to the date of last dose of study drug(s) (either F/TAF-based regimen alone or in combination 
with LDV/SOF) plus 30 days will be summarized overall, according to the study drug(s) 
received. 
Additionally, safety data collection on or after the first dose of LDV/SOF until the last dose of 
LDV/SOF plus 30 days (ie, during coadministration of HIV/HCV study drugs), will also be 
summarized.
Data for pretreatment and post-last-dose-plus-30-days will be included in data listings. 
8.5.1.
Extent of Exposure
A subject’s extent of exposure to each study drug will be generated from the corresponding study 
drug administration data. Duration of exposure to each study drug will be expressed as the 
number of weeks between the first and last dose for each study drug, inclusive, regardless of 
temporary interruptions in study drug administration. 
Dosing information for individual subjects will be listed. 
8.5.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
HIV treatment-emergent AEs are events that meet one of the following criteria up to 30 days 
after the permanent discontinuation of HIV study drug(s): 

AEs with onset dates on or after the first dose date of HIV study drug(s) and no later than 
30 days after permanent discontinuation of HIV study drug(s), or,

AEs that result in permanent study drug discontinuation of HIV study drug(s).
The number and percentage of subjects with treatment-emergent AEs (by SOC and PT) will be 
summarized as described in Section 8.5. A similar definition will be used to define HCV 
treatment-emergent AEs during coadministration of HIV/HCV study drugs. Additional 
summaries will include summaries for AEs by grade, Investigator’s assessment of relationship to 
study drug, and effect on study drug dosing.
All treatment-emergent and non-treatment emergent AEs will be included in a data listing.


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8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 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 HIV 
study drug(s) plus 30 days, will be summarized as described in Section 8.5. Similarly, 
treatment-emergent abnormalities during coadministration of HIV/HCV study drugs will also be 
summarized. 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 HIV study drug(s) or after the subject 
has been discontinued from HIV study drug(s) plus 30 days will be included in a data listing.
8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Population PK assessments may be conducted for some of the relevant analytes: TAF, TFV, 
RPV, FTC, EVG, COBI, LDV, SOF, or GS-331007. Population PK assessments will be 
summarized in a separate report.
8.7.
Biomarker Analysis
The renal, vascular and inflammatory markers (see Sections 6.8.2 – 6.8.4 for details) will be 
summarized by treatment group and visit using descriptive statistics. The difference in change 
from baseline in these biomarkers between the treatment groups (E/C/F/TAF and F/R/TAF) will 
be tested using Wilcoxon rank sum test.
8.8.
Sample Size
A sample size of 240 subjects will provide at least 85% power to detect an improvement of at 
least 6 percentage points in SVR12 rate from the performance goal of 88% by using a two-sided 
exact one-sample binomial test at significance level of 0.05.


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


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


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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures.  eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system.  Prior to database lock (or 
any interim time points as described in the clinical data management plan), the investigator will 
use his/her log in credentials to confirm that the forms have been reviewed, and that the entries 


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accurately reflect the information in the source documents. The eCRF capture the data required 
per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (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.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead Quality Assurance (QA), the site may destroy used (empty or partially empty) and unused 
IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP 
will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, 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 IRB/IEC in 
accordance with local requirements and receive documented IRB/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, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/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 CRF/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), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Amendment 1
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10.
REFERENCES
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Bhagani S, Sulkowski MS, Cooper C, Kwo PY, Kowdley K, Mertens M, et al. 
Ledipasvir/Sofosbuvir is Safe and Effective for the Treatment of Patients with 
Genotype 1 Chronic HCV Infection in Both HCV  Mono-and HCV/HIV Co-
infected Patients [Abstract: 386]. European AIDS Clinical Society (EACS); 2015 
21-24 October; Barcelona, Spain. 
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.
Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated 
interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic 
hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 
2004;292 (23):2839-48.
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30 
(Suppl 2):S-171-S6.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Custodio J, Doyle E, Pang PS, Das M, H. C, Ma G, et al. Lack of Drug Interactions between 
Boosted and Unboosted Tenofovir Alafenamide-based Antiretroviral Single 
Tablet Regimens (Emtricitabine/Rilpivirine/Tenofovir Alafenamide and 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) and the anti-HCV 
Single Tablet Regimen Ledipasvir/Sofosbuvir [Abstract 727]. Infectious Diseases 
Society of America (IDSA); 2015 7-11 October; San Diego, CA. 
Deng LP, Gui XE, Zhang YX, Gao SC, Yang RR. Impact of human immunodeficiency virus 
infection on the course of hepatitis C virus infection: a meta-analysis. World J 
Gastroenterol 2009;15 (8):996-1003.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.


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Amendment 1
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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.
Gay CL, Mayo AJ, Mfalila CK, Chu H, Barry AC, Kuruc JD, et al. Efficacy of NNRTI-based 
antiretroviral therapy initiated during acute HIV infection. AIDS 2011;25 (7):941-
9.
Gilead Sciences Canada Inc. SOVALDI® (Sofosbuvir) Tablets 400 mg. Product Monograph.  
Mississauga, ON. December 2013:
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised November 2015:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA October 2014:
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of Product 
Characteristics.  County Cork Ireland. January 2014.  2014:
Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human 
immunodeficiency virus infection on the course of hepatitis C virus infection: a 
meta-analysis. Clin Infect Dis 2001;33 (4):562-9.
HCV Guidelines. Recommendations for Testing, Managing, and Treating Hepatitis C.  2015.
Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, et al. 
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus 
ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004;18 (13):F27-
36.
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17 (2):107-
15.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.


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Amendment 1
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Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study 
[Supplementary Webappendix]. Lancet 2015.
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.
Myers RP, Liu M, Shaheen AA. The burden of hepatitis C virus infection is growing: a Canadian 
population-based study of hospitalizations from 1994 to 2004. Can J 
Gastroenterol 2008;22 (4):381-7.
Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and 
Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med 2015.
Nakano T, Lau GM, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus 
genotypes and subtypes based on the complete coding region. Liver Int 2012;32 
(2):339-45.
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.
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 
August 22.  2012.
Salmon-Ceron D, Lewden C, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Liver disease as 
a major cause of death among HIV infected patients: role of hepatitis C and B 
viruses and alcohol. J Hepatol 2005;42 (6):799-805.
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;385:2606-15.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.


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Gilead Sciences, Inc. 
Amendment 1
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Smith BD, Morgan ML, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. 
Recommendations for the Identification of Chronic Hepatitis C Virus Infection 
Among Persons Born During 1945–1965. Centers for Disease Control and 
Prevention MMWR  August, 2012.
Staples CT, Jr., Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) 
Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the 
effect of coinfection on survival. Clin Infect Dis 1999;29 (1):150-4.
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.
Stone VE JJ, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to HAART 
[abstract]. . 40th Annual Meeting of the Infectious Disease Society of America; 
2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
The Joint United Nations Programme on HIV/AIDS (UNAIDS). Regional Fact Sheet 2012. 
North America, Western and Central Europe.  2012.
Thomas DL. The challenge of hepatitis C in the HIV-infected person. Annu Rev Med 
2008;59:473-85.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. 
Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in 
HIV-infected patients. N Engl J Med 2004;351 (5):438-50.
World Health Organization (WHO). World Health Organization, UNAIDS, UNICEF. Global 
HIV/AIDS Response: Epidemic update and health sector progress towards 
universal access. Progress Report 2011.  2011.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only)
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.
CDC Classification Systems, AIDS-Indicator Conditions


FTC/RPV rr AF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences, lnc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Randomized, Open-label, Controned Study ofthe Efficacy, Safety and 
Tolerability of 12 Weeks of Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HJV /HCV 
Co-infected Subjects who Switch to Elvitegravir/Cobicistat/Emtricitabineffenofovir 
Alafenamide (E/C/F/TAF) or Emtricitabine/Rilpivirinc/Tenofovir Alaltmamide (F/RJTAF) 
prior to LDV/SOF HCV Treatment, tbe HIV/HCV Co-STARs study (Co-infection 
treatment with Single Tablet Antiviral Regimens) 
GS-US-366-1992 Amendment 1, 27 May 2016 
This protocol has been approved by Gilead Sciences Inc. The followine: signature documents 
iliis approval. 
p p D 
f< '·c_)rv.-rP 
~0. I.A. b '< ). L I-., 
Richard Haubrich (Printed) 
Medical Monitor 
1. J v'~"'~e '2 0 1 tO 
Date 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
deLails for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, .Lnc. 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 
CON FJDENTIA L 
Page 92 
27 May 2016 


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Appendix 2.
Study Procedures Table
Screeninga Day 1b
End of Weekc 
Part 1
On Treatment
End of Weekc – Part 2
30-Day 
Follow-Upd
ESDDe
On Treatment
Post-HCV Treatment
4
6
8
12
16
20
4
12
Written Informed Consent
X
Medical History 
X
Liver Cirrhosis Determination
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examinationf
X
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-Lead ECG (performed supine)
X
X
Urinalysis & Urine Chemistry
X
X
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
X
Urine Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Testg
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
X
Hematology Profilei
X
X
X
X
X
X
X
X
X
X
X
Coagulation Assessmentsj
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsk
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X


FTC/RPV/TAF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
Plasma HIV -1 RNA 
HIV -1 Provu·al Genotype1 
HlV -1 Genotype/Phenotypem 
Plasma HCV RNA 
HCV Genotype & Subtype 
HCV IL28B Genotype 
HIV, HBV & HCV Serologiesn 
Evaluations of Bone & Renal Safety, 
Inflammation and Platelet and 
Coagulation Ftmction° 
Plasma Storage SampleP 
Senun Storage Sample!' 
rpo I 
I 
Estimated GFRCGr 
Population PK
5 
Health Related Questiormaires
1 
Randomization 
Study Drug Dispensation and 
Accountabilityu 
Screening• Day 1b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Evaluations to be completed within 42 days prior to the Day 1 visit 
End ofWeE'kc 
Part 1 
On TrE-atment 
4 
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of Week<- Part 2 
On Treatment 
Post-HCV Treatment 
8 
12 
16 
20 
4 
12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 1 
30-Day 
Follow-Upd Es nn• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xv 
b 
Subjects will be dispensed HIV study dmos only at the Day 1 visit; initiation ofHIV treatment with the study dmgs must take place within 24 hours after the Day 1 visit. 
c 
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are± 2 days of the protocol specified date through Post-HCV Treatment We.ek 4 visit, and 
± 4 days of the protocol specified date at Post-HCV Treatment Week 12. 
CONFIDENTIAL 
Page 94 
27 May 2016 


FTC/RPV IT AF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
d 
For the purpose of scheduling a 30-Day Follow-Up Visit, a± 6 days window may be used 
Final 
Amendment 1 
e 
Early Study Drug Discontinuation visit to occur within 72 hours oflast dose of study drug. Refer to Section 6.5. 1 for management of early study drug discontinuation of 
Parts 1 and 2. 
f 
Symptom-directed physical examination as needed 
g 
For females of childbearing potential only as defined by Appendix 5. Positive urine pregnancy tests will be confirmed with a serum test. 
h 
Chemistry profile: alkaline phosphatase, AST, AL T, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid. At visits in which metabolic assessments are to be performed, analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry profile 
CBC with differential and platelet count 
J 
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) 
k 
Metabolic assessments (collected fasted, 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) 
If a historical genotype report prior to first AR Vis not available, or subject has 3 or more prior ARV regimens, whole blood sample for proviral genotype analysis of archived 
resistance 
m 
HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic rebound with HIV-1 RNA value ?: 400 copies/mL 
n 
Serology testing includes HIV and HCV antibody, and HBV core antibody (HBcAb), surfuce antibody (HBsAb), surface antigen (HBsAg), e-antibody (HBeAg), e-antibody 
(HBeAb), andHBVDNA. 
o 
Blood for bone safety, parathyroid (PTH) and serum OH-25 vitamin D; Inflammation may include cystatin-C, IL-6, hs-CRP, sCD14, sCD163, sTNF-lR, and Lp-PLA2; 
Platelet and coagulation function 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, beta-2-microglobulin, urine albumin, and urine protein will be collected. Samples 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 fasted state. 
p 
Plasma storage samples for safe!Y, virology, and/or PK tes~. Serum storage sam les for ossible additional clinical testing. 
q 
, PD 
r 
Estimateo GFR according to llie CocKcroft-Gaii:ltformula'lor creatirnne clearance (see Section 4.2 for detmls 
s 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior to observed study drug dosing; 2) the postdose sample should be drawn between 
15 mins and 4 hours postdose 
Health related questionnaires: adherence for HIV (VAS), HIVTSQs- Status version (at Day 1 only), HIVTSQc -Change version (at all other visits), SF-36, FA CIT -F, 
CLDQ-HCV, and WPAI: Hepatitis C. 
u 
Part 1: HIV study drugs are dispensed after all Day 1 assessments are completed and randomization occurred, and through the duration of the study. Part 2: After 
determination ofHIV suppression (< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability ofHIV study drugs, LDV/SOF will be dispensed at Weeks 8, 12, 
and 16 only. Post-HCV Treatment Week 12: drug accountability only; study drug will not be dispensed at this visit. 
v 
If subjects discontinue during Part 1, only drug accountability will be performed; study drug will not be dispensed at this visit. In Part 2, if subject discontinues LDV/SOF but 
still continues with HIV study drug, HIV study drug will be dispensed until the last study visit. If subject discontinues HIV study drug but still continues with LDV/SOF, 
LDV/SOF will be dispensed. If subject discontinues both HIV and HCV study drugs, only drug accountability will be performed; no dispensation will occur at this visit. 
CONFIDENTIAL 
Page 95 
27 May 2016 


FTCIRPV/TAF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only) 
Grade 1 
L_ ______ G_r_a_d_e-2------~~ 
Ll _______ 
G_r_a_d_e_3 ______ _JI 
Ll ----------G--r-a-de--4----------~ 
~ 
~ 
l\fay continue 
Repeatlab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
1. Withhold investigational medicinal products until s Grade 2 
2. Restart all investigational medicinal products at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently 
1 
.--------------. 
Repeatlab to 
confirm toxicity 
grade 
1 
Ifc onfirmed and unrelated to 
stigational medicinal products, 
mg may continue at the 
inve 
dos 
disc retion ofthe investigator 
If confirmed and 
possibly or probably 
-----. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
othenvise explained 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion ofthe 
investigator 
CONFIDENTIAL 
Page 96 
27 May 2016 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 97
27 May 2016
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 98
27 May 2016
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 99
27 May 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 100
27 May 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 101
27 May 2016
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
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 102
27 May 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 103
27 May 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.  


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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27 May 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 105
27 May 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 106
27 May 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 107
27 May 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 108
27 May 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 109
27 May 2016
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 110
27 May 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 111
27 May 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 112
27 May 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 113
27 May 2016
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 114
27 May 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 115
27 May 2016
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 116
27 May 2016
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 117
27 May 2016
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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


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


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Amendment 1
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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. 
Women who are not post-menopausal or permanently sterile in accordance with these definitions 
will be considered of childbearing potential.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of E/C/F/TAF have demonstrated that 
E/C/F/TAF reduces the exposure of ethinyl estradiol in hormonal contraceptives. No clinically 
significant interactions between the components of F/R/TAF and LDV/SOF and hormonal 
contraception are known. Female subjects who choose hormonal contraception will be required 
to select a second backup method as defined below. 
Non-clinical toxicity studies of LDF/SOF, F/R/TAF, and E/C/F/TAF have demonstrated no 
adverse effect on fertility or embryo-fetal development.  However, there is insufficient clinical 
data available on use of these products in pregnant women. Please refer to the latest version of 
the IB (F/R/TAF) and package inserts (E/C/F/TAF and LDV/SOF) for additional information.
b. Contraceptive Methods allowed for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure.  Women must also not rely solely on hormone-containing 
contraceptives (except for intrauterine devices [IUDs] that may release hormones) as a form of 
birth control during the study.  Women may continue oral, injectable, transdermal, or other 
hormonally based contraceptives that are designed to inhibit ovulation, if desired, but these will 


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Amendment 1
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not be acceptable as a sole form of contraception; an additional form of acceptable effective 
contraception (methods below) must be chosen even if hormonal ovulation-inhibiting 
contraception is continued. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Day 1 visit prior to randomization.  At minimum, a pregnancy test 
will be performed at the end of relevant systemic exposure.  In the event of a delayed menstrual 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is even true for women of childbearing potential with infrequent or irregular 
periods.  
Women of child bearing potential in this study must agree to use the following forms of 
contraception from Screening until 30 days after the last dose of study drug.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of < 1% per year. Hormonal IUDs meeting 
this criterion are acceptable as a sole method.
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Combined barrier methods: 
■
Diaphragm with spermicide and a male condom without spermicide
Or 
■
Cervical cap with spermicide and male condom without spermicide 

Women who choose to continue on their hormonal contraceptive method (eg, combined oral 
contraceptives, injectable, transdermal, and intravaginal contraceptives) are asked to also 
choose one of the above methods to supplement the hormonally based method given the 
effect of E/C/F/TAF  on ethinyl estradiol. These women may, however, use their hormonal 
contraceptive method and choose a single barrier method to supplement their hormonal 
contraceptive method (preferably the male condom). 
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.


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Amendment 1
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3) Contraception Requirements for Male Subjects
During the study and for 30 days after the last dose of study drug, male subjects with female 
partners of childbearing potential should use condoms without spermicide when engaging in 
intercourse of reproductive potential.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately.  Male subjects should 
also notify the investigator if their female partner becomes pregnant during the study or within 
30 days of last dose of study drugs. Instructions for reporting pregnancy and pregnancy outcome 
are outlined in Section 7.7.2.1.


FTC/RPV/TAF
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Amendment 1
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Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions

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)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month 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

Wasting syndrome attributed to HIV Infection
CDC Revised Surveillance Case Definition for HIV Infection – 2014 {Selik et al 2014}

Prot_000.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F IT AF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) prior to LDV/SOF HCV Treatment, the HIV/HCV 
Co-STARs study (Co-infection treatment with Single Tablet Antiviral 
Regimens) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
123098 
2014-004545-27 
TBD 
HIV-1 Infection 
GS-US-366-1992 
Gilead Clinical 
Name: 
PPD 
PPD 
PPD 
Program Manager: 
Telephone: 
Fax: 
Gilead Co-Medical 
Name: 
Monitor: 
Telephone: 
Mobile: 
Gilead Co-Medical 
Name: 
Monitor: 
Telephone: 
Mobile: 
Protocol Version/Date: 
Original: 
Richard Haubrich, MD 
PPD 
PPD 
Thai N~en-Clemy, MD 
PPD 
PPD 
18 December 2015 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particulm·ly 1mpublished data, is the prope1iy or 
under conti"ol 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 info1mation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
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Original
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................19
1.2.1.
General Information .............................................................................................................19
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®).................................................................................19
1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) Fixed Dose Combination ...................................................................................21
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination..............................................22
1.3.1.
General Information .............................................................................................................22
1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant 
to the Proposed Study...........................................................................................................22
1.4.
Rationale for This Study ........................................................................................................................27
1.5.
Risk/Benefit Assessment for the Study..................................................................................................28
1.6.
Compliance ............................................................................................................................................29
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................31
3.1.
Endpoints ...............................................................................................................................................31
3.2.
Study Design..........................................................................................................................................31
3.3.
Study Treatments ...................................................................................................................................31
3.4.
Duration of Treatment............................................................................................................................32
3.5.
Samples for Optional Exploratory Assessments ....................................................................................33
4.
SUBJECT POPULATION..................................................................................................................................34
4.1.
Number of Subjects and Subject Selection ............................................................................................34
4.2.
Inclusion Criteria....................................................................................................................................34
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................40
5.1.
Randomization .......................................................................................................................................40
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF .....................................................40
5.2.1.
Formulation..........................................................................................................................40
5.2.2.
Packaging and Labeling .......................................................................................................41
5.2.3.
Storage and Handling...........................................................................................................42
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF...................................................42
5.4.
Prior and Concomitant Medications.......................................................................................................42
5.5.
Accountability for Investigational Medicinal Product (IMP).................................................................48
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49


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6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Day 1 Assessments...............................................................................................................51
6.3.
Randomization .......................................................................................................................................53
6.4.
Treatment Assessments..........................................................................................................................53
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20).........................................53
6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) .................................................................................................56
6.5.
Post-treatment Assessments ...................................................................................................................58
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................58
6.5.2.
30-Day Follow-Up Visit.......................................................................................................60
6.6.
Assessments for Premature Discontinuation from Study.......................................................................61
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................61
6.8.
Other Assessments .................................................................................................................................62
6.8.1.
Blood and Urine Storage......................................................................................................62
6.8.2.
Bone Safety and Inflammation.............................................................................................62
6.8.3.
Markers of Platelet Function and Coagulation.....................................................................62
6.8.4.
Markers of Renal Tubular Function .....................................................................................62
6.9.
HIV Virologic Failure............................................................................................................................63
6.9.1.
Management of HIV Virologic Rebound .............................................................................63
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit ........................................65
6.10.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................66
6.11.
End of Study...........................................................................................................................................66
6.12.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69
7.4.
Gilead Reporting Requirements.............................................................................................................70
7.5.
Toxicity Management ............................................................................................................................71
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................71
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................72
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.5.4.
Management of Potential Nephrotoxicity.............................................................................72
7.6.
Stopping Rules for HCV Treatment.......................................................................................................73
7.7.
Special Situations Reports......................................................................................................................73
7.7.1.
Definitions of Special Situations..........................................................................................73
7.7.2.
Instructions for Reporting Special Situations.......................................................................74
8.
STATISTICAL CONSIDERATIONS................................................................................................................76
8.1.
Analysis Objectives and Endpoints........................................................................................................76
8.1.1.
Analysis Objectives..............................................................................................................76
8.1.2.
Primary Endpoint .................................................................................................................76
8.1.3.
Secondary Endpoint .............................................................................................................76
8.1.4.
Other Endpoints of Interest ..................................................................................................77
8.2.
Analysis Conventions.............................................................................................................................77
8.2.1.
Analysis Sets ........................................................................................................................77


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8.3.
Demographic Data and Baseline Characteristics ...................................................................................78
8.4.
Efficacy Analysis ...................................................................................................................................78
8.4.1.
Primary Analysis..................................................................................................................78
8.4.2.
Secondary Analyses .............................................................................................................78
8.5.
Safety Analysis.......................................................................................................................................79
8.5.1.
Extent of Exposure...............................................................................................................79
8.5.2.
Adverse Events.....................................................................................................................79
8.5.3.
Laboratory Evaluations ........................................................................................................80
8.5.4.
Other Safety Evaluations......................................................................................................80
8.6.
Pharmacokinetic Analysis......................................................................................................................80
8.7.
Biomarker Analysis................................................................................................................................80
8.8.
Sample Size............................................................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only)..............96
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............97
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120
Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions ...................................................123


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Original
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LIST OF IN-TEXT TABLES
Table 1-1.
Combined Analysis from Phase III ION Studies....................................................................24
Table 1-2.
Study 1: F/R/TAF and LDV/SOF...........................................................................................25
Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter................................................................26
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen .........................................................34
Table 4-2.
Disallowed Agentsa ................................................................................................................38
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF ............................................43
Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF................................................47
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................32
Figure 6-1.
HIV Virologic Rebound Schema............................................................................................65


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Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404
Study Title: 
A Phase 3b Randomized, Open-label, Controlled Study of the 
Efficacy, Safety and Tolerability of 12 Weeks of 
Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to  
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) prior to LDV/SOF HCV Treatment, the HIV/HCV 
Co-STARs study (Co-infection treatment with Single Tablet Antiviral 
Regimens)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
123098
2014-004545-27
TBD
Study Centers 
Planned:
Approximately 50 centers in North America
Objectives:
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the proportion 
of subjects achieving HCV RNA below the lower limit of 
quantification (LLOQ) 12 weeks after the last dose of LDV/SOF 
(sustained virologic response [SVR12]).
The secondary objectives of this study are:

To determine the proportion of subjects achieving HCV RNA 
below LLOQ 4 weeks after the last dose of LDV/SOF (SVR 4);

To evaluate maintenance of HIV-1 RNA suppression after 
switching to E/C/F/TAF or F/R/TAF 24 weeks from the start of 
the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to E/C/F/TAF 
or F/R/TAF from the current antiretroviral (ARV) therapy in 
virologically-suppressed, HIV-1/HCV co-infected subjects;


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
To evaluate the safety and tolerability of 12 weeks of treatment 
for HCV with LDV/SOF in virologically-suppressed, HIV-1/HCV 
co-infected subjects who switched to E/C/F/TAF or F/R/TAF.
Study Design:
Randomized, multicenter, open-label, 2-part study in adult male and 
female subjects with HIV who are co-infected with chronic genotype 
(GT) 1 HCV infection.  Subjects will have one of the following: 
1) no cirrhosis and no prior HCV treatment (treatment-naïve); 
2) no cirrhosis and have received HCV treatment only with 
interferon (IFN) +/- ribavirin (RBV) or IFN + RBV + an HCV 
protease inhibitor (PI) (treatment-experienced); or 
3) compensated cirrhosis and be naïve to HCV therapy
(treatment-naïve).  
Subjects will be on stable ARV therapy for 6 months prior to 
screening and with HIV RNA < 50 copies/mL.
Part 1: Approximately 240 subjects will be randomized 1:1 to switch 
from stable ARV therapy to one of the following treatments.  
Randomization will be stratified by race (black vs. non-black).

Treatment Group 1: Switch from 2 nucleoside/nucleotide
reverse transcriptase inhibitor (NRTI) plus a third ARV agent to 
E/C/F/TAF fixed dose combination (FDC) (n = 120) 

Treatment Group 2: Switch from 2 NRTI plus a third ARV
agent to F/R/TAF FDC (n = 120) 
All subjects will receive 8 weeks of treatment and will have an 
assessment of safety, tolerability and HIV-1 RNA values at the 
conclusion of 8 weeks. Plasma samples collected at Week 6 
(laboratory visit only) will be included in assessing virologic 
suppression of HIV-1 RNA at Week 8. Subjects who tolerate the 
switch to E/C/F/TAF FDC or F/R/TAF FDC and maintain virologic 
suppression of HIV-1 RNA < 50 copies/mL will continue to 
Part 2. HIV treatment will be continued until their SVR12 
assessment.
Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or 
F/R/TAF FDC treatment, subjects will continue their HIV treatment
and initiate 12 weeks of LDV/SOF HCV therapy.  

LDV/SOF FDC tablet once daily for 12 weeks
After LDV/SOF therapy, subjects will continue their HIV treatment
and be followed for safety and efficacy for an additional 12 weeks to 
determine the HCV SVR12 endpoint and HIV safety and efficacy 
endpoints.


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Number of Subjects 
Planned:
240 subjects (approximately 120 subjects randomized to each of 
E/C/F/TAF FDC or F/R/TAF FDC).
Target Population:
Chronic GT 1 HCV, HIV-coinfected adults who do not have cirrhosis 
and are HCV treatment-naïve or treatment-experienced with IFN +/-
RBV +/- PI.  Compensated cirrhotic subjects must be treatment-naïve. 
Subjects are on a stable HIV regimen with 2 NRTI + 3rd agent with 
suppressed HIV RNA.
Duration of 
Treatment:
Part 1: Subjects will be randomized to receive E/C/F/TAF or 
F/R/TAF for 8 weeks. 
Part 2: Subjects will receive 12 weeks of LDV/SOF and continue 
their randomized F/TAF-based regimen for 12 weeks after 
completion of LDV/SOF (total approximately 24 weeks in Part 2).
Diagnosis and Main 
Eligibility Criteria:
HIV/HCV co-infected adult subjects who meet the following criteria 
will be given the option to participate in the study:

Chronic GT 1, HCV infected, male and non-
pregnant/non-lactating female subjects, without cirrhosis, 
treatment-naïve or treatment-experienced with IFN +/- RBV +/-
HCV PI.  Compensated cirrhotic subjects must be HCV 
treatment-naïve. No prior treatments with NS5A and NS5B or any 
HCV direct acting antivirals, except boceprevir, telaprevir and 
simeprevir, in combination with IFN and RBV.

Currently on the first or second ARV regimen (2 NRTI + a third 
agent) without change for 6 months prior to screening. 
Documented plasma HIV-1 RNA levels < 50 copies/mL (or 
undetectable HIV-1 RNA level according to the local assay being 
used if the limit of detection is ≥ 50 copies/mL) for ≥6 months 
preceding the Screening visit. After reaching HIV-1 RNA 
< 50 copies/mL, single values (“blips”) of HIV-1 RNA 
≥50 copies/mL followed by resuppression is allowed. 

Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.

Have no documented resistance to any of the HIV study agents at 
any time in the past, including but not limited to the reverse 
transcriptase resistance mutations K65R, K70E, K101E/P, 
E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, 
F227C, M230I/L, the combination of K103N+L100I, or 3 or more 
thymidine analog associated mutations (TAMs) that include 
M41L or L210W (TAMs are M41L, D67N, K70R, L210W, 
T215Y/F, K219Q/E/N/R).

No history of HIV virologic failure.


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
No evidence of Hepatitis B infection.

Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min as
estimated by Cockcroft-Gault formula.
Study Procedures/
Frequency:
Screening assessments will be completed within 42 days of the Day 1 
visit.
After consent is obtained, screening assessments will include physical 
examination, medical history, historical HIV resistance test collection 
(if available; HIV DNA archive genotype if no historical HIV 
genotype available), height, weight, vital signs, 12-lead 
electrocardiogram (ECG), screening procedure related adverse events 
(AEs), concomitant medications (CM), safety laboratory tests 
(including hematology, chemistry, and coagulation), HCV and HIV 
RNA, serology (HIV, HCV, HBV), HCV genotyping, assessment of 
the absence of cirrhosis, serum β-hCG (females of child bearing 
potential only), IL28B genotyping, and urinalysis.
On treatment assessment:

Part 1: F/TAF-based ARV regimen switch: 
Day 1 and Weeks 4, 6 (lab only), and 8 

Part 2: LDV/SOF therapy and follow-up
First dose of LDV/SOF at Week 8, then Weeks 12, 16, and 
20 (4, 8, and 12 weeks after HCV start) and post LDV/SOF 
follow up at 4 and 12 weeks posttreatment (SVR 4 and 12).
On treatment assessments will include AEs, CMs, study drug dosing 
adherence (including pill count), physical examination, weight, vital 
signs, safety laboratory tests, HCV and HIV RNA, urine pregnancy 
tests (females of child bearing potential only).
Fasting lipid profile measurements and fasting glucose will be 
performed at Day 1, Weeks 8, 20, and at Post-HCV Treatment 
Week 12. Lipids will include total cholesterol (TC), high density and 
low density lipoproteins (HDL, LDL), non-HDL cholesterol, 
triglycerides (TG) and cholesterol ratios.  
Post treatment assessments will include AEs and CMs collected 
through 30 days after the last dose of HIV study drug, HCV and HIV 
RNA, safety laboratory tests (including hematology and chemistry), 
and urine pregnancy tests (females of childbearing potential only).
Plasma samples for viral HIV RNA will be collected at Day 1 and 
every visit thereafter (except HCV RNA at Week 4). Stored samples 
for HCV RNA sequencing/phenotyping and HIV RNA 


FTC/RPV/TAF 
Protocol GS-US-366-1992 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Original 
genotyping/phenotyping will be collected at Day 1 and evety visit 
thereafter. Blood will be collected at Screening for analysis ofHIV 
proviral DNA genotype, as needed. 
Calculated creatinine clearance, hematology, serum chemistly, and 
urinalysis tests will be perf01med at all visits. 
Health Related Quality of Life (HRQoL) Surveys will be conducted 
at Day 1, Week 8, 20, and Post-HCV Treatment Week 12 visits. 
PPD 
Phannacokinetic (PK) blood samples will be collected at specified 
time points pre- and/or postdose at post-Day 1 visits. 
Elvitegravir 150 mg/cobicistat 150 mg/emtt·icitabine 200 mg/ 
tenofovir alafenamide 10 mg (E/C/F/TAF) FDC administered once 
daily with food. 
Emtl'icitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg 
(FIR/TAF) FDC administered once daily with food. 
Ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) FDC administered 
once daily with or without food. 
None. 
Adverse events will be collected at all visits. Clinicallaborat01y tests 
will be perf01med at all visits. 
The safety and tolerability of the treatment regimens will be assessed 
with adverse event and clinicallaboratOIJ,: tests (includin selected 
evaluations of renal ftmction and PPD 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perf01med using COBAS® Ampliprep I COBAS® TaqMan® HCV 
Quantitative Test, v2.0 and COBAS® TaqMan® HIV RNA Test, v2.0. 
Primmy endpoint 
• 
HCV RNA < lower limit of quantification (LLOQ) 12 weeks after 
completion ofLDV/SOF treatlnent (SVR12) 
Page 10 
18 December 2015 


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Secondary endpoints
Efficacy:

HCV RNA < LLOQ 4 weeks after completion of LDV/SOF 
treatment (SVR4)

HIV-1 RNA ≥50 copies/mL (virologic failure) 24 weeks after 
start of the F/TAF-based regimen using modified FDA snapshot 
algorithm
Safety:

Grades 1 through 4 adverse events after switching to E/C/F/TAF 
or F/R/TAF throughout the study and during coadministration 
with LDV/SOF treatment.
Pharmacokinetics:
Samples collected for potential population PK assessment.
Health Related 
Questionnaires:
Health related questionnaires will be administered, including the 
Adherence Visual Analogue Scale (VAS), HIV Treatment 
Satisfaction (HIVTSQ), Medical Outcome Study Short Form-36 
(SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue 
scale (FACIT-F), chronic liver disease questionnaire (CLDQ-HCV) 
and work productivity and activity impairment questionnaire (WPAI).
Statistical Methods:
This is a two part, randomized (for HIV therapy) multicenter study to 
evaluate the efficacy and safety of switching to a F/TAF-based 
regimen in HCV co-infected subjects on a current suppressive ARV 
regimen.  
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 
12 weeks post HCV treatment) in the HCV Full Analysis Set. The 
primary analysis will use a two-sided exact one-sample binomial test
at the 0.05 significance level and construct an associated two-sided 
exact 95% confidence interval (CI).   
Secondary efficacy analyses will evaluate the proportion of subjects 
with HCV RNA < LLOQ at 4 weeks post coadministration of 
LDV/SOF treatment.  Assessment of HIV-1 RNA ≥50 copies/mL 
(virologic failure) will be done at 24 weeks after start of the 
F/TAF-based regimen using modified FDA snapshot algorithm. 
Safety analyses will evaluate adverse events (clinical and laboratory) 
during switch to F/TAF-based regimen and during coadministration 
with LDV/SOF treatment. Additional safety analyses will evaluate 
the proportion of subjects who discontinued from study treatment 
(HIV or HCV) for an AE.
Additional endpoints to be studied will include the effect of therapy 
on health-related quality of life.


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Assuming that at least 94% of subjects achieve HCV SVR12, the 
95% CI around the SVR12 rate will be ± 3.2% using exact methods.
The assumed SVR12 rate will have at least 85% power to be greater 
than 6 percentage points from a performance goal of 88% by using a 
two-sided exact one-sample binomial test at significance level of 
0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
3TC
lamivudine
AASLD/IDSA
American Association for The Study of Liver Diseases/Infectious Diseases Society of 
America
ABC
abacavir
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT (SGPT)
alanine aminotransferase
APTT
activated partial thromboplastin time
ART
antiretroviral therapy
ARV
antiretroviral
AST (SGOT)
aspartate aminotransferase
APRI
AST: platelet ratio index
ATR
Atripla®
ATV
atazanavir
AUC
area under the concentration vs. time curve
AUCinf
area under the concentration verses time curve extrapolated to infinite time, calculated as 
AUC0-last + (Clast/z)
AUClast
area under the concentration curve verses time curve from time zero to the last 
quantifiable concentration
AZT
zidovudine
BMD
bone mineral density
Clast
last observed quantifiable plasma concentration of drug
Cmax
maximum observed plasma concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
Cx
minimum observed quantifiable plasma concentration x hours after the last dose of drug
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatinine kinase
CLcr
creatinine clearance 
CLDQ-HCV
chronic liver disease questionnaire
CM
concomitant medications
CMH
Cochran-Mantel-Haenszel
COBI
cobicistat, C
CRO
Contract Research Organization
CSR
clinical study report
DAA
direct acting antiviral(s)
DDI
drug-drug interaction


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DF
disoproxil fumarate
dL
deciliter
DNA
deoxyribonucleic acid
DP
diphosphate
DRV
darunavir
DSPH
Drug Safety and Public Health
DTG
dolutegravir, Tivicay®
ECG
electrocardiogram
eCRF
electronic case report forms(s)
EDC
electronic data capture
EFV
efavirenz, Sustiva®
eGFR
estimated glomerular filtration rate
eGFRcg
estimated glomerular filtration rate, Cockcroft-Gault
ESA
erythropoiesis-stimulating agents
eSAE
electronic serious adverse event
ESDD
Early Study Drug Discontinuation
ETR
etravirine
EVG
elvitegravir, E
EU
European Union
E/C/F/TAF
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide, Genvoya®
FACIT-F
functional assessment of chronic illness therapy-fatigue scale
FAS
full analysis set
FDA
(U.S.) Food and Drug Administration
FDC
fixed dose combination
FTC
emtricitabine, F
FTC/RPV/TAF
emtricitabine/rilpivirine/tenofovir alafenamide  
FTC/RPV/TDF 
emtricitabine/rilpivirine/tenofovir disoproxil fumarate  
FTC/TAF
emtricitabine/tenofovir alafenamide
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate  
g
gram(s)
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GLSM/GMR
geometric least squares mean ratio
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
genotype
h
hour(s)
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCC
Hepatocellular carcinoma


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HCV
hepatitis C virus
HDL
high density lipoprotein
HDPE
high-density polyethylene
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIVTSQc
HIV Treatment Satisfaction Questionnaire – Change version
HIVTSQs
HIV Treatment Satisfaction Questionnaire – Status version
HLGT
high-level group term
HLT
high-level term
HRQoL
Health Related Quality of Life
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IFN
interferon
IEC
Independent Ethics Committee
IMP
investigational medicinal product
INR
International Normalized Ratio
INSTI
integrase strand transfer inhibitor
IRB
Institutional Review Board
IUD
intrauterine device
IWRS
Interactive Web Response System 
kg
kilogram
kPa
kilopascal
KS
Kaposi's sarcoma
LDL
low density lipoprotein
LDV/SOF
ledipasvir/sofosbuvir, Harvoni®
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower–level term
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
min
minute
mL
milliliter
m2
square meter
mm3
cubic millimeter(s)
g
microgram
m
micrometer
ng
nanogram
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
NVP
nevirapine, Viramune®


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PEG-IFN
pegylated interferon 
P-gp
P-glycoprotein
PEP
post-exposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term
PT
prothrombin time
QA
Quality Assurance
QD
once daily
RAL
raltegravir, Isentress®
RBV
ribavirin
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
ritonavir
RPV
rilpivirine, R, Edurant®
SAE
serious adverse event
SADR
serious adverse drug reactions
SF-36
medical outcome study short form-36
sGPVI
soluble glycoprotein VI
SOC
system organ class
SOF
sofosbuvir, Sovaldi®
SOP
standard operation procedure
STB
Stribild®
STR
Single Tablet Regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
TAF  
tenofovir alafenamide 
TAF fumarate
tenofovir alafenamide fumarate
TAM
thymidine analog associated mutations
TDF
tenofovir disoproxil fumarate, Viread®
TFV
tenofovir
TPO
thrombopoietin 
TVD
Truvada®
ULN
upper limit of the normal range
US
United States
VAS
visual analogue scale
VR
virologic rebound
wt
Weight
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
HIV Infection
Human Immunodeficiency Virus type 1 (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 {Campsmith et al 
2010}, {World Health Organigation (WHO) 2011}. 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 {The Joint United Nations Programme on HIV/AIDS (UNAIDS) 2012}.
If left untreated or suboptimally treated, HIV infection 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 {Palella et al 1998}, {Mocroft et al 
1998}, {Sterne et al 2005}. 
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 {Department for Health and 
Human Services (DHHS) 2015}. 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 {Stone VE 2002}, {Chesney 2000}, {Department for Health and Human 
Services (DHHS) 2015}.
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 (BMD) {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. 
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 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 


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use of TAF in the E/C/F/TAF FDC 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 {Sax et al 2015}.
HCV and HIV/HCV Co-Infection
Hepatitis C virus (HCV) infection is a global health challenge with an estimated 150 million 
individuals infected worldwide {Gay et al 2011}. Currently there are 6 major HCV genotypes 
recognized {Nakano et al 2012}. Genotypes 1, 2, and 3 are common throughout North America 
and Europe and when combined account for approximately 75% of the chronic HCV infections 
globally. Genotype 4, which is common in the Middle East and Africa, accounts for 
approximately 20% of the global HCV population. Genotypes 5 and 6 are the least prevalent and 
are generally found in South Africa and South East Asia, respectively {Lavanchy 2011}.
In the United States (US), approximately 2.7 million people have chronic HCV infection 
{Denniston et al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, 
although under-reporting of HCV infection on death certificates may contribute to as much as a 
5-fold underestimation of the actual number of deaths {Mahajan et al 2014}. Of the HCV related 
deaths that are reported, almost three quarters occurred in the baby-boomer generation with a 
median age of death of 57 years, which is approximately 20 years less than the average lifespan 
{Smith et al 2012}. Successful treatment of chronic HCV infection reduces the need for liver 
transplant, the incidence of hepatocellular carcinoma (HCC) and overall mortality {Backus et al 
2011}. Thus, the public health benefit of safe and effective HCV treatment regimens is high. 
HIV-infected patients are frequently co-infected with HCV because of the shared routes of 
infection. HIV/HCV co-infection is estimated to occur in one quarter of HIV-infected persons in 
Europe, Australia, and the United States, {Thomas 2008}, and in a study from the Veterans 
Affairs Medical Center in Atlanta, Georgia, HCV infection occurred as many as 33% of the 
patients with HIV infection {Staples et al 1999}. The use of antiretroviral therapy (ART) has 
markedly reduced opportunistic infections and HIV-infected persons are living longer. 
However, liver disease has emerged as the main cause of morbidity and mortality in the HIV 
positive patient {Salmon-Ceron et al 2005}, and the development of end stage liver disease 
seems to be unrelated to the CD4 count and the immune virological status of the patient 
{Salmon-Ceron et al 2005}. In two meta-analyses published 8 years apart, co-infected patients 
were 5 to 6 times more likely to develop decompensated liver failure and 1.5 to 2 times more 
likely to develop histological cirrhosis {Graham et al 2001}, {Deng et al 2009}. In the latter 
analysis, the risk of death in the co-infected patients was nearly 4 times greater compared with 
that in mono-infected individuals {Myers et al 2008}. As might be expected, hospitalization rates 
due to liver disease in the co-infected patient have increased {Laguno et al 2004}. Furthermore, 
the previous gold standard therapy for the treatment of HCV infection, pegylated nterferon alfa 
(PEG-IFN) plus ribavirin (RBV), appears to be less effective in patients with co-infection than in 
patients with HCV mono-infection {Torriani et al 2004}, {Carrat et al 2004}. 


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The development of Sovaldi® (sofosbuvir, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated and result in higher sustained virologic response (SVR) rates than 
prior therapies. SOF in combination with ribavirin (RBV) pegylated interferon (PEG-IFN) for 
varying durations was approved in the US and Canada in December 2013 for the treatment of 
genotype 1, 2, 3 and 4 HCV infection and was granted marketing authorization by the European 
Commission in January 2014 for the treatment of genotypes 1-6 HCV infection {Gilead Sciences 
Inc 2013}, {Gilead Sciences Canada Inc. 2013}, {Gilead Sciences Limited 2014}. LDV/SOF is the first 
IFN-free regimen with high SVR rates following 8-24 weeks of treatment across treatment-naïve 
and treatment-experienced patients, including patients who failed to achieve SVR with PEG + 
RBV NS3/4A protease inhibitors, irrespective of cirrhosis {Gilead Sciences Inc. 2014}.
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 TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is 
metabolized intracellularly to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 
reverse transcriptase (RT) that terminates the elongation of the viral DNA chain. In the 
development of TAF, three forms of the drug substance have been used in various studies: 
GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate 
(1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio 
of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable 
based on physical/chemical properties to GS-7340-02 that has been used in previous studies. 
GS-7340-02 and GS-7340-03 exist as the free base, TAF (GS-7340), in blood and biological 
fluids.
For further information on the preclinical pharmacology and toxicology of TAF, refer to the 
current Investigator’s Brochure (IB).
1.2.2.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF, Genvoya®)
Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, 
and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse 
transcriptase inhibitors (NRTIs) are co-formulated into a single-tablet regimen, E/C/F/TAF, or 
Genvoya®. E/C/F/TAF is indicated as a complete regimen for the treatment of HIV-1 infection in 
adults and pediatric patients 12 years of age and older who have no antiretroviral treatment 
history or to replace the current antiretroviral regimen in those who are virologically suppressed 
(HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months 
with no history of treatment failure and no known substitutions associated with resistance to the 
individual components of the regimen.  E/C/F/TAF is not recommended in patients with 
estimated creatinine clearance below 30 mL per minute. The efficacy and safety of E/C/F/TAF 
continue to be evaluated in a broad clinical development program. Available data from key 
studies are described in the most current version of the E/C/F/TAF IB. The details of the key 
clinical studies are provided below.


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
Study GS-US-292-0102, a Phase 2, randomized, double-blind, double-dummy, multicenter, 
active-controlled study evaluate the safety and efficacy of the novel tenofovir prodrug, 
tenofovir alafenamide (TAF), as part of a single-tablet regimen  for the initial treatment of 
HIV-1 infection. Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter 
and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo 
for 48 weeks. Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates 
of virologic suppression (< 50 HIV copies per milliliter) at Week 24 (86.6%; 89.7%) and at 
week 48 (88.4%; 87.9%), and had similar improvements in CD4 at Week 48 (177; 204), 
respectively. Both treatments were well tolerated, and most adverse events were self-limiting 
and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on 
E/C/F/TAF had smaller reductions in estimated creatinine clearance (-5.5 vs. -10.1 mL/min, 
p = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral 
density for hip (-0.62% vs. -2.39%, p < 0.001) and spine (-1.00% vs. -3.37%, p < 0.001). 
Patients on E/C/F/TAF had higher increases in total cholesterol, low density lipoprotein, and 
high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was 
unchanged for both. Treatment-naive patients given the STR that contained either TAF or 
TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients 
on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, 
renal tubular proteinuria, and bone mineral density.  The efficacy data from this Phase 2 
study supported the Phase 3 studies and provided initial evidence of durable efficacy; 87.5% 
of subjects who received E/C/F/TAF achieved and maintained HIV-1 RNA < 50 copies/mL 
through Week 96 (M = F).

GS-US-292-0104 and GS-US-292-0111, two Phase 3, randomized double-blind, 
double-dummy, multicenter, active-controlled studies which evaluated the efficacy and 
safety of two single-tablet regimens, E/C/F/TAF vs E/C/F/TDF. Key inclusion criteria were 
estimated creatinine clearance of at least 50 mL per min and genotypic sensitivity to study 
drugs. 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 Adminstration (FDA) 
snapshot algorithm (pre-specified noninferiority margin of 12%) and pre-specified renal and 
bone endpoints at 48 weeks. Secondary endpoints are at Week 96 and 144.  1733 patients 
(866 E/C/F/TAF and 867 E/C/F/TDF). E/C/F/TAF was non-inferior to E/C/F/TDF, with 92% 
of (800/866) patients in the TAF group and 90% of (784/867) 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 < 0.001), significantly less 
proteinuria (median % change –3 vs 20; p < 0.001), and a significantly smaller decrease in 
bone mineral density at spine (mean % change –1.30 vs –2.86; p < 0.001) and hip (–0.66 vs –
2.95; p < 0.001) at 48 weeks. At 96 weeks, 86.6% in the E/C/F/TAF arm and 85.2% in the 
E/C/F/TDF arm had HIV-1 RNA < 50 c/mL (difference 1.5%; 95%CI [-1.8%, 4.8%]). With 
E/C/F/TAF, decreases in lumbar spine and hip bone mineral density and proteinuria were 
significantly less and creatinine increases were significantly smaller. These longer-term data 
support the use of E/C/F/TAF as a safe, well-tolerated and durable regimen for initial HIV-1 
treatment.


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
Study GS-US-292-0109 is a Phase 3, randomized, active controlled, multicenter, open-label, 
non-inferiority trial evaluating efficacy, safety, and tolerability of switching to E/C/F/TAF 
versus continuing a TDF-containing regimen (ie,  Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF). Key inclusion criteria included virological suppression (HIV-1 RNA 
< 50 copies per mL) for at least 6 months on Atripla, Stribild, or COBI- or RTV-boosted 
ATV with FTC/TDF and an estimated creatinine clearance of at least 50 mL per min. The 
primary endpoint was the proportion of patients who received at least one dose of study drug 
who had undetectable viral load (HIV-1 RNA < 50 copies per mL) at Week 48.  959 patients 
were randomly assigned to E/C/F/TAF and 477 continued Atripla, Stribild, or COBI- or 
RTV-boosted ATV with FTC/TDF. Viral suppression at Week 48 was noted in 97% 
(932/959) patients switched to E/C/F/TAF and 93% (444/477) of patients who continued a 
TDF-containing regimen (adjusted difference 4.1%, 95% CI 1.6–6.7), with virological failure 
noted in ten and six patients, respectively. The number of adverse events was similar between 
the two groups, but study drug-related adverse events were more common in the tenofovir 
alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density 
and glomerular filtration were each significantly improved in patients in the E/C/F/TAF 
group compared with those in the TDF-containing regimen group.

GS-US-292-0112, is a Phase 3, single-arm, open-label study which evaluate the efficacy and 
safety of E/C/F/TAF in virologically suppressed, HIV-infected subjects with estimated 
creatinine clearance 30-69 mL/min over 144 weeks. The primary endpoint was the change 
from baseline in glomerular filtration rate estimated using various formula. A total of 
242 virologically suppressed patients enrolled and switch treatment to E/C/F/TAF.  Subject 
baseline characteristics are mean age 58 years, 18% black, 39% hypertension, 14% diabetes. 
Through Week 48, no significant change in estimated CrCl was observed. Two patients 
(0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of 
renal tubulopathy and both had uncontrolled hypertension. Subjects had significant 
improvements in proteinuria, albuminuria, and tubular proteinuria (p < 0.001 for all). Hip and 
spine bone mineral density significantly increased from baseline to Week 48 (mean percent 
change +1.47 and +2.29, respectively, p < 0.05). 92% (222 patients) maintained HIV-1 RNA 
< 50 copies/mL at Week 48. The findings of this study support the use of E/C/F/TAF in 
patients with renal impairment down to an eGFRCG of 30 mL/min.
1.2.3.
Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide 
(F/R/TAF) Fixed Dose Combination
The details of the key clinical studies are provided below. Please refer to the IB for additional 
information on the FTC/RPV/TAF FDC.

GS-US-366-1159 was a randomized, open-label, single-dose, 3-way, 6-sequence, crossover 
study to determine the bioequivalence of FTC and TAF, administered as E/C/F/TAF FDC 
tablet or as FTC/RPV/TAF FDC tablet, and the bioequivalence of RPV administered as RPV 
single tablet or as FTC/RPV/TAF FDC tablet. The FTC and TAF components of the 
FTC/RPV/TAF (200/25/25 mg) FDC were found to be bioequivalent to the E/C/F/TAF 
(150/150/200/10 mg) FDC. The RPV component of the FTC/RPV/TAF (200/25/25 mg) FDC


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was found to be bioequivalent to RPV 25 mg tablet (Edurant®). FTC, RPV, and TAF 
administered as FTC/RPV/TAF (200/25/25 mg) FDC, RPV (25 mg), and E/C/F/TAF 
(150/150/200/10 mg) FDC were generally safe and well-tolerated in healthy volunteers;

GS-US-366-1651 was a randomized, open-label, single-dose, 2-period, crossover, food-effect 
study. Two cohorts of subjects were enrolled to assess the effect of moderate-fat food and the 
effect of high-calorie, high-fat food, on the PK of a single-dose FTC/RPV/TAF FDC tablet.  
Overall TAF exposure (AUClast) increased by approximately 45% and 54%, FTC exposure 
(AUCinf) decreased by approximately 9% and 12%, and RPV exposure (AUCinf) increased by 
approximately 13% and 75% (moderate-fat and high-calorie, high-fat conditions,
respectively) when the RPV/FTC/TAF FDC tablet (200/25/25 mg) was administered under 
fed compared with fasted conditions;
1.3.
Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Fixed Dose Combination
1.3.1.
General Information
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC, or Harvoni®) combines two 
HCV specific DAA agents into a single tablet for the treatment of chronic HCV infection. 
Sofosbuvir is a nucleotide analog that is a potent and selective inhibitor of NS5B-directed HCV 
replication, irrespective of HCV genotype. Ledipasvir is a novel HCV NS5A inhibitor that has 
demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV infection. 
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF
FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology
1.3.2.
Clinical Trials of Ledipasvir/Sofosbuvir (LDV/SOF, Harvoni®) Relevant to 
the Proposed Study 

Study GS-US-337-0102 (ION-1) was a Phase 3, multicenter, randomized, open-label study 
designed to investigate the efficacy and safety of LDV/SOF FDC + RBV for 12 and 
24 weeks.  Subjects were HCV treatment- naive with chronic genotype 1 HCV infection. 
ION-1 was based on data from phase 2 studies, which demonstrated high SVR rates in 
subjects with HCV genotype 1 infection. Subjects were randomized 1:1:1:1 to receive 
LDV/SOF once daily for 12 weeks, LDV/SOF + RBV for 12 weeks, LDV/SOF for 
24 weeks, or LDV/SOF + RBV for 24 weeks. The primary end point was SVR12.
Baseline characteristics of the 865 randomized and treated subjects included 16% with 
cirrhosis, 12% black, and 67% with HCV genotype 1a infection. The rates of SVR12 were 
99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of 


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LDV/SOF; 97% (95% CI, 94 to 99) in the group that received 12 weeks of LDV/SOF plus 
ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of LDV/SOF; and 
99% (95% CI, 97 to 100) in the group that received 24 weeks of LDV/SOF plus ribavirin. No 
subject in either 12-week group discontinued LDV/SOF owing to an adverse event. The most 
common adverse events were fatigue, headache, insomnia, and nausea. The study 
demonstrated that once-daily LDV/SOF+/- RBV for 12 or 24 weeks was highly effective in 
previously untreated patients with HCV genotype 1 infection.

Study GS-US-337-0109 (ION-2) was a phase 3, randomized, open-label study of HCV 
genotype 1 subjects with prior virologic failure of peg-interferon and ribavirin +/- an HCV
protease inhibitor. Subjects were randomized to i) LDV/SOF for 12 weeks, ii) LDV/SOF + 
RBV for 12 weeks, iii) LDV/SOF for 24 weeks, or iv) LDV/SOF + RBV for 24 weeks. The 
primary end point was SVR12. Baseline characteristics of the 440 randomized and treated 
subject included: 20% with cirrhosis and 79% with HCV genotype 1a infection. SVR12 rates 
were: 94% (95% confidence interval [CI], 87 to 97) for 12 weeks of LDV/SOF; 96% (95% 
CI, 91 to 99) for 12 weeks of LDV/SOF + RBV; 99% (95% CI, 95 to 100) for 24 weeks of 
LDV/SOF; and 99% (95% CI, 95 to 100) for 24 weeks of LDV/SOF + RBV. No patient 
discontinued treatment owing to an adverse event. The most common adverse events were 
fatigue, headache, and nausea.  The study demonstrated that treatment with daily LDV/SOF 
resulted in high rates of SVR12 in HCV-infected subjects who had not had a sustained 
virologic response to prior interferon based treatment.

Study GS-US-337-0108 (ION-3) was a phase 3, open-label study, which randomly assigned 
647 previously untreated subjects with HCV genotype 1 infection without cirrhosis to receive 
LDV/SOF +/- RBV for 8 weeks or LDV/SOF for 12 weeks. The primary end point was 
SVR12. The rate of sustained virologic response was 94% (95% confidence interval [CI], 
90 to 97) with 8 weeks of LDV/SOF, 93% (95% CI, 89 to 96) with 8 weeks of LDV/SOF + 
RBV, and 95% (95% CI, 92 to 98) with 12 weeks of LDV/SOF. As compared with the 
SVR12 rate in the group that received 8 weeks of LDV/SOF, the rate in the 12-week group 
was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that received 
8 weeks of LDV/SOF + RBV was 1 percentage point lower (95% CI, −6 to 4) demonstrating 
noninferiority of the 8-week LDV/SOF regimen (noninferiority margin of 12%). Adverse 
events were more common in the group that received ribavirin than in the other two groups. 
No patient who received 8 weeks of only LDV/SOF discontinued treatment owing to adverse 
events.  Overall, previously untreated subjects treated with 8 weeks of LDV/SOF achieved 
high rates of SVR. No additional benefit was associated with the inclusion of ribavirin in the 
regimen or with extension of the duration of treatment to 12 weeks.

GS-US-337-0115 (ION-4) was a multicenter, single-arm, open-label study that enrolled 
HIV/HCV (genotype 1 or 4) coinfected subjects to receive 12 weeks of LDV/SOF. Subjects 
were stable on antiretroviral regimens of F/TDF with EFV, RPV or RAL. The primary end 
point was SVR12. Of the 335 patients enrolled, 34% were black, 55% had been previously 
treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had SVR12 (95% 
confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with 
HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% 


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CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were 
similar regardless of previous treatment or the presence of cirrhosis. Of the 13 subjects who 
did not have a sustained virologic response, 10 had a relapse after the end of treatment. No 
subject had confirmed HIV-1 virologic rebound. The most common adverse events were 
headache (25%), fatigue (21%), and diarrhea (11%). No subejct discontinued treatment 
because of adverse events.  The study concluded that LDV/SOF for 12 weeks provided high 
rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 
or 4.
Combined Analyses of LDV/SOF Data {Bhagani et al 2015}
A combined analysis compared the safety and efficacy of the single tablet regimen of LDV/SOF 
in HCV genotype (GT) 1 patients co-infected with HIV-1 in the Phase III ION-4 study with 
HCV mono-infected GT1 patients in the Phase III ION 1-3 studies. 
In the ION-4 study, 327 GT1 HCV/HIV co-infected patients (126 treatment-naïve, non-cirrhotic, 
134 treatment-experienced, non-cirrhotic, 20 treatment-naïve, cirrhotic, 
47 treatment-experienced cirrhotic) received LDV/SOF for 12 weeks. In the ION 1-3 studies, 
538 GT1 HCV mono-infected patients (395 treatment-naïve, non-cirrhotic, 
87 treatment-experienced, non-cirrhotic, 34 treatment-naïve, cirrhotic, 22 treatment-experienced 
cirrhotic) received LDV/SOF for 12 weeks. The pooled analysis assessed safety and sustained 
virologic response at week 12 (SVR12).
Overall, 865 patients were treated with 12 weeks. In ION 1-3, the majority of patients were male 
(329, 61%), non-black (449, 83%), and treatment-naïve (430, 80%) while 56 (10%) patients had 
cirrhosis. In ION-4, the majority of patients were male (276, 82%), non-black (220, 66%), and 
treatment-experienced (185, 55%). Sixty-seven (67) (20%) patients had cirrhosis. SVR12 and 
relapse data are reported in the table. Treatment was well tolerated in both mono-infected and
co-infected patients. Most common adverse events (> 10% reported in any arm) were fatigue, 
headache, diarrhea, and nausea. Only two patients discontinued treatment due to an adverse 
event.  The investigators concluded that the once daily, single tablet regimen of LDV/SOF for 
12 weeks provided high rates of SVR regardless of presence of HIV infection and was a safe, 
well-tolerated option for patients with both HCV mono-infection and HIV/HCV co-infection.
Table 1-1.
Combined Analysis from Phase III ION Studies
Study
ION 1
ION 2
ION 3
ION 1-3 Combined
ION 4
N (GT 1)
213
109
216
538
327
SVR12 (%)
99
94
96
97
96
Relapse rates (%)
<1
6
1
2
3
Discontinuation rates (%)
0
0
1
<1
0


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LDV/SOF Drug Interactions with E/C/F/TAF and F/R/TAF {Custodio et al 2015}
Use of anti-HCV agents such as LDV, a P-glycoprotein (P-gp) and BCRP inhibitor, with HIV 
ARV such as TAF, a P-gp and BCRP substrate, may be complicated by drug-drug interactions 
(DDIs). Two Phase 1 studies evaluated DDIs between TAF-based regimens F/R/TAF or 
E/C/F/TAF and the fixed-dose combination anti-HCV regimen of LDV/SOF. In two 
multiple-dose, randomized, crossover studies, healthy volunteers received R/F/TAF (Study 1) or 
E/C/F/TAF (Study 2), alone or in combination with LDV/SOF, daily with food for 11 [Study 1] 
or 10 [Study 2] days. Plasma concentrations of RPV, EVG, COBI, FTC, TAF, TFV (TAF 
metabolite), LDV, SOF, and GS-331007 (predominant circulating metabolite of SOF) were 
analyzed and PK parameters calculated via noncompartmental analysis. Geometric least squares 
mean ratio (GMR; combination vs. alone) and 90% confidence intervals (CI) for analytes' 
AUCtau, Cmax and Ctau were estimated by linear mixed effect modeling and compared to lack of 
PK alteration bounds (70-143% except RPV: 80-125%). Safety was assessed throughout the 
studies.
Forty (40) of 42 subjects (Study 1) and 30/30 subjects (Study 2) completed the study. Treatments 
were generally well tolerated.
The GMR and 90% CI for all analytes’ PK parameters are:
Table 1-2.
Study 1: F/R/TAF and LDV/SOF
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
FTC/RPV/TAF
(Treatment B)
(N = 42)
LDV/SOF+FTC/RPV/TAF 
(Treatment C)
(N = 42)
FTC
AUCtau (h*ng/mL)
10,764.1 (14.3)
10,805.1 (15.3)
100.29 (98.43,102.19)
Cmax (ng/mL)
1707.6 (20.2)
1650.3 (17.6)
97.02 (92.72,101.53)
Ctau (ng/mL)
87.9 (28.2)
88.7 (25.1)
101.59 (98.47,104.81)
RPV
AUCtau (h*ng/mL)
3040.1 (27.3) 
2857.6 (25.6)
94.59 (91.20,98.10)
Cmax (ng/mL)
203.3 (25.4) 
197.1 (28.3)
96.65 (91.73,101.84)
Ctau (ng/mL)
109.1 (31.6) 
100.0 (26.0)
93.33 (89.38,97.45)
TAF
AUClast (h*ng/mL)
277.2 (37.5) 
362.3 (34.4)
132.39 (124.99,140.22)
Cmax (ng/mL)
200.0 (43.5) 
204.5 (45.7)
103.12 (93.58,113.63)
TFV
AUCtau (h*ng/mL)
268.4 (22.6) 
467.2 (21.0)
174.72 (168.78,180.86)
Cmax (ng/mL)
15.8 (21.7) 
25.4 (20.0)
161.50 (155.60,167.62)
Ctau (ng/mL)
9.0 (24.8) 
16.7 (22.0)
184.86 (177.57,192.46)


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PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF
(Treatment A)
(N = 41)
LDV/SOF+FTC/RPV/TAF 
(Treatment C)
(N = 42)
SOF
AUCtau (h*ng/mL)
2909.4 (32.8)
3068.9 (30.5)
104.69 (100.51,109.04)
Cmax (ng/mL)
1469.5 (35.4) 
1390.6 (32.3)
95.99 (88.80,103.76)
GS-331007
AUCtau (h*ng/mL)
11,766.4 (12.8) 
12,883.3 (16.1)
107.98 (106.20,109.79)
Cmax (ng/mL)
884.4 (13.7) 
960.4 (14.8)
108.09 (105.05,111.20)
Ctau (ng/mL)
339.8 (16.4) 
378.1 (18.9)
109.92 (107.46,112.44)
LDV
AUCtau (h*ng/mL)
11,590.4 (40.3)
11,944.8 (42.7)
101.53 (97.36, 105.88)
Cmax (ng/mL)
647.4 (35.8) 
658.4 (37.7)
100.62 (96.76, 104.63)
Ctau (ng/mL)
419.7 (45.9) 
434.3 (47.4)
102.40 (98.02, 106.99)
Table 1-3.
Study 2: E/C/F/TAF and LDV/SOF PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
E/C/F/TAF
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
EVG
AUCtau (h*ng/mL)
26,888.6 (22.74)
29,750.7 (23.26)
110.62 (102.40, 119.50)
Cmax (ng/mL)
2184.3 (23.29)
2155.3 (27.49)
97.85 (89.57, 106.91)
Ctau (ng/mL)
513.3 (40.06)
731.3 (35.57)
145.70 (127.99, 165.86)
COBI
AUCtau (h*ng/mL)
11,354.2 (36.34)
17,046.0 (30.36)
153.17 (144.87, 161.95)
Cmax (ng/mL)
1381.4 (25.98)
1668.0 (17.14)
123.35 (115.35, 131.91)
Ctau (ng/mL)
56.1 (99.59)
175.2 (90.42)
325.08 (287.62, 367.43)
FTC
AUCtau (h*ng/mL)
12,035.7 (15.39)
11,622.9 (15.53)
96.59 (93.22, 100.08)
Cmax (ng/mL)
1777.0 (18.40)
1840.3 (22.12)
103.04 (95.93, 110.67)
Ctau (ng/mL)
103.5 (26.84)
98.5 (27.24)
95.02 (90.82, 99.42)
TAF
AUClast (h*ng/mL)
238.6 (45.87)
194.8 (29.21)
85.67 (77.63, 94.54)
Cmax (ng/mL)
165.9 (50.79)
148.2 (48.24)
90.45 (73.41, 111.45)
TFV
AUCtau (h*ng/mL)
314.8 (18.68)
396.8 (15.90)
126.61 (122.55, 130.81)
Cmax (ng/mL)
17.8 (20.43)
20.7 (16.14)
116.85 (111.71, 122.23)
Ctau (ng/mL)
11.7 (20.05)
15.5 (16.62)
132.89 (127.74, 138.25)


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PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI)
LDV/SOF FDC
(N = 30)
LDV/SOF + E/C/F/TAF
(N = 30)
LDV
AUCtau (h*ng/mL)
12,657.2 (36.26)
22,939.3 (35.71)
178.99 (163.62, 195.81)
Cmax (ng/mL)
684.2 (32.25)
1136.0 (32.14)
164.74 (152.60, 177.86)
Ctau (ng/mL)
459.2 (40.34)
896.1 (37.74)
193.16 (173.91, 214.55)
SOF
AUCtau (h*ng/mL)
2336.2 (37.40)
3308.4 (24.84)
146.53 (135.44, 158.53)
Cmax (ng/mL)
1220.3 (37.87)
1573.2 (34.88)
128.48 (112.51, 146.72)
GS-331007
AUCtau (h*ng/mL)
12,611.4 (20.91)
18,739.0 (22.60)
148.15 (143.54, 152.91)
Cmax (ng/mL)
950.9 (18.74)
1228.7 (18.57)
129.36 (123.92, 135.04)
Ctau (ng/mL)
358.7 (24.66)
599.5 (27.40)
165.96 (159.61, 172.57)
GLSM and 90% CIs for all analytes were contained within the prespecified bounds except: 
i) TFV when RPV/FTC/TAF was administered with LDV/SOF; ii) COBI, when E/C/F/TAF was 
coadministered with LDV/SOF; and iii) LDV, GS-331007 and SOF and EVG when administered 
with E/C/F/TAF.
Despite an increase in TFV exposure upon coadministration of R/F/TAF + LDV/SOF, the mean 
TFV AUCtau is ~ 5 times lower than TFV from TDF, and within the range of TFV that did not 
lead to renal AEs or bone loss (E/C/F/TAF Phase 3). There is no association between higher 
COBI exposure and incidence of AEs, renal function parameters (E/C/F/TAF Phase 2/3 data). 
Higher plasma exposures of LDV, SOF and GS-331007 in the presence of E/C/F/TAF are not 
considered to be clinically important based on the established exposure-safety analyses for 
LDV/SOF. Thus, F/R/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose 
modification.
1.4.
Rationale for This Study
Currently, LDV/SOF is approved by the US FDA for treatment of HCV genotype 1- infected 
HCV mono and HIV co-infected patients. This Phase 3 open-label study is designed to extend 
this data to examine the efficacy and safety of LDV/SOF treatment regimen for chronic genotype 
1 HCV infection in HIV-infected patients who are receiving HIV therapy with E/C/F/TAF or 
F/R/TAF. Current guidelines for treatment of HCV in HIV co-infected patients emphasize the 
added need to treat co-infected patients due to higher rates of liver disease progression even if 
the HIV infection is treated with antiretroviral agents. The complex drug interactions that can 
occur between HIV ARV and HCV DAA further the need for safe, simple regimens that cure 
HCV in HIV-infected subjects without threatening the underlying HIV suppression. Current 


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IDSA/AASLD guidelines recommend that “Antiretroviral drug switches may be performed to 
allow compatibility of DAAs, with the goal of maintaining HIV suppression without 
compromising future options.” {HCV Guidelines 2015} Prior HIV treatment history, underlying 
HIV drug resistance and tolerability of regimens needs to be considered. 
LDV/SOF has been used successfully to treat HIV/HCV co-infected patients and the cure rates 
are 96%, comparable to HCV mono-infected patients {Naggie et al 2015}, which has led to a 
recent update to the LDV/SOF package insert that now includes HIV/HCV co-infection in the 
list of indications {Gilead Sciences Inc 2015}. However, few ARV regimens were evaluated in 
clinical studies of HCV treatment of HIV co-infected subjects.  Only RAL, EFV and RPV were 
used in the ION-4 study with FTC/TDF as the dual NRTI component of the regimen. In the 
presence of a boosting agent, such as RTV or COBI (which increase plasma TFV 
concentrations), further increases in plasma TFV concentrations are noted when coadministered 
with LDV/SOF + TDF.  Guidelines recommend avoiding RTV or COBI-boosted ARV regimens 
with TDF when treating HCV in HIV-infected patients, mainly due to lack of data.  The 
availability of TAF-based regimens will obviate the problem of excessive TFV concentrations 
due to the 91% lower plasma TFV levels when TAF is used in place of TDF.  The PK drug 
interaction studies (GS-US-366-1689 and Study 2) further justify the ability to use LDV/SOF in 
HIV-infected patients who are receiving TAF-based regimens (including COBI).
Drug-drug interactions of LDV/SOF coadministered with E/C/F/TAF and F/R/TAF were 
evaluated in healthy volunteers; the studies found no significant interactions and concluded that 
LDV/SOF and TAF-regimens can be coadministered without dose modification. The duration of 
the healthy volunteer drug-interaction studies were 10 and 11 days. Although, the US package 
insert for Genvoya® (E/C/F/TAF) suggests there should be no clinically significant drug 
interaction with LDV/SOF, there is no study to date that has evaluated the safety or efficacy of 
LDV/SOF administered with E/C/F/TAF or F/R/TAF for treatment of HCV in suppressed, HIV
co-infected population. Careful assessment of safety/tolerability of LDV/SOF with TAF 
regimens for 12 weeks is needed to ensure that the safety data, noted in healthy volunteers PK 
studies,is replicated during 12 weeks of coadministration in HIV/HCV co-infected subjects. The 
goal of this study is to evaluate E/C/F/TAF FDC or F/R/TAF FDC with LDV/SOF by 
determining the efficacy of HCV therapy (SVR 12 weeks after completion of LDV/SOF) and 
safety and tolerability of coadministration of dual STRs.
1.5.
Risk/Benefit Assessment for the Study
The risk/benefit for this study is acceptable due to the following considerations: i) treatment of 
HCV is indicated and important in all HIV co-infected patients due to accelerated progression of 
liver disease; ii) 12 weeks of LDV/SOF provides high HCV SVR rates in HIV/HCV co-infected 
subjects; iii) changing ARV regimens is an accepted strategy for management of patients prior to 
initiation of HCV therapy (AASLD/ IDSA Guidelines); iv) changing to E/C/F/TAF from other 
ART has been shown to be safe, effective and have superior treatment outcome than maintaining 
a current suppressive regimen {Mills et al 2015}; v) F/R/TAF is bioequivalent to approved HIV 
regimens and achieves plasma concentrations of FTC, RPV and TAF that have proven to be safe, 
well tolerated and effective in maintaining virologic suppression in HIV-infected patients. Thus, 
for individual subjects there is benefit to treating their HCV and for all co-infected patients, 
finding safe, tolerable, efficacious and simple regimens will be a major advance in treatment.


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1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are:

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4);

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen;

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects;

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment)
The secondary endpoints of this study are:

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment);

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using modified FDA snapshot algorithm;

Grades 1 through 4 adverse events after switching to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment .
3.2.
Study Design
This protocol describes a randomized, multicenter, open-label, 2-part study to evaluate the 
efficacy, safety, and tolerability of switching to E/C/F/TAF FDC or F/R/TAF FDC HIV 
treatments and adding LDV/SOF HCV treatment for 12 weeks in adult male and female subjects 
with HIV who are co-infected with chronic GT 1 HCV infection.
3.3.
Study Treatments
Subjects will participate in 2 parts of the study. In Part 1, subjects will be randomized in a 1:1 
ratio to one of the following 2 HIV treatment groups:
Part 1: Approximately 240 subjects will be randomized 1:1 to switch from stable ARV therapy 
to one of the following treatments.  Randomization will be stratified by race (black vs. non-
black) at screening.

Treatment Group 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC 
(n = 120)

Treatment Group 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC 
(n = 120)
Subjects maintaining HIV-1 RNA < 50 copies/mL and tolerating E/C/F/TAF or F/R/TAF 
through Part 1 will continue to Part 2 where they will receive the HCV treatment.  Subjects with 
confirmed virologic failure or who discontinue the HIV study drugs due to toxicity in Part 1 will 
be discontinued from the study.


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Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or F/R/TAF FDC treatment, subjects 
will maintain their HIV treatment and will initiate 12 weeks of LDV/SOF HCV treatment.  
At the end of their LDV/SOF HCV treatment, subjects will continue to maintain their HIV 
treatment and be followed for safety and efficacy for an additional 12 weeks to determine the 
SVR12 endpoint and HIV safety and efficacy endpoints.
3.4.
Duration of Treatment
The HIV treatment duration is from the Day 1 visit until the last study visit at the Post-HCV 
Treatment Week 12. The HCV treatment duration is 12 weeks. Screening assessments will be 
completed within 42 days of the Day 1 visit.
All subjects will complete the following study visits: Screening, Day 1, Weeks 4, 6 (laboratory 
visit only), 8 (start of HCV treatment), 12, 16, and 20 (end of HCV treatment), and post-HCV 
treatment visits 4 and 12 weeks after the last LDV/SOF dose. 
Subjects who complete the study through the last study visit at the Post-HCV Treatment
Week 12 visit will be required to return to the clinic 30 days after the completion of the study 
treatment for a 30-Day Follow-Up visit.
Figure 3-1.
Study Schema
a
Following the Day 1 visit, subjects will return for study visits at Weeks 4, 6 (laboratory visit only), 8, 12, 16, 20, and 
Post-HCV Treatment 4 and 12 weeks after the last LDV/SOF dose.
b
Part 1: subjects are randomized to either E/C/F/TAF FDC or F/R/TAF FDC on Day 1 and maintain HIV treatment to the 
Week 8 visit.
c
Part 2: At Week 8, once HIV-1 RNA suppression (< 50 copies/mL) is confirmed (based on the Week 6 HIV-1 RNA value), 
subjects will start on LDV/SOF FDC for 12 weeks (until Week 20) while maintaining their HIV treatment. At Week 20, 
LDV/SOF FDC will be discontinued while continuing HIV treatment. Subjects will continue in the study for another 
12 weeks to determine SVR4 (4 weeks post-HCV treatment) and SVR12 (12 weeks post-HCV treatment).
d
Subjects who complete the study through the Post-HCV Treatment Week 12 visit will be required to return to the clinic 
30 days after the completion of the study treatment for a 30-Day Follow-Up Visit. 
e
At the Day 1 visit, subjects will switch to either E/C/F/TAF FDC or F/R/TAF FDC and continue on HIV treatment until the 
last study visit at the Post-HCV Treatment Week 12 visit.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 240 subjects with HIV-1 who are coinfected with chronic HCV infection and 
who meet the eligibility criteria will be enrolled. In order to manage the total study enrollment, 
Gilead Sciences, Inc., at its sole discretion, may suspend screening and/or enrollment at any site 
or study-wide at any time.
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 any study procedures.
2) Age ≥ 18 years.
3) Currently on the first or second ARV regimen (2 NRTI + a third agent, see Table 4-1) 
without change for 6 months prior to screening. Documented plasma HIV-1 RNA levels 
< 50 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if 
the limit of detection is ≥ 50 copies/mL) for ≥ 6 months preceding the Screening visit. After 
reaching HIV-1 RNA < 50 copies/mL, single values (“blips”) of HIV-1 RNA ≥50 copies/mL 
followed by resuppression are allowed.
Table 4-1.
Allowable ARV Agents of Pre-Existing HIV Regimen
Antiretroviral Class
Agents
Boosted PI
ATV+COBI (or ATV/COBI FDC), darunavir (DRV)+COBI (or DRV/COBI FDC), 
DRV+RTV, lopinavir (LPV)+RTV, ATV+RTV
NNRTI
EFV, etravirine (ETR), nevirapine (NVP), RPV
NRTI
FTC, TDF, abacavir (ABC), lamivudine (3TC), zidovudine (AZT)
INSTI
dolutegravir (DTG), RAL, EVG/COBI or EVG+RTV
4) No history of HIV virologic failure
5) If the current regimen is a PI/r, the previous regimen cannot contain an NNRTI or INSTI
6) Plasma HIV-1 RNA level < 50 copies/mL at the Screening visit.
7) Have no documented resistance to any of the HIV study agents at any time in the past, 
including but not limited to the reverse transcriptase resistance mutations K65R, K70E, 
K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, 
M230I/L, the combination of K103N+L100I, or 3 or more TAMs that include M41L or 
L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R).


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8) Chronic HCV infection (≥ 6 months) documented by prior medical history.
9) HCV genotype 1 at screening as determined by the Central Laboratory. Any non-definitive
genotype results will exclude the subject from study participation.
10) Classification as one of the following criteria:
a) Without cirrhosis and no prior HCV treatment (treatment-naïve, defined as having never 
been exposed to approved or investigational HCV-specific direct-acting antiviral agents 
or prior treatment of HCV with IFN and RBV)
b) Without cirrhosis and have received HCV treatment only with IFN +/- RBV +/- HCV PI 
(treatment-experienced, defined as prior treatment failure to a regimen containing IFN
either with or without RBV that was completed at least 8 weeks prior to Day 1. The 
subject’s medical records must include sufficient detail of prior treatment experience for 
categorization, as either:
i.
Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
ii.
Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR, or
iii.
HCV Treatment-Intolerant: Subjects who discontinued HCV treatment of a regimen 
containing IFN (either with or without RBV) due to toxicity  
c) Compensated cirrhosis and no prior HCV treatment (treatment-naïve)
11) Cirrhosis Determination 
a) Presence of cirrhosis is defined as any one of the following:
i.
FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
screening
ii.
Fibroscan with a result of > 12.5 kPa 
iii.
Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score ≥5)
b) Absence of cirrhosis is defined as any one of the following:
i.
FibroTest® score ≤ 0.48 AND APRI ≤ 1 performed during screening 
ii.
Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
iii.
Liver biopsy within 2 years of screening showing absence of cirrhosis
If historical report of a fibroscan or liver biopsy is available, the reports must be within 
6 months of screening. In the absence of a definitive diagnosis of presence or absence of 
cirrhosis by Fibrotest® /APRI using the above criteria, a liver biopsy or fibroscan is required. 
Liver biopsy results will supersede Fibrotest® /APRI or fibroscan results and be considered 
definitive.


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12) Liver imaging within 6 months of Day 1 is required in cirrhotic subjects only to exclude 
hepatocellular carcinoma (HCC)
13) HCV RNA 104 IU/mL at the Screening visit
14) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
15) Adequate renal function: estimated GFR ≥ 30 mL/min according to the Cockcroft-Gault 
formula (eGFRCG) for creatinine clearance {Cockcroft et al 1976}:
Male:
(140 – age in years) × (wt in kg) CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female:
(140 – age in years) × (wt in kg) × 0.85 CLcr (mL/min)
72 × (serum creatinine in mg/dL)
16) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
17) 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)
18) Adequate hematologic function:

Absolute neutrophil count ≥1,000/mm3

Platelets ≥50,000/mm3

Hemoglobin ≥ 8.5 g/dL
19) Albumin 3.0 g/dL
20) INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
21)
A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant or nursing
b) Of non-childbearing potential (ie, women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
≥54 years of age with cessation [for 12 months] of previously occurring menses), or
c) Of childbearing potential and agrees to utilize protocol-specified contraceptive methods
or be non-heterosexually active or practice sexual abstinence from screening throughout 
the duration of study treatment and for 30 days following the last study drug dose (see 
Appendix 5 for definitions and protocol-acceptable contraceptive methods)


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22)
Male subjects must agree to utilize a protocol-approved method of contraception (as 
defined in Appendix 5) during heterosexual intercourse or be non-heterosexually active, or 
practice sexual abstinence from first dose throughout the study period and for 30 days 
following the last study drug dose.
23)
Male subjects must agree to refrain from sperm donation from first dose until at least 
30 days after the last study drug dose.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) A new AIDS-defining condition diagnosed within the 30 days prior to the Screening visit
(except CD4+ cell count and/or percentage criteria) (refer to Appendix 6)
2) Prior HCV treatments with NS5A and NS5B or any HCV directly acting antivirals except 
boceprevir, telaprevir and simeprevir in combination with IFN +/- RBV.
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
4) History or current decompensation of liver disease; varices at low risk of bleeding are 
allowed.
5) Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B virus (HBV) DNA
6) Chronic use of systemically administered immunosuppressive agents (eg, prednisone 
equivalent > 10 mg/day).
7) Females who are breastfeeding
8) Positive serum pregnancy test 
9) Have an implanted defibrillator or pacemaker
10) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 42 days of Day 1visit and must not be 
anticipated to require systemic therapy during the study.
12) Active, serious infections (other than HIV-1 and HCV infections) requiring parenteral 
antibiotic or antifungal therapy within 42 days prior to Day 1


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13) Gastrointestinal disorder or post-operative condition that could interfere with the absorption 
of the study drugs
14) Solid organ transplantation
15) Significant pulmonary disease or significant cardiac disease
16) 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
17) Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
18) Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
19) 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 HIV study drugs (COBI, EVG, FTC, 
RPV, or TAF. For COBI, EVG, FTC, or RPV, refer to the individual agents’ Prescribing 
Information; for TAF, refer to the E/C/F/TAF FDC or F/R/TAF FDC Investigator’s 
Brochures) or HCV study drugs (LDV or SOF); or subjects with any known allergies to the 
excipients of E/C/F/TAF, F/R/TAF, or LDV/SOF tablets.
Table 4-2.
Disallowed Agentsa
Drug Class
Agents Disallowedb
Acid Reducing Agents
Proton pump inhibitors, such as Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, Rabeprazole
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Antiarrythmics
Amiodaroned, Quinadine
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifampin, Rifapentine, Rifabutin
Calcium Channel Blockers
Bepridil
Corticosteroids: Systemic
Dexamethasone (more than a single dose)
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplementsc
St. John’s Wort, Echinacea, Milk thistle (ie, silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin, Rosuvastatine
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide


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Drug Class
Agents Disallowedb
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a.
Disallowed agents are inclusive of all HIV and HCV study drugs (E/C/F/TAF, F/R/TAF, and LDV/SOF).
b.
Administration of any of the following medications must be discontinued at least 42 days prior to the Day 1 visit and for the 
duration of the study, with the exception of amiodarone (see footnote d).
c.
May result in a decrease in the concentrations of all HIV and HCV study drugs.
d.
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to the Day 1 visit and for the duration of the study.
e.
Use with LDV/SOF may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
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. Once a subject number has 
been assigned to a subject, it will not be reassigned to any other subject. Prior to or during the 
Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web 
Response System (IWRS). The subject number assignment and randomization may be performed 
up to 7 days prior to the in-clinic Day 1 visit provided that all screening procedures have been 
completed and subject eligibility has been confirmed.
Subjects will be randomized in a 1:1 ratio to one of the following two treatment arms: 
Treatment Arm 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC (n = 120)
Treatment Arm 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 120)
Randomization will be stratified by race (black vs. non-black).
The IWRS will assign study drug bottle numbers to be dispensed to the subject at each study 
visit, for all HIV and HCV study drugs. All Day 1 assessments and procedures must be 
completed prior to the administration of the first dose of HIV study drug. Initiation of 
treatment with the HIV study drug must take place within 24 hours after the Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF, F/R/TAF, and LDV/SOF
5.2.1.
Formulation
5.2.1.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are capsule-shaped, film-coated green tablets debossed with “GSI” on one 
side of the tablet and “510” on the other side. Each E/C/F/TAF tablet contains 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.
5.2.1.2.
F/R/TAF 
F/R/TAF tablets are capsule-shaped, film-coated gray tablets debossed with “GSI” on one side 
and “255” on the other side. Each F/R/TAF tablet contains 200 mg of FTC, 25 mg of RPV (as 
27.5 mg RPV hydrochloride), and 25 mg of TAF (as 28 mg of TAF fumarate). 


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In addition to the active ingredients, the tablets contain lactose monohydrate, microcrystalline 
cellulose, polysorbate, povidone, croscarmellose sodium and magnesium stearate. The tablet
cores are film-coated with polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
black iron oxide.
5.2.1.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are orange, diamond-shaped, film-coated tablets debossed with “GSI” on one 
side and “7985” on the other side. Each LDV/SOF FDC tablet contains 90 mg of LDV and 
400 mg of SOF.
In addition to the active ingredients, the tablets contain lactose monohydrate, copovidone, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and FD&C yellow # 6 /sunset 
yellow FCF aluminium lake.
5.2.2.
Packaging and Labeling
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA) and/or other local regulations.
5.2.2.1.
E/C/F/TAF, Genvoya®
E/C/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles.  Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Genvoya® may 
also be used for the study.
5.2.2.2.
F/R/TAF
F/R/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles.  Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner.
5.2.2.3.
LDV/SOF, Harvoni®
LDV/SOF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 28 or 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, and aluminum-faced liner. Commercially available product of Harvoni® may 
also be used for the study.


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5.2.3.
Storage and Handling
E/C/F/TAF, F/R/TAF, and LDV/SOF 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 drugs 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 by avoiding direct eye contact or exposure when 
handling.
Commercial product of Genvoya® and Harvoni® may be used for the study. Further information 
regarding storage and handling are available in the Prescribing Information for commercial 
products.
5.3.
Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF
E/C/F/TAF FDC, F/R/TAF FDC, and LDV/SOF FDC tablets will be provided by 
Gilead Sciences.
The two HIV study treatments will be administered orally, once daily with food at approximately 
the same time each day:

Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg 
(E/C/F/TAF) FDC

Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg (F/R/TAF) FDC
HCV study treatment (ledipasvir 90 mg/sofosbuvir 400 mg [LDV/SOF] FDC) is to be 
administered orally, once daily with or without food at approximately the same time each day.
For a missed dose of E/C/F/TAF FDC, F/R/TAF FDC, and/or LDV/SOF FDC tablet, subjects 
should be instructed to take the missed dose of study drug as soon as possible during the same 
day.  Subjects should be cautioned never to double the next dose with a missed dose of study 
drug under any circumstances.
5.4.
Prior and Concomitant Medications
The use of medications for the treatment of HIV and HCV, other than the study treatments 
(ie, E/C/F/TAF, F/R/TAF, or LDV/SOF) is prohibited.
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.


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Concomitant medications taken within 30 days prior to the Screening visit and up to and 
including 30 days after the last dose of study drug need to be recorded in the source documents 
and electronic case report form(s) (eCRFs).
Medications listed in Table 5-1 (E/C/F/TAF + LDV/SOF) and Table 5-2 (F/R/TAF + LDV/SOF) 
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.
Table 5-1.
Prior and Concomitant Medications – E/C/F/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agents
Antacidsa
Elvitegravir plasma concentrations are lower with 
antacids due to local complexation in the GI tract 
and not to changes in gastric pH. It is recommended 
to separate study drug and antacid administration by 
at least 2 hours. 
Proton- Pump Inhibitors, H2-Receptor Antagonists, 
Antacids
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antiarrhythmics
Amiodaronec, Quinadine
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.
Antibacterials
Concentrations of clarithromycin and/or cobicistat 
may be altered when clarithromycin is 
coadministered with study drug(s). 
Patients with CLcr greater than or equal to 
60 mL/min: 
No dose adjustment of clarithromycin is required. 
Patients with CLcr between 30 mL/min and 
60 mL/min: 
The dose of clarithromycin should be reduced by 
50%. 
Concentrations of telithromycin and/or cobicistat 
may be increased when telithromycis in 
coadministered with study drug. Clinical monitoring 
is recommended upon coadministration with study 
drug. 
Anticoagulants
Warfarin: Concentrations may increase or decrease 
with study drug(s); appropriate INR 
(International Normalized Ratio) monitoring 
is recommended.


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Drug Class
Agents Disallowed
Use With Caution
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine: 
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs): 
A dose reduction may be required for most drugs of 
this class with the exception of sertraline.
Tricyclics:
Concentrations may increase or decrease with study 
drug(s). Concentration monitoring is recommended 
to ensure adequate clinical response.
Trazodone:
Concomitant use with CYP3A inhibitors results in 
increased concentrations and adverse events; dose 
reduction should be considered.
Antifungals
Ketoconazole and Itraconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Daily dose of 
ketoconazole and itraconazole should be restricted 
to 200 mg. Subjects receiving ketoconazole or 
itraconazole should be monitored for adequate 
clinical response.
Voriconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Clinical monitoring may 
be needed.
Antigout
Dose reductions of colchicine may be required. 
Study drug(s) should not be coadministered with 
colchicine in patients with renal or hepatic 
impairment.
Antihistamines
Concentrations of astemizole and terfenadine may 
be increased when coadministered with cobicistat. 
Clinical monitoring is recommended when these 
agents are coadministered with study drug(s).
Antimycobacterialsb
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
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
Cardiac Medications
Digoxind


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Drug Class
Agents Disallowed
Use With Caution
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 Supplementsb
St. John’s Wort, 
Echinacea, Milk thistle 
(ie, silymarin), Chinese 
herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin, 
Rosuvastatine
Atorvastatin:
Concentrations may increase with study drug(s). 
Start with the lowest dose; gradual increase in dose 
may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s).
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine: 
A dose decrease may be needed.


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Drug Class
Agents Disallowed
Use With Caution
Opiates
Methadone:
Methadone exposures are unaffected upon 
coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required upon 
coadministration with study drug(s).
Meperidine (Pethidine):
Dosage increase and long-term use are not 
recommended due to increased levels of metabolite 
normeperidine, which has analgesic and 
CNS stimulant (eg, seizures) activities.
Buprenorphine:
Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and cobicistat, 
with no effect on opioid pharmacodynimcs.
The concentration changes are not considered 
clinically relevant and no dose adjustment of 
buprenorphine/naloxone is required upon
coadministration with study drug(s).
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil:
Caution should be exercised, including 
consideration of dose reduction, when 
coadministered for treatment of pulmonary arterial 
hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil:
It is recommended that a single dose of Sildenafil 
no more than 25 mg in 48 hours, Vardenafil no 
more than 2.5 mg in 72 hours, or Tadalafil no more 
than 10 mg in 72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem:
A dose decrease may be needed for these drugs. 
Clinical monitoring is recommended.
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of E/C/F/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when coadministered with E/C/F/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis


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Table 5-2.
Prior and Concomitant Medications – F/R/TAF + LDV/SOF
Drug Class
Agents Disallowed
Use With Caution
Acid Reducing Agentsa
Proton pump inhibitors, such as 
Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, 
Rabeprazole
H2-Receptor Antagonists, Antacids
Cimetidine, Famotidine, Nizatidine, 
Ranitidine
Coadministration of H2-receptor antagonists 
(H2RA) may cause significant decreases in 
RPV plasma concentrations (increase in 
gastric pH). H2RAs should only be 
administered at least 12 hours before or at 
least 4 hours after F/R/TAF
Alkaline antacids: antacids (eg, 
aluminum or magnesium 
hydroxide, calcium carbonate)
Antacids should be used with caution as 
coadministration may cause significant 
decreases in RPV plasma concentrations 
(increase in gastric pH). Antacids should 
only be administered either at least 2 hours 
before or at least 4 hours after F/R/TAF.
Antiarrhythmics
Amiodaronec, Quinidine
Anticonvulsantsb
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Fluconazole, Itraconazole, Ketoconazole, 
Posaconazole, Voriconazole: may increase 
concentration of RPV.
Antimycobacterialsb
Rifapentine, Rifabutin, Rifampin
Cardiac Medications
Digoxind
Corticosteroids: Systemic
Dexamethasone (more than a 
single dose)
Herbal/Natural Supplementsb
St. John’s Wort, Echinacea, Milk 
thistle (ie, silymarin), Chinese 
herb Sho-Saiko-To (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorse
Rosuvastatin
Narcotic analgesics
Methadone
Clinical monitoring is recommended as 
methadone maintenance therapy may need 
to be adjusted in some patients upon 
coadministration with RPV
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with study drugs. Proton-pump inhibitors should not be taken before study drugs. 
b
May result in a decrease in the concentrations of study drugs.
c
May result in symptomatic bradycardia. Mechanism is currently unknown. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
d
Coadministration of F/R/TAF or LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted 
and therapeutic concentration monitoring of digoxin is recommended when co-administered with F/R/TAF or LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of 
myopathy including rhabdomyolysis.


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5.5.
Accountability for Investigational Medicinal Product (IMP)
The investigator is responsible for ensuring adequate accountability of all used and unused IMP. 
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
IMP accountability records will be provided by Gilead Sciences (or equivalent documentation 
maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify Gilead or 
contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment. Please refer to Section 5.1 for details about randomization and treatment 
assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 42 days prior to the Day 1 visit to determine eligibility for 
participation in the study. The following assessments will be completed and documented at 
screening:

Obtain written informed consent

Determine eligibility including cirrhosis determination (see Section 4.2 for details)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging (CT or 
Ultrasound) should be performed within 6 months of Day 1 to exclude the presence of 
hepatocellular carcinoma 

Obtain medical history, including: 
History of HIV-1 disease-related events and prior medications within 30 days of the 
Screening visit.
Collection of historical HIV genotype, if available
If HCV treatment-experienced, record the duration of the prior treatment and the type of 
IFN +/- RBV + HCV PI administered. Record whether the subject had a Non-Response 
or Relapse/Breakthrough during prior treatment or was Treatment Intolerant.
■
Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. 
■
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment, but did not achieve SVR
■
Treatment Intolerant: Subject discontinued HCV treatment of a regimen containing 
IFN either with or without RBV due to toxicity


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
Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Obtain 12-lead ECG (performed supine)

Obtain height and weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry

Obtain blood samples for the following laboratory analyses:
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid. 
Hematology profile: complete blood count (CBC) with differential and platelet count
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), 
and activated partial thromboplastin time (APTT)
CD4+ cell count 
Plasma HIV-1 RNA (COBAS® TaqMan® HIV RNA Test, v2.0) 
Whole blood sample for HIV proviral genotype analysis of archived resistance (if a 
historical genotype is not available)
Plasma HCV RNA (COBAS® TaqMan® HCV Quantitative Test, v2.0)
HCV genotype and subtype, and IL28B genotype testing 
Serology for:
■
HIV antibody 
■
HBV core antibody (HBcAb), surface antibody (HBsAb), surface antigen (HBsAg), 
e-antibody (HBeAg), e-antibody (HBeAb), and HBV DNA
■
HCV antibody


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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula (see 
Section 4.2 for details)

Obtain details of adverse events related to screening procedures

Review concomitant medications
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 42 days after the Screening visit for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events (AE) 
related to protocol-mandated procedures on the adverse events electronic case report form 
(eCRF).  All other untoward medical occurrences observed until dosing of study drugs, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  See 
Section 7, Adverse Events and Toxicity Management, for additional details.
6.2.2.
Day 1 Assessments
The following assessments are to be completed at the Day 1 visit. The Investigator must have 
received the results from the screening assessments before proceeding with the visit. Subjects 
must complete all Day 1 procedures before being dispensed the study drugs.  Initiation of 
treatment with HIV study drugs must take place within 24 hours after the Day 1 visit.

Review AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive at Day 1, study drugs will not be dispensed. The positive result will be 
confirmed with a serum pregnancy test. If the serum pregnancy test is positive, the 
subject will not be able to participate.  
Renal tubular function assessments (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection): retinol binding protein, beta-2 microglobulin, 
urine albumin, and urine protein
Urine sample storage for possible additional clinical testing


FTC/RPV/TAF 
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• 
Obtain blood samples for the following laboratory analyses: 
-
Chemistly profile 
-
Hematology profile 
-
Coagulation assessments 
Final 
Original 
-
Metabolic assessments (collected fasted, 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). 
• 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 to draw blood for the metabolic 
assessments. 
-
CD4+ cell count 
-
PlasmaHIV-1 RNA 
-
Plasma HCV RNA 
-
Serum bone safety assessments: (collected fasted, no food or drink, except water, at 
least 8 hours prior to blood collection) parathyroid hormone (PTH) and serum 25-0H 
Vitamin D 
• If the subject has not fasted prior to the visit, the visit may proceed, but the subject 
must retw.n within 72 hours in a fasted state to draw blood for these assessments. 
-
Platelet and coagulation ftmction assessments may include: Soluble glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and D-dimer 
-
Inflammation assessments may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, 
sTNF-Rl, and Lp-PLA2 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Sennn storage sample for possible additional clinical testing 
-PPD 
• 
Obtain estimated glomemlar filu·ation rate according to the Cockcroft-Gault f01mula (see 
Section 4.2 for details) 
CONFIDENTIAL 
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
Complete questionnaires: subject is to read questionnaire by her/himself and write/mark 
answers directly onto the questionnaires.
Adherence for HIV (VAS)
HIV Treatment Satisfaction Questionnaire – Status version (HIVTSQs)
Medical Outcomes Short Form-36 (SF-36)
Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F)
Chronic Liver Disease Questionnaire (CLDQ-HCV)
Work Productivity and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: 
Hepatitis C)
6.3.
Randomization

Obtain subject number and randomize the subject via the IWRS. The subject number 
assignment and randomization may be performed up to 7 days prior to the in-clinic Day 1
visit provided that all screening procedures have been completed and subject eligibility has 
been confirmed.

Dispense HIV study drugs. Subjects should initiate dosing of HIV study drugs after Day 1
visit assessments. Initiation of treatment with the study drugs must take place within 24 hours 
after the Day 1 visit.
Subjects should also be counseled regarding the importance of adherence and taking their 
study drug daily with food at approximately the same time each day.
6.4.
Treatment Assessments
6.4.1.
HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20)
The following assessments are to be completed at the end of Weeks 4, 8, 12, 16, and 20, unless 
otherwise specified. The Week 6 visit is a laboratory visit only – please see Section 6.4.1.1 for 
details.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the protocol-specified visit date based on the Day 1 visit through 
Week 20. 

Review AEs and changes in concomitant medications

Perform symptom-directed physical examination as needed 

Obtain vital signs, including weight


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Obtain urine samples for the following laboratoty analyses: 
-
Urinalysis and urine c.hemistiy 
Final 
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-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confmned with a sennn test. If the se1um test is positive, the subject will be 
discontinued. 
-
Renal tubular function assessments (Weeks 4, 8, 12, and 20 only) 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratoty analyses: 
-
Chemistly profile 
-
Hematology profile 
-
Coagulation assessments 
-
Metabolic assessments (Weeks 8 and 20 only) 
-
CD4+ cell count 
-
Plasma HIV-1 RNA 
-
Plasma HCV RNA (Weeks 8, 12, 16, and 20 only) 
-
Samples for population PK (Weeks 4, 8, 12, 16, and 20) 
• 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior 
to observed study dmg dosing; 2) the postdose sample should be drawn between 15 
millS and 4 hours postdose. 
-
Semm bone safety assessments (Weeks 4, 8, 12, and 20 only) 
-
Platelet and coagulation function assessments (Weeks 4, 8, 12, and 20 only) 
-
Inflammation assessments (Weeks 4, 8, 12, and 20 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Se1um storage sample for possible additional clinical testing 
-PPD 
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
Obtain estimated glomerular filtration rate according to the Cockcroft-Gault formula (see 
Section 4.2 for details)

Complete questionnaires (Weeks 8 and 20 only): subject is to read questionnaire by 
her/himself and write/mark answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version 
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

Subjects who meet the criteria for virologic rebound should be managed according to 
Management of HIV Virologic Failure (Section 6.9)

Document study drugs dispensation and accountability for all study drugs dispensed. Counsel 
all subjects regarding the importance of adherence and maintaining consistency to study drug 
administration.
HIV study drugs are dispensed at every visit (with the exception of Week 6 
laboratory visit).
HCV treatment will commence at Week 8, after determination of HIV suppression 
(< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability of HIV study 
drugs. Once confirmed, dispense HCV study drug (LDV/SOF) at Weeks 8, 12, and 16 
only.
6.4.1.1.
Week 6 (Laboratory Visit Only)
The Week 6 visit is a laboratory visit only, to confirm HIV suppression prior to initiation of 
HCV treatment. 
The following will be performed and documented at the Week 6 visit:

Obtain blood samples for plasma HIV-1 RNA testing

Plasma storage sample for safety and virology testing


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6.4.2.
HIV Treatment and Post-HCV Treatment Assessments (Post-HCV 
Treatment Weeks 4 and 12) 
The following evaluations are to be completed at the end of 4 and 12 weeks after completion of 
HCV treatment (Post-HCV Treatment Weeks 4 and 12 visits, respectively) and should be timed 
from the date of last administration of the HCV treatment. The Post-HCV Treatment Week 4 
visit is to be completed ± 2 days, and the Post-HCV Treatment Week 12 visit is to be completed 
within ± 4 days; however, unless notified by Gilead Sciences, the Post-HCV Treatment Week 12 
should be completed within 4 days of the protocol-specified visit date.
All subjects must complete the Post-HCV Treatment Weeks 4 and 12 visits. The end of study 
will occur at the Post-HCV Treatment Week 12 visit.
The following assessments are to be completed:

Review AEs and changes in concomitant medications

Complete physical examination (Post-HCV Treatment Week 12 only) (urogenital/anorectal 
exams will be performed at the discretion of the Investigator)

Perform symptom-directed physical examination as needed 

Obtain vital signs, including weight

Obtain urine samples for the following laboratory analyses: 
Urinalysis and urine chemistry 
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the serum test is positive, the subject will be 
discontinued.
Renal tubular function assessments (Post-HCV Treatment Week 12 only)
Urine sample storage for possible additional clinical testing

Obtain blood samples for the following laboratory analyses:
Chemistry profile 
Hematology profile
Coagulation assessments 
Metabolic assessments (Post-HCV Treatment Week 12 only)
CD4+ cell count


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Plasma HIV -1 RNA 
-
Plasma HCV RNA 
-
Semm bone safety assessments (Post-HCV Treatment Week 12 only) 
Final 
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-
Platelet and coagulation function assessments (Post-HCV Treatment Week 12 only) 
-Inflammation assessments (Post-HCV Treatment Week 12 only) 
-
Plasma storage samples for virology, safety, and/or PK testing 
-
Sennn storage sample for possible additional clinical testing 
-PPD 
• 
Obtain estimated glomemlar filtration rate according to the Cockcroft-Gault f01mula (see 
Section 4.2 for details) 
• 
Complete questionnaires (Post-HCV Treatment Week 12 only): subject is to read 
questionnaire by her/himself and write/mark answers directly onto the questionnaires. 
-
VAS for HIV adherence 
-
HIVTSQc - Change version 
-
SF-36 
-
FACIT-F 
-
CLDQ-HCV 
-
WP AI: Hepatitis C 
• 
Subjects who meet the criteria for virologic rebound should be managed according to 
Management of HIV Virologic Failure (Section 6.9) 
• 
Document study chugs dispensation and accmmtability for all HIV study drugs dispensed. 
Counsel all subjects regarding the importance of adherence and maintaining consistency to 
HIV study dmg administration. 
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6.5.
Post-treatment Assessments
6.5.1.
Early Study Drug Discontinuation (ESDD) Visit
Early study drug discontinuation during Part 1 (Day 1 through Week 8):
If the subject discontinues HIV study drug dosing in Part 1, the subject will be discontinued from 
the study and will not continue to Part 2 of the study. The subject will be asked to return to the 
clinic within 72 hours of stopping HIV study drugs for the ESDD visit, followed by the 30-Day 
Follow-Up visit. 
Early study drug discontinuation during Part 2 (after initiation of HCV treatment):
If the subject discontinues HCV study drug dosing only prior to completing the 12-week HCV 
treatment, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HCV study drug for the ESDD 
visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.

Continue to receive HIV study drugs (see ESDD procedures below).
If the subject discontinues HIV study drug dosing only, the following will occur:

Be asked to return to the clinic within 72 hours of stopping HIV study drugs for the ESDD 
visit. 

HIV regimen may be changed, after discussion with the Medical Monitor. The new HIV 
regimen should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be 
continued unless an HIV regimen cannot be constructed that would allow coadministration 
with the new HIV regimen. 

Remain in the study to complete the 12-week HCV treatment (see Section 6.4.1) and follow-
up visits 4 and 12 weeks after the last dose of LDV/SOF, as described in Section 6.4.2.
If the subject discontinues both HIV and HCV study drug dosing, the following will occur:

Be asked to return to the clinic within 72 hours of stopping study drugs for the ESDD visit. 

Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of 
LDV/SOF, as described in Section 6.4.2.


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At the ESDD Visit, any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drugs, should be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at the ESDD Visit: 
• 
Review of AEs and changes in concomitant medications 
• 
Complete physical examination (urogenitaVanorectal exams will be perf01med at the 
discretion of the Investigator) 
• 
Obtain vital signs, including weight 
• 
Obtain 12-lead ECG (perfom1ed supine) 
• 
Obtain urine samples for the following laboratory analyses: 
-
Urinalysis and urine chemistry 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a se1um test. 
-
Urine sample storage for possible additional clinical testing 
• 
Obtain blood samples for the following laboratory analyses: 
-
Chelnistly profile 
-
Hematology profile 
-
CD4+ cell count 
-
Plasma HIV-1 RNA 
-
Plasma HCV RNA 
-
Plasma storage samples for virology, safety, and/or PK testing 
PD 
• 
Obtain estimated glomemlar filn·ation rate according to the Cockcroft-Gault f01mula (see 
Section 4.2 for details) 
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
Complete questionnaires: subject is to read questionnaire by her/himself and write/mark 
answers directly onto the questionnaires.
VAS for HIV adherence
HIVTSQc – Change version
SF-36
FACIT-F
CLDQ-HCV
WPAI: Hepatitis C

HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 400 copies/mL.

Perform study drug accountability:
For subjects that discontinue during Part 1 of the study, perform study drug 
accountability on HIV study drugs.
For subjects that discontinue during Part 2 of the study, perform study drug 
accountability for HIV and HCV study drugs. 
■
If the subject discontinues HCV study drug and is staying on HIV study drug, 
dispense HIV study drug until the last study visit. 
■
If the subject discontinues HIV study drug, HCV study drug will be dispensed at the 
scheduled visits as described in Section 6.4.1
6.5.2.
30-Day Follow-Up Visit
Subjects who complete the study through the Post-HCV Treatment Week 12 visit 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 HIV study drug in Part 1 of the study will be asked to 
return to the clinic after the completion of the ESDD visit for a 30-Day Follow-Up visit.
A ± 6 days window may be used to schedule this visit. The following evaluations are to be 
completed at this visit:

Review of AEs and changes in concomitant medications

Perform symptom-directed physical examination 


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
Obtain vital signs measurement, including weight

Obtain urine samples for the following laboratory analyses:
Urinalysis and urine chemistry
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. 

Obtain blood samples for the following laboratory analyses:
Chemistry profile
Hematology profile
CD4+ cell count
Plasma HIV-1 RNA
Plasma HCV RNA
At the 30-Day Follow-Up Visit, any evaluations showing abnormal results indicating that there is 
a reasonable possibility of a causal relationship with the study drug will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
6.6.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (refer to Appendix 2). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study and asked to return for the 
ESDD Visit followed by the 30-Day Follow-Up Visit.
6.7.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree.

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the Investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Lack of efficacy (virologic failure)


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
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 Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.8.
Other Assessments
6.8.1.
Blood and Urine Storage
A portion of the blood drawn and urine collected at all visits (except Screening, Week 6, 30-Day 
Follow-Up, or Unscheduled) will be frozen and stored. From subjects who provide additional 
consent, a portion of the blood draw at Day 1, Weeks 4, 8, 20, Post-HCV Treatment Week 12, 
and ESDD visit will be frozen and stored. These stored samples may be used by Gilead or our 
research partners to help answer questions about the study drug, HIV-1 infection and its 
associated conditions, or clinical laboratory testing to provide additional safety data. No human 
genetic testing will be performed without express consent of the study subjects. At the 
conclusion of this study, these samples may be retained in storage for Gilead for a period of up to 
15 years.
6.8.2.
Bone Safety and Inflammation
For all subjects, blood will be collected for selected assessments of bone safety, including serum 
25-OH Vitamin D and PTH. Assessments 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, 8, 
12, 20, and Post-HCV Treatment Week 12.
6.8.3.
Markers of Platelet Function and Coagulation
For all subjects, blood will be collected for selected assessments of platelet function and 
coagulation that may include: soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand
and D-dimer. Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment 
Week 12.
6.8.4.
Markers of Renal Tubular Function
For all subjects, urine will be collected for selected assessments of renal tubular function that 
may include retinol binding protein, beta-2 microglobulin, urine albumin, and urine protein. 
Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment Week 12.


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6.9.
HIV 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 at any visit has an HIV-1 RNA value 
50 copies/mL confirmed at the next scheduled or unscheduled visit (2 to 4 weeks later).
6.9.1.
Management of HIV Virologic Rebound
The management of virologic rebound during Part 1 and Part 2 are different; subjects that have 
confirmed virologic failure during Part 1 will be discontinued from the study and not begin 
Part 2, while subjects that have virologic failure in Part 2 will be managed as described below.
Management of HIV-1 RNA ≥50 copies/mL during Part 1 (Day 1 through Week 8)

All HIV-1 RNA values ≥ 50 copies/mL should be discussed with the Medical Monitor. 

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If virologic failure is confirmed during Part 1 (regardless of detection of HIV drug 
resistance), the subject should be discontinued from HIV study drug and have the ESDD and 
30 Day Follow-Up visit.

If the viral load at the Week 6 visit is ≥ 50 copies/mL (and this is not a confirmation of 
virologic failure value), the HIV-1 RNA will be repeated at an unscheduled visit in about 
2 weeks from the Week 6 visit. This unscheduled visit for confirmation of virologic failure 
must be completed prior to the Week 8 visit (which subsequently means that the Week 8 visit 
will be delayed). The subject should not start Part 2 (nor should the subject start LDV/SOF 
therapy) until the repeat HIV-1 RNA value is available.  If the repeat HIV-1 RNA confirms 
virologic rebound (≥ 50 copies/mL), then the subject will be discontinued from HIV study 
drugs as above.  If the repeat HIV-1 RNA is < 50 copies/mL, then the subject may proceed to 
Part 2 and maintain the same visit schedule. Initiation of LDV/SOF therapy must occur 
within 2 to 4 weeks of the original visit window of the Week 8 visit. 


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Management of HIV-1 RNA ≥50 copies/mL during Part 2 (at or after Week 8)

If the viral load at any visit 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 HIV-1 RNA ≥50 copies/mL, potential causes of virologic failure 
should be documented. Assessment should include:
Adherence 
Concomitant medication
Comorbidities (eg, active substance abuse, depression, other intercurrent illnesses)

All subjects with confirmed virologic failure should be discussed with the Medical Monitor.

If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA 
value is ≥400 copies/mL, the blood samples from that visit will be used for HIV-1 
genotype/phenotype testing.

If genotypic/phenotypic resistance to study drug is documented, HIV study drugs 
(E/C/F/TAF or F/R/TAF) should be discontinued. 

If the HIV study drugs (E/C/F/TAF or F/R/TAF) are discontinued, a new HIV regimen 
should be constructed, after discussion with the Medical Monitor. The new HIV regimen 
should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued 
unless an HIV regimen cannot be constructed that would allow coadministration with the 
new HIV regimen.
If no resistance is detected from genotype/phenotype testing, the subject may remain on HIV 
study drugs and an HIV-1 RNA should be repeated (2 to 4 weeks after date of test with viral load
≥50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on 
HIV study drug for each individual subject and document this assessment in the source 
documents. Investigators who opt to discontinue HIV study drugs for an individual subject must 
discuss with the Medical Monitor prior to study drug discontinuation.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
rebound.


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Figure 6-1.
HIV Virologic Rebound Schema
a.
If virologic rebound is not confirmed, the subject will remain on their current HIV regimen.
b.
If virologic rebound is confirmed, and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, integrase, and protease) will be analyzed.
c.
Based on the results of the genotype/phenotype assays, the subject will remain on HIV study drugs or study drugs will be 
discontinued. If genotyping/phenotyping fails, a new ARV regimen may be configured at the discretion of the Investigator.
d.
If no resistance detected, HIV-1 RNA will be repeated (2 to 4 weeks later). Investigator reviews HIV study drug 
continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation.
e.
A new ARV regimen will be configured, after discussion with the Medical Monitor.  The new HIV regimen should be 
designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued unless an HIV regimen cannot be 
constructed that would allow coadministration with the new HIV regimen.
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at the Post-HCV Treatment Week 12 visit, or last visit while receiving HIV 
study drugs (or within 72 hours of discontinuation of study treatment).


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6.10.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed > 1 log10 increase from on treatment nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure during the HCV on treatment phase.  
All subjects who terminate LDV/SOF treatment early will complete the ESDD visit (see 
Section 6.5.1) and post-HCV treatment follow-up visits at 4 and 12 weeks after the last dose of 
LDV/SOF (see Section 6.4.2).
6.11.
End of Study
End of study is defined as completion of the Post-HCV Treatment Week 12 visit and the 30-Day 
Follow-Up visit.
6.12.
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.


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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, 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be 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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (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. 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 Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. 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 medication, 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 medication, collect all AEs, regardless of cause or relationship, 
until 30 days or 4 weeks after last administration of study IMP and report 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 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
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 unable to be accessed, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above.
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations (CFR), 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 


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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management 

All clinical and clinically significant laboratory toxicities relating to HIV ARV agents will be 
managed according to uniform guidelines detailed in Appendix 3.

Management for toxicity should be differentiated between ARV and HCV medications.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose after discussion with the 
Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Medical Monitor
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.


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7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.

If a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase (CK) after 
strenuous exercise or triglyceride elevation that is nonfasting or that can be medically 
managed) or a clinical event considered unrelated to investigational medicinal product
7.5.4.
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 eGFR 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.


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CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73 m2) = 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.
7.6.
Stopping Rules for HCV Treatment
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF unless the 
investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Administration of study drug may be discontinued in the event of a clinical or laboratory event. 
There is no option for dose reduction of LDV/SOF. If LDV/SOF FDC is stopped due to toxicity, 
it must not be restarted. The ESDD visit should be completed after discontinuation of LDV/SOF. 
The Post-HCV Treatment Week 4 and Week 12 visits must also be completed. 
Subjects who meet any of the following laboratory criteria must stop HCV study treatment:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to LDV/SOF
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. The same reporting obligations shall apply to female partners of male study 
subject (ie, partner pregnancies).
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 
Sections 7.1.2 and 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.


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The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome (of both female subject pregnancies and male subject’s partner 
pregnancies) 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: 
GSI Drug Safety and Public Health (DSPH):
Fax:
+1 (650) 522-5477
E-mail:
safety_fc@gilead.com
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV
RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of 
LDV/SOF (SVR 12).
The secondary objectives of this study are:

To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the 
last dose of LDV/SOF (SVR 4);

To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or 
F/R/TAF 24 weeks from the start of the F/TAF-based regimen; 

To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the 
current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects;

To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in 
virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or 
F/R/TAF.
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
LDV/SOF treatment).
8.1.3.
Secondary Endpoint
Secondary efficacy endpoints are: 

SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment).

The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using modified FDA snapshot algorithm
Note: Most often, 24 weeks of HIV therapy will coincide with the Post-HCV Treatment Week 4 
visit
Secondary safety endpoint is:


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
Grades 1 through 4 adverse events after switch to E/C/F/TAF or F/R/TAF throughout the 
study and during coadministration with LDV/SOF treatment.
8.1.4.
Other Endpoints of Interest
No other endpoints of interest will be considered.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
HIV Full Analysis Set: The primary analysis set for HIV efficacy analysis will be the HIV full
analysis set (HIV FAS) and is defined as all subjects randomized and who received at least one 
dose of F/TAF-based regimen. 
HCV Full Analysis Set: The primary analysis set for HCV efficacy analysis will be the HCV full 
analysis set (HCV FAS) and is defined as all subjects who received at least one dose of
LDV/SOF.
Subjects will be grouped according to the treatment they were randomized to.
8.2.1.2.
Safety
HIV Safety Analysis Set: The primary analysis set for HIV safety analyses will be the HIV 
safety analysis set and is defined as all subjects randomized to the study and who received at 
least one dose of F/TAF-based regimen. 
HCV Safety Analysis Set: The primary analysis set for HCV safety analyses with 
coadministration with the F/TAF-based regimen in Part 2 will be the HCV safety analysis set and 
is defined as all subjects who received at least one dose of LDV/SOF.
All data collected during treatment will be included in the safety summaries. Subjects will be 
grouped according to the treatment they actually received.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who were randomized and have received at least one 
dose of either the F/TAF-based regimen (at Week 4) or coadministration of the F/TAF-based 
regimen and LDV/SOF, and for whom concentration data of any analyte of interest are available. 
The PK analysis set will be used for listing PK concentration data and summaries.


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8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by standard descriptive methods
using the safety analysis set. Demographic and baseline measurements will be summarized by 
treatment group (E/C/F/TAF; F/R/TAF) and overall. 
Summaries will include sex, race/ethnicity, age, height, weight and body-mass index.
Baseline data will include a summary of risk factors for HIV-1 infection and HCV 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 the treatment groups.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
therapy). The primary analysis will be performed after all enrolled subjects have been followed 
through post-HCV treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate will be compared to the performance goal of 
88% by using two-sided exact one-sample binomial test at the 0.05 significance level. The basis 
for this benchmark includes the overall trend toward increasing SVR rates in recent years; and 
the general appeal of using a fixed clinically relevant threshold as a measure of treatment benefit 
of LDV/SOF.
The null (H0) and alternative (H1) hypotheses used to assess superiority of LDV/SOF relative to
the performance goal of 88% are:

H0: SVR12 = 88%

H1: SVR12 ≠ 88%
The primary efficacy analysis will also include the construction of an associated two-sided exact 
95% CI.
Furthermore, SVR12 will also be summarized by the HIV treatment arms (F/TAF-based 
regimen).
8.4.2.
Secondary Analyses
The methods to assess proportion of HIV-1 RNA ≥50 copies/mL (virologic failure) 24 weeks 
after start of the F/TAF-based regimen using a modified FDA snapshot algorithm will be 
provided in detail in the Statistical Analysis Plan.


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The changes from baseline in CD4+ count at Week 8 and Post-HCV Treatment Week 12 will be 
summarized using descriptive statistics.
The analysis of SVR4 will be summarized using similar methods as for the primary endpoint.
8.5.
Safety Analysis
All safety data collected on or after the date F/TAF-based ARV regimen was first dispensed up 
to the date of last dose of study drug(s) (either F/TAF-based regimen alone or in combination 
with LDV/SOF) plus 30 days will be summarized overall, according to the study drug(s)
received. 
Additionally, safety data collection on or after the first dose of LDV/SOF until the last dose of 
LDV/SOF plus 30 days (ie, during coadministration of HIV/HCV study drugs), will also be 
summarized.
Data for pretreatment and post-last-dose-plus-30-days will be included in data listings. 
8.5.1.
Extent of Exposure
A subject’s extent of exposure to each study drug will be generated from the corresponding study 
drug administration data. Duration of exposure to each study drug will be expressed as the 
number of weeks between the first and last dose for each study drug, inclusive, regardless of 
temporary interruptions in study drug administration.
Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
HIV treatment-emergent AEs are events that meet one of the following criteria up to 30 days 
after the permanent discontinuation of HIV study drug(s):

AEs with onset dates on or after the first dose date of HIV study drug(s) and no later than 
30 days after permanent discontinuation of HIV study drug(s), or,

AEs that result in permanent study drug discontinuation of HIV study drug(s).
The number and percentage of subjects with treatment-emergent AEs (by SOC and PT) will be 
summarized as described in Section 8.5. A similar definition will be used to define HCV 
treatment-emergent AEs during coadministration of HIV/HCV study drugs. Additional 
summaries will include summaries for AEs by grade, Investigator’s assessment of relationship to 
study drug, and effect on study drug dosing.


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All treatment-emergent and non-treatment emergent AEs will be included in a data listing.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of 
Adverse Events and Laboratory Abnormalities (Appendix 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 HIV 
study drug(s) plus 30 days, will be summarized as described in Section 8.5. Similarly, 
treatment-emergent abnormalities during coadministration of HIV/HCV study drugs will also be 
summarized. 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 HIV study drug(s) or after the subject 
has been discontinued from HIV study drug(s) plus 30 days will be included in a data listing.
8.5.4.
Other Safety Evaluations
Weight will be summarized by visit. 
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Pharmacokinetic Analysis
Population PK assessments may be conducted for some of the relevant analytes: TAF, TFV, 
RPV, FTC, EVG, COBI, LDV, SOF, or GS-331007. Population PK assessments will be 
summarized in a separate report.
8.7.
Biomarker Analysis
The renal, vascular and inflammatory markers (see Sections 6.8.2 – 6.8.4 for details) will be 
summarized by treatment group and visit using descriptive statistics. The difference in change 
from baseline in these biomarkers between the treatment groups (E/C/F/TAF and F/R/TAF) will 
be tested using Wilcoxon rank sum test.
8.8.
Sample Size
A sample size of 240 subjects will provide at least 85% power to detect an improvement of at 
least 6 percentage points in SVR12 rate from the performance goal of 88% by using a two-sided 
exact one-sample binomial test at significance level of 0.05.


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


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


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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures.  eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system.  Prior to database lock (or 
any interim time points as described in the clinical data management plan), the investigator will
use his/her log in credentials to confirm that the forms have been reviewed, and that the entries 


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accurately reflect the information in the source documents. The eCRF capture the data required 
per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (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.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead Quality Assurance (QA), the site may destroy used (empty or partially empty) and unused 
IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP 
will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, 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 IRB/IEC in 
accordance with local requirements and receive documented IRB/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, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/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 CRF/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), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Bhagani S, Sulkowski MS, Cooper C, Kwo PY, Kowdley K, Mertens M, et al. 
Ledipasvir/Sofosbuvir is Safe and Effective for the Treatment of Patients with 
Genotype 1 Chronic HCV Infection in Both HCV  Mono-and HCV/HIV Co-
infected Patients [Abstract: 386]. European AIDS Clinical Society (EACS); 2015 
21-24 October; Barcelona, Spain. 
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.
Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated 
interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic 
hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 
2004;292 (23):2839-48.
Chesney M. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30 
(Suppl 2):S-171-S6.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Custodio J, Doyle E, Pang PS, Das M, H. C, Ma G, et al. Lack of Drug Interactions between 
Boosted and Unboosted Tenofovir Alafenamide-based Antiretroviral Single 
Tablet Regimens (Emtricitabine/Rilpivirine/Tenofovir Alafenamide and 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) and the anti-HCV 
Single Tablet Regimen Ledipasvir/Sofosbuvir [Abstract 727]. Infectious Diseases 
Society of America (IDSA); 2015 7-11 October; San Diego, CA. 
Deng LP, Gui XE, Zhang YX, Gao SC, Yang RR. Impact of human immunodeficiency virus 
infection on the course of hepatitis C virus infection: a meta-analysis. World J 
Gastroenterol 2009;15 (8):996-1003.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.


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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.
Gay CL, Mayo AJ, Mfalila CK, Chu H, Barry AC, Kuruc JD, et al. Efficacy of NNRTI-based 
antiretroviral therapy initiated during acute HIV infection. AIDS 2011;25 (7):941-
9.
Gilead Sciences Canada Inc. SOVALDI® (Sofosbuvir) Tablets 400 mg. Product Monograph.  
Mississauga, ON. December 2013:
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised November 2015:
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA October 2014:
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of Product 
Characteristics.  County Cork Ireland. January 2014.  2014:
Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human 
immunodeficiency virus infection on the course of hepatitis C virus infection: a 
meta-analysis. Clin Infect Dis 2001;33 (4):562-9.
HCV Guidelines. Recommendations for Testing, Managing, and Treating Hepatitis C.  2015.
Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, et al. 
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus 
ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004;18 (13):F27-
36.
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17 (2):107-
15.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.


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Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study 
[Supplementary Webappendix]. Lancet 2015.
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.
Myers RP, Liu M, Shaheen AA. The burden of hepatitis C virus infection is growing: a Canadian 
population-based study of hospitalizations from 1994 to 2004. Can J 
Gastroenterol 2008;22 (4):381-7.
Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and 
Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med 2015.
Nakano T, Lau GM, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus 
genotypes and subtypes based on the complete coding region. Liver Int 2012;32 
(2):339-45.
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.
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 
August 22.  2012.
Salmon-Ceron D, Lewden C, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Liver disease as 
a major cause of death among HIV infected patients: role of hepatitis C and B 
viruses and alcohol. J Hepatol 2005;42 (6):799-805.
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.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.


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Final
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Original
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Smith BD, Morgan ML, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. 
Recommendations for the Identification of Chronic Hepatitis C Virus Infection 
Among Persons Born During 1945–1965. Centers for Disease Control and 
Prevention MMWR  August, 2012.
Staples CT, Jr., Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) 
Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the 
effect of coinfection on survival. Clin Infect Dis 1999;29 (1):150-4.
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.
Stone VE JJ, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to HAART 
[abstract]. . 40th Annual Meeting of the Infectious Disease Society of America; 
2002 Oct 24-27; Chicago. pp. p.129, Abstract 486.
The Joint United Nations Programme on HIV/AIDS (UNAIDS). Regional Fact Sheet 2012. 
North America, Western and Central Europe.  2012.
Thomas DL. The challenge of hepatitis C in the HIV-infected person. Annu Rev Med 
2008;59:473-85.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. 
Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in 
HIV-infected patients. N Engl J Med 2004;351 (5):438-50.
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HIV/AIDS Response: Epidemic update and health sector progress towards 
universal access. Progress Report 2011.  2011.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only)
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.
CDC Classification Systems, AIDS-Indicator Conditions


FTC/RPV rr AF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences. Inc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Randomized, Open-label, Controlled Study of the Efficacy, Safety and 
Tolerability of 12 Weeks ofLedipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV 
Co-infected Subjects who Switch to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/CJF/TAF) or Emtricitabine/Rilpivirineffenofovir Alafenamide (F/R/TAF) 
prior to LDV/SOF HCV Treatment, the HIV/HCV Co-STARs study (Co-infection 
treatment with Single Tablet Antiviral Regimens) 
GS-US-366-1992 Original Protocol, 18 December 2015 
~~;sa~;~~~i has been approved by Gilead Scienc p P'D 
<io,nabrre...dnc-'"'""n" 
Richard Haubrich, MD 
Richard Haubrich (Printed) 
Medical Monitor 
22 December, 2015 
Date 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 92 
18 December2015 


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Appendix 2.
Study Procedures Table
Screeninga Day 1b
End of Weekc
Part 1
On Treatment
End of Weekc – Part 2
30-Day 
Follow-Upd
ESDDe
On Treatment
Post-HCV Treatment
4
6
8
12
16
20
4
12
Written Informed Consent
X
Medical History 
X
Liver Cirrhosis Determination
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examinationf
X
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-Lead ECG (performed supine)
X
X
Urinalysis & Urine Chemistry
X
X
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
X
Urine Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Testg
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
X
Hematology Profilei
X
X
X
X
X
X
X
X
X
X
X
Coagulation Assessmentsj
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsk
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X


FTC/RPV/TAF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
Plasma HIV -1 RNA 
HIV -1 Provu·al Genotype1 
HlV -1 Genotype/Phenotypem 
Plasma HCV RNA 
HCV Genotype & Subtype 
HCV IL28B Genotype 
HIV, HBV & HCV Serologiesn 
Evaluations of Bone & Renal Safety, 
Inflammation and Platelet and 
Coagulation Ftmction° 
Plasma Storage SampleP 
Senun Storage Sample!' 
rpo I 
I 
Estimated GFRCGr 
Population PK
5 
Health Related Questiormaires
1 
Randomization 
Study Drug Dispensation and 
Accountabilityu 
Screening• Day1b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Evaluations to be completed within 42 days prior to the Day 1 visit 
End ofWeE'kc 
Part 1 
On TrE-atment 
4 
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of Week<- Part 2 
On Treatment 
Post-HCV Treatment 
8 
12 
16 
20 
4 
12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
30-Day 
Follow-Upd 
X 
X 
Final 
Original 
Esnn• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xv 
b 
Subjects will be dispensed HIV study dmos only at the Day 1 visit; initiation ofHIV treatment with the study dmgs must take place within 24 hours after the Day 1 visit. 
c 
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are± 2 days of the protocol specified date through Post-HCV Treatment We.ek 4 visit, and 
± 4 days of the protocol specified date at Post-HCV Treatment Week 12. 
CONFIDENTIAL 
Page 94 
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FTC/RPV IT AF 
Protocol GS-US-366-1992 
Gilead Sciences, Inc. 
d 
For the purpose of scheduling a 30-Day Follow-Up Visit, a± 6 days window may be used 
Final 
Original 
e 
Early Study Drug Discontinuation visit to occur within 72 hours oflast dose of study drug. Refer to Section 6.5.1 for management of early study drug discontinuation of 
Parts 1 and 2. 
f 
Symptom-directed physical examination as needed 
g 
For females of childbearing potential only as defined by Appendix 5. Positive urine pregnancy tests will be confirmed with a serum test. 
h 
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, and uric acid. At visits in which metabolic assessments are to be performed, analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry profile 
CBC with differential and platelet count 
J 
Coagulation assessments: International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) 
k 
Metabolic assessments (collected fasted, 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) 
If a historical genotype report is not available, whole blood sample for proviral genotype analysis of archived resistance 
m 
HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic rebound with HIV-1 RNA value 2' 400 copies/mL 
n 
Serology testing includes HIV and HCV antibody, and HBV core antibody (HBcAb), surface antibody (HBsAb), surface antigen (HBsAg), e-antibody (HBeAg), e-antibody 
(HBeAb), andHBVDNA. 
o 
Blood for bone safety, parathyroid (PTH) and serum OH-25 vitamin D; Inflammation may include cystatin-C, IL-6, hs-CRP, sCD14, sCD163, sTNF-lR, and Lp-PLA2; 
Platelet and coagulation function 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, beta-2-microglobulin, urine albumin, and urine protein will be collected. Samples 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 fasted state. 
p 
Plasma storage samples for safety, virology, and/or PK testing. Serum storage samples for possible additional clinical testing. 
q 
PPD 
r 
Estrmateo GFR: accoriling to the COckcrott-liaii.It lormula'for creatmme clearance (see Secuoo4~2 tOr"detmis) 
s 
Two (2) blood samples will be collected: 1) the predose sample should be drawn prior to observed study drug dosing; 2) the postdose sample should be drawn between 
15 mins and 4 hours postdose 
Health related questionnaires: adherence for HIV (VAS), HIVTSQs- Status version (at Day 1 only), HIVTSQc -Change version (at all other visits), SF-36, FA CIT -F, 
CLDQ-HCV, and WPAI: Hepatitis C. 
u 
Part 1: HIV study drugs are dispensed after all Day 1 assessments are completed and randomization occurred, and through the duration of the study. Part 2: After 
determination ofHIV suppression(< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability ofHIV study drugs, LDV/SOF will be dispensed at Weeks 8, 12, 
and 16 only. Post-HCV Treatment Week 12: drug accountability only; study drug will not be dispensed at this visit. 
v 
If subjects discontinue during Part 1, only drug accountability will be performed; study drug will not be dispensed at this visit. In Part 2, if subject discontinues LDV/SOF but 
still continues with HIV study drug, HIV study drug will be dispensed until the last study visit. If subject discontinues HIV study drug but still continues with LDV/SOF, 
LDV/SOF will be dispensed. If subject discontinues both HIV and HCV study drugs, only drug accountability will be performed; no dispensation will occur at this visit. 
CONFIDENTIAL 
Page 95 
18 December 2015 


FTCIRPV/TAF 
Protocol GS-US-366-1992 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events (HIV ARV Agents only) 
Grade 1 
L_ ______ G_r_a_d_e-2------~~ 
Ll _______ 
G_r_a_d_e_3 ______ _JI 
Ll ----------G--r-a-de--4----------~ 
~ 
~ 
l\fay continue 
Repeatlab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
1. Withhold investigational medicinal products until s Grade 2 
2. Restart all investigational medicinal products at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently 
1 
.--------------. 
Repeatlab to 
confirm toxicity 
grade 
1 
Ifc onfirmed and unrelated to 
stigational medicinal products, 
mg may continue at the 
inve 
dos 
disc retion ofthe investigator 
If confirmed and 
possibly or probably 
-----. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
othenvise explained 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion ofthe 
investigator 
CONFIDENTIAL 
Page 96 
18 December 2015 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 97
18 December 2015
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 98
18 December 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 99
18 December 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 100
18 December 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 101
18 December 2015
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
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 102
18 December 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 103
18 December 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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.  


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 104
18 December 2015
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 105
18 December 2015
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 106
18 December 2015
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 107
18 December 2015
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 108
18 December 2015
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)


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 109
18 December 2015
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 110
18 December 2015
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 111
18 December 2015
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 112
18 December 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 113
18 December 2015
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 114
18 December 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 115
18 December 2015
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 116
18 December 2015
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 117
18 December 2015
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


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 118
18 December 2015
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


FTC/RPV/TAF
Protocol GS-US-366-1992
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 119
18 December 2015
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 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.
Women who are not post-menopausal or permanently sterile in accordance with these definitions 
will be considered of childbearing potential.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of E/C/F/TAF have demonstrated that 
E/C/F/TAF reduces the exposure of ethinyl estradiol in hormonal contraceptives. No clinically 
significant interactions between the components of F/R/TAF and LDV/SOF and hormonal 
contraception are known. Female subjects who choose hormonal contraception will be required 
to select a second backup method as defined below. 
Non-clinical toxicity studies of LDF/SOF, F/R/TAF, and E/C/F/TAF have demonstrated no 
adverse effect on fertility or embryo-fetal development.  However, there is insufficient clinical 
data available on use of these products in pregnant women. Please refer to the latest version of 
the IB (F/R/TAF) and package inserts (E/C/F/TAF and LDV/SOF) for additional information.
b. Contraceptive Methods allowed for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure.  Women must also not rely solely on hormone-containing 
contraceptives (except for intrauterine devices [IUDs] that may release hormones) as a form of 
birth control during the study.  Women may continue oral, injectable, transdermal, or other 
hormonally based contraceptives that are designed to inhibit ovulation, if desired, but these will 


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not be acceptable as a sole form of contraception; an additional form of acceptable effective 
contraception (methods below) must be chosen even if hormonal ovulation-inhibiting 
contraception is continued. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Day 1 visit prior to randomization.  At minimum, a pregnancy test 
will be performed at the end of relevant systemic exposure.  In the event of a delayed menstrual 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is even true for women of childbearing potential with infrequent or irregular 
periods.  
Women of child bearing potential in this study must agree to use the following forms of 
contraception from Screening until 30 days after the last dose of study drug.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of < 1% per year. Hormonal IUDs meeting 
this criterion are acceptable as a sole method.
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Combined barrier methods:
■
Diaphragm with spermicide and a male condom without spermicide
Or
■
Cervical cap with spermicide and male condom without spermicide

Women who choose to continue on their hormonal contraceptive method (eg, combined oral 
contraceptives, injectable, transdermal, and intravaginal contraceptives) are asked to also 
choose one of the above methods to supplement the hormonally based method given the 
effect of E/C/F/TAF  on ethinyl estradiol. These women may, however, use their hormonal 
contraceptive method and choose a single barrier method to supplement their hormonal 
contraceptive method (preferably the male condom). 
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.


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3) Contraception Requirements for Male Subjects
During the study and for 30 days after the last dose of study drug, male subjects with female 
partners of childbearing potential should use condoms without spermicide when engaging in 
intercourse of reproductive potential.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately.  Male subjects should 
also notify the investigator if their female partner becomes pregnant during the study or within 
30 days of last dose of study drugs. Instructions for reporting pregnancy and pregnancy outcome 
are outlined in Section 7.7.2.1.


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Appendix 6.
CDC Classification Systems, AIDS-Indicator Conditions

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)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month 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

Wasting syndrome attributed to HIV Infection
CDC Revised Surveillance Case Definition for HIV Infection – 2014 {Selik et al 2014}