A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate Versus Placebo in Pediatric Patients With Chronic Hepatitis B Infection
Phase: PHASE3
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
ClinicalT rials.gov 
Identifier 
Indication: 
Protocol ID: 
Gilead Sciences 
Medical Monitor/Study 
Director: 
Protocol Version/Date: 
(r} GILEAL> 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind Evaluation of the Antiviral 
Efficacy, Safety, and Tolerability ofTenofovir Disoproxil 
Fumarate Versus Placebo in Pediau·ic Patients with Chronic 
Hepatitis B Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
71,576 
2012-000586-20 
NCT01651403 
Chronic Hepatitis B 
GS-US-174-0144 
Name: 
Telephone: 
Fax: 
Mobile 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
John Flahe1iy, PhannD 
PPD 
PPD 
PPD 
1-'1-'U 
I 
22 July 2011 
07 March 2012 
08 November 2012 
29 Febmmy 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy or 
under conu·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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocoL 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 

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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....................................................................14
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
Tenofovir Disoproxil Fumarate (Tenofovir DF) ....................................................................................20
1.2.1.
General Information .............................................................................................................20
1.2.2.
Pre-Clinical Pharmacology and Toxicology.........................................................................20
1.2.3.
Clinical Trials of Tenofovir DF............................................................................................23
1.3.
Rationale for the Current Study and Dose Selection..............................................................................31
1.3.1.
Rationale for Dose Selection................................................................................................32
1.3.2.
Rationale for Bone Mineral Density Evaluations.................................................................32
2.
OBJECTIVES.....................................................................................................................................................34
3.
STUDY DESIGN................................................................................................................................................35
4.
SUBJECT POPULATION..................................................................................................................................38
4.1.
Number of Subjects and Subject Selection ............................................................................................38
4.2.
Inclusion Criteria....................................................................................................................................38
4.3.
Exclusion Criteria...................................................................................................................................39
5.
STUDY DRUGS.................................................................................................................................................41
5.1.
Randomization, Blinding and Unblinding..............................................................................................41
5.2.
Description and Handling of Study Drugs – Tenofovir DF Tablet/Oral Powder and Matching 
Placebos .................................................................................................................................................42
5.2.1.
Formulation..........................................................................................................................42
5.2.2.
Packaging and Labeling .......................................................................................................43
5.2.3.
Storage and Handling...........................................................................................................44
5.3.
Dosage and Administration of Study Drugs...........................................................................................44
5.3.1.
Dosing Recommendation – Tenofovir DF or Matching Placebo Tablet..............................45
5.3.2.
Dosing Recommendation - Oral Powder..............................................................................45
5.4.
Prior and Concomitant Medications.......................................................................................................46
5.4.1.
Prior to Study Entry..............................................................................................................46
5.4.2.
During the Study ..................................................................................................................46
5.5.
Study Drug Accountability.....................................................................................................................47
5.6.
Study Drug Return or Disposal ..............................................................................................................47
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.1.1.
Screening Visit .....................................................................................................................49
6.1.2.
Baseline Assessments...........................................................................................................51
6.2.
Treatment Assessments..........................................................................................................................52
6.2.1.
Week 4, 8, 16, 24, 32, 40 Assessments ................................................................................52
6.2.2.
Week 48 Assessments – End of Blinded Randomized Treatment........................................54
6.2.3.
Assessments for Weeks 56, 64, 72, 80, 88, 96, 108, 120, 132, 144, 156, 
168, 180................................................................................................................................55

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6.2.4.
Week 192 Assessments/Early Discontinuation ....................................................................57
6.3.
Post-Treatment/Treatment-Free Follow-up Assessments ......................................................................58
6.3.1.
Follow-Up Assessments.......................................................................................................58
6.3.2.
Assessments for Premature Discontinuation from the Study (Early Study 
Drug Discontinuation Visit).................................................................................................59
6.4.
Bone Mineral Density ............................................................................................................................60
6.5.
Bone Biochemical Markers....................................................................................................................60
6.6.
Pharmacokinetic Assessment .................................................................................................................61
6.7.
Drug Administration and Fasting Criteria for the Pharmacokinectic (PK) Substudy ............................62
6.8.
Serum and Plasma for Storage ...............................................................................................................62
6.9.
Subject Dosing Diary Card ....................................................................................................................62
6.10.
Resistance Surveillance..........................................................................................................................62
6.11.
Criteria for Discontinuation of Study Treatment....................................................................................63
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................64
7.1.
Adverse Events.......................................................................................................................................64
7.2.
Assessment of Adverse Events ..............................................................................................................65
7.3.
Serious Adverse Events..........................................................................................................................65
7.3.1.
Special Situations Report .....................................................................................................67
7.4.
Serious Adverse Event Reporting Requirements ...................................................................................68
7.4.1.
All Serious Adverse Events..................................................................................................68
7.4.2.
Investigator and Sponsor Reporting Requirements for SAEs ..............................................69
7.4.3.
Post-Study Reporting Requirements ....................................................................................70
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................70
7.6.
Toxicity Management ............................................................................................................................71
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................71
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................71
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.6.4.
Management of Elevated Serum Creatinine and Decreased Creatinine 
Clearance..............................................................................................................................72
7.6.5.
Special Considerations During Blinded Treatment – Grade 4 ALT 
Management.........................................................................................................................73
7.6.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................73
7.7.
Risks for Women of Childbearing Potential or During Pregnancy ........................................................75
7.7.1.
Definition of Childbearing Potential ....................................................................................76
7.7.2.
Contraceptive Requirements ................................................................................................76
7.7.3.
Procedures to be Followed in the Event of Pregnancy.........................................................77
8.
STATISTICAL CONSIDERATIONS................................................................................................................78
8.1.
Analysis Objectives................................................................................................................................78
8.2.
Primary Endpoint ...................................................................................................................................78
8.3.
Key Secondary Endpoint........................................................................................................................78
8.4.
Secondary Endpoints..............................................................................................................................78
8.5.
Other Endpoints of Interest ....................................................................................................................79
8.6.
Methods of Analysis ..............................................................................................................................80
8.6.1.
Analysis Sets ........................................................................................................................80
8.6.2.
Data Handling Conventions .................................................................................................80
8.6.3.
Multiplicity Adjustments......................................................................................................80
8.6.4.
Interim Analysis ...................................................................................................................81
8.7.
Demographic Data and Baseline Characteristics ...................................................................................81
8.8.
Efficacy Analysis ...................................................................................................................................81
8.8.1.
Primary Analysis..................................................................................................................81

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8.8.2.
Key Secondary Analysis ......................................................................................................81
8.8.3.
Secondary Analyses .............................................................................................................81
8.9.
Safety Analysis.......................................................................................................................................82
8.9.1.
Extent of Exposure...............................................................................................................82
8.9.2.
Adverse Events.....................................................................................................................82
8.9.3.
Laboratory Evaluations ........................................................................................................83
8.9.4.
Analyses of Bone Mineral Density and Bone Biochemical Markers ...................................83
8.10.
Pharmacokinetic Analysis......................................................................................................................84
8.11.
Sample Size............................................................................................................................................84
8.12.
Data Monitoring Committee ..................................................................................................................84
9.
RESPONSIBILITIES..........................................................................................................................................85
9.1.
Investigator Responsibilities ..................................................................................................................85
9.1.1.
Good Clinical Practice..........................................................................................................85
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................85
9.1.3.
Informed Consent/Assent.....................................................................................................85
9.1.4.
Confidentiality......................................................................................................................86
9.1.5.
Study Files and Retention of Records ..................................................................................86
9.1.6.
Case Report Forms...............................................................................................................87
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................88
9.1.8.
Inspections............................................................................................................................88
9.1.9.
Protocol Compliance............................................................................................................88
9.2.
Sponsor Responsibilities ........................................................................................................................89
9.2.1.
Protocol Modifications.........................................................................................................89
9.2.2.
Study Report and Publications .............................................................................................89
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................89
9.3.1.
Payment Reporting...............................................................................................................89
9.3.2.
Access to Information for Monitoring..................................................................................90
9.3.3.
Access to Information for Auditing or Inspections ..............................................................90
9.3.4.
Study Discontinuation..........................................................................................................90
10.
REFERENCES ...................................................................................................................................................91
11.
APPENDICES ....................................................................................................................................................96
Appendix 1.
Investigator Signature Page....................................................................................................97
Appendix 2.
Study Procedures Table..........................................................................................................98
Appendix 3.
Clinical Laboratory Assessments .........................................................................................102
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............104
Appendix 5.
Management of Clinical and Laboratory Adverse Events....................................................126
Appendix 6.
Lactic Acidosis Guidelines...................................................................................................127

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LIST OF IN-TEXT TABLES
Table 5-1.
Dosing Recommendations for Pediatric Patients 2 Years of Age and Weighing 
17 kg Using VIREAD Tablets..............................................................................................45
Table 5-2.
Dosing Recommendations for Pediatric Patients 2 Years of Age Using VIREAD 
Oral Powder............................................................................................................................46
Table 7-1.
Protocol-Recommended Contraceptive Methods ...................................................................76
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................37

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404 USA
Study Title:
A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, 
Safety, and Tolerability of Tenofovir Disoproxil Fumarate Versus 
Placebo in Pediatric Patients with Chronic Hepatitis B Infection
IND Number:
EudraCT Number:
71,576
2012-000586-20
Study Centers 
Planned:
Approximately 35 centers in North America, Europe, and Asia
Objectives:
The primary objective of this study is:

To evaluate the antiviral efficacy of tenofovir DF versus placebo 
in pediatric patients (aged 2 to < 12 years, at the time of 
enrollment) with chronic hepatitis B infection
The key secondary objective is:

To evaluate the proportion of subjects with HBeAg 
seroconversion at Week 48 (in subjects with baseline HBeAg 
sero-positivity). 
Secondary objectives are:

To characterize the safety and tolerability profile of tenofovir DF 
in pediatric patients (aged 2 to < 12 years, at the time of 
enrollment) with chronic hepatitis B infection

To evaluate the biochemical and serological responses to 
tenofovir DF versus placebo

To evaluate the incidence of potential resistance mutations to 
tenofovir DF in the hepatitis B virus polymerase/reverse 
transcriptase (pol/RT)

To assess the pharmacokinetics of tenofovir in subjects receiving 
the tablet formulation and those receiving the oral powder
formulation.

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Study Design:
This is a Phase 3, randomized, prospective, double-blind study 
comparing the antiviral efficacy, safety, and tolerability of tenofovir 
DF to placebo in pediatric patients with chronic HBV infection. 
One hundred (100) tenofovir DF-naive pediatric patients aged 2 to 
< 12 years, at the time of enrollment, with chronic HBV infection
(either HBeAg-positive or HBeAg-negative), HBV 
DNA 105 copies/mL AND ALT 1.5 × ULN at screening will be 
randomized in a 2:1 ratio to treatment arm A or B:

Treatment A (n = 67): tenofovir DF PO once daily for 48 weeks

Treatment B (n = 33): matching placebo PO once daily for 
48 weeks
After 48 weeks of blinded randomized treatment, each subject will 
switch to open-label tenofovir DF treatment for an additional 
144 weeks. Subjects under Protocol Amendment 3 who are beyond 
Week 48 of blinded randomized treatment will switch to open-label 
tenofovir DF at the Week 72 visit and will continue on open-label 
treatment until Week 192.
Randomization will be stratified by age (2 to < 6 and 6 to < 12, at the 
time of enrollment) and geographical location of study site 
(North America/Europe and Asia).
Randomization cannot occur until after the Baseline 
(pre-treatment) dual-energy X-ray absorptiometry (DEXA) scan 
has been performed.
Tenofovir DF tablets or oral powder, and their corresponding 
matching placebos will be provided by the Sponsor. During either the 
blinded randomized treatment or the open-label tenofovir DF 
treatment period, subjects whose body weight increases to 17 kg 
may be switched from the oral powder to the tenofovir DF tablet (or 
matching placebo tablet, if applicable).
Subjects must be naive to tenofovir DF, but could have received 
interferon-alfa and/or other oral anti-HBV nucleoside/nucleotide 
therapy. Subjects experienced on oral anti-HBV 
nucleoside/nucleotide therapy must have discontinued therapy 
16 weeks prior to screening. Subjects must have discontinued 
interferon-alfa 6 months prior to screening.

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Subjects who experience a Grade 4 ALT elevation while on blinded 
study medication will be evaluated weekly with serum chemistry and 
liver function test monitoring. In the event that any subject has a 
sustained Grade 4 ALT for 16 weeks (i.e., failure to resolve ALT to 
grade 3 or baseline), the serial HBV DNA valueson study will be 
provided to the investigator, and the subject can be offered open-label 
tenofovir DF after discussion with the Gilead Medical Monitor. 
Such events should be recorded as an adverse event (AE) leading to 
blinded study drug discontinuation.
All subjects will take a daily multivitamin with no additional mineral 
components that contain a minimum of 400 IU of vitamin D or higher 
per country specific regulations.
The primary analysis will be conducted at the completion of 
double-blinded treatment, after the last randomized subject reaches 
Week 48. Subsequently, efficacy and safety analyses of all subjects 
continuing on open-label tenofovir DF will be performed after the last 
randomized subject reaches Weeks 144 and 192, respectively.
During the blinded portion of the study, HBV DNA results will not be 
distributed to investigators, subjects, or clinical research personnel 
involved with the clinical conduct of the study. The only exception, 
as mentioned earlier, will be in the event of a subject having Grade 4 
ALT values that persist for 16 weeks and in the case of an ALT flare, 
both of which are considered situations of medical need, such that the 
patient’s serial HBV DNA values from the Screening visit through 
the time of the event will be made available to the investigator.
An external independent multidisciplinary Data Monitoring 
Committee (DMC) will review the progress and safety of this study 
approximately every 24 weeks following the time of randomization of
the first subject. During the open-label duration of the study, the 
DMC will convene approximately every 52 weeks. At each meeting, 
the DMC will review routine safety and DEXA data and will make 
recommendations regarding modification of study treatment.
Number of Subjects 
Planned:
One hundred (100) subjects, randomized in a 2:1 ratio to receive 
treatment with tenofovir DF or placebo.
Target Population:
Pediatric subjects, aged 2 to < 12, at the time of enrollment, with 
chronic HBV infection
Duration of 
Treatment:
Subjects will be treated with blinded randomized therapy for 
48 weeks (approximately 1 year), followed by an additional 
144 weeks (approximately 3 years) of open-label tenofovir DF 
therapy.

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Diagnosis and Main 
Eligibility Criteria:
At screening, pediatric subjects (2 to < 12 years of age, at the time of 
enrollment) with chronic HBeAg-positive or HBeAg-negative HBV 
infection (HBsAg-positive for at least 6 months; with HBV DNA 
105 copies/mL, ALT 1.5 × ULN and creatinine clearance
80 mL/min/1.73 m2 at screening) will be eligible for the study. 
Subjects must be naive to tenofovir DF, but could have received 
interferon-alfa and/or other oral anti-HBV nucleoside/nucleotide
therapies. Subjects experienced on oral anti-HBV 
nucleoside/nucleotide therapy must have discontinued therapy 
16 weeks prior to screening. Subjects must have discontinued 
interferon-alfa 6 months prior to screening. Subjects must be 
without serological evidence of co-infection with HIV, HCV, HDV or 
acute HAV. Subjects with a history of significant renal disease, bone 
disease, decompensated liver disease, evidence of hepatocellular 
carcinoma (i.e., α-fetoprotein 50 ng/mL), or any chronic liver 
disease not related to HBV-infection will not be eligible for the study.
Study Procedures/
Frequency:
Plasma HBV DNA levels, laboratory analyses (serum chemistry, liver 
tests, hematology, and urinalysis), pregnancy test (females of 
childbearing potential only), vital signs, adverse events and 
concomitant medications will be measured or assessed at screening, 
baseline, Weeks 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, then 
every 12 weeks thereafter until the end of the study (and at Early 
Discontinuation, if applicable).
HBV serology (HBsAg, HBeAg, and reflex HBeAb and HBsAb if 
Ag negative) will be conducted at Screening, Baseline, Weeks 16, 32, 
48, 64, 72, 80, and 96, then every 12 weeks through the end of study
(and at Early Discontinuation, if applicable). 
DEXA scans of the spine and whole body will be performed at
Baseline, and Weeks 24, 48, 72, and 96, then annually until 
completion of the study (and at Early Discontinuation if applicable). 
Bone biochemical markers will be measured at Screening, Baseline, 
every 24 weeks through Week 96, then annually until the end of study
(and at Early Discontinuation, if applicable). DEXA and bone 
biochemical markers will also be required at time of switching from 
placebo to tenofovir DF, if the last measurement was performed 
> 12 weeks prior to switch.
Complete physical examinations (including Tanner Staging starting at 
Baseline) will be performed at Screening, Baseline, Week 24 and then 
every 24 weeks through the end of study (and at Early 
Discontinuation, if applicable).
Determination of HBV viral genotype (A-H) will be performed at 
baseline for all subjects.

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Subjects will maintain a Subject Dosing Diary Card to monitor 
subjects’ compliance to study treatment at Weeks 4, 24, and 56. 
Subjects will maintain a diary for 10 days prior to the next visit. 
In addition, for subjects participating in the PK substudy, a diary card 
will be maintained for at least 10 days prior to the intensive PK visit.
Resistance surveillance will be conducted at Baseline for all subjects, 
and attempted for all viremic subjects (HBV DNA 400 copies/mL
[69 IU/mL]) at Weeks 48, 96, 144, and 192 (and at Early 
Discontinuation, if applicable).
Plasma and serum for storage will be collected at every visit starting 
at Baseline for possible pharmacokinetic and/or virological analyses 
(including resistance surveillance, HBsAg and HBeAg quantification 
and adherence assessment).
For subjects in whom a separate consent is provided, a blood sample
for biomarker (including pharmacogenomic analysis) will be 
collected for the exploration of appropriate markers that may be 
predictive of virologic response and/or the tolerability of HBV 
therapies.
Test Product, Dose, 
and Mode of 
Administration:
Tenofovir disoproxil fumarate oral tablet

subjects ≥17 kg: one tablet once daily (150, 200, 250 or 300 mg 
tablets based on body weight)
Tenofovir disoproxil fumarate oral powder

subjects < 17 kg and subjects ≥17 kg who are unable to swallow 
a tablet: once daily in a dose of 8 mg/kg up to a maximum daily 
dose of 300 mg
Reference Therapy, 
Dose, and Mode of 
Administration:
Matching placebo oral tablet

subjects ≥17 kg: one tablet once daily (matching of physical 
appearance as the corresponding active tablet)
Matching oral placebo powder

subjects < 17 kg and subjects ≥17 kg who are unable to swallow 
a tablet: once daily with matching dose 

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Criteria for 
Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of patients with 
serum HBV DNA 400 copies/mL (69 IU/mL) at Week 48 in each 
arm.
The key secondary endpoint is the proportion of patients with HBeAg 
seroconversion (in subjects with baseline HBeAg sero-positivity
only) at Week 48 in each arm.
At Week 48, the secondary endpoints are:

proportion of subjects with normal ALT and normalization of 
ALT

composite endpoint of proportion of subjects with HBV DNA 
400 copies/mL (69 IU/mL) and normalized ALT

proportions of subjects with HBV DNA 169 copies/mL
(29 IU/mL)

proportions of subjects with HBsAg loss and seroconversion

proportions of subjects with HBeAg loss (in patients with baseline 
HBeAg positive patients only)

sequence changes from baseline within the HBV polymerase for 
subjects who were viremic (HBV DNA 400 copies/mL
[69 IU/mL]) at Weeks 48, 96, 144, 192 or Early Discontinuation;
including subjects with confirmed virologic breakthrough
Similar secondary efficacy endpoints will also be explored at 
Weeks 144 and 192.
For the primary endpoint, key secondary endpoint, and categorical 
secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach.
Safety:
Adverse events and clinical laboratory tests will be collected and 
characterized at every visit throughout the study.
At Week 48, the safety endpoints are:

cumulative incidence of at least a 4% decrease from baseline in 
bone mineral density of lumbar spine

percent change from baseline in bone mineral density of lumbar 
spine

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PK:
To evaluate the PK of different formulations of tenofovir DF in a 
pediatric population, two intensive PK substudies (oral powder and 
tablet cohorts) will be performed on a subset of subjects. 
The intensive PK sampling will be performed over 8 hours during one 
day between Week 2 and Week 12.
A target of 12 randomized subjects at each dosage level (150, 200, 
250, 300 mg) will be enrolled in the tablet cohort, and up to a total of 
30 randomized subjects will be enrolled in the oral powder cohort.
Subjects are allowed to participate in up to two intensive PK 
substudies with the second intensive PK substudy occurring after
Week 12, but prior to the end of the double-blind phase.
Subjects who are eligible to take the oral powder (either tenofovir DF 
or matching placebo) based on body weight and/or preference for this 
dosage form, and subjects who qualify for the tablet formulation but 
are willing to initiate treatment with the oral powder for purposes of 
accruing additional PK data, will be offered the opportunity to 
participate in the oral powder cohort. Those subjects who opt to 
initiate treatement with oral powder and subsequently switch to 
tablets following completion of the powder intensive PK visit,or those 
subjects who are required to change dose strengths of the tablet based 
on the weight-based dosing requirements (see protocol Section 5.3) 
will also have the option to participate in a second tablet intensive PK 
visit.
Irrespective of choice of formulation (tablet versus oral powder), if a 
subject is switching from tablets to powder, the subject must be 
taking powder for at least 2 weeks prior to the powder intensive PK 
visit. Similarly, subjects must be taking tablets for at least 2 weeks
prior to the tablet intensive PK visit.
Statistical Methods:
The primary efficacy analysis will be conducted at the end of 
double-blind treatment, after the last randomized subject reaches 
Week 48. The analysis will evaluate the difference in the proportion 
of subjects achieving the primary efficacy endpoint between the 
tenofovir DF and placebo treatment groups using a two-sided Fisher’s 
exact test with missing data handled using a missing = failure 
approach. Efficacy analyses of all subjects continuing on open-label 
tenofovir DF will be performed after the last randomized subject 
reaches Weeks 144 and 192.
Subgroup analyses of efficacy endpoints may include analyses by 
randomization stratification group (age [2 to < 6 and 6 to < 12] and 
geographical location of study site [North America/Europe and 
Asia]).

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The proportion of subjects in each treatment arm with an adverse 
event or an abnormal laboratory test will be summarized at Week 48
and also at Weeks 144 and 192.
All continuous endpoints will be summarized using n, mean, standard 
deviation, median, Q1, Q3, minimum and maximum by treatment 
group. All categorical secondary endpoints will be summarized by 
number and percentage of subjects who meet the endpoint.
A sample size of 100 subjects (67 tenofovir DF, 33 placebo) would 
provide at least 85% power to detect a 20% treatment difference 
between tenofovir DF and placebo in the primary efficacy endpoint. 
This calculation is based on a two-sided Fisher’s exact test with a 
significance level of 0.05, assuming a response rate of 1% in the 
placebo group. A similar placebo-response rate was observed in study 
GS-US-174-0115.
The following plasma pharmacokinetic parameters will be calculated 
for the PK substudy populations: CL/F,Cmax, Tmax, Clast, Tlast, Ctau, z,
T½, AUC0-last, AUCtau.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C
degrees Celsius
F
degrees Fahrenheit
ACTG
AIDS Clinical Trials Group
ADV
adefovir dipivoxil, Hepsera
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CHB
Chronic hepatitis B
CC50
median concentration curve
Cl/F
apparent oral clearance following administration of the drug
CPK
creatine phosphokinase
CPMP
Committee for Proprietary Medicinal Products
CRF
Case Report Form(s)
CRO
Contract Research Organization
d4T
stavudine, Zerit
dATP
deoxyadenosine triphosphate
DAVG48
time-weighted average change from baseline through Week 48
DEXA
dual-energy x-ray absorptiometry
DHBV
duck hepatitis B virus
dL
Deciliter
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC50
median effective concentration
ECG
Electrocardiogram
EEG
Electroencephalogram
EFV
Efavirenz
EMEA
European Medicines Evaluation Agency
ETV
Entecavir
EU
European Union
EudraCT
European clinical trials database
FAS
full analysis set
FDA
(U.S.) Food and Drug Administration

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FTC
emtricitabine, Emtriva
g
gram(s)
GCP
Good Clinical Practice (Guidelines)
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
HAART
highly-active antiretroviral therapy
HAV
hepatitis A virus
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high-density polyethylene
HDV
hepatitis D virus
HLGT
high level group term
HLT
high level term
HIV
human immunodeficiency virus
IC50
median inhibitory concentration
ICH
International Conference on Harmonization
ID
Identification
IEC
Independent Ethics Committee
IL-2
interleukin-2
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
Institutional Review Board
IV
Intravenous
kg
kilogram(s)
Ki
inhibition constant
L
liter 
LAM
lamivudine, Epivir, Zeffix, 3TC
LAMR
lamivudine resistant
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
LLT
lower level term
LOD
limit of detection
m2
square meter(s)

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MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalent(s)
mg
milligram(s)
min
minute(s)
mL
milliliter(s)
mm3
cubic millimeter(s)
mmol
millimole(s)
ng
nanogram(s)
NRTI
nucleoside reverse transcriptase inhibitor
OBR
optimized background (antiretroviral) regimen
OLT
orthotopic liver transplant
PA
Protocol Amendment
PBMC
peripheral blood mononuclear cell(s)
PCR
polymerase chain reaction
PK
Pharmacokinetic
PO
by mouth/oral (per os)
PT
prothrombin time
PTH
parathyroid hormone
RAT
randomized and treated
RBC
red blood cell
RDA
recommended daily allowance
RNA
ribonucleic acid
SAE
serious adverse event
SCr
serum creatinine
SOC
system organ class
TDF
tenofovir DF, tenofovir disoproxil fumarate, Viread
TFV-DP
tenofovir diphosphate
µg
Microgram
µM
Micromolar
ULN
upper limit of the normal range
WBC
white blood cell
WHV
woodchuck hepatitis virus

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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B is a serious global health care problem and a major cause of chronic liver 
disease, cirrhosis, and hepatocellular carcinoma (HCC). Worldwide, approximately 350 to 
400 million people have developed chronic hepatitis B, including approximately 1.2 million in 
the United States {Wright 2006}. Globally, approximately 1 million people die annually of 
complications of chronic hepatitis B {World Health Organization (WHO) 2000}, {Wright 2006}. 
In the United States, an estimated 5,000 people die each year of complications of HBV infection 
{Poterucha et al 1997}.
Despite the availability of hepatitis B virus (HBV) vaccine programs in many countries, new 
hepatitis B infections are still common, even in areas of low endemnicity. For example, 
approximately 70,000 people in the United States (US) become acutely infected each year, 
according to estimates from the US Centers for Disease Control and Prevention {Centers for 
Disease Control and Prevention (CDC) 2007}. Following acute hepatitis B infection, 
approximately 5% of adults and up to 90% of children fail to produce an immune response 
adequate to clear the infection; these individuals become chronic carriers of the virus 
{Zuckerman 1996},{Lok et al 2007}.
Chronic hepatitis B has a broad clinical spectrum, ranging from asymptomatic, slowly 
progressive illness to severe, more rapidly progressive liver disease. Chronic hepatitis B may 
remain quiescent for many years. However, 15% to 40% of patients with chronic hepatitis B will 
ultimately develop serious liver disease and complications, such as cirrhosis, hepatic 
decompensation, and HCC {Wright 2006}. In patients with chronic hepatitis B, the annual 
probability of developing cirrhosis varies from 0.1% to 1.0%, depending on the duration of 
active HBV replication, the severity of disease, and the presence of concomitant risk factors 
{Merican et al 2000}. Patients with chronic viral replication are at increased risk of 
complications and poor outcomes {Chen et al 2006}. Effective suppression of viral replication 
alters the course of the disease and decreases morbidity. However, the clinical benefit is lost if 
viral replication resumes as a result of emerging resistance mutations.
Following acute hepatitis B infection, up to 90% of children become chronic carriers of the virus. 
Hepatitis B virus infection in children is usually asymptomatic, with a low rate of disease 
progression during the first 2 decades of life. There are four characteristic immunologic phases 
to this disease. In the first phase, the immune tolerant phase, patients have high HBV DNA 
levels and have detectable hepatitis B surface antigen (HBsAg) and hepatitis B early antigen 
(HBeAg). The hallmark of this phase is a normal ALT. The second phase that follows, known as 
the immune active stage, is characterized by persistently elevated ALT levels, an indicator of 
liver damage, even though children may shown no signs or symptoms of disease. The third 
phase, the inactive HBsAg carrier stage, is characterized by undetectable or low levels of HBV 
DNA and the presence of anti-HBe antibodies. This third stage can evolve into a fourth stage, 
reactivation, in which ALT levels are abnormal and HBV DNA levels are increased.

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The management of chronic hepatitis B in children and adolescents is still evolving {Jonas et al 
2010}. Current consensus is that no treatment is indicated in the immune tolerant (stage 1) or the 
inactive carrier state (stage 3). For children and adolescents in stages 2 or 4, however, treatment 
may be warranted to in order to suppress viral replication and to prevent the emergence of 
complications, such as cirrhosis, decompensated liver disease, and HCC. Although histological 
abnormalities are usually less severe in children than in adults, HBV-infected infants and 
children are at higher risk for the eventual development of cirrhosis and primary HCC. 
In hepatitis B early antigen (HBeAg)-positive patients, treatment can lead to HBeAg loss and, 
more rarely, anti-HBe seroconversion, with the goal of subsequent hepatitis HBsAg loss and 
seroconversion to anti-HBs. Achieving durable viral suppression in chronic HBV infection 
usually requires long-term therapy, preferably utilizing potent regimens that limit the 
development of resistance.
The optimal treatment for children and adolescents with chronic HBV infection is not well 
established. Over the past decade, interferon-alfa has been shown to be relatively effective in this 
patient population, resulting in viral suppression or HBeAg seroconversion in 20% to 58% of 
treated patients, compared with 8% to 17% of untreated controls {Sokal 2002}, {Jonas 2006}. 
Interferon-alfa is administered for a treatment duration of 24 weeks in patients 2 years of age, 
and higher response rates have been reported in western countries. Some experts consider 
interferon to be the treatment of choice, and suggest that alternative, oral agents be limited to 
clinical trials. This is in large part due to concerns over the development of drug resistance {Jonas 
et al 2010}. Unfortunately, interferon-alfa treatment has significant limitations, including 
undesirable side effects, such as growth impairment, flu-like symptoms, neutropenia, and mood 
disturbances; inconvenient injectable dosage form; and a low rate of efficacy in patients with 
higher serum HBV DNA levels or only minimally elevated ALT levels {Sokal 2002},
{Bortolotti 2003}.
The oral nucleoside analog lamivudine is approved for the treatment of pediatric chronic HBV 
infection (ages 2 to 17 years of age) in the United States, Switzerland, and Australia. Lamivudine 
has been shown to induce a virologic response, defined by the clearance of HBeAg and serum 
HBV DNA, in 23% of treated pediatric patients after 52 weeks (compared to 13% of controls, 
p = 0.04) {Jonas et al 2002}, with maintained HBeAg seroconversion {Jonas 2006}. Lamivudine 
therapy is usually administered for 1 year and continued for 6 months after seroconversion. 
In contrast to interferon alfa, lamuvidine is available in a patient-friendly oral dosage form, and 
is well tolerated, with no growth development changes observed after 3 years of treatment {Jonas 
2006}. However, the long-term efficacy of lamivudine is limited by the development of viral 
resistance. As in adults, the development of the rtL180M and/or rtM204V/I mutations in the 
HBV DNA polymerase have been detected in children and adolescents treated with lamivudine 
for chronic HBV infection. In the lamivudine HBV pediatric pivotal trial, resistance mutations 
were detected in 19%, 49% and 64% of subjects after 1, 2, and 3 years of treatment, respectively 
{Jonas et al 2002}, {Sokal et al 2006}. Hepatitis B viral resistance may be associated with a 
recurrence or acute exacerbation of hepatitis.

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The oral nucleotide analog adefovir dipivoxil is approved for the treatment of chronic HBV 
infection in adults and children 12 years of age in the United States. Adefovir has activity 
against both wild-type and lamivudine-resistant HBV {Gilead Sciences Inc 2009}, {Hadziyannis 
et al 2003}, {Hadziyannis et al 2005}. Adefovir dipivoxil was evaluated in a large 
(n = 173 subjects) placebo-controlled, international trial in pediatric patients (ages 2 to 17) 
(Study GS-US-103-0518) {Jonas et al 2008}. After 48 weeks of treatment, adefovir dipivoxil 
showed modest benefits over placebo in older children and adolescents. At 48 weeks, more 
adefovir dipivoxiltreated subjects in the 12 to 17 years age group achieved the primary efficacy 
endpoint (serum HBV DNA 1000 copies/mL and normal ALT at the end of blinded treatment), 
compared with placebo-treated subjects (23% vs. 0%, p = 0.007). In children aged 2 to 11 years, 
the efficacy difference between adefovir-treated and placebo-treated patients at the end of 
blinded treatment was not significantly significant, despite achievement of plasma adefovir 
concentrations in younger children that were comparable to those measured in older children.
Adefovir dipivoxil treatment was well tolerated, and no subjects developed the rtA181V or 
rtN236T mutations associated with ADV resistance by Week 48.
Entecavir and telbivudine, both oral nucleoside analogs, are approved for the treatment of 
chronic HBV infection in patients 16 years of age in the United States and other countries. 
Cross-resistance exists between entecavir and lamivudine, requiring a higher dose of entecavir in 
patients with lamivudine-refractory HBV infection. Safety and efficacy of entecavir and 
telbivudine have not been established in pediatric and adolescent patients 16 years of age.
Tenofovir disoproxil fumarate (TDF), an oral, once-daily nucleotide analog, has antiviral activity 
against both HBV and HIV. TDF is approved for use in the treatment of chronic HBV infection 
in adults in the United States, Canada, and Europe. TDF in combination with other antiretroviral 
agents is also approved for the treatment of HIV infection in adults and in pediatric patients 
> 12 years of age in the United States and Canada. The anti-HBV activity of TDF is equipotent 
to that of adefovir dipivoxil in vitro; however, the safety profile of TDF allows the 
administration of higher doses {Lok et al 2007}. In two ongoing phase 3 international comparative 
trials in adults, TDF was shown to be superior to adefovir dipivoxil for the treatment of 
HBeAg-negative (GS-US-174-0102) and HBeAg-positive (GS-US-174-0103) patients with 
chronic HBV infection {Marcellin et al 2007}, {Heathcote et al 2007}.
Tenofovir DF is currently being evaluated in study GS-US-174-0115, a large (n = 106 subjects) 
placebo-controlled, international trial in adolescent patients (12 to 17 years). After 72 weeks of 
treatment, tenofovir showed significant virologic response benefits over placebo (Data on file, 
Gilead Sciences, 2011). At 7 weeks, more tenofovir DFtreated subjects achieved the primary 
efficacy endpoint (serum HBV DNA 400 copies/mL [69 IU/mL] at the end of blinded 
treatment), compared with placebo-treated subjects (88.5% vs. 0%, p < 0.001). Tenofovir DF 
treatment was well tolerated and no patients met the primary safety endpoint of a 6% decrease in
lumbar spine bone mineral density (BMD). As expected for an adolescent population, both arms 
experienced an overall increase in mean lumbar spine BMD. Both populations also experienced 
an overall increase in mean whole body BMD; however, the percent increase in whole body 
BMD in tenofovir-treated subjects was less than the percent increase in whole body BMD 
attained by placebo-treated subjects (2.8% [TDF] vs. 5.4% [Placebo], p = 0.013).

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With the possibility that antiviral and biochemical response in adolescents might be attainable in
pediatric chronic HBV infected patients, a study in pediatric patients between 2 to11 years is 
proposed. Because the spontaneous clearance rate is significant but somewhat variable in this age 
group and serious complications of chronic HBV often require years to develop, and with no 
consensus regarding optimal timing of treatment in pediatric patients, a placebo-controlled study 
allows clearer conclusions regarding efficacy without putting patients at undue risk. In order to 
better define the safety profile of TDF, a more thorough analysis of the bone effects of TDF on 
adolescent subjects (12 to 17 years) with chronic HBV will be completed before proceeding in 
patients with chronic HBV age 2 to < 12.
1.2.
Tenofovir Disoproxil Fumarate (Tenofovir DF)
1.2.1.
General Information
Tenofovir disoproxil fumarate (TDF; 9-[(R)-2-[[bis[[(isopropoxycarbonyl) 
oxy]methoxy]phosphi-nyl] methoxy]propyl] adenine fumarate (1:1); GS4331-05) is an oral 
prodrug (bisPOC-PMPA) of tenofovir (PMPA), an acyclic nucleoside phosphonate (nucleotide) 
analogue of adenosine 5’-monophosphate. Tenofovir DF has activity against HBV and HIV and 
is indicated for use in combination with other antiretroviral agents in the treatment of HIV-1
infection in adults.
Tenofovir DF (300 mg once daily) was approved by the US FDA in October 2001, the European 
Commission in February 2002, and other markets worldwide for use in combination with other 
antiretroviral agents for the treatment of HIV-1 infection. Cumulative patient exposure to 
tenofovir DF since first marketing approval in the US on 26 October 2001 to 31 July 2007 is 
estimated to be more than 3 million patient-years of treatment.
Tenofovir DF is approved for the treatment of CHB in adults in the United States, Canada, the 
EU, Turkey, Australia, New Zealand, Brazil, Argentina, Uruguay, South Korea, Hong Kong, 
Taiwan, and Singapore; marketing applications are also under review in other regions.
Further information is available in the Investigator’s Brochure for tenofovir DF and the Package 
Insert for Viread{Gilead Sciences Inc 2010}.
1.2.2.
Pre-Clinical Pharmacology and Toxicology
1.2.2.1.
Mechanism of Action
Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir (PMPA), an acyclic 
nucleotide (nucleoside monophosphate) analogue. Tenofovir DF is converted to tenofovir by 
serum esterases. Intracellularly, tenofovir is then converted through two phosphorylation 
reactions to its active phosphorylated anabolite, tenofovir diphosphate (TFV-DP), an obligate 
chain terminator {Robbins et al 1998}. Tenofovir is efficiently anabolized to TFV-DP in human 
hepatic cells, and has a half-life of 95 hours in primary human hepatocytes {Delaney et al 2006}. 
TFV-DP inhibits recombinant HBV polymerase with a Ki of 0.18 M {Delaney et al 2006}. 
TFV-DP inhibits viral polymerases by direct binding competition with the natural 

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deoxyribonucleotide substrate (deoxyadenosine triphosphate - dATP) and, after incorporation 
into DNA, by DNA chain termination {Cherrington et al 1995}. TFV-DP is a very weak inhibitor 
of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ {Kramata et al 
1996}, {Cherrington et al 1995}.
1.2.2.2.
Anti-Hepatitis B Virus Activity
Tenofovir is a potent and selective inhibitor of HBV in vitro. The in vitro antiviral activity of 
tenofovir against an HBV laboratory strain was assessed in the HepG2 2.2.15 cell line. The EC50
values (50% effective concentration) for tenofovir were in the range of 0.14 to 1.5 M, with 
CC50 (50% cytotoxicity concentration) values 100 M. In a parallel analysis, tenofovir 
inhibited various wild-type HBV clinical isolates with a comparable activity (Report 
No. PC-174-2005). It also inhibited replication of duck HBV (DHBV) in primary duck 
hepatocytes with an EC50 of 0.11 M {Heijtink et al 1994}. As observed with anti-HIV-1 activity, 
the prodrug tenofovir DF had a 55-fold increased in vitro potency against HBV in comparison 
with tenofovir {Delaney et al 2006}.
Tenofovir demonstrated anti-HBV activity similar to adefovir in the same cell lines. TFV-DP 
and adefovir diphosphate also showed comparable inhibition constants for HBV polymerase in 
enzyme assays. The EC50 values of lamivudine for HBV are approximately 10-fold lower than 
that of tenofovir in same cell lines. However, the inhibition constants of TFV-DP and lamivudine 
triphosphate for HBV polymerase were similar, suggesting that the intrinsic anti-HBV potency 
of tenofovir is similar to that of lamivudine. The higher EC50 values of tenofovir versus 
lamivudine in cell culture may be attributed to the lower cell permeability of the 
negatively-charged molecule of tenofovir.
Using HBV-expressing cell lines (Report Nos. PC-174-2006, PC-164-2004) {Delaney et al 
2004a}, tenofovir demonstrated additive to slightly synergistic anti-HBV activity when tested in 
combination with nucleoside anti-HBV reverse transcriptase inhibitors. Specifically, tenofovir in 
combination with lamivudine, telbivudine, entecavir and adefovir, each produced additive 
anti-HBV activity (Report Nos. PC-174-2006, PC-164-2004) {Delaney et al 2004a}. 
The combination of tenofovir and emtricitabine demonstrated additive to slightly synergistic 
anti-HBV activity (Report No. PC-174-2006).
The anti-viral activity of tenofovir was also evaluated in woodchucks chronically infected with 
WHV in short-term (4 weeks) {Menne et al 2005} and long-term (48 weeks) antiviral efficacy 
studies (Report No. PC-174-2004). Oral administration of tenofovir DF at 0.5, 1.5, and 
5.0 mg/kg of body weight/day for 4 weeks reduced serum viral load significantly, at 
0.2 (p 0.01), 1.1 (p 0.01), and 1.5 log10 (p 0.05) from the pretreatment levels {Menne et al 
2005}. Oral administration of tenofovir DF at 15 mg/kg for 48 weeks resulted in a mean serum 
viral load reduction of 2.9 log10 copies/mL of WHV DNA. Administration of tenofovir DF in 
combination with lamivudine or emtricitabine for 48 weeks resulted in a mean serum viral load 
reduction of 5.8 and 6.1 log10, respectively. Over the 48-week dosing period, there was no 
evidence of toxicity in woodchucks treated with tenofovir DF, either alone or in combination 
(Report No. PC-174-2004).

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1.2.2.3.
Resistance
Hepatitis B virus resistance to tenofovir is yet to be identified. An rtA194T mutation was 
reported to emerge in two patients receiving antiretroviral treatments including tenofovir DF, and 
an in vitro susceptibility assay indicated reduced susceptibility to tenofovir {Sheldon et al 2005}. 
The patients developed this mutation in the background of the rtL180MrtM204V 
lamivudine-associated mutations, and its development was not clearly associated with HBV viral 
load rebound. To further characterize the rtA194T mutation, viruses containing the rtA194T 
mutation alone or in combination with the rtL180MrtM204V lamivudine resistance mutations 
were created and their in vitro tenofovir susceptibilities were tested in parallel with the parent 
wild-type and lamivudine-resistant strains. The data showed that rtA194T mutation alone had no 
significant effect on tenofovir susceptibility (1.5-fold increase in tenofovir EC50). The rtA194T 
mutation in combination with the rtL180MrtM204V mutations led to a 2.4-fold increase in 
tenofovir EC50, which was not significantly different than the 2.1-fold increase observed against 
virus containing the rtL180M+rtM204V mutations alone (Report No. PC-104-2012) {Delaney et 
al 2006}. Various clinical studies have shown potent inhibition of lamivudine-resistant HBV by 
tenofovir DF, suggesting that a 2- to 3- fold change in in vitro susceptibility to tenofovir is not 
clinically relevant. Other mutations have not been reported to date.
Four major patterns of lamivudine resistance mutations, rtL180M/rtM204V, 
rtV173L/rtL180M/rtM204V, rtL180M/rtM204I, and rtM204I have been identified in patients 
who failed lamivudine therapy {Delaney et al 2004b}. In cell-based assays, HBV laboratory 
strains {Delaney et al 2004b}, {Yang et al 2005}, {Brunelle et al 2005}, {Delaney et al 2006}, as well 
as those identified in clinical isolates {Brunelle et al 2007}, {Lacombe et al 2006}, {Lada et al 2004}
expressing the rtV173L, rtL180M, and rtM204I/V mutations, showed a susceptibility to 
tenofovir ranging from 0.7 to 3.4-fold that of wild-type virus.
Resistance to adefovir dipivoxil is associated with development of the rtA181V/T and/or 
rtN236T mutations in the HBV reverse transcriptase. These mutations resulted in a 2.9- to
4.5-fold, respectively, reduced sensitivity to tenofovir in vitro {Qi et al 2007}, {Delaney et al 
2006}, {Brunelle et al 2005}, {Qi et al 2005}. The effects on susceptibility to tenofovir by other 
adefovir resistance associated mutations or combinations of mutations (rtA181T, 
rtA181V/rtN236T and rtA181T/rtN236T) were also evaluated using stably transfected cell lines. 
The results demonstrated a reduction in susceptibility to tenofovir of 1.5-, 10.0- and 3.0-fold 
each, respectively {Qi et al 2007}. The clinical significance of these in vitro results is currently 
unknown.
The mutations conferring resistance to entecavir have been identified as changes at rtI169T, 
rtT184G, rtS202I/G and/or rtM250V in combination with the pre-existing lamivudine resistance 
mutations (rtL180M +/- rtM204V/I) {Tenney et al 2004}, {Colonno et al 2006}, {Tenney et al 2007}. 
In vitro phenotypic analysis showed that the tested entecavir resistance mutations resulted in 
increased EC50 values for tenofovir ranging from 0.6- to 6.9-fold (Report No. PC-174-2003), 
{Villet et al 2007}, {Brunelle et al 2007}.

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Virus harboring combinations of mutations resulting in resistance to both lamivudine and 
adefovir (rtV173L/rtL180M/rtA181V/rtN236T) were observed to emerge in a patient receiving 
combination therapy with these drugs. Virus obtained from this patient remained susceptible to 
inhibition by tenofovir in vitro {Villet et al 2006}, {Brunelle et al 2007}. Virus containing the 
rtL180M+rtM204V+rtN236T mutations created in a laboratory strain of HBV had greatly 
impaired replication capacity. These mutations resulted in a 4.4-fold increase in the tenofovir 
EC50 in vitro {Brunelle et al 2005}.
1.2.3.
Clinical Trials of Tenofovir DF
1.2.3.1.
Gilead Sciences Sponsored Clinical Trials of Tenofovir DF in HBV 
Mono-infected Subjects
There are 6 completed and 3 ongoing Gilead Sciences sponsored clinical trials that are designed 
to study the safety and antiviral activity of tenofovir DF as monotherapy or in combination with 
emtricitabine in subjects mono-infected with HBV.
1.2.3.1.1.
Study GS-US-174-0102: A Randomized, Double-Blind, Controlled Evaluation of 
Tenofovir DF versus Adefovir Dipivoxil for the Treatment of Presumed Pre-core 
Mutant Chronic Hepatitis B
1.2.3.1.2.
Study GS-US-174-0103: A Randomized, Double-Blind, Controlled Evaluation of 
Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive 
Chronic Hepatitis B
Approval of TDF for treatment of CHB was based primarily on results from these two Phase 3 
studies. In the initial 48 weeks of the trials, the studies evaluated safety and antiviral activity of 
TDF versus adefovir dipivoxil (ADV) in 641 HBeAg- (375) and HBeAg+ (266) patients with 
compensated liver function. In Study 102 at Baseline, patients had a mean Knodell 
necroinflammatory score of 7.8, a mean HBV DNA of 6.9 log10 copies/mL, and a mean ALT of 
140 U/L. In Study 103 at Baseline, patients had a mean Knodell necroinflammatory score of 8.4, 
a mean HBV DNA of 8.7 log10 copies/mL, and a mean ALT of 147 U/L. The studies are 
currently ongoing with all remaining subjects in their 5th year in the study treatment.
In both studies at 48 weeks, TDF was superior than ADV by the comparison of subjects 
achieving complete response (HBV DNA < 400 copies/mL [69 IU/mL] and histologic 
improvement characterized by ≥2 point reduction in the Knodell necroinflammatory score 
without increase in fibrosis) in the 2 treatment arms (102: 71% vs. 49%; 103: 66% vs. 12%). 
TDF treatment also produced superior viral suppression (HBV DNA < 400 copies/mL
[69 IU/mL]) compared to the ADV treatment (102: 93% vs. 63%; 103: 76% vs. 13%). In Studies 
102 and 103, both drugs produced similar results with regard to histologic improvement at 
Week 48. Normalization of ALT at the end of blinded treatment was similar in both arms of 
Study 102; however, in Study 103, the TDF treated group had a greater proportion of subjects 
with normalized ALT at Week 48. In Study 103, a significantly greater proportion of 
TDF-treated subjects than adefovir dipivoxil-treated subjects had achieved HBsAg loss at 
Week 48 (3.2% vs. 0%) {Marcellin et al 2008}.

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At the end of the Week 48 double-blind period, all eligible subjects from both ADV and TDF 
arms in Studies 102 and 103 were switched to open-label TDF (ADV-TDF and TDF-TDF, 
respectively). The studies have been extended to 8 years. Beginning at Week 72, subjects with a 
confirmed HBV DNA ≥400 copies/mL (69 IU/mL) were eligible to receive emtricitabine plus 
TDF combination therapy. The following describes year-4 (Week 192) data from this ongoing 
trial {Marcellin et al 2010}, {Heathcote et al 2010}.
In Study 102, 315 HBeAg- subjects completed W192 (84% retention). In an ITT analysis (ITT), 
86% of subjects had HBV DNA <400 copies/mL (69 IU/mL) (85% TDF-TDF; 87% ADV-TDF). 
In an on-treatment analysis 99% of subjects treated with TDF for 4 years had HBV DNA 
< 400 copies/mL at W192. 100% of ADV treated subjects (regardless of their prior response to 
ADV treatment, i.e., viremic or suppressed on ADV therapy at W48) responded favorably to 
TDF treatment with HBV DNA <400 copies/mL (69 IU/mL) at W192. Four subjects (3 on TDF 
monotherapy) had HBV DNA ≥400 copies/mL (69 IU/mL) at W192 or time of discontinuation. 
Three of the four subjects from Study 102 that qualified for resistance testing during Year 4 were 
confirmed to be nonadherent to study medication {International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Steering Committee 
2004}, {Arimilli et al 1998}, and {Piketty et al 2004}. Resistance analyses showed no amino acid 
substitutions that could be associated with TDF resistance in subjects with detectable HBV DNA 
at W192, at discontinuation, or when FTC was added. Of the 12 subjects who were eligible to 
add FTC between W72 and W192 for confirmed HBV DNA ≥400 copies/mL (69 IU/mL), 
4 subjects added FTC and 8 subjects remained on TDF monotherapy. Of the subjects who 
remained on TDF monotherapy, 6 had HBV DNA <400 copies/mL (69 IU/mL) at W192. Overall 
mean ALT at W192 was 33 U/L or less than the upper limit of the normal laboratory range. TDF
was well tolerated during both treatment periods with a safety profile consistent with the known 
safety profile of TDF. Of the 13 subjects who discontinued treatment during year 4, two had an 
AE that led to discontinuation (considered unrelated to TDF). Cumulatively, 4 cases (1%) of 
hepatocellular carcinoma were reported during open-label TDF treatment. Mean creatinine 
values showed minimal change through year 4. Two subjects experienced a confirmed 0.5 mg/dL 
increase in creatinine, one associated with advanced hepatocellular carcinoma and the other 
improved with QOD dosing. In summary, TDF was well tolerated and produced potent, 
continuous viral suppression through 4 years of TDF treatment with no detectable resistance 
mutations found to arise in association with TDF in this HBeAg- patient population. No subject 
in either treatment group had confirmed HBsAg loss or seroconverted to anti-HBs by Week 192. 
One subject in the ADV−TDF group was HBsAg− at Week 156; however, this subject was 
HBsAg+ at subsequent visits.
In Study 103, 198 HBeAg+ subjects completed W192 (74% retention). In an ITT analysis 77% 
of subjects had HBV DNA <400 copies/mL (69 IU/mL) (74% TDF-TDF; 84% ADV-TDF). 
In an on-treatment analysis 96% (TDF-TDF) and 99% (ADV-TDF) had HBV DNA 
<400 copies/mL (69 IU/mL) at W192. 100% of patients virally suppressed on ADV and 98% of 
suboptimal responders on ADV, responded favorably to a switch to TDF with HBV DNA 
<400 copies/mL (69 IU/mL) at W192. Overall 7 subjects (2 on TDF monotherapy and 5 on 
FTC/TDF) had HBV DNA ≥400 copies/mL (69 IU/mL) at W192 or after discontinuing between 
W144 and W192. Resistance analyses showed no amino acid substitutions that could be 

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associated with TDF resistance in subjects with detectable HBV DNA at W192, at 
discontinuation or when FTC was added. 34 subjects added FTC to TDF W192, 83% achieved 
HBV DNA <400 copies/mL (69 IU/mL). 9 subjects were eligible to add FTC, but did not, and of 
the 6 subjects on treatment at W192, 100% had HBV DNA <400 copies/mL (69 IU/mL). 
At W192 the mean ALT was 35.2 U/L and HBeAg loss/seroconversion were observed in 
41%/31% of subjects (on-treatment analysis). Cumulatively, 10% of subjects lost HBsAg and 
7.5% seroconverted to anti-HBs (Kaplan-Meier Estimate). TDF was well tolerated during both 
treatment periods with a safety profile consistent with the known safety profile of TDF.
Mean creatinine levels remained stable through Year 4. One subject who remains on study 
experienced a confirmed 0.5 mg/dL increase in serum creatinine during Year 4. In summary, 
TDF was well tolerated and produced potent, continuous viral suppression with increasing 
HBeAg and HBsAg loss, with no detectable resistance mutations found to arise in association 
with TDF in this HBeAg+ patient population.
Among 641 total subjects enrolled in both studies, 189 (29%) were Asian (94 HBeAg- CHB; 
95 HBeAg+ CHB). Mean age at entry for Asians was 40 years and 68% were male. 
Mean Baseline HBV DNA levels were 7.66 log10 copies/mL for both Asians and non-Asians. 
As expected, most Asian subjects had HBV genotype B or C (n=166). 163 Asians entered the 
open-label phase and 145 completed W192. Overall at W192, HBV DNA was <400 copies/mL
(69 IU/mL) in 79% of all Asians (74% HBeAg+, 84% HBeAg-) and 83% of all non-Asians (79% 
HBeAg+, 86% HBeAg-) (ITT analysis) (p≥0.2 for all comparisons). 97% of Asians and 99% of 
non-Asians had HBV DNA <400 copies/mL (69 IU/mL) by on-treatment analysis. 7 Asian 
subjects (3.7%) started FTC+TDF (none in year 4), 1 discontinued, and 4 of 6 remaining on 
study had HBV DNA <400 copies/mL (69 IU/mL). Among Asian subjects on treatment 86% had 
ALT within normal range: mean value of 31 U/L (vs. 79% of non-Asian subjects, p=0.100). 
Of 65 HBeAg+ Asian subjects with W192 serology results 35%/26% had HBeAg loss/HBeAg 
seroconversion (none had HBsAg loss). During open-label TDF treatment the safety profile was 
similar for both groups: serious adverse events (AEs) developed in 6%/14%, Grade 3/4 AEs in 
10%/12%, and Grade 3/4 laboratory abnormalities in 15%/16% of Asian/non-Asian subjects, 
respectively. There was 1 Asian subject with confirmed phosphorus <2 mg/dL (normal at 
W192), and 1 had a confirmed creatinine 0.5 mg/dL greater than Baseline and remains on study; 
none had creatinine clearance <50 mL/min. Antiviral efficacy and safety of TDF were similar in
Asians and non-Asians over 192 weeks of treatment with good tolerability congruent with the 
results of the overall studies.
1.2.3.1.3.
Study GS-US-174-0106: A Phase 2, Randomized, Double-Blind Study Exploring 
the Efficacy, Safety and Tolerability of Tenofovir Disoproxil Fumarate (DF) 
Monotherapy Versus Emtricitabine plus Tenofovir DF Fixed-Dose Combination 
Therapy in Subjects Currently Being Treated with Adefovir Dipivoxil for Chronic 
Hepatitis B and having Persistent Viral Replication
Study GS-US-174-0106 was fully enrolled and has been completed. This 168-week study was 
conducted to compare treatments of TDF versus emtricitabine (FTC) plus TDF Fixed-Dose 
Combination for CHB patients who had an incomplete response to ADV. The 48-week data 
show that TDF monotherapy and the combination of FTC and TDF had similar efficacy in the 

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patients with suboptimal viral suppression after therapy with ADV. Response to the treatment 
was not influenced by the presence of baseline LAM- or ADV-associated mutations. Initial 
monotherapy followed by combination therapy was as effective as early combination therapy 
{Berg et al 2010}.
1.2.3.1.4.
Study GS-US-174-0108: A Phase 2, Double-Blind, Multi-center, Randomized 
Study Comparing Tenofovir Disoproxil Fumarate, Emtricitabine Plus Tenofovir 
Disoproxil Fumarate, and Entecavir in the Treatment of Chronic Hepatitis B 
Subjects with Decompensated Liver Disease and in the Prevention of Hepatitis B 
Recurrence Post-Transplantation
Study GS-US-174-0108 is a Phase 2, double-blind, randomized study to evaluate the safety and 
efficacy of tenofovir disoproxil fumerate, the fixed-dose combination 
emtricitabine/tenofovir DF, and entecavir in the treatment of CHB with decompenstated liver 
disease in the prevention of HB recurrence post-transplantation. The study was fully enrolled 
(N = 112) by Jan 2008. 81 subjects completed the study and 31 were early terminated. Reasons 
for early termination (n = 31) were investigators discretion (8 patients), patient withdrew consent
(8 patients), lost to follow up (1 patient), and 14 patient deaths occurred due to various reasons. 
Week 48 data for this study was published in {Liaw et al 2011}.This study is now complete, and 
the database has been locked. Safety and efficacy analyses were performed in the fourth quarter 
of 2011 and the final Clinical Study Report was completed in the first quarter of 2012.
1.2.3.1.5.
Study GS-US-174-0115: A Randomized, Double-Blind Evaluation of the 
Antiviral Efficacy, Safety, and Tolerability of TDF versus Placebo in Adolescents 
with CHB Infection
Study GS-US-174-0115 was a large (n = 106 subjects) placebo-controlled, international trial in 
adolescent patients (12 to < 18 years). Preliminary analysis of the data suggest the following: 
after 72 weeks of treatment, tenofovir showed significant virologic response benefits over 
placebo. At 72 weeks, more tenofovir DFtreated subjects achieved the primary efficacy 
endpoint (serum HBV DNA 400 copies/mL (69 IU/mL) at the end of blinded treatment), 
compared with placebo-treated subjects (88.5% vs. 0%, p < 0.001). Tenofovir DF treatment was 
well tolerated and no patients met the primary safety endpoint of a 6% decrease in lumbar spine 
bone mineral density (BMD). As expected for an adolescent population, both arms experienced 
an overall increase in mean lumbar spine BMD. Both populations also experienced an overall 
increase in mean whole body BMD; however, the percent increase in whole body BMD in 
tenofovir-treated subjects was less than the percent increase in whole body BMD attained by 
placebo-treated subjects (2.8% [TDF] vs. 5.4% [Placebo], p = 0.013).

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1.2.3.1.6.
Study GS-US-174-0121: A Randomized, Double-Blind, Double-Dummy Study 
Evaluating the Antiviral Efficacy, Safety, and Tolerability of TDF Monotherapy 
versus FTC plus TDF Fixed-Dose Combination Therapy in Subjects with CHB 
who are Resistant to Lamivudine
Study GS-US-174-0121 is fully enrolled (N = 280). As of January, 2011, 266 (95%) enrolled 
patients remain on study. Reasons for early termination (n = 14) are investigator’s discretion 
(3 patients), protocol violation (3 patients), safety or tolerability reasons (3 patients), lost to 
follow-up (2 patients), withdrew consent (2 patients), and failure to meet entrance criteria 
(1 patient). This is a 5-year study; after all subjects complete the 96 week study visit a 96-week 
analysis was performed in the first quarter of 2012 for an interim Clinical Study Report.
1.2.3.1.7.
Study GS-US-174-0123: A Phase 4, open-label, single-arm 48-week study 
evaluating the antiviral efficacy, safety, and tolerability of TDF in HBV 
mono-infected Asian-American adults
Study GS-US-174-0123 was fully enrolled and has been completed. Safety, efficacy and 
tolerability of TDF were evaluated in Asian-American adult patients with CHB. Ninety patients 
(HBeAg- or HBeAg+) treated by community physicians were enrolled and treated with once 
daily open-label 300 mg TDF for 48 week. As previously demonstrated in wider populations of 
HBV-infected patients, this study confirms that TDF is safe and potent in Asian-American CHB 
patients with greater than 80% achieving HBV-DNA < 400 copies/mL (69 IU/mL) by Week 48 
and improved FibroTest fibrosis scores.
1.2.3.1.8.
Study GS-US-203-0101: A Randomized, Double-Blind Study Evaluating 
Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus the Combination of 
Emtricitabine and Tenofovir DF for the Treatment of Chronic Hepatitis B
Study GS-US-203-0101 is a double-blind, multi-center, randomized study to compare the safety 
and antiviral activity of tenofovir DF versus emtricitabine/tenofovir DF in the treatment of 
chronic HBV in subjects with high viral load (HBV DNA 108 copies/mL) and normal ALT 
values. One hundred and twenty-six subjects were randomized 1:1 to tenofovir DF or 
emtricitabine/tenofovir DF. Key eligibility criteria for study entry include HBV 
DNA 108 copies/mL; serum ALT ULN; and seronegative for HIV, HCV, and HDV. 
The study is 192 weeks in duration and has recently been completed. Final results are pending.
1.2.3.1.9.
Study GS-US-203-0107: A Phase 2, Open-Label Randomized Study to Evaluate 
the Efficacy and Safety of the Combination Product, Emtricitabine/Tenofovir 
Disoproxil Fumarate in the Presence or Absence of Hepatitis B Immunoglobulin 
(HBIG) in Preventing Recurrence of Chronic Hepatitis B (CHB) Post-Orthotopic 
Liver Transplant (OLT)
Study GS-US-203-0107 is a Phase 2, open-label, randomized study to evaluate the safety and 
efficacy of the fixed-dose combination emtricitabine/tenofovir DF in the presence or absence of 
hepatitis B immunoglobulin in preventing recurrence of CHB after orthotopic liver 
transplantation. The study was fully enrolled (N = 40) by May 2009. Thirty-four subjects 

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completed the study and 6 were early terminated. Reasons for early termination (n = 6) were 
investigators discretion (2 patients), patient withdrew consent (2 patients), lost to follow up 
(1 patient), and 1 patient expired due to stroke. Study is now complete, and the database has been
locked. Safety and efficacy analyses were performed in the fourth quarter of 2011, and the final 
Clinical Study Report was completed in the first quarter of 2012
1.2.3.1.10.
Clinical Trials of Tenofovir DF in HIV-1-Infected Pediatric and Adolescent 
Subjects
Two open-label, single-arm, single-center clinical studies have been performed to evaluate the 
safety and pharmacokinetics of tenofovir DF in a small number of HIV-1-infected children. 
Studies 926 and 927 were 96-week open-label pharmacokinetic and safety studies, which 
enrolled treatment-experienced children with advanced HIV disease. All subjects received 
open-label tenofovir DF as a component of a new antiretroviral regimen.
Study 926 was a Phase 1, open-label study in which subjects received six days of tenofovir DF 
monotherapy followed by the addition of individualized antiretroviral regimens. Monitoring for 
bone toxicity included measurement of lumbar spine bone mineral density by dual-energy x-ray 
absorptiometry (DEXA). Study 926 was conducted at the National Cancer Institute, National 
Institutes of Health. Eighteen subjects with a median (range) age of 11.9 years (6.2-16.2 years) 
were studied. Subjects received tenofovir DF at a dose of ~ 175 mg/m2 (administered in 
multiples of 75 mg tablets) once daily. Single-dose pharmacokinetic (PK) studies were evaluated 
with the first dose during the 7-day tenofovir DF monotherapy period and again at Week 4 when 
tenofovir DF was administered with an optimized background regimen (OBR) based on 
genotypic testing. Subjects had extensive treatment experience: median (range) duration of prior 
antiretroviral therapy was 9.7 years (4.813.5). Baseline resistance testing showed a median 
(range) of 7 (28) major NRTI mutations and 8 (110) major protease mutations.
At Week 48, median (range) decrease in log10 HIV RNA was 1.52 (4.0 to 0.52). HIV RNA 
was 50 copies/mL in 4 children (400 copies/mL in 6 children). Results from Study 926 
demonstrated that tenofovir DF-containing HAART regimens were effective and well tolerated 
in heavily treatment-experienced, HIV-infected children. However, five of 15 subjects evaluated 
at 48 weeks of treatment developed a 6% decrease from baseline in bone mineral density. 
Of these subjects, two required discontinuation of tenofovir DF, but decreases in BMD had 
partially or completed resolved by week 96. One additional subject developed a 6% decrease 
from baseline in bone mineral density by Week 96. None of the six subjects experienced a bone 
fracture {Hazra et al 2005},{Gafni et al 2006}.
Study 927 was designed to assess safety and single-dose and steady-state pharmacokinetics (PK) 
of tenofovir DF in HIV-1 infected, treatment-experienced children. Seven subjects were enrolled, 
including three children who were naive to tenofovir DF and four patients who were 
tenofovir DF experienced. Subjects received tenofovir DF once daily at a dose of approximately 
5 mg/kg (administered in multiples of 75 mg tablets). In the three children who were naive to 
tenofovir DF, single dose PK studies were assessed over 48 hours after the first dose. In the four 
tenofovir DF-experienced children, steady-state PK studies were assessed over 10 hours on 
Day 7, when tenofovir DF was administered with an optimized background antiretroviral 
regimen.

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The primary efficacy endpoint was virologic response, measured as a change from baseline in 
log10 HIV-1 RNA. Limited data available from these patients showed that, overall, treatment 
with tenofovir DF resulted in a decline in mean plasma HIV-1 RNA of 0.95 log10 copies/mL 
from baseline to Week 72, and a decline in median plasma HIV-1 RNA of 0.39 log10 copies/mL 
from baseline at Week 108. These overall declines were seen despite high prior exposure and 
virological failure/intolerance to multiple antiretrovirals in all patients. Steady state PK 
parameters of tenofovir DF in children and adolescents treated with tenofovir DF-containing 
regimens were similar to those seen in HIV-infected adults treated with 300 mg once daily. 
Tenofovir DF was safe and well tolerated when given for a mean duration of 100 weeks in 
combination with other antiretrovirals. A renal tubular disorder and increase in urinary 
beta-2 microglobulin were the only events to occur that were considered possibly/probably 
related to tenofovir DF. These events, in a subject who had a history of probable tubulopathy 
while receiving tenofovir DF before the study, resolved after withdrawal of tenofovir DF. 
The limited available bone mineral density data in this study do not suggest a decline in BMD 
with increased exposure to tenofovir DF. No bone fractures occurred during the study.
In a third study, 28 HIV-infected pediatric subjects (ages 5–17.9 years) receiving HAART 
therapy consisting of lamivudine, stavudine and a protease inhibitor (PI) with stable undetectable 
viral loads were randomized to switch the PI to efavirenz and stavudine to tenofovir at baseline 
(Group 1) or at Week 24 (Group 2). At 96 weeks, virological suppression and unchanged CD4 
counts were maintained in all subjects {Vigano et al 2007a}. Tenofovir DF therapy was well 
tolerated. Through 96 weeks, no child experienced a Grade 1 or higher increase in serum 
creatinine or phosphate, and mean serum creatinine, phosphate and bicarbonate values were 
unchanged {Vigano et al 2007b}. The authors concluded that no evidence of impaired glomerular 
filtration or tubular renal function was observed in HIV-infected children treated with tenofovir 
DF for 96 weeks. The authors also evaluated bone mineral content (lumbar spine and 
whole-body bone mineral content (BMC) and bone mineral density (BMD) via DEXA scan in 
16 subjects in this study through 12 months of tenofovir DF treatment {Giacomet et al 2005}. 
DEXA scans were obtained 12 months prior to therapy switch, at baseline, and 12 months after 
switch to tenofovir DF. The authors calculated expected changes in bone measurements from 
data obtained from 166 healthy children. The BMC and BMD increments observed before and 
after switching to tenofovir DF did not differ significantly from those calculated in healthy 
controls. Although the sample size is small, results from this study suggest that 12 months of 
tenofovir DF treatment does not impair bone mineral accrual in HIV-infected children.
Two clinical trials of tenofovir DF in pediatric and/or adolescent HIV-1-infected subjects are 
currently ongoing. Study GS-US-104-0352 is evaluating 100 HIV-infected children and 
adolescents (2 to 16 years of age) who are virologically suppressed (HIV-1 RNA 
400 copies/mL) on their current antiretroviral regimen containing either stavudine or 
zidovudine. Subjects are randomized 1:1 to continue on the same stavudine- or 
zidovudine-containing regimen, or to replace stavudine or zidovudine with tenofovir DF while 
continuing their other background antiretroviral agents. The study will assess the efficacy, safety 
(including BMD) and tolerability of switching to tenofovir DF, compared to continuing 
stavudine or zidovudine therapy.

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The 48-week results of Study GS-US-104-0352 showed tenofovir DF did not meet the criteria 
for treatment noninferiority at Week 48 (missing = failure; ITT analysis set). However, it did 
meet treatment noninferiority from baseline through Week 24. The lack of noninferiority by this 
analysis was driven by the higher number of discontinuations as well as transient low-level 
increases in viral load at Week 48 in the tenofovir DF group. In post hoc analyses to explore the 
effect of subjects who had discontinued from the study early, tenofovir DF met the criteria for 
treatment noninferiority at Week 48 and all timepoints from baseline to Week 48 
(missing = excluded; ITT analysis set).
The development of virologic resistance in these antiretroviral-experienced children was 
consistent with current therapy or archived mutations from previous therapies. Tenofovir 
pharmacokinetics following administration of the oral powder formulation of tenofovir DF at a 
dose of 8 mg/kg daily in HIV-1 infected children (2 to < 12 years of age) is similar to that 
achieved following administration of tenofovir DF 300 mg tablets in HIV-1 infected adults, 
confirming the appropriateness of this dose in this age range.
Tenofovir DF was generally safe and well tolerated in this study and was consistent with the 
known safety profile in adult. There were no clinically relevant differences in renal function 
between tenofovir DF and stavudine or zidovudine groups in the randomized treatment 
period. At the Week 96 analysis, 4 subjects discontinued due to renal AEs (3 subjects with 
hypophosphatemia and 1 subject with glycosuria and chronic renal failure) that were clinically 
consistent with proximal renal tubulopathy, a renal disorder identified in postmarketing 
surveillance of tenofovir DF in adults; no additional discontinuations due to renal AEs occurred 
in the Week 144 analysis. No clinically relevant differences were seen between the tenofovir DF 
and stavudine or zidovudine groups in spine BMD. Percentage increases from baseline in total 
body BMD were smaller in the tenofovir DF group than in the stavudine or zidovudine group 
and there was a modest reduction in total body BMD Z score in the tenofovir DF group 
compared to no change in the stavudine or zidovudine group. The long-term clinical relevance of 
these observations is unknown. Biochemical markers of both bone formation (serum 
osteocalcin and bone-specific alkaline phophatase) and bone resorption (N- and C-telopeptides)
demonstrated greater and significant changes in the tenofovir DF group compared with the 
stavudine or zidovudine group; however, there was no evidence of imbalance between bone 
formation and bone resorption. The clinical relevance of these changes in bone biochemical 
markers appears to be minimal given the lack of clinically relevant changes in BMD and the 
absence of bone fractures reported in the study.
Study GS-US-104-0321 enrolled antiretroviral treatment-experienced HIV-1 infected 
adolescents that were treated with tenofovir DF or placebo in addition to a reconfigured and 
optimized background regimen (OBR) for 48 weeks. The Week 48 results of this study showed 
that adolescents in both treatment groups demonstrated a virologic response to treatment. 
There were no statistically significant differences between tenofovir DF and placebo groups for 
any of the efficacy endpoints for the ITT analysis set. Treatment response was demonstrated by 
reductions in viral load and increases in CD4 cell count in both treatment groups. Analyses of the 
primary efficacy endpoint using the subgroup of subjects with a maximum of 1 active drug in 
their OBR (ANRS scoring system) and confirmation using post hoc analyses (Stanford database 
scoring system; 3- and 5-point scales) provide evidence for the antiretroviral activity of 
tenofovir DF in HIV-1 infected adolescents.

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The development of virological resistance in these antiretroviral-experienced adolescents with 
extensive resistance in their HIV at screening was comparable to that observed in heavily 
treatment-experienced adults. Mutation K65R developed in one subject in the tenofovir DF 
group.
Tenofovir DF was generally safe and well tolerated when given in combination with an OBR in 
this study. The safety profile in adolescent subjects with HIV-1 infection was consistent with the 
known safety profile in adults; the most marked differences between tenofovir DF and placebo 
groups in reported AEs were for mild to moderate gastrointestinal disorders (vomiting, nausea, 
and diarrhea). No deaths or SAEs considered related to study drug were reported, and only 
1 subject discontinued due to an AE (vomiting). There was no evidence of compromised renal 
function due to tenofovir DF.
In Study 321, bone effects were similar to adult subjects. Under normal circumstances BMD 
increases rapidly in this age group. In this study, the mean rate of bone gain was less in the 
tenofovir DF-treated group compared to the placebo group. Six tenofovir DF treated subjects and 
one placebo treated subject had significant (> 4%) lumbar spine BMD loss in 48 weeks. Among 
28 subjects receiving 96 weeks of tenofovir DF, Z-scores declined by 0.341 for lumbar spine 
and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone 
turnover in tenofovir DF-treated pediatric subjects 12 years of age and older suggest increased 
bone turnover, consistent with the effects observed in adults.
1.3.
Rationale for the Current Study and Dose Selection
The aim of treatment for chronic hepatitis B infection is to maintain suppression of viral 
replication to prevent the development of complications. Achieving this goal requires potent, 
durable, well-tolerated, patient-friendly antiviral regimens. Clinical data in adults and 
adolescents with HBeAg-positive and HBeAg-negative/anti-HBe-positive chronic HBV 
infection demonstrate the efficacy and safety of tenofovir DF for the treatment of chronic HBV 
disease. Tenofovir DF is a promising agent for use in adolescent subjects with chronic HBV
because of its favorable efficacy, safety and tolerability profiles as indicated from preliminary 
data from Study GS-US-174-0115. The pharmacokinetic profile of tenofovir DF allows
convenient, once-daily dosing, which can facilitate adherence in this patient population.
The optimal treatment for pediatric patients with chronic HBV infection is currently evolving. 
As summarized in Section 1.1, treatment with interferon alfa, lamivudine, and adefovir in 
pediatric populations has been shown to be less than optimal. Further, the safety and efficacy of 
entecavir and telbivudine have not been established in patients 16 years of age. Risk-benefit 
evaluation supports use of a blinded study design using placebo for 48 weeks as an appropriate 
comparator. After 48 weeks of blinded treatment, all subjects will switch to open-label 
tenofovir DF, provided that no safety concerns are identified by the independent Data 
Monitoring Committee monitoring the study. Use of the placebo comparator allows a more 
robust evaluation of tenofovir DF safety and tolerability (e.g., bone metabolism, renal safety), 
and does not expose subjects randomized to the placebo arm to risk of development of resistance 
during the blinded portion of the study.

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A study evaluating tenofovir DF in pediatric patients (ages 2 to < 12, at the time of enrollment) is
needed to assess the safety and efficacy of this agent in the treatment of chronic hepatitis B in 
this patient population. In addition, the study will help to further elucidate the pharmacokinetic 
and resistance profiles of tenofovir DF. Through their participation, study subjects will help 
generate critical new information to help guide the most optimal treatment of chronic HBV 
infection in pediatric patients.
1.3.1.
Rationale for Dose Selection
1.3.1.1.
Tenofovir DF
The selection of the 300 mg dose for tenofovir DF for use in adults is based upon the following 
rationale: (1) The 300 mg dose has been demonstrated to be the optimal dose of tenofovir DF for 
the treatment of HIV-1 infection; the Ki of tenofovir against HIV-1 reverse transcriptase 
(0.02-1.6 M) is similar to the Ki against HBV polymerase (0.18 M); (2) The safety profile of 
tenofovir DF 300 mg once daily has been well characterized in patients with HIV infection, and 
tenofovir DF 300 mg once daily has been shown to be safe in that patient population; 
(3) Reducing the dose of tenofovir DF may lead to an increased risk of the emergence of 
resistance as documented with other antivirals; (4) In the dose-ranging study GS-98-902, the 
safety profile of tenofovir DF 300 mg once daily was not different from the safety profiles of 
lower doses of tenofovir DF (75 mg and 150 mg); and (5) The safety of the 300 mg dose is 
similar in HIV-infected patients with or without co-infection with chronic hepatitis B, as 
supported by study GS-99-910. Further, in the GS-US-174-0102 and GS-US-174-0103 studies, 
the 300 mg dose of tenofovir DF was shown to be an effective dose for treatment of chronic 
hepatitis B infection in adults with HBeAg-negative/ anti-HBe-positive disease and 
HBeAg-positive disease, respectively.
Studies in HIV-infected children (Studies GS-01-926, GS-01-927 and GS-02-983) indicate that 
an 8 mg/kg dose in a pediatric population will result in a tenofovir DF systemic exposure similar 
to that in HIV-infected adults receiving the commercially available tenofovir DF 300 mg tablet. 
The recommended oral dose of tenofovir DF in children is 8 mg/kg of actual body weight, to a 
maximum of 300 mg/day (35 kg). All pediatric subjects in this study who weigh 17 kg and 
are able to swallow tablets will receive tenofovir DF as a 150, 200, 250, or 300 mg tablet 
(or matching placebo tablets), administered once daily with or without regard to food. Subjects 
weighing < 17 kg and subjects ≥17 kg who are unable to swallow a tablet, will be given 
tenofovir DF oral powder (or matching placebo). Tenofovir pharmacokinetics, following 
administration of both the oral powder and tablet formulations will be assessed in this study in 
pediatric patients ages 2 to < 12 years old.
1.3.2.
Rationale for Bone Mineral Density Evaluations
Osteopenia and osteoporosis have been reported in both children and adults with HIV-1 
infection. The pathophysiology associated with these findings is unclear and may be related to 
HIV infection, antiretroviral therapy, and/or associated co-morbidities. Preclinical data showed 
that high doses of tenofovir DF in animals are associated with significant effects in bone 
metabolism. As seen in Study 926, some HIV-1-infected children receiving salvage therapy with 

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tenofovir DF experienced decreases in bone mineral density (BMD) {Hazra et al 2005}, {Gafni et 
al 2006}. Many of the children in that study had abnormal BMD results at baseline, suggesting 
that other factors were related to the decrease in BMD. As seen in a preliminary analysis of 
Study 115, in which adolescents age 12 to 17 with chronic HBV were treated with tenofovir or 
placebo and followed with DEXA scans at baseline, 24, 48, and 72 weeks, tenofovir was 
associated with a statististically significant difference in the mean percent increase in whole body 
BMD (2.8% [TDF] vs. 5.4% [Placebo], p = 0.013). Using whole body BMD Z-scores to account 
for age specific changes, and when comparing average values, it appears that this difference is 
unlikely to be of clinical relevance. Individual adolescent subjects who experienced the largest 
decreases in Z-scores were in the tenofovir arm; however, the largest changes in Z-scores in the 
study did not reach a change of -1.0.
The current study was designed to evaluate, in a controlled fashion, changes from baseline in 
BMD in a pediatric population following 48 weeks of study drug treatment. Changes from 
baseline in BMD will be evaluated every 24 weeks through Week 96, then annually until each 
subject reaches Week 192 (approximately 4 years on study), or at the Early Study Drug 
Discontinuation Visit (if applicable).

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2.
OBJECTIVES
The primary objective of this study is:

To evaluate the antiviral efficacy of tenofovir DF versus placebo in pediatric patients (aged 
2 to < 12 years, at the time of enrollment) with chronic hepatitis B infection
The key secondary objective is:

To evaluate the proportion of subjects with HBeAg seroconversion at Week 48 (in subjects 
with baseline HBeAg sero-positivity). 
Secondary objectives are:

To characterize the safety and tolerability profile of tenofovir DF in pediatric patients (aged 
2 to < 12 years, at the time of enrollment) with chronic hepatitis B infection

To evaluate the biochemical and serological responses to tenofovir DF versus placebo

To evaluate the incidence of potential resistance mutations to tenofovir DF in the hepatitis B 
virus polymerase/reverse transcriptase (pol/RT)

To assess the pharmacokinetics of tenofovir in subjects receiving the tablet formulation and 
those receiving the oral powder formulation.

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3.
STUDY DESIGN
This is a Phase 3, randomized, double-blind study to evaluate the antiviral efficacy, safety and 
tolerability of tenofovir DF versus placebo in pediatric subjects with chronic HBV infection. 
One hundred (100) tenofovir DF-naïve subjects with HBV DNA 105 copies/mL and ALT 
1.5 × ULN will be randomized in a 2:1 ratio to treatment arm A or B:

Treatment A (n = 67): tenofovir DF PO once daily for 48 weeks

Treatment B (n = 33): matching placebo PO once daily for 48 weeks
After 48 weeks of blinded randomized treatment, each subject will switch to open-label 
tenofovir DF treatment for additional 144 weeks (see study schema at end of Section 3). Subjects 
under Protocol Amendment 3 who are beyond Week 48 of blinded randomized treatment will 
switch to open-label tenofovir DF at the Week 72 visit and will continue on open-label treatment 
until Week 192.
Randomization will be stratified by age (2 to < 6 and 6 to < 12) and geographical location of 
study site (North America/Europe and Asia).
Randomization cannot occur until after the Baseline (pre-treatment) DEXA scan has been 
performed.
Subjects who experience Grade 4 ALT while on blinded study medication will be evaluated 
weekly with serum chemistry and liver function test monitoring. In the event that any subject has 
sustained Grade 4 ALT for 16 weeks (i.e., failure to resolve ALT to grade 3 or baseline), the 
serial HBV DNA values on study will be provided to the investigator, and the subject can be 
offered open-label tenofovir DF, after discussion with the Gilead Medical Monitor. Such events 
should be recorded as an adverse event leading to blinded study drug discontinuation.
All subjects will take a daily multivitamin with no additional mineral components that contain a 
minimum of 400 IU of vitamin D or higher per country specific regulations.
The primary efficacy and safety analysis will be conducted at the end of double-blind treatment, 
after the last randomized subject reaches Week 48. Subsequently, efficacy and safety analyses of 
all subjects continuing on open-label tenofovir DF will be performed after the last randomized
subject reaches Weeks 144 and 192.
An external independent multidisciplinary Data Monitoring Committee (DMC) will review the 
progress and safety of this study approximately every 24 weeks after the first subject is 
randomized. During the open-label duration of the study, the DMC will convene approximately 
every 52 weeks. At each meeting, the DMC will review routine safety and DEXA data and will 
make recommendations regarding modification of study treatment.

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Subjects with the following characteristics will be eligible for enrollment: 2 to < 12 years of age 
with chronic HBeAg-positive or HBeAg-negative HBV infection (HBsAg-positive for at least 
6 months; HBV DNA levels 105 copies/mL, ALT 1.5 × ULN, and creatinine clearance 
80 mL/min/1.73 m2 at screening). Subjects must be without serological evidence of 
co-infection with HCV, HIV, acute HAV, or HDV. Subjects with decompensated liver disease, 
significant renal disease, significant bone disease, evidence of hepatocellular carcinoma 
(i.e., -fetoprotein 50 ng/mL), or any chronic liver disease not related to HBV-infection, as 
well as pregnant or breast-feeding females, will be excluded from the study. Subjects must be 
naïve to tenofovir DF, but could have received prior treatment with other anti-HBV 
nucleoside/nucleotide therapy or interferon. Previous treatment with interferon must have ended 
6 months prior to the Screening Visit. Subjects experienced on other oral anti-HBV 
nucleoside/nucleotide therapy must have discontinued therapy 16 weeks prior to screening to 
avoid flare if randomized to the placebo arm.
Plasma HBV DNA levels, laboratory analyses (serum chemistry, liver tests, hematology, and 
urinalysis), pregnancy test (females of childbearing potential only), vital signs, adverse events 
and concomitant medications will be measured or assessed at screening, baseline, Weeks 4, 8, 
16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, then every 12 weeks thereafter until the end of the study 
(and at Early Discontinuation, if applicable). HBV serology (HBsAg, HBeAg, and reflex HBeAb 
and HBsAb if Ag negative) will be conducted at Screening, Baseline, Weeks 16, 32, 48, 64, 72, 
80, and 96, then every 12 weeks through the end of study (and at Early Discontinuation, if 
applicable). DEXA scans of the spine and whole body will be performed at Baseline, and 
Weeks 24, 48, 72, and 96, then annually until completion of the study (and at Early 
Discontinuation if applicable). Bone biochemical markers will be measured at Screening, 
Baseline, every 24 weeks through Week 96, then annually until the end of study (and at Early 
Discontinuation, if applicable). DEXA and bone biochemical markers will also be required at 
time of switching from placebo to tenofovir DF, if the last measurement was performed 
> 12 weeks prior to switch. Complete physical examinations (including Tanner Staging starting 
at Baseline) will be performed at Screening, Baseline, Week 24 and then every 24 weeks through 
the end of study (and at Early Discontinuation, if applicable). Determination of HBV viral 
genotype (A-H) will be performed at baseline for all subjects. Resistance surveillance will be 
conducted at Baseline for all subjects, and attempted for all viremic subjects (HBV DNA 
400 copies/mL [69 IU/mL]) at Weeks 48, 96, 144, and 192 (and at Early Discontinuation, if 
applicable).
Plasma and serum for storage will be collected at every visit for possible pharmacokinetic and/or 
virological analyses (including resistance surveillance, HBsAg and HBeAg quantification and 
adherence assessment).
For subjects for whom a separate consent is provided, an appropriate blood sample for biomarker 
(including pharmacogenomic) analysis will be collected for the exploration of markers that may 
be predictive of virologic response and/or the tolerability of HBV therapies.

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Subjects who permanently discontinue study drug will be asked to return for an end of treatment 
visit within 72 hours of the last dose of study drug. Subjects who permanently discontinue study 
drug will be followed for 24 weeks off treatment or up to initiation of active treatment, 
whichever occurs first. For subjects off treatment, post-treatment follow-up evaluations, i.e., 
serum chemistry, liver function tests and plasma HBV DNA, will be performed every 4 weeks
for 24 weeks. The treatment-free follow-up period could occur for early discontinuation subjects 
or at Week 192 study completion.
After the completion of the study at Week 192, all subjects who completed the study will be 
offered open label tenofovir DF under another protocol until it is commercially available in that 
country for chronic HBV in patients for this age range. The subject will be asked to sign another 
informed consent form to continue to receive tenofovir DF after this study has been completed.
Figure 3-1.
Study Schema

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of 100 tenofovir DF-naïve pediatric subjects with chronic HBV will be randomized 2:1 to 
receive blinded tenofovir DF PO once daily (Treatment A, n = 67) or blinded matching placebo
PO once daily (Treatment B, n = 33).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.

Male or female

2 years to < 12 years of age (consent of parent or legal guardian required)

Body weight 10kg

Documented chronic HBV infection, defined as positive serum HBsAg 6 months

HBeAg-positive or HBeAg-negative

HBV DNA 105 copies/mL (PCR method)

ALT 1.5 × ULN at screening

Estimated glomerular filtration rate (creatinine clearance) 80 mL/min/1.73m2
Estimated creatinine clearance using Schwartz Formula 
(mL/min/1.73m2) = k L/Scr
[(k is proportionality constant: pediatric males/females 2 years to < 12 years k = 0.55; for 
adolescent females 12 years old, k = 0.55, and for adolescent males 12 years, k = 0.70); 
L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]

Adequate hematologic function (absolute neutrophil count 1,500/mm3;
hemoglobin 10.0 g/dL)

Negative serum -HCG pregnancy test (for females of childbearing potential only)

Male and female subjects of childbearing potential (defined in Section 7.7.1) identified as 
choosing to become sexually active must agree to utilize highly effective contraception 
methods or agree to abstain from heterosexual intercourse while on study treatment and for 
30 days following the last dose of study drugs (refer to Section 7.7.2).

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
Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements

Subject able to provide written assent as determined by IRB/IEC/local requirements and 
Investigator’s discretion.

No prior tenofovir DF therapy (subjects may have received prior interferon-alfa and/or other 
oral anti-HBV nucleoside/nucleotide therapy; subjects must have discontinued interferon-alfa
therapy 6 months prior to screening; subjects experienced on other anti-HBV 
nucleoside/nucleotide therapy must have discontinued therapy 16 weeks prior to screening 
to avoid flare if randomized to the placebo arm)
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

Pregnant or lactating subjects.

Sexually-active males or females of childbearing potential who are not willing to use a highly 
effective method of contraception during the study. (see Section 7.7.2 for further details).

Decompensated liver disease defined as PT 1.2 ULN, platelets 150,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage).

Receipt of interferon (pegylated or not) therapy within 6 months of the Screening Visit

Receipt of anti-HBV nucleoside/nucleotide therapy within 16 weeks of the Screening Visit

-fetoprotein 50 ng/mL

Evidence of hepatocellular carcinoma (HCC)

Co-infection with HIV, acute HAV, HCV, or HDV

Chronic liver disease of non-HBV etiology (e.g., hemochromatosis, alpha-1 antitrypsin 
deficiency, cholangitis)

History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic 
kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)

History of significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis 
imperfecta, osteochrondroses, multiple bone fractures)

Significant cardiovascular, pulmonary or neurological disease

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
Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications

History of solid organ or bone marrow transplantation

Ongoing therapy with any of the following:
Nephrotoxic agents
Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin)
Cidofovir
Cisplatin
Foscarnet
IV amphotericin B
IV pentamidine
Oral or IV ganciclovir
Cyclosporine
Tacrolimus
IV vancomycin

Chronic daily non-steroidal anti-inflammatory drug therapy
Competitors of renal excretion (e.g., probenecid)
Systemic chemotherapeutic agents
Systemic corticosteroids (pulmonary administration via MDI/nebulizer and oral steroids 
administered for less that 5 days are permitted)
Interleukin-2 (IL-2) and other immunomodulating agents
Investigational agents (except with the expressed approval of the Sponsor)
Administration of any of the above medications must be discontinued at least 45 days 
prior to the Baseline Visit and for the duration of the study period.

Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Any other condition (including alcohol or substance abuse) 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

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5.
STUDY DRUGS
5.1.
Randomization, Blinding and Unblinding
Approximately 100 tenofovir DF-naïve subjects will be randomized in a 2:1 ratio to receive 
blinded tenofovir DF PO once daily (Treatment A, N = 67), or blinded matching placebo PO 
once daily (Treatment B, N = 33). Randomization will be stratified by age (2 to < 6, 6 to < 12) 
and geographical location of study site (North America/Europe and Asia). Subjects will be 
assigned a screening number at the time of consent/assent. Once eligibility has been confirmed, 
subjects will be assigned a subject number and treatment arm at the time of randomization. 
A centralized randomization procedure will be used, whereby numbered bottles of tenofovir DF 
or placebo are assigned to subjects via an interactive voice response system (IVRS) according to 
the randomization code. For the first 48 weeks of the study (blinded phase), study drugs will be 
dispensed to the subject in a blinded fashion in numbered bottles from supplies stored at the 
study site. After Week 48 (open-label portion of the study), open-label tenofovir DF tablet or 
tenofovir DF oral powder will be provided to the study site.
Randomization cannot occur until after the Baseline (pre-treatment) DEXA scan has been 
performed. All Baseline tests and procedures must be completed prior to the 
administration of the first dose of study drugs. Initiation of treatment with study drugs 
should take place on-site within 24 hours of the Baseline Visit.
For the double-blind treatment period, tenofovir DF tablet or tenofovir DF oral powder and 
matching placebo (tablet or powder) will be supplied by Gilead. For the open-label treatment 
period, tenofovir DF tablet or tenofovir DF oral powder will be supplied by Gilead. Throughout 
the entire study period (blinded and open-label), all subjects will take a daily multivitamin with 
no additional mineral components that contains a minimum of 400 IU of vitamin D or higher per 
country specific regulations.
During the blinded portion of the study, HBV DNA results will not be distributed to 
investigators, subjects, or clinical research personnel involved in the clinical conduct of the 
study. The only exception will be in the event where Grade 4 ALT is maintained for 16 weeks 
and in the case of ALT flare, both considered situations of medical need, when serial HBV DNA 
values from Screening through time of event will be made available to the investigator. 
Additionally, Gilead Drug Safety and Public Health will be provided with unblinding 
information upon request for expedited reporting of Suspected Unexpected Serious Adverse 
Reactions (SUSARs).
In the event of a medical emergency where unblinding is required for treating the subject, the 
investigator may unblind via the IXRS. Gilead recommends but does not require that the 
investigator contact the Gilead Sciences medical monitor before unblinding in such instances. 
Treatment assignment should remain blinded unless that knowledge is necessary to determine 
emergency medical care for the subject. The rationale for unblinding must be clearly explained 
in source documentation and on the electronic case report form (eCRF), along with the date on 
which the code was broken. Additionally, the investigator is requested to inform the Gilead 
medical monitor within 24 hours of obtaining the treatment code.

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Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. The subject can be offered open-label tenofovir DF after discussion with 
the Gilead Medical Monitor. All subjects will be followed until study completion unless consent 
to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drugs – Tenofovir DF Tablet/Oral 
Powder and Matching Placebos
5.2.1.
Formulation
5.2.1.1.
Tenofovir DF Tablets
For pediatric patients weighing ≥17 kg who can swallow an intact tablet, one Tenofovir DF 
tablet, 150, 200, 250 or 300 mg based on body weight, can be taken orally once daily.
Tenofovir DF tablets 300 mg contain 300 mg of tenofovir disoproxil fumarate, which is 
equivalent to 245 mg of tenofovir disoproxil. The tablets are light blue, almond-shaped, 
plain-faced, and film-coated containing 300 mg of tenofovir DF. Each tablet contains the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized 
starch, croscarmellose sodium, and magnesium stearate. The film coating contains lactose 
monohydrate, hypromellose (hydroxypropyl methylcellulose), glycerol triacetate, titanium 
dioxide, and indigo carmine aluminum lake.
Tenofovir DF tablets 250 mg contain 250 mg of tenofovir disoproxil fumarate, which is 
equivalent to 204 mg of tenofovir disoproxil. The tablets are capsule-shaped, white, debossed
and film-coated.
Tenofovir DF tablets 200 mg contain 200 mg of tenofovir disoproxil fumarate, which is 
equivalent to 163 mg of tenofovir disoproxil. The tablets are round-shaped, white, debossed, and 
film-coated.
Tenofovir DF tablets 150 mg contain 150 mg of tenofovir disoproxil fumarate, which is 
equivalent to 123 mg of tenofovir disoproxil. The tablets are triangle-shaped, white, debossed, 
and film-coated.
In addition to the active ingredient, the tenofovir DF tablets 150, 200, and 250 mg contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized 
starch, croscarmellose sodium, and magnesium stearate. The film-coating contains: hypromellose 
(hydroxypropyl methylcellulose), lactose monohydrate, titanium dioxide, and glycerol triacetate.

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5.2.1.2.
Tenofovir DF Powder
Tenofovir DF oral powder formulation consists of polymer coated particles containing 40 mg of 
tenofovir disoproxil fumarate per 1 gram (1 scoop) of powder. In addition to the active 
ingredient, the oral powder contains the following inactive ingredients: hydroxypropyl cellulose, 
mannitol, ethylcellulose, and silicon dioxide.
5.2.1.3.
Placebo Tablets
Placebo tablets to match tenofovir DF 300 mg are light blue, almond shaped, plain faced, 
film-coated tablets. Each tablet contains the following inactive ingredients: denatonium 
benzoate, lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium 
stearate. The film coating contains the following inactive ingredients: lactose monohydrate, 
hypromellose (hydroxypropyl methylcellulose), glycerol triacetate, titanium dioxide, and indigo 
carmine aluminum lake.
Placebo tablets to match tenofovir DF 150 mg, 200 mg, and 250 mg are white and of identical 
dimensions as the corresponding active tablet. Each tablet contains the following inactive 
ingredients: denatonium benzoate, lactose monohydrate, pregelatinized starch, croscarmellose 
sodium, and magnesium stearate. The film coating contains the following inactive ingredients: 
lactose monohydrate, hypromellose (hydroxypropyl methylcellulose), glycerol triacetate, and 
titanium dioxide.
5.2.1.4.
Placebo Powder
Placebo powder to match tenofovir DF oral powder formulation is a white to off white powder. 
The placebo to match tenofovir DF oral powder contains the following inactive ingredients: 
hydroxypropyl cellulose, mannitol, ethylcellulose, and silicon dioxide.
5.2.1.5.
Multivitamin Supplement
All subjects will take a daily multivitamin with no additional mineral components that contain a 
minimum of 400 IU of vitamin D or higher per country specific regulations.
The multivitamin is to be provided by the study site.
5.2.2.
Packaging and Labeling
Thirty (30) tenofovir DF tablets or matching placebo tablets are packaged in white, high-density 
polyethylene (HDPE) bottles with one gram of desiccant and fiber packing present in each bottle. 
Each bottle is enclosed with a white, continous thread, child-reststant polypropylene screw cap 
with an induction-sealed, aluminium-faced liner.
Sixty (60) grams of tenofovir DF oral powder formulation or matching placebo powder 
formulation are packaged in white, high density polyethylene (HDPE) bottles. Each bottle is 
capped with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner. One or more polypropylene dosing scoops will be 
provided with each bottle.

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Study drug to be distributed to centers in the US and other participating countries shall be labeled 
to meet applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.3.
Storage and Handling
Tenofovir DF tablets and matching placebo should be stored at 25C (77F); excursions are 
permitted to 15–30C (59–86F). Storage conditions are specified on the label.
Tenofovir DF oral powder formulation and matching placebo powder formulation should be 
stored at 25C (77F); excursions permitted to 15C30C (59F86F). Storage conditions are 
specified on the label.
Until dispensed to the subjects, all bottles of study drugs should be stored in a securely locked 
area, accessible only to authorized site personnel.
To ensure product stability, study drugs should not be dispensed in a container other than the one 
supplied.
5.3.
Dosage and Administration of Study Drugs
Subjects will be randomly assigned (2:1) to receive one of the following treatments in a blinded
fashion:
Treatment A:

for subjects ≥ 17 kg - blinded tenofovir DF oral tablet (150, 200, 250, or 300 mg based on 
body weight) once daily for 48 weeks (oral powder may be administered to subjects if unable 
to swallow a tablet)

for subjects < 17 kg or ≥17 kg who are unable to swallow a tablet - blinded tenofovir DF 
oral powder administered in a dose of 8 mg/kg PO once daily up to a maximum dose of 
300 mg (ie, subjects weighing more than 35 kg will continue to receive only 300 mg) for 
48 weeks
Treatment B:

for subjects ≥ 17 kg – matching blinded placebo oral tablet once daily for 48 weeks 
(oral placebo powder may be administered to subjects if unable to swallow a tablet)

for subjects < 17 kg or ≥17 kg who are unable to swallow a tablet - matching oral placebo 
powder formulation of tenofovir DF PO once daily up to a maximum corresponding dose of 
300 mg for 48 weeks.

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After 48 weeks of blinded randomized treatment, each subject will switch to open-label tenofovir 
DF treatment for an additional 144 weeks. Subjects under Protocol Amendment 3 who are 
beyond Week 48 of blinded randomized treatment will switch to open-label tenofovir DF at the 
Week 72 visit and will continue on open-label treatment until Week 192.
Subjects who weigh ≥ 17 kg may be switched from the oral power formulation to tenofovir DF 
oral tablet once daily. For subjects < 17 kg, tenofovir DF oral powder will be administered 
through 192 weeks or switch to tenofovir DF tablets when subjects weigh more than 17 kg.
All subjects will take a daily multivitamin with no additional mineral components that contain a 
minimum of 400 IU of vitamin D or higher per country specific regulations.
5.3.1.
Dosing Recommendation – Tenofovir DF or Matching Placebo Tablet
One tenofovir DF tablet or its matching placebo (as the comparator treatment) will be 
administered once daily to subjects who weigh ≥17 kg. Administration of study drug will be
followed by 240 mL (8 fluid ounces) of water and will be dosed with or without food.
Table 5-1.
Dosing Recommendations for Pediatric Patients 2 Years of Age and 
Weighing 17 kg Using VIREAD Tablets
Body Weight
Tablets Once Daily
Kilogram (kg)
Pound (lbs)
17 to <22
37 to <49
150 mg
22 to <28
49 to <62
200 mg
28 to <35
62 to <77
250 mg
35
77
300 mg
5.3.2.
Dosing Recommendation - Oral Powder
The tenofovir DF oral powder containing 4% weight/weight tenofovir DF can be administered at 
a dose of 8 mg/kg once daily to subjects who are 35 kg, in the following manner:
Spoon 2-4 ounces (1/4-1/2 cup) of soft food that can be swallowed without chewing (Examples 
of soft foods you can use are: applesauce, baby food, or yogurt) into a plastic cup or bowl 
without grooves. Do not mix powder with liquid (powder may float to the top even after stirring). 
Determine the appropriate number of level scoops (see below) of tenofovir DF oral powder that 
should be removed from the labeled high density polyethylene (HDPE) bottle. Use the flat edge 
of clean knife to make the powder even with the top of the scoop. Note that each scoop of 
powder covers a 5 kg body weight increment. The scoop provided contains a line marking for 
half scoops. The appropriate number of scoops of powder should be sprinkled on the soft food. 
Stir with a spoon until well mixed and give the entire dose to patient to consume right away after 
mixing to avoid a bad taste.

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Table 5-2.
Dosing Recommendations for Pediatric Patients 2 Years of Age 
Using VIREAD Oral Powder
Body Weight
Oral Powder Once Daily
Kilogram (kg)
Pound (lbs)
Scoops of Powder
10 to <12
22 to <26
2.0
12 to <14
26 to <31
2.5
14 to <17
31 to <37
3.0
17 to <19
37 to <42
3.5
19 to <22
42 to <49
4.0
22 to <24
49 to <53
4.5
24 to <27
53 to <60
5.0
27 to <29
60 to <64
5.5
29 to <32
64 to <71
6.0
32 to <34
71 to <75
6.5
34 to <35
75 to <77
7.0
35a
77
7.5
Subjects 35 kg who are unable to swallow tablet may dose with oral powder at 7.5 level scoops once daily.
5.4.
Prior and Concomitant Medications
5.4.1.
Prior to Study Entry
Refer to Exclusion Criteria in Section 4.3. Subjects must not have received therapy with 
interferon within six months prior to screening for this study. Subjects must not have received 
therapy with anti-HBV nucleotide/nucleoside within 16 weeks prior to screening for this study.
5.4.2.
During the Study
Use of the following medications is prohibited while subjects are on study drug:

Antiviral agents with anti-HBV activity, including lamivudine, emtricitabine, entecavir, 
adefovir, telbivudine, clevudine, or others

Interferon-alfa and pegylated interferon-alfa

Nephrotoxic agents such as aminoglycoside antibiotics, cidofovir, cisplain, foscarnet, IV 
amphotericin B, IV pentamidine, ganciclovir, cyclosporine, tacrolimus, chronic daily 
non-steroidal anti-inflammatory drugs, or other agents with significant nephrotoxic potential

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
Hepatotoxic agents such as anabolic steroids, isoniazid, itraconazole, ketoconazole, 
lovastatin, rifabutin, rifampin, simvastatin, and other agents with significant hepatotoxic 
potential

Competitors of renal excretion, such as probenecid

Systemic chemotherapeutic agents

Interleukin-2 [IL-2]) and other immunomodulating agents

Systemic corticosteroids (pulmonary administration via MDI/nebulizer and oral steroids 
administered for less that 5 days are permitted)

Investigational agents, except with written approval of the Sponsor
Should subjects need to start treatment with any excluded concomitant medication, the Sponsor 
must be consulted prior to initiation of the new medication. In instances where an excluded 
medication is initiated prior to discussion with the Sponsor, the Investigator must notify the 
Sponsor as soon as s/he is aware of the use of the excluded medication.
All concomitant medications, including vitamin supplements, herbal remedies and hormonal 
contraception, must be recorded in the appropriate section of the Case Report Forms.
5.5.
Study Drug Accountability
The investigator or designee (e.g., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgement of receipt of 
each shipment of study drug (quantity and condition). All used and unused study drug dispensed 
to subjects must be returned to the site.
Investigational Drug Accountability records will be provided to each study site to:

Record the date received and quantity of study drug.

Record the date, subject number, subject initials, the study drug dispensed.

Record the date, quantity of used and unused study drug returned. Dispensing records will 
include the initials of the person dispensing the study drug or supplies.
5.6.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for drug 

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destruction, arrangements will be made between the site and Gilead Sciences (or 
Gilead Sciences’ representative) for return of unused study drug supplies. A copy of the site’s 
SOP will be obtained for central files. Where possible, study drug will be destroyed at the site. 
Upon study completion, a copy of the drug accountability records must be filed at the site. 
Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the investigator 
must maintain accurate records for all study drug destroyed. Records must show the 
identification and quantity of each unit destroyed, the method of destruction, and person who 
disposed of the drug. All study drug records must be maintained at the site and copies must be 
submitted to Gilead Sciences at the end of the study.

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6.
STUDY PROCEDURES
Study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and in the text that follows. Additional information on the study procedures 
will be provided in written materials by the Contract Research Organization (CRO).
Any deviation from protocol procedures should be noted in the Case Report Forms (CRFs) and 
the sponsor or Contract Research Organization (CRO) should be notified.
All protocol-specified laboratory tests on blood and urine samples must be performed at the 
selected central laboratory. Refer to the appropriate central laboratory instruction manuals for 
information on sample collection and shipment of all required study samples.
6.1.
Subject Enrollment and Treatment Assignment
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the 
conduct of any screening procedures. Each study candidate must sign an Assent Form, as 
required by IRB/IEC/local requirements. Screening evaluations will be used to determine the 
eligibility of each candidate for study enrollment. Candidates who fail to meet eligibility criteria 
by screening evaluations may be re-screened once 45 days after the initial screen if there is a 
reasonable expectation that the candidate will be eligible after repeat screening.
Retesting of exclusionary laboratory values during the Screening period is permitted only if, in 
the Principal Investigator’s opinion, there is reason to believe the retest value will be within 
accepted parameters; if the initial value was deemed to be inaccurate, inconsistent with the 
subject’s previous result(s); in error (e.g. mishandled sample); or due to an extenuating 
circumstance.
6.1.1.
Screening Visit
The following assessments and procedures will be performed and recorded on CRFs at the initial 
Screening Visit:

Written informed consent from parent or legal guardian and assent from subject, if/when
applicable (see above)

Medical history, including hepatitis B history, hepatitis B treatment history, and family 
history

Complete physical examination (excluding breast, anorectal, and urogenital exams), vital
signs (temperature, blood pressure, pulse, respiratory rate)

Body weight and height

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
Blood samples for the following will be collected. If all the blood samples cannot be 
collected in one screening visit, subject may come in at a different visit prior to Baseline to 
have the remainder of the blood samples collected.
Hematology (complete blood count [CBC] with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN),
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, total iron, uric 
acid, and amylase (reflex lipase testing if total amylase is 1.5 ULN)
Prothrombin time (PT), international normalized ratio (INR)
Alpha-1 antitrypsin and protease inhibitor (PI) typing
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative)
Plasma HBV DNA (PCR method)
HIV, HAV, HCV and HDV serology
Serum -HCG test (females of childbearing potential only)
α-fetoprotein (AFP)
Serum bone biochemical markers, including serum c-telopeptides, osteocalcin, 
bone-specific alkaline phosphatase, PTH, vitamin D levels (25-hydroxy), 
1,25 (dihydroxyvitamin) D levels, and fasting creatinine and fasting phosphate 

Urine samples for:
Urinalysis (protein, glucose, blood)
Urine bone biochemical markers, including urine bicarbonate, urine n-telopeptide, and 
spot urine creatinine and phosphate

Review of AEs and concomitant medications

Review of all inclusion and exclusion criteria

Dual energy x-ray absorptiometry (DEXA) scan of spine and whole body (DEXA scan may 
be performed between Screening and Baseline Visits, but must be performed no later than the 
Baseline Visit, and prior to receipt of study drugs).

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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days of the initial Screening Visit for entry into the study. All candidates who 
meet screening requirements will be randomized and enrolled into the study until the planned 
enrollment of 100 subjects has been met.
Randomization cannot occur until after the Baseline (pre-treatment) DEXA scan has been 
performed.
6.1.2.
Baseline Assessments
The Baseline Visit should occur within 45 days of the initial Screening Visit. Once eligibility has 
been confirmed, subjects will be assigned a subject number and treatment arm at the time of 
randomization. All baseline tests and procedures must be completed prior to the receipt of the 
first dose of study drugs. Subjects will be dispensed study medication at the Baseline Visit.
Study medication should be initiated on-site at the Baseline Visit.
The following assessments and procedures will be performed and recorded on CRFs at the 
Baseline Visit:

Review of medical history, hepatitis B history and hepatitis B treatment history and any 
changes since Screening Visit

Complete physical examination including Tanner Staging and vital signs

Body weight and height

Blood samples for:
Hematology (CBC with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
Prothrombin time (PT), international normalized ratio (INR)
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative)
Plasma HBV DNA (PCR method)
Serum bone biochemical markers, including serum c-telopeptides, osteocalcin, 
bone-specific alkaline phosphatase, PTH, vitamin D levels (25-hydroxy), 
1,25 (dihydroxyvitamin) D levels, and fasting creatinine and fasting phosphate

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Serum -HCG pregnancy test (females of childbearing potential only)
Serum for HBV viral genotyping (A–H) and resistance surveillance (sequence analysis of 
the HBV pol/RT for resistance mutations)
Plasma for determination of tenofovir concentration
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays,
including HBsAg and HBeAg quantification and compliance assessment)
For subjects for whom a separate consent is provided, an appropriate blood sample for 
biomarker (including pharmacogenomic) analysis will be collected at Baseline (or at the 
subsequent visits if necessary)

Urine samples for:
Urinalysis (protein, glucose, blood)
Urine bone biochemical markers, including urine bicarbonate, urine n-telopeptide, and 
spot urine creatinine and phosphate

DEXA scan of spine and whole body (DEXA scan may be performed between Screening and 
Baseline Visits, but must be performed no later than the Baseline Visit), and prior to receipt 
of study drugs.

Review of AEs and concomitant medications

Study drug dispensing (including multivitamin) and instructions on appropriate dosing and 
administration
6.2.
Treatment Assessments
6.2.1.
Week 4, 8, 16, 24, 32, 40 Assessments
The following evaluations will be performed at Weeks 4, 8, 16, 24, 32, and 40, unless otherwise 
specified. Study visits are to be completed 4 days of the protocol-specified visit date, based on 
the Baseline Visit. Week 48 assessments are outlined in the following section (Section 6.2.2).
The following assessments and procedures will be performed and recorded on CRFs:

Symptom-directed physical examination, including vital signs (complete physical 
examination including Tanner Staging at Week 24 only)

Body weight and height

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
Blood samples for:
Hematology (CBC with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative; 
Weeks 16 and 32 only)
Plasma HBV DNA (PCR method)
Plasma for determination of tenofovir concentration
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays, 
including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment)

Urine samples for:
Urinalysis (protein, glucose, blood)
At Week 24 only: urine biochemical markers (refer to Section 6.5. for details)
Urine pregnancy test (for females of childbearing potential only; positive urine pregnancy 
test will be immediately confirmed with a serum pregnancy test)

At Week 24 only: dual energy x-ray absorptiometry (DEXA) scan of spine and whole body 
(DEXA scan must be performed 10 days from visit)

Review of AEs and changes in concomitant medications

Retrieval of study medication and assessment of medication adherence

Study drug dispensing (including multivitamin) and instructions on appropriate dosing and 
administration

At Weeks 4 and 24 only: Provide all subjects with a Subject Dosing Diary Card to complete 
the diary daily for 10 days prior to the next visit

At Weeks 8 and 32 only: Collect the Subject Dosing Diary Card completed by the subject 
daily for 10 days prior to these visits

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Subjects who experience Grade 4 ALT while on blinded study medication will be evaluated 
weekly with serum chemistry and liver function test monitoring. In the event that any subject has 
sustained Grade 4 ALT for 16 weeks (i.e., failure to resolve ALT to grade 3 or baseline), the 
serial HBV DNA values on study will be provided to the investigator, and the subject can be 
offered open-label tenofovir DF, after discussion with the Gilead Medical Monitor.
6.2.2.
Week 48 Assessments – End of Blinded Randomized Treatment
Study Visit for Week 48 should be completed 4 days of the protocol-specified visit date, based 
on the Baseline Visit. The following assessments and procedures will be performed and recorded 
on CRFs:

Complete physical examination including Tanner Staging and vital signs

Body weight and height

Blood samples for:
Hematology (CBC with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
Serum bone biochemical markers, including serum c-telopeptides, osteocalcin, 
bone-specific alkaline phosphatase, PTH, vitamin D levels (25-hydroxy), 
1,25 (dihydroxyvitamin) D levels, and fasting creatinine and fasting phosphate
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative)
Plasma HBV DNA (PCR method)
Serum -HCG pregnancy test (females of childbearing potential only)
Serum for resistance surveillance
Plasma for determination of tenofovir concentration
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays, 
including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment)

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
Urine samples for:
Urinalysis (protein, glucose, blood)
Urine bone biochemical markers, including urine bicarbonate, urine n-telopeptide, and 
spot urine creatinine and phosphate

DEXA scan of spine and whole body (DEXA scans may be performed 10 days from the
Week 48 visit).

Review of AEs and concomitant medications

Retrieval of study medication and assessment of medication adherence

Study drug dispensing (including multivitamin) and instructions on appropriate dosing and 
administration
After 48 weeks of blinded randomized treatment, each subject will switch to open-label 
tenofovir DF treatment for an additional 144 weeks. Subjects under Protocol Amendment 3 who 
are beyond Week 48 of blinded randomized treatment will switch to open-label tenofovir DF at 
the Week 72 visit and will continue on open-label treatment until Week 192.
Subjects who discontinue the study prior to the Week 48 Visit will complete an Early Study 
Drug Discontinuation Visit as detailed in Section 6.3. Subsequent off-study therapy, if any, is at 
the discretion of the subject/physician and will not be provided by Gilead Sciences. Subjects who 
have received at least one dose of study drug and permanently discontinue study drug will be 
followed for 24 weeks off treatment or up to initiation of active treatment, whichever occurs 
first.
6.2.3.
Assessments for Weeks 56, 64, 72, 80, 88, 96, 108, 120, 132, 144, 156, 168, 180
After Week 48 through the end of the study treatment (each subject completes Week 192), 
subjects will return for visits at Weeks 56, 64, 72, 80, 88, 96, 108, 120, 132, 144, 156, 168, 
and 180. Each study visit will occur 6 days from the protocol-specified visit date, based on the 
Baseline Visit.
The following assessments and procedures will be performed during these visits and recorded on 
CRFs:

Symptom-directed physical examination, including vital signs (complete physical 
examination including Tanner Staging at Weeks 72, 96, 120, 144, 168)

Body weight and height

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
Blood samples for:
Hematology (CBC with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
At Weeks 96 and 144: Serum bone biochemical markers, including serum c-telopeptides, 
osteocalcin, bone-specific alkaline phosphatase, PTH, vitamin D levels (25-hydroxy), 
1,25 (dihydroxyvitamin) D levels, and fasting creatinine and fasting phosphate
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative) 
(Weeks 64, 72, 80, 96, and then every 12 weeks until the end of the study)
Plasma HBV DNA (PCR method)
Plasma for determination of tenofovir concentration
At Weeks 96 and 144: Serum for resistance surveillance
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays, 
including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment)

Urine samples for:
Urinalysis (protein, glucose, blood)
Urine pregnancy test (for females of childbearing potential only; positive urine pregnancy 
test will be immediately confirmed with a serum pregnancy test)
At Weeks 72, 96 and 144: Urine bone biochemical markers, including urine bicarbonate, 
urine n-telopeptide, and spot urine creatinine and phosphate

Weeks 72, 96 and 144 only: DEXA scan of spine and whole body (DEXA scan must be 
performed 10 days from scheduled study visit)

Review of AEs and concomitant medications

Retrieval of study medication and assessment of medication adherence

Study drug dispensing (including multivitamin) and instructions on appropriate dosing and 
administration

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
At Week 56 only: Provide all subjects with a Subject Dosing Diary Card to complete the 
diary for 10 days prior to the next visit.

At Week 64 only: Collect the Subject Dosing Diary Card completed by the subject daily for 
10 days prior to these visits.
6.2.4.
Week 192 Assessments/Early Discontinuation
Study Visit for Week 192 should be completed 6 days of the protocol-specified visit date, 
based on the Baseline Visit. The following assessments and procedures will be performed and 
recorded on CRFs:

Complete physical examination including Tanner Staging and vital signs

Body weight and height

Blood samples for:
Hematology (CBC with differential and platelet count)
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
Serum bone biochemical markers, including serum c-telopeptides, osteocalcin, 
bone-specific alkaline phosphatase, PTH, vitamin D levels (25-hydroxy), 
1,25 (dihydroxyvitamin) D levels, and fasting creatinine and fasting phosphate
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative)
Plasma HBV DNA (PCR method)
Serum -HCG pregnancy test (females of childbearing potential only)
Serum for resistance surveillance
Plasma for determination of tenofovir concentration
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays, 
including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment)

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
Urine samples for:
Urinalysis (protein, glucose, blood)
Urine bone biochemical markers, including urine bicarbonate, urine n-telopeptide, and 
spot urine creatinine and phosphate

DEXA scan of spine and whole body (DEXA scans may be performed 10 days from the 
Week 192 visit).

Review of AEs and concomitant medications

Retrieval of study medication and assessment of medication adherence
Subjects who discontinue the study prior to the Week 192 Visit will complete all Week 192
assessments and procedures at an Early Study Drug Discontinuation Visit, to be completed 
within 72 hours of last dose of study drug. Subsequent off-study therapy, if any, is at the 
discretion of the subject/physician and will not be provided by Gilead Sciences. Subjects who 
have received at least one dose of study drug and permanently discontinue study drug will be 
followed for 24 weeks off treatment or up to initiation of active treatment, whichever occurs 
first.
The study treatment will end after the each subject reaches Week 192. At Week 192, all active 
subjects will be offered tenofovir DF through a roll-over protocol until it becomes commercially 
available for the indication and age group studied in this protocol. If subject is off treatment 
following Week 192, the treatment-free follow-up period is required (Section 6.3.1).
6.3.
Post-Treatment/Treatment-Free Follow-up Assessments
6.3.1.
Follow-Up Assessments
For subjects with known bridging fibrosis or cirrhosis, study drug discontinuation with 
treatment-free follow-up is contraindicated due to the potential risk of exacerbation of 
hepatitis in the setting of low hepatic reserve which could lead to decompensation. Subjects 
with bridging fibrosis or cirrhosis should be placed on commercially available HBV 
therapy following study drug discontinuation.
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug will be followed for 24 weeks off treatment or up to initiation of active treatment, 
whichever occurs first. The treatment-free follow-up period could occur for early discontinuation 
subjects or at Week 192 study completion.

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For those subjects who remain off treatment, the following evaluations are to be completed every 
4 weeks through the Week 24 Follow-Up Visit (Follow-Up Weeks 4, 8, 12, 16, 20 and 24). 
Each follow up visit should be conducted within 3 days from the protocol-specified visit date, 
calculated from the date of last dose.

Symptom-directed physical examination, including vital signs

Body weight and height

Blood samples for:
Serum chemistry and liver function tests, including albumin, alkaline phosphatase, AST, 
ALT, total bilirubin (reflex to direct [conjugated] bilirubin if total bilirubin 1.5 ULN), 
bicarbonate, BUN, calcium, chloride, CPK, creatinine (and calculated creatinine 
clearance), glucose, LDH, magnesium, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing if total amylase is 1.5 ULN)
Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative) 
(Follow-Up Week 24 only)
Plasma HBV DNA (PCR method)
Serum and plasma for storage (for potential pharmacokinetic and/or virologic assays, 
including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment)
Prothrombin time (PT), international normalized ratio (INR) (reflex test in case of 
post-treatment exacerbation of hepatitis)

Review of AEs and concomitant medications
Subjects experiencing post-treatment exacerbation of hepatitis during the 24-week post-treatment 
period should be followed weekly until their ALT levels return to Grade 2 or baseline, as 
described in the Toxicity Management section of the protocol (Section 7.6.)
6.3.2.
Assessments for Premature Discontinuation from the Study (Early Study 
Drug Discontinuation Visit)
Subjects who permanently discontinue study drug prior to the end of the study will be asked to 
return to the clinic within 72 hours of stopping study drug for an Early Study Drug 
Discontinuation Visit. Subjects who discontinue the study prior to the Week 192 Visit will 
complete all Early Discontinuation assessments and procedures (see Section 6.3.1 above). DEXA 
scans (spine and whole body) and bone biochemical markers will not be required at the Early 
Discontinuation Visit if the last measurement was performed 12 weeks earlier. Subjects who 
have received at least one dose of study drug and permanently discontinue study drug will be 
followed with visits every 4 weeks for 24 weeks off treatment or up to initiation of active 
treatment, whichever occurs first. Subsequent off-study therapy, if any, is at the discretion of the 
subject/physician and will not be provided by Gilead Sciences.

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Subjects experiencing post-treatment exacerbation of hepatitis during the 24-week post-treatment
period should be followed weekly until their ALT levels return to Grade 2 or baseline, as 
described in the Toxicity Management section of the protocol (Section 7.6).
6.4.
Bone Mineral Density
Dual energy x-ray absorptiometry (DEXA) scans will be performed between the Screening and 
the Baseline Visits, at Weeks 24, 48, 72, 96, 144, 192, and the Early Study Drug Discontinuation 
Visit, if applicable, using pediatric software approved by the DEXA vendor selected by 
Gilead Sciences. Randomization may not occur until after the Baseline (pre-treatment) 
DEXA scan has been performed. Subsequent DEXA scans should be performed within 10 days
of the scheduled visit. In addition, a DEXA scan will be performed at the time of switch in 
subjects switching from placebo to tenofovir DF. DEXA scan will not be required at the Early 
Discontinuation Visit or at the time of switch if the last DEXA scan was performed 12 weeks 
earlier. Scans will be made of the spine and whole body to measure changes in bone mineral 
density and bone mineral content. All DEXA scan results (spine bone mineral density, whole 
body bone mineral density) will be provided to the study sites.
A complete description of the procedures to be performed for the DEXA scans will be provided 
by the DEXA vendor in a DEXA procedure manual.
6.5.
Bone Biochemical Markers
Laboratory samples will be taken at screening, baseline and at Weeks 24, 48, 72, 96, 144, 192,
and the Early Study Drug Discontinuation Visit, if applicable, for measuring bone biochemical 
markers. In addition, bone biochemical markers will be measured at the time of switch in 
subjects switching from placebo to tenofovir DF. Bone biochemical marker measurements will 
not be required at the Early Discontinuation Visit or at the time of switch if the last measurement 
was performed 12 weeks earlier.
Analyses will include measurements of urine bicarbonate and n-telopeptide; measurements of 
serum c-telopeptides, osteocalcin, bone-specific alkaline phosphatase, PTH, and vitamin D levels 
(25-hydroxy) and 1,25 (dihydroxyvitamin) D levels; and fasting serum creatinine/phosphate and 
urine creatinine (spot)/phosphate for measurement of the renal phosphate threshold (TmP/GFR).
The mean of the Screening and Baseline Visit values will constitute the study baseline value to 
which all subsequent values will be compared. Bone biochemical markers can be affected by the 
time of day (diurnal variation) and food. Therefore, subjects will be asked to report for each of 
these visits in the morning in a fasted state or, if fasting is not feasible, at the same time 
(2 hours from the Baseline Visit draw time) at each subsequent visit. All samples will be sent 
to a central laboratory in accordance with the laboratory procedure manual. Bone biochemical 
marker results will not be provided to the study sites.

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6.6.
Pharmacokinetic Assessment
Two intensive PK substudies will be performed on a subset of subjects in two separate cohorts; 
an oral powder and a tablet cohort. Each cohort will have an intensive PK substudy performed 
over one day between Week 2 and Week 12 to evaluate the PK of different tenofovir DF 
formulations in a pediatric population.
Powder Cohort
Subjects who are eligible to take the oral powder (either tenofovir DF or matching placebo) 
based on body weight and/or preference for this dosage form, and subjects who qualify for the 
tablet formulation but are willing to initiate treatment with the oral powder for purposes of 
accruing additional PK data, will be offered the opportunity to participate in the oral powder 
cohort. Up to 30 randomized subjects will be able to participate in the powder cohort. In order to 
participate in the oral powder cohort, the subject must be taking the oral powder for at least 
2 weeks prior to the intensive PK visit.
Tablet Cohort
Randomized subjects who are assigned to take tablet (either tenofovir DF or matching placebo) 
will be offered the opportunity to participate in the tablet cohort. A target of 12 subjects will be 
enrolled in the tablet cohort at each dosage level (150, 200, 250, 300 mg). Subjects may 
participate in both the powder and the tablet cohorts intensive PK substudies, with the second 
intensive PK substudy occurring after the Week 12, but prior to the end of the double-blind 
phase. For those subjects who opt to initiate treatment with oral powder and subsequently switch 
to tablets following completion of the powder intensive PK visit, or those subjects who are 
required to change dose strengths of the tablet based on the weight-based dosing requirement 
(see protocol Section 5.3) will also have the option to participate in a second tablet intensive PK 
visit. Subjects initially treated with tablets or subjects switching from oral powder to tablet, must 
be receiving tablets for at least two weeks prior to the tablet intensive PK visit.
Intensive and Sparse PK Sampling
Both cohorts (oral powder and tablets) will have the intense PK sampling occurring over a single 
day for a period of 8 hours. Specimens will be drawn at 0 hours (pre-dose), and at 1, 2, 4, and 
8 hours after study drug dosing (tenofovir DF or placebo).
Additionally, sparse PK sampling will be performed on all subjects at every study visit to 
monitor for adherence and potentially for other PK analyses (e.g. population pharmacokinetics).
At the time each blood sample is collected (both intensive and sparse sampling), the following 
information will be recorded:

The date and time of last dose taken

Whether last dose was taken with or without food

The date and time of blood draw 

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All specimens will be sent to an external lab for analysis. Details of the substudy procedures and 
specimen management will be described in the PK manual.
6.7.
Drug Administration and Fasting Criteria for the Pharmacokinectic (PK) 
Substudy
In order to allow for ease of PK sampling over an 8-hour period, subjects participating in the PK 
substudy should be taking their tenofovir DF dose in the AM on the day of the PK visit. 
Therefore, subjects who have been routinely dosing in the PM will need to switch to an AM 
dosing regimen at least 10 days prior to the intensive PK visit. The AM dose should be taken on 
each day with a meal (breakfast). In addition, subjects should fast overnight (a minimum of 
8 hours) prior to the scheduled intensive PK visit.
6.8.
Serum and Plasma for Storage
Additional blood (plasma and serum) samples will be collected at each visit starting at Baseline 
for long-term storage and possible future testing for potential pharmacokinetic and/or virologic 
assays (including resistance surveillance, HBsAg and HBeAg quantification and compliance 
assessment). No human genetic testing will be performed. At the conclusion of this study, these 
samples may be retained in storage for a period of up to 15 years.
6.9.
Subject Dosing Diary Card
As an added measure to assess adherence to treatment, all subjects will be provided with a 
Subject Dosing Diary Card at Weeks 4, 24, and 56. Subjects will complete the card daily for 
10 days prior to the next visit. Subjects will return their completed card at Week 8, 32 and 64. 
The Investigator or designee will review the diary card to monitor subject compliance with study 
drug regimen.
In addition to the above, all subjects participating in the intensive PK substudy will be required 
to complete the Subject Dosing Diary Card for at least 10 days prior to the intensive PK visit.
6.10.
Resistance Surveillance
The objectives of the resistance surveillance are: (1) to identify mutations in the HBV 
polymerase gene from HBV subject isolates that are potentially associated with virological 
resistance to tenofovir DF, (2) to determine the correlation of the effects of these mutations to the 
clinical response to tenofovir DF therapy, (3) to determine whether these mutations alter antiviral 
susceptibility to tenofovir DF using in vitro HBV replication assays, and (4) to evaluate the cross 
resistance profile of these mutations.
Sequence analysis of the HBV polymerase/reverse transcriptase for resistance mutations will be 
conducted at Baseline for all subjects, and attempted for all viremic subjects (HBV 
DNA 400 copies/mL [69 IU/mL]) at Weeks 48, 96, 144, and 192, as well as at the Early 
Discontinuation Visit, if applicable. Serum for storage will be collected at every visit for possible 
virologic analyses (see Section 6.8).

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6.11.
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

Subject or legal guardian requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study

Discontinuation of the study at the request of Gilead Sciences, regulatory agency or an 
IRB/IEC
If a subject discontinues study medication dosing, every attempt should be made to keep the 
subject in the study and continue to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
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 also include the following:

Pre-or post-treatment complications that occur as a result of protocol mandated procedures 
(e.g., invasive procedures such as venipuncture, biopsy) during or after screening (before the 
administration of study drug).

Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE.

Complications and terminations of pregnancy (see Section 7.7 for additional information)

Reports of adverse reactions in infants following exposure from breastfeeding
All AEs that occur after the subject consents to participate in the study and throughout the 
duration of the study, including the follow-up off-study medication period should be recorded as 
an AE.
An AE does not include the following:

Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure is an adverse event

Pre-existing diseases or 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 7.3.1, Special Situations Report).

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 
eCRF.

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
Uncomplicated pregnancy

An induced elective abortion to terminate a pregnancy without medical reason
7.2.
Assessment of Adverse Events
All AEs will be assessed by the investigator and recorded on the AE CRF page. The AE entry 
should indicate whether or not the AE was serious, the start date (AE onset), the stop date (date 
of AE resolution), whether or not the AE was related to study drug or to a study procedure, the 
action taken with study drug due to the AE, and the severity of the AE.
The relationship to study drug therapy should be assessed using clinical judgment and the 
following definitions:

No: Evidence exists that the adverse event has an etiology other than the study drug. 
For SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: A temporal relationship exists between the AE onset and administration of the study 
drug that cannot be readily explained by the subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be related, based on the known 
therapeutic and pharmacologic actions or adverse event profile of the study drug. In case of 
cessation or reduction of the dose, the AE abates or resolves and reappears upon rechallenge.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following definitions:

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-mandated procedures such as 
venipuncture, biopsy or diagnostic tests.
7.3.
Serious Adverse Events
A serious adverse event (SAE) is defined as follows:
Any adverse drug experience occurring at any dose that results in any of the following outcomes:

Death

Life-threatening situation. Life-threatening means that the subject was at immediate risk of 
death from the reaction as it occurred.

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
In-patient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other SAEs)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a subject who received study drug

Other: medically significant events that may not be immediately life-threatening or result in 
death or hospitalization, but based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above

Examples of such events are as follows:
Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias or convulsions that do not result in hospitalization
Development of drug dependency or drug abuse
For the purposes of this study, in addition to the above criteria, the following must be reported 
as SAE’s:

Serum ALT 2 baseline and 10 ULN, with or without associated symptoms.

Confirmed ALT elevation (defined as 1-grade shift or 2 previous value) associated with 
confirmed changes outside of the normal range in other laboratory parameters suggestive of 
worsening hepatic function (abnormal PT 2 seconds or INR 0.5 over baseline, abnormal 
serum albumin 1 g/dL below baseline or elevated serum lactate levels (if available), 
defined as 2 ULN per the Adult AIDS Clinical Trials Group (AACTG) guidelines).

Any clinical manifestations of hepatic decompensation (variceal bleeding, hepatic 
encephalopathy, or worsening of ascites requiring diuretics or paracentesis).
Clarification of Serious Adverse Events

Death is an outcome; therefore, not an AE in itself; the SAE is the condition(s) that leads to 
death.

The subject may not have been on study drug at the occurrence of the event. Dosing may 
have been given as treatment cycles or interrupted temporarily before the onset of the SAE, 
but may have contributed to the event.

“Life-threatening” refers to an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it was 
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
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE.

“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department.

The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.

A distinction should be drawn between seriousness and severity of AEs. An AE that is 
assessed as Grade 4 (potentially life-threatening) should not be confused with an SAE. 
Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs 
can be assessed as Grade 4. An event is defined as “serious” when it meets one of the 
predefined outcomes described above in Section 7.3.
7.3.1.
Special Situations Report
Defintions 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 and pregnancy 
reports.
A pregnancy report is used to report pregnancies occurring in subjects during the study whether 
or not exposure to the product occurred.
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.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
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).

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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.
Instructions for Reporting Special Situations: Pregnancies
The Investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the study, including the 
post-study drug follow-up period, to the CRO using the Pregnancy Report form within 24 hours 
of becoming aware of the pregnancy. 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.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the adverse event 
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
the Adverse and Serious Adverse Events section. Furthermore, any SAE occurring as an adverse 
pregnancy outcome post-study must be reported to the CRO.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported. Please refer to Section 7.4.1 All Serious Adverse 
Events and 7.4.3 Post-Study Reporting Requirements for contact information for reporting.
Instructions for Reporting Other Special Situations
Please refer to Section 7.4.1 All Serious Adverse Events and 7.4.3 Post-Study Reporting 
Requirements for contact information for reporting.
These reports must consist of situations that involve study investigational medicinal products 
(IMPs), but do not apply to concomitant medications (i.e., except for situations that result in 
adverse events, special situations involving concomitant medications will not be reported). 
Any inappropriate use of non-protocol approved medications should not be reported as “misuse” 
but may be more appropriately documented as a protocol deviation if applicable.
7.4.
Serious Adverse Event Reporting Requirements
7.4.1.
All Serious Adverse Events
Gilead is required to expedite to worldwide regulatory authorities reports of Serious Adverse 
Events, Serious Adverse Drug Reactions or Suspected Unexpected Serious Adverse Reactions 
(SUSARs) in line with relevant legislation, including the European Commission Clinical Trials 

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Directive (2001/20/EC); therefore, Gilead (or the CRO on the behalf of Gilead) must be notified 
immediately regarding the occurrence of any SAE or SADR that occurs after the subject 
consents to participate in the study, including SAEs/SADRs resulting from protocol-associated 
procedures as defined in relevant legislation including 2001/20/EC, performed from screening 
onwards. The procedures for reporting all SAEs, regardless of causal relationship, are as follows:

Record the SAE on the AE CRF and complete the “Serious Adverse Event Report” form. 

Fax or email the SAE form within 24 hours of the Investigator’s knowledge of the event. 
Contact information listed below.
For US (PPD):
Fax:
1-888-529-3580
For EU and Asia (PPD):
Fax:
+44 1223-374-102
For India (KlinEra): 
Email: Safetyreporting@klinera.com
Fax:
+91-22-25004588
Tel:
+91-22-25091470, if you have questions

For post-study reporting, SAE forms will be reported as outlined in Section 7.4.3 Post-Study 
Reporting Requirements.

For fatal or life-threatening events, also fax copies of hospital case reports, autopsy report, 
and other documents when requested and applicable. Transmission of such documents should 
occur with Personal Subject Details de-identified, without losing the traceability of a 
document to the Subject Identifiers.

Gilead Sciences may request additional information from the investigator to ensure the 
timely completion of accurate safety reports.
The investigator must take all therapeutic measures necessary for resolution of the SAE. 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF.
Follow-up of adverse events will continue through the last day on study (including the follow-up 
off-study medication period of the study) and/or until the investigator and/or Gilead Sciences 
determine that the subject’s condition is stable. Gilead Sciences may request that certain adverse 
events be followed until resolution.
7.4.2.
Investigator and Sponsor Reporting Requirements for SAEs
An event may qualify for expedited reporting to worldwide regulatory authorities if it is a 
Serious Adverse Event, Serious Adverse Drug Reaction or Suspected Unexpected Serious 
Adverse Reaction (SUSAR) in line with relevant legislation, including the European 
Commission Clinical Trials Directive (2001/20/EC). Expectedness of SAEs will be determined 
by Gilead using the reference safety information specified in the Investigator’s Brochure.

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All investigators will receive a safety letter notifying them of relevant SUSAR rep01is. 
The investigator should notify the IRB or IEC as soon as is practical, of serious events in writing 
where this is required by local regulat01y authorities, and in accordance with the local 
institutional policy. 
In accordance with the Emopean Commission Directive 2001/20/EC, Gilead Sciences or 
specified designee will notify worldwide regulat01y authorities and the relevant Ethics 
Committees in concemed Member States of applicable SUSARs as individual notifications or 
through a periodic line listing. 
7.4.3. 
Post-Study Reporting Requirements 
All AEs and SAEs including deaths, regardless of cause or relationship, must be rep01ied for 
subjects on study through the protocol-required post-u·eatment follow-up. 
Any SAEs and deaths that occm after the post-u·eatment follow-up visit but within 30 days of the 
last dose of investigational medicinal product, regardless of causality, should also be rep01ied. 
Investigators are not obligated to actively seek out SAEs beyond the follow-up period for 
subjects. However, if the investigator leam s of an AE or SAE occmTing after the 
completion/tennination visit and the event is deemed by the investigator to be relevant to the use 
of study <hugs, he/she should promptly document and rep01i the event to Gilead Sciences DSPH. 
For all SAE rep01iing, the SAE fonn should be completed and fax or email to the attention of 
Gilead Sciences DSPH within 24 homs of the Investigator's knowledge of the event. Contact 
infonnation is listed below. 
Gilead Sciences DSPH 
Representative: 
Gilead Sciences Medical 
Monitor/Study Director: 
Fax: 
Email: 
Name: 
Telephone: 
Fax: 
Mobile: 
E-mail: 
1-650-522-5477 
Safety_ FC@gilead.com 
John Flaherty, Phan nD 
PPD 
PPD 
PPD 
PPD 
I 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laborat01y abn01malities are usually not recorded as AEs or SAEs. However, laborat01y 
abn01malities (e.g. clinical chemistry, hematology, minalysis) independent of the underlying 
medical condition that require medical or smgical intervention or lead to study <hug intenuption 
or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laborat01y or other abnonnal assessments (e.g., elecu·ocardiogram, 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 and 7.3. If the laborat01y abnonnality 
is pmi of a syndrome, record the syn<h·ome or diagnosis (i.e, anemia), not the labotat01y results 
(i.e., decreased hemoglobin). 
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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.
7.6.
Toxicity Management
All clinical toxicities and/or abnormal laboratory findings should be investigated for etiology and 
graded according to the uniform guidelines detailed in Appendix 4. The Gilead Sciences Medical 
Monitor is available for consultation on all medical and toxicity-related issues.
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before study drug discontinuation, unless 
such a delay is not consistent with good medical practice.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities Appendix 4).
When restarting study drug following resolution of the adverse event, there should be discussion 
with the Medical Monitor prior to restarting drug; unlike therapy for adults, the protocol does not 
allow for dose modification in children.
Any recurrence of the study drug-related Grade 3 or 4 clinical or clinically significant laboratory 
adverse event following dose interruption mandates permanent discontinuation of study drug.
Any questions regarding toxicity management should be directed to the Gilead Sciences Medical 
Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event
For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.
For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by repeat 
testing, that is considered to be related to study drug, study drug should be withheld until the 
toxicity returns to Grade 2.
If a laboratory abnormality recurs to Grade 3 following rechallenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued and the 
subject managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to study drug may not require permanent discontinuation.

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7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to study drug, study drug should be permanently 
discontinued and the subject managed according to local practice. The subject should be 
followed as clinically indicated until the laboratory abnormality returns to baseline or is 
otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
algorithm for the new toxicity grade.
Study drug may be continued without dose interruption for a clinically non-significant Grade 4 
laboratory abnormality (e.g., Grade 4 CPK after strenuous exercise, or triglyceride elevation that 
is nonfasting or that can be medically managed) or a clinical event considered unrelated to study 
drug.
7.6.4.
Management of Elevated Serum Creatinine and Decreased Creatinine 
Clearance

Glomerular filtration rate (estimated creatinine clearance) will be calculated at each visit 
using the Schwartz Formula for subjects ages 2 to <12 as follows:
Schwartz Formula (mL/min/1.73 m2) = k L/Scr
[(k is proportionality constant: pediatric males/females 2 years to < 12 years k = 0.55; for 
adolescent females 12 years old, k = 0.55, and for adolescent males 12 years, k = 0.70); 
L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]

If creatinine clearance decreases to 50 mL/min/1.73 m2 (confirmed) at any time during the 
study, study drug should be permanently discontinued, followed by 24 weeks of monthly 
monitoring in treatment-free follow up if alternative HBV therapy is not initiated.

Subjects with estimated creatinine clearance 70 mL/min/1.73 m2 and serum creatinine 
increased 0.5 mg/dL above baseline should have the serum creatinine and creatinine 
clearance confirmed by repeating testing within three calendar days of receipt of results and 
before study drug discontinuation, unless such a delay is not consistent with good medical 
practice.

Subjects with confirmed estimated creatinine clearance 70 mL/min/1.73 m2 and serum 
creatinine increased 0.5 mg/dL above baseline should have study medication discontinued, 
and the subject should be followed weekly for two weeks. After two weeks, if the estimated 
creatinine clearance is 70 mL/min/1.73/m2, study medication may be resumed, with 
monitoring as described below. If the estimated estimated creatinine clearance remains 
70 mL/min/1.73 m2, study drug should be permanently discontinued, followed by 24 weeks 
of monthly monitoring in treatment-free follow up if alternative HBV therapy is not initiated.

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
The serum creatinine and estimated creatinine clearance should be rechecked within 
two weeks after restarting treatment to ensure that the subject has stabilized. Once this has 
been determined, the subject should be evaluated at regularly scheduled study visits.

If creatinine clearance decreases to 70 mL/min/1.73 m2 (confirmed) following rechallenge 
with study drug, study drug should be permanently discontinued, followed by 24 weeks of 
monthly monitoring in treatment-free follow up if alternative HBV therapy is not initiated.
7.6.5.
Special Considerations During Blinded Treatment – Grade 4 ALT 
Management
Subjects who experience Grade 4 ALT while on blinded study medication will be evaluated 
weekly with serum chemistry and liver function test monitoring. In the event that any subject has
sustained Grade 4 ALT for 16 weeks (i.e., failure to resolve ALT to grade 3 or baseline), the 
serial HBV DNA values on study will be provided to the investigator, and the subject can be 
offered open-label tenofovir DF, after discussion with the Gilead Medical Monitor.
7.6.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with 
treatment-free follow-up is contraindicated due to the potential risk of exacerbation of 
hepatitis in the setting of low hepatic reserve which could lead to decompensation. Subjects 
with bridging fibrosis or cirrhosis should be placed on commercially available HBV 
therapy following study drug discontinuation.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis are defined as:

Serum ALT 2 baseline and 10 ULN, with or without associated symptoms OR

Confirmed ALT elevation (defined as 1-grade shift or 2 previous value) associated with 
confirmed changes outside of the normal range in other laboratory parameters suggestive of 
worsening hepatic function (abnormal PT 2 seconds or INR 0.5 over baseline, abnormal 
serum albumin 1 g/dL below baseline or elevated serum lactate levels (if available), 
defined as 2 ULN per the Adult AIDS Clinical Trials Group (AACTG) guidelines).
7.6.6.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate (1) elevation of ALT 2 baseline and 10 ULN OR 
(2) abnormal laboratory parameters suggestive of worsening hepatic function (abnormal 
PT 2 sec above baseline, INR 0.5 above baseline, abnormal albumin 1 g/dL decrease from 
baseline or elevated serum lactate levels 2 ULN along with any ALT elevation (i.e., grade 
shift or 2 previous value), the following is recommended:

Schedule the subject to return to the clinic as soon as possible and ideally no later than 
one week after the initial labs were drawn. During the visit, perform a clinical assessment of 
the subject. The assessment should include a physical examination and evaluation of the 
subject’s mental status.

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
Draw blood samples, request lactate testing and send for confirmation of elevated serum 
transaminases (ALT/AST), total bilirubin and PT/INR, and albumin. [Note: If, in the 
investigator’s judgment, the central laboratory cannot provide adequate turn around time, the 
confirmation test may also be performed at a local laboratory. However, the central 
laboratory results are considered definitive].
If the elevations are confirmed, request the central clinical laboratory to conduct reflex testing 
for serum HBV DNA, HBV serology (HBeAg, HBeAb, and HBsAg), HDV, HAV IgM, and 
HCV serology.
Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal Bilirubin, Normal PT/INR, Normal Albumin, Normal 
Lactate
If ALT and/or AST levels are elevated (i.e., 2 baseline and 10 ULN) but total bilirubin 
and PT/INR, albumin and lactate are normal, the subject may remain on study medication and 
should be monitored every week until ALT/AST return to normal or baseline levels. 
During monitoring:

If ALT/AST levels decline within 4 weeks, the subject should remain on study and return to 
the clinic per protocol.

If after 4 weeks of monitoring, ALT/AST values remain elevated (e.g., 2 baseline 
and 10 ULN) or have worsened, with bilirubin 2.5 × ULN, PT 1.5 ULN, or 
abnormal albumin or lactate levels, the investigator should consult with the Gilead Medical 
Monitor.

If ALT remains 2 baseline and 10 ULN and the bilirubin or PT values are confirmed 
at 2.5 ULN or 1.5 ULN, respectively, the investigator should consider discontinuing 
study medication and initiating alternative HBV therapy (see below). However, prior to 
initiating alternative therapy, medical management of the subject should be discussed with 
the Gilead Medical Monitor. (Note: Once a subject has started alternative therapy, s/he must 
be discontinued from the study.)
Elevated Liver Enzymes, Elevated Bilirubin and PT/INR (Grade 2), Symptomatic 
Elevated Lactate (2 ULN) or Asymptomatic Elevated Lactate (4 ULN)
If ALT/AST values are elevated (i.e., 2 baseline and 10 ULN) and bilirubin or PT values 
are confirmed at 2.5 ULN or 1.5 ULN , respectively, or lactate levels are increased 
(symptomatic and 2 ULN or asymptomatic and 4 ULN) the investigator should consider 
discontinuing study medication and initiating alternative HBV treatment. The subject must be 
monitored weekly for as long as enzyme levels and bilirubin and PT/INR remain elevated or 
above baseline values. Refer to Appendix 6 for specific guidelines for the management of 
symptomatic and asymptomatic hyperlactatemia.

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
If the ALT/AST levels return to the baseline level and/or Grade 2 or lower during the first 
8 weeks of monitoring, study medication may be resumed.

If the ALT/AST levels, bilirubin, PT/INR or lactate levels remain elevated up through 
Week 8 or deteriorate at any point, the investigator should consult with the Gilead Medical 
Monitor.
7.6.6.2.
Management of Exacerbation of Hepatitis in Subjects Who Have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation 2 baseline and 10 ULN OR 
(2) abnormal laboratory parameters suggestive of worsening hepatic function (abnormal 
PT 2 secs above baseline, abnormal albumin 1 g/dL below baseline or elevated lactate 
levels 2 ULN) along with any ALT elevation (i.e., 1 grade shift or 2 previous value) and 
the subject is on no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible and ideally no later 
than 1 week after the initial labs were drawn. During the visit, perform a clinical assessment 
of the subject. The assessment should include a physical examination and evaluation of the 
subject’s mental status.

Draw blood samples and request lactate testing and confirmation of elevated serum 
transaminases (ALT/AST), bilirubin, PT/INR, and albumin. [Note: If, in the investigator’s 
judgment, the central lab cannot provide adequate turn around time, the confirmation test 
may also be performed at a local lab. However, the central lab results are considered 
definitive].

If the elevations are confirmed (e.g., ALT 2 baseline and > 10 ULN) OR (2) abnormal 
laboratory parameters suggestive of worsening hepatic function (abnormal PT 2 secs above 
baseline, abnormal albumin 1 g/dL below baseline, or elevated lactate levels 2 ULN) 
along with any ALT elevation (i.e., 1 grade shift or 2 previous value), request the clinical 
laboratory to conduct reflex testing for serum HBV DNA, HBV serology (HBeAg, HBeAb, 
and HBsAg), HDV, HAV IgM and HCV. If serum HBV DNA is increasing, the investigator 
should consider immediate initiation of approved therapy.

The subject should be followed until the abnormal ALT/AST values, PT/INR, albumin or 
lactate laboratory parameters return to normal or baseline up to a maximum of 6 months after 
the initial occurrence of the event. Refer to Appendix 6 for specific guidelines for the 
management of symptomatic and asymptomatic hyperlactatemia.
7.7.
Risks for Women of Childbearing Potential or During Pregnancy
The risks of treatment with tenofovir DF during pregnancy have not been evaluated in pregnant 
women. Animal studies do not indicate direct or indirect harmful effects of TDF with respect to 
pregnancy. Please refer to the latest version of the Investigator’s Brochure for additional 
information.

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7.7.1.
Definition of Childbearing Potential
For the purposes of this study, a female subject of childbearing potential is a pubertal female 
regardless of whether or not she has had a menses (premenarchal, Tanner Stage 3). This also 
includes a female subject who has not had any of the following conditions or procedures 
considered very rare in this age group: hysterectomy, bilateral oophorectomy, or medically 
documented ovarian failure.
7.7.2.
Contraceptive Requirements
Male study subjects and female study subjects of childbearing potential who are not 
heterosexually active should have periodic confirmation of continued abstinence from 
heterosexual intercourse and regular pregnancy testing while taking tenofovir DF. Female study 
subjects of childbearing potential who have been identified during the study as choosing to 
become sexually active should be counseled appropriately on the protocol-recommended 
method(s) for avoiding pregnancy in case the subject chooses to continue with heterosexual 
intercourse.
Male and female subjects of childbearing potential who engage in heterosexual intercourse must 
either agree to use protocol-recommended method(s) of contraception or agree to abstain from 
heterosexual intercourse from the Screening/Enrollment Visit throughout the study period and 
for 30 days following the last dose of tenofovir DF. The investigator should identify those 
subjects at risk for becoming sexually active and provide counsel appropriately on the 
protocol-recommended method(s) for avoiding pregnancy during the trial. These methods are 
recommended due to the low failure rate (i.e., less than 1% per year). See Table 7-1 for the 
protocol-recommended methods.
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and Baseline (Day 1) prior to receiving the first dose of study drug. Lactating females 
will not be enrolled in this study.
Table 7-1.
Protocol-Recommended Contraceptive Methods
Single Methods
Combination Methods
Intra-uterine devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Progesterone

Implant
Estrogen and Progesterone

Oral contraceptives plus barrier

Transdermal patch plus barrier

Vaginal ring plus barrier
Progesterone

Injection plus barrier
Barrier methods

Diaphragm

Cervical cap

Male condom

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Other contraceptive methods may be acceptable after discussion with the Medical Monitor.
7.7.3.
Procedures to be Followed in the Event of Pregnancy
The investigator must report all pregnancies to Gilead Sciences DSPH via the CRO within 
24 hours of becoming aware of the pregnancy. Any pregnancies that occur within 30 days of last 
investigational medicinal product dose should also be reported. The subject must be instructed to 
discontinue all investigational medicinal products and inform the investigator immediately if she 
becomes pregnant or suspects that she is pregnant during the study.
The investigator should counsel the subject regarding the possible effects of prior investigational 
medicinal product exposure on the fetus and the need to inform the study site of the outcome of 
the pregnancy.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
However, an induced therapeutic abortion to terminate any pregnancy due to complications or 
other medical reasons will be recorded as an AE or an SAE. The underlying medical reason for 
this procedure should be recorded as the adverse event term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
the Adverse and Serious Adverse Events section. Furthermore, any SAE occurring as an adverse 
pregnancy outcome post-study must be reported to Gilead Sciences DSPH or the CRO.
All pregnancies of female study subjects that occur during the study should be reported using the 
Pregnancy Report CRF page and the Gilead DSPH Pregnancy form and Pregnancy Outcome 
form. Monitoring of the subject should continue until the conclusion of the pregnancy. If the end 
of the pregnancy occurs after the study has been completed, the outcome should be reported 
directly to Gilead Sciences DSPH, fax number +1 650 522-5477 or email safety_fc@gilead.com.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives 
The primary objective of this study is:

To evaluate the antiviral efficacy of tenofovir DF versus placebo in pediatric patients 
(aged 2 to <12 years, at the time of enrollment) with chronic hepatitis B infection
The key secondary objective is:

To evaluate the proportion of subjects with HBeAg seroconversion at Week 48 (in subjects
with baseline HBeAg sero-positivity).
Secondary objectives are:

To characterize the safety and tolerability profile of tenofovir DF in pediatric patients 
(aged 2 to <12 years, at the time of enrollment) with chronic hepatitis B infection

To evaluate the biochemical and serological responses to tenofovir DF versus placebo

To evaluate the incidence of potential resistance mutations to tenofovir DF in the hepatitis B 
virus polymerase /reverse transcriptase (pol/RT)

To assess the pharmacokinetics of tenofovir in subjects receiving the tablet formulation and 
those receiving the oral powder formulation.
8.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with serum HBV DNA 
400 copies/mL (69 IU/mL) at Week 48. A missing = failure approach will be employed for 
handling missing data.
8.3.
Key Secondary Endpoint
The key secondary endpoint is the proportion of subjects with HBeAg seroconversion at 
Week 48 (in subjects with baseline HBeAg sero-positivity). A missing = failure approach will be 
employed for handling missing data.
8.4.
Secondary Endpoints
For Week 48, secondary endpoints to be evaluated in all subjects include:

proportion of subjects with normal ALT and normalization of ALT

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL and normal 
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
proportion of subjects with HBV DNA 169 copies/mL (29 IU/mL)

proportions of subjects with HBsAg loss and seroconversion

sequence changes from baseline within the HBV polymerase for subjects who were viremic 
(HBV DNA 400 copies/mL [69 IU/mL]) at Weeks 48, 96, 144, 192 or Early 
Discontinuation; including subjects with confirmed virologic breakthrough

cumulative incidence of at least a 4% decrease from baseline in bone mineral density of
lumbar spine

percent change from baseline in bone mineral density of lumbar spine
8.5.
Other Endpoints of Interest
For Week 48, secondary endpoints to be evaluated in HBeAg-positive subjects include:

proportions of subjects with HBeAg loss

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL (69 IU/mL), 
normal ALT and HBeAg loss

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL (69 IU/mL), 
normal ALT, and HBeAg seroconversion.
For Week 48, secondary endpoints to be evaluated in subjects with abnormal ALT at baseline 
include:

proportion of subjects with normalized ALT

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL (69 IU/mL) 
and normalized ALT
For Week 48, secondary endpoints to be evaluated in HBeAg-positive subjects with abnormal 
ALT at baseline include:

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL (69 IU/mL), 
normalized ALT and HBeAg loss

composite endpoint of proportion of subjects with HBV DNA 400 copies/mL (69 IU/mL), 
normalized ALT, and HBeAg seroconversion.
Secondary endpoints to be evaluated in PK substudy populations on tablet formulation and oral 
powder are the plasma pharmacokinetic parameters including CL/F,Cmax, Tmax, Clast, Tlast, Ctau, z,
T½, AUC0-last, AUCtau.

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For all categorical secondary endpoints, missing data will be handled using a missing = failure 
approach.
All endpoints at Week 48 will also be analyzed at Weeks 144 and 192.
8.6.
Methods of Analysis 
All summary tables for efficacy endpoints will present data by treatment group (TDF or Placebo)
and overall.
8.6.1.
Analysis Sets
8.6.1.1.
Efficacy
The primary analysis set for efficacy analyses will be defined as all randomized subjects who 
received at least one dose of study drug (referred to hereafter as the full analysis set [FAS]). 
Subjects who withdraw after randomization prior to receiving study drug will be excluded from 
the FAS. Subjects discontinuing randomized therapy prior to Week 48 will be handled using a 
missing = failure approach, as noted in Section 8.2 and 8.3, for the purpose of the primary and 
key secondary efficacy analyses. Subjects will be analyzed according to the randomized 
treatment assignment.
8.6.1.2.
Safety
The primary analysis set for safety analyses will include all randomized subjects who received at 
least one dose of study drug. All data collected during the course of the study (on treatment and 
during treatment-free follow up) will be included in the safety summaries. Subjects will be 
analyzed according to the treatment actually received.
8.6.1.3
Pharmacokinetics
The PK analysis set will include all subjects who have evaluable pharmacokinetic data.
8.6.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed.
For the primary endpoint and categorical secondary efficacy endpoints, missing data will be 
considered a failure, as noted in Section 8.2 and 8.3.
Sensitivity analyses will be performed if warranted.
8.6.3.
Multiplicity Adjustments
A sequential gatekeeping procedure will be employed. The key secondary endpoint will only be 
tested at a 0.05 level if the primary endpoint is statistically significant at a 0.05 level.

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8.6.4.
Interim Analysis
An external independent multidisciplinary Data Monitoring Committee (DMC) will review the 
progress and safety of this study approximately every 24 weeks after the first subject is 
randomized. During the open-label duration of the study, the DMC will convene approximately 
every 52 weeks. See Section 8.12 for discussion of Data Monitoring Committee interim analyses.
No efficacy analyses are planned prior to the primary efficacy analysis, which will be conducted 
at the end of double-blind treatment, after the last randomized subject reaches Week 48.
8.7.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group, and overall.
Demographic summaries will include gender, ethnic origin (with Asian-Chinese, Asian-Indian, 
Asian-Other all combined to Asian), racial minority, age, and geographical location of study site 
[North America/Europe, and Asia]).
Baseline data will include a summary of body weight, height, body mass index, log10 (HBV 
DNA) level, HBV serology, ALT/AST values, previous nucleoside and interferon exposure, 
genotype, bone mineral density (via DEXA scan), and serum bone biochemical markers.
8.8.
Efficacy Analysis
8.8.1.
Primary Analysis
The primary efficacy analysis will be conducted at the end of double-blind treatment, after the 
last randomized subject reaches Week 48. The analysis will evaluate the difference between 
treatment groups in the proportion of subjects achieving the primary endpoint, using a two-sided 
Fisher’s exact test.
8.8.2.
Key Secondary Analysis
The key secondary efficacy analysis will be conducted at the end of double-blind treatment, after 
the last randomized subject reaches Week 48. The analysis will evaluate the difference between 
treatment groups in the proportion of subjects achieving the key secondary efficacy endpoint, 
using a two-sided Fisher’s exact test.
8.8.3.
Secondary Analyses
Continuous secondary efficacy endpoints will be summarized using conventional descriptive 
statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum) by treatment 
group, and a Wilcoxon rank sum test may be used to compare treatment groups. Categorical 
secondary efficacy endpoints will be summarized by number and percentage of subjects that 
meet the endpoint, and a two-sided Fisher’s exact test may be used to compare treatment groups. 
For analyses of categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach.

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Subgroup analyses of efficacy endpoints may include analyses by geographical location of study 
site (North America/Europe, and Asia), and also by presence/absence of prior oral anti-HBV 
treatment.
Efficacy analyses of all subjects continuing on open-label tenofovir DF will also be performed 
after the last randomized subject reaches Weeks 144 and 192.
8.9.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed will be 
summarized by randomized treatment group. Data for the pretreatment and treatment-free 
follow-up periods will be included in listings.
The proportion of subjects in each treatment group with an AE leading to permanent 
discontinuation of study drug through Week 48 (also at Weeks 144 and 192) will be summarized.
8.9.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized by treatment group.
8.9.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High Level Group Term (HLGT), 
High Level Term (HLT), Preferred Term, and Lower Level Term (LLT) will be attached to the 
clinical database. Severity of adverse events will be graded using the grading scale defined in 
Appendix 4.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
HLT and Preferred Term) will be provided by treatment group as follows:

all treatment-emergent adverse events,

all related treatment-emergent adverse events,

combined Grade 2, 3, and 4 treatment-emergent adverse events,

combined Grade 3 and 4 treatment-emergent adverse events,

combined Grade 2, 3, and 4 related treatment-emergent adverse events,

combined Grade 3 and 4 related treatment-emergent adverse events,

all adverse events that caused permanent discontinuation from study drug,

all adverse events that caused change in dose or temporary interruption of study drug,

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
all serious adverse events, and

all serious related adverse events.
Events will be summarized based on the date of onset for the event.
Treatment-emergent AEs are defined as follows:

Any AE with onset date on or after the study drug start date and no later than the study drug 
stop date for those who discontinued study drug permanently, or

Any AE with onset date on or after the study drug start date for those who haven’t 
discontinued study drug permanently, or

Any AE leading to study drug discontinuation.
8.9.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized by the observed data and 
by the change from baseline across time.
Graded laboratory abnormalities will be defined using the grading scheme defined in 
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, will be summarized 
by treatment group. If baseline data are missing, then any graded abnormality (i.e., at least a 
Grade 1) will be considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the last dose of 
study drug will be included in a data listing.
8.9.4.
Analyses of Bone Mineral Density and Bone Biochemical Markers
Cumulative incidence of at least a 4% decrease from baseline in bone mineral density of lumbar 
spine will be summarized and compared between treatment groups using 95% confidence 
intervals for the difference in proportions.
The percent change from baseline in bone mineral density of lumbar spine will be summarized 
over time and compared between treatment groups using the Wilcoxon rank sum test.
Lumbar spine Z-scores (derived from BMD assessment obtained via DEXA scan) and lumbar 
spine changes in Z-scores from study baseline will be summarized (n, mean, standard deviation, 
median, Q1, Q3, minimum and maximum) by treatment group and study week.
BMD assessments for whole body (via DEXA scan) and serum bone biochemical markers will 
be summarized over time. Changes from study baseline in bone biochemical markers will be 
summarized by treatment group, where study baseline will be defined as the mean of the 
Screening and Baseline Visit values.

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Correlations between renal parameters and measurements of bone minerals density will be 
explored including exploration of the potential relationship between renal phosphate threshold 
(TmP/GFR) and measurements of bone mineral density.
8.10.
Pharmacokinetic Analysis
Pharmacokinetic parameters {CL/F, Cmax, Tmax, Clast, Tlast, Ctau, z, T½, AUC0-last and AUCtau} will 
be listed and summarized for tenofovir using descriptive statistics (e.g., sample size, arithmetic 
mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum). Plasma concentrations of the investigational medicinal product over time will be 
plotted in semilogarithmic and linear formats as mean standard deviation.
8.11.
Sample Size
With respect to the primary efficacy endpoint, a sample size of 100 subjects (67 in TDF and 
33 in placebo) would provide at least 85% power to detect a difference of 20% between the 
groups, based on a two-sided Fisher’s exact test with a significance level of 0.05, assuming a 
placebo response rate of 1%. A placebo response rate of 0% was observed in 
Study GS-US-174-0115 evaluating 54 adolescent patients aged 12- 17 years, treated with 
placebo and in Study GS-US-103-0158 evaluating 58 pediatric patients aged 2-17 years. For the 
purpose of this sample size calculation, we assume a placebo response rate of 1%.
8.12.
Data Monitoring Committee
An external independent multidisciplinary Data Monitoring Committee (DMC) will review the 
progress of the study and perform interim reviews of the safety data approximately every 
24 weeks after the first subject is randomized, in order to protect subject welfare and preserve 
study integrity. Specifically, the DMC will review bone mineral density data, in addition to other 
laboratory (particularly renal) safety data and adverse events. During the open-label duration of 
the study, the DMC will convene approximately every 52 weeks. At each meeting, the DMC will 
review routine safety and DEXA data and will make recommendations regarding modification of
study treatment.The DMC will also provide recommendations as needed regarding study design, 
modification and conduct.
While the Data Monitoring Committee is being asked to advise Gilead regarding future conduct 
of the study, including possible early study termination, Gilead retains final decision-making 
authority on all aspects of the study.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
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 or IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent/Assent
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. 

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The 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 local 
requirements. The consent form will inform subjects about pharmacogenomic testing and sample 
retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB [or] IEC, or laboratory. Laboratory 
specimens must be labeled in such as 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, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
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);

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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all 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 

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verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. 
If return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs [or] IECs, or to regulatory authority or health 
authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.

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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or]
IEC in accordance with local requirements and receive documented IRB [or] IECapproval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.

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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
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.
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.
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CONFIDENTIAL
Page 96
29 February 2016
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Clinical Laboratory Assessments
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Management of Clinical and Laboratory Adverse Events
Appendix 6.
Lactic Acidosis Guidelines

Tenofovir DisoproxiJ Fumarate 
Protocol GS-US-174-0144 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 USA 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment3 
A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, Safety, and Tolerability 
ofTenofovir Disoproxil Fumarate Versus Placebo in Pediatric Patients with Chronic 
Hepatitis B Infection 
GS-US-174-0144 Protocol Amendment 3, 29 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
_PPD 
Author 
~STIGATORSTATEMENT 
1 have read the protocol, including all appendices, and 1 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 reasonabie effort to complete the study within the time 
designated. 
J 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 97 
29 Febn1ary 2016 

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 98
29 February 2016
Appendix 2.
Study Procedures Table
Study Procedures
Screeninga
Baseline
Study Week
4
8
16
24
32
40
48
Written Informed Consent, Subject Assent
X
Medical History
X
Xe
Complete Physical Examination (including Tanner Staging 
starting at Baseline)
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
Vitals Signs, Height, Weightf
X
X
X
X
X
X
X
X
X
HIV-1, HAV, HCV, HDV, α-fetoprotein
X
HBV DNA Levels (PCR-Based Assay)
X
X
X
X
X
X
X
X
X
HBV Serologyg
X
X
X
X
X
HBV Genotyping, Resistance Surveillanceh
X
X
Hematology Profile
X
X
X
X
X
X
X
X
X
Serum Chemistry and Liver Testsi
X
X
X
X
X
X
X
X
X
Prothrombin Time/INRj
X
X
Alpha-1 antitrypsin and protease inhibitor (PI) typing
X
Urinalysis
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
Plasma for Tenofovir Concentration
X
X
X
X
X
X
X
X
Serum and Plasma for Storagel
X
X
X
X
X
X
X
X
DEXA Scan – Spine and Whole-Bodym
X
X
X
X
Bone Biochemical Markersn
X
X
X
X
Blood sample storage for genomic testingso
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 99
29 February 2016
Study Procedures
Screeninga
Baseline
Study Week
4
8
16
24
32
40
48
Subject Dosing Diary Card Dispensing
X
X
Subject Dosing Diary Card Return
X
X
Study Drug Dispensing/Returnp
X
X
X
X
X
X
X
X
Drug Accountability/Adherence Assessment
X
X
X
X
X
X
X

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 100
29 February 2016
Appendix 2.
Study Procedures Table (continued)
Study Procedures
Study Week
Early 
DCc
FUd
56
64
72
80
88
96b
108
120
132
144
156
168
180
192
Complete Physical Examination
(including Tanner Staging starting at 
Baseline)
X
X
X
X
X
X
X
Symptom-Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Vital Signs, Height, Weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV DNA Levels (PCR-Based Assay)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyg
X
X
X
X
X
X
X
X
X
X
X
X
X
Xq
Hematology Profile
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV Genotyping, Resistance 
Surveillanceh
X
X
X
X
Serum Chemistry and Liver Testsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prothrombin Time/INRj
Xj
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for Tenofovir Concentration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum and Plasma for Storagel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DEXA Scan – Spine and Whole-Bodym
X
X
X
X
Xr
Bone Biochemical Markersn
X
X
X
X
Xr
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Dosing Diary Card Dispensing
X

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 101
29 February 2016
Study Procedures
Study Week
Early 
DCc
FUd
56
64
72
80
88
96b
108
120
132
144
156
168
180
192
Subject Dosing Diary Card Return
X
Study Drug Dispensing/Returnp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Accountability/Adherence 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 45 days prior to Baseline Visit.
b
After Week 96, subjects will return for study visits every 12 weeks until each subject reaches Week 192.
c
The Early Study Drug Discontinuation Visit should be completed within 72 hours of last dose of study drug.
d
Subjects who receive at least one dose of study drug will complete Follow Up visits every 4 weeks post treatment discontinuation for 24 weeks or up to initiation of active 
treatment, whichever occurs first. The treatment-free follow-up period could occur for early discontinuation subjects or at Week 192 study completion.
e
Review of medical history and any changes since Screening Visit, including changes in concomitant medications.
f
Vital signs = temperature, blood pressure, pulse, respiratory rate.
g
HBeAg and HBsAg and, if negative, reflex HBeAb and HBsAb, respectively.
h
Determination of HBV viral genotype (A–H) will be performed at the Baseline Visit for all subjects. Resistance surveillance will be conducted at Baseline for all subjects, and 
attempted for all viremic subjects (HBV DNA 400 copies/mL [69 IU/mL]) at Weeks 48, 96, 144, and 192, as well as at the Early Discontinuation Visit, if applicable.
i
Including estimated creatinine clearance, by the Schwartz Formula (2 to <12 years old).
j
PT/INR will be performed at the Screening and Baseline Visits, then as a reflex test in subjects experiencing exacerbation of hepatitis thereafter.
k
For females of childbearing potential only; a serum β-HCG pregnancy test will be performed at Screening, Baseline, Weeks 48, 72, 192 and Early Study Drug Discontinuation 
Visit (if applicable). Urine pregnancy testing will be performed at all other study visits through the end of the study. A positive urine pregnancy test must be confirmed 
immediately with a serum pregnancy test.
l
Blood (serum and plasma) collected for long-term storage and possible future testing (e.g., pharmacokinetic and/or virologic analysis).
m
DEXA scan will be performed between the Screening and Baseline Visits, and must be performed prior to randomization and receipt of study drugs. All other DEXA scans 
must be performed within 10 days of the scheduled study visits. DEXA scan will be performed at the time of switch for subjects switching from placebo to tenofovir DF, 
unless the most recent DEXA scan was performed within 12 weeks earlier.
n
Specimens for bone biochemical markers must be collected in the morning in a fasted state, or, if fasting is not feasible, within two hours of the time of day that the Baseline 
Visit specimen was collected. For example, if the bone biochemical markers were drawn at 7:00 AM for the Baseline Visit, they must be drawn no earlier than 5:00 AM and no 
later than 9:00 AM for Week 24, 48, 72, 96, and subsequent specified visits. Bone biochemical markers will also be collected at the time of switch for subjects switching from 
placebo to tenofovir DF if not done within 12 weeks prior to switch. Bone biochemical markers will also be collected at the Screening Visit; the mean of the Screening and 
Baseline Visit values will constitute the study baseline, to which subsequent values will be compared.
o
For subjects in whom a separate consent is provided, an appropriate blood sample will be collected for biomarker (including pharmacogenomic) analysis that may be 
predictive of virologic response and/or the tolerability of HBV therapies. This sample may be obtained after the Baseline visit, if necessary.
p
Initiation of study drugs (including multivitamin) must occur within 24 hours after the Baseline Visit. At every study visit, subjects will return unused study medication, and 
new study medication will be dispensed.
q
During the 24-week follow-up period, HBV serology testing will only be performed at the Follow-Up Week 24 Visit.
r
DEXA scan is required at Early Discontinuation Visit if most recent DEXA scan was 12 weeks prior to the date of the Early Discontinuation Visit. Bone biochemical 
markers are required at Early Discontinuation Visit if most recent measurement was 12 weeks prior.

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 102
29 February 2016
Appendix 3.
Clinical Laboratory Assessments
Hematology:
Erythrocytes
Hemoglobin 
Hematocrit
Platelets
Total leukocytes and differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils)
Liver Tests:
Total bilirubin (reflex direct [conjugated]
bilirubin)
AST
ALT
Alkaline phosphatase
Prothrombin time, INR
Alpha-1 antitrypsin and protease inhibitor (PI) 
typing
Chemistry:
Creatine phosphokinase
Lactic dehydrogenase (LDH)
Creatinine and calculated creatinine clearance
Albumin
Glucose
Serum amylase
Lipase (if serum amylase is ≥1.5 ULN)
α-fetoprotein (Screening Visit)
Blood urea nitrogen (BUN)
Uric acid
Total iron (Screening Visit)
Urinalysis:
Urine Pregnancy 
Test:
Protein
Blood
Glucose
Post-menarchal females only (reflex serum β-
HCG if positive)
Electrolytes:
Sodium
Potassium
Bicarbonate
Phosphorus+
Calcium
Magnesium
Chloride
HBV Serology:
HBsAg, HBeAg (reflex HBsAb and HBeAb).

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
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Bone Biochemical 
Markers:

urine bicarbonate and n-telopeptide; 

serum c-telopeptides, osteocalcin, bone-specific 
alkaline phosphatase, PTH, and vitamin D levels 
(25-hydroxy) and 1,25 (dihydroxyvitamin) D levels;

fasting serum creatinine/phosphate and urine 
creatinine (spot)/phosphate for measurement of the 
renal phosphate threshold (TmP/GFR)
Virology:
Plasma and serum for HBV DNA and serology
HIV, HAV, HDV and HCV (Screening Visit)
Viral genotyping (A–H), resistance surveillance
Tenofovir DF 
Concentration:
Plasma concentration
Serum -HCG 
Pregnancy Test:
Post-menarchal females only;
at Screening, Baseline, Weeks 48, 72, 192, or Early Study 
Discontinuation Visits; reflex if urine test positive at all 
other study visits
Storage:
Plasma and serum for storage

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 104
29 February 2016
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
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

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 105
29 February 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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
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
100.0 to 125.0 GI/L
50,000 to 100,000/mm3
50.0 to 100.0 GI/L
25,000 to 50,000/mm3
25.0 to 50.0 GI/L
25,000/mm3
25.0 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.0 GI/L to 2.5 GI/L
1.5 to 2.0 GI/L
1.0 to 1.5 GI/L
1.0 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
—
—

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 107
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 mEq/L to LLN
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 mmol/L to LLN
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146 to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146 to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4 mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
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

Tenofovir Disoproxil Fumarate
Protocol GS-US-174-0144
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 108
29 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 mg/dL to LLN
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63 mmol/L to LLN
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 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 4.5 mg/dL
1.12 to 1.46 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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol /L
25.0 to 30.0 mg/dL
> 428 to 513 μmol /L
30.0 mg/dL
> 513 μmol /L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol /L
25.0 mg/dL
> 428 μmol /L
Blood Urea Nitrogen
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Hyperuricemia
ULN to 10.0 mg/dL
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
ULN to 597 μmol /L
597 to 716 μmol /L
716 to 895 μmol /L
895 μmol /L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol /L to LLN
57 to 87 μmol /L
27 to 57 μmol /L
27 μmol /L
Creatinine 
1.50 to 2.0 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol L
177 to 265 μmol /L
265 to 530 μmol /L
530 μmol /L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*Calcium should be corrected for albumin if albumin is < 4.0 g/dL
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
3.0 g/dL to LLN
2.0 to 3.0 g/dL
2.0 g/dL
NA
30 g/L to LLN
20 to 30 g/L
20 g/L

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

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

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

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RESPIRATION
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 Respiration
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 
Respiration failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiration 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%
Respiration failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)

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

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

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

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

Tenofovir Disoproxil Fumarate
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Gilead Sciences, Inc.
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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 
weakness 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 
Respiration muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions

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

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

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

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

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

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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with 
life-threatening hypotension 
OR Operative intervention 
indicated
Urinary Tract 
obstruction (e.g., 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 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Systemic antimicrobial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

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Appendix 5.
Management of Clinical and Laboratory Adverse Events
Grade 1
(Mild)
Grade 4
(Possibly Life-Threatening)
Grade 3
(Severe)
Grade 2
(Moderate)
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
If confirmed and possibly and/or probably 
related to study drugs:
1.
Withhold study drugs until Grade 2
2.
Restart all study drugs at full dose
If confirmed and unrelated to 
study drugs, dosing may 
continue at the discretion of the 
investigator
If confirmed and 
possibly or probably 
related to study drugs, 
discontinue study drugs 
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 confirmed and possibly or 
probably related to study drugs, discontinue all study drugs 
dosing permanently
If Grade 3 or 4 recurrence that is considered unrelated 
to study drugs, continue all study drugs at the same dose 
at the discretion of the investigator

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Appendix 6.
Lactic Acidosis Guidelines
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported 
with the use of nucleoside analogues alone or in combination with other antiretrovirals. 
A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may 
be risk factors; however, cases have also been reported in subjects with no known risk factors.
Guidelines for management of symptomatic hyperlactatemia and asymptomatic hyperlactatemia 
are outlined in Section A and B below and are derived from the AIDS Clinical Trials Group 
(ACTG) Lactic Acidosis Guidelines. Section C outlines venous lactate collection techniques.
Section A.
Symptomatic Hyperlactatemia
Symptomatic hyperlactatemia is defined as a clinical suspicion of hyperlactatemia characterized 
by new, otherwise unexplained and persistent (2 weeks) occurrence of 1 or more of the 
following symptoms:

Nausea and vomiting

Abdominal pain or gastric discomfort

Abdominal distention

Increased LFTs

Unexplained fatigue

Dyspnea
AND
Venous lactate level greater than twice the upper normal limit (ULN) confirmed by repeat 
venous lactate analysis within 1 week and, if persistently elevated, arterial lactate with blood gas 
analysis.
If the repeat venous lactate is elevated confirmation with an arterial lactate specimen and arterial 
blood gas (pH, PO2, PCO2, bicarbonate, oxygen saturation) should be performed within 48 hours. 
If the arterial specimen contains lactate at a level more than two times the upper limit of normal, 
the patient should be discontinued from the study and alternative therapy instituted. Subjects 
should be monitored weekly until signs and symptoms resolve. Hyperlactatemia should be 
followed until levels return to below two times the ULN.
An elevated anion gap in a patient with metabolic acidosis suggests the diagnosis of lactic 
acidosis. It can be suspected when the sum of cations minus the sum of 
anions [(Na+ + K+) (Cl- + HCO3
-)] exceeds 18 mEq/L (18 mmol/L) in the absence of other 
causes of increased anion gap such as renal failure, salicylate ingestion or other poisoning, or 
significant ketonemia (e.g., diabetic ketoacidosis, alcohol).

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Management of symptomatic subjects with lactate levels of 1 to 2 times the ULN is left to the 
discretion of the Investigator. As some of the symptoms are sufficiently vague (e.g., fatigue) to 
be present in everyone, serial repeat testing is encouraged with plans to modify the regimen if the 
lactate level rises to greater than two times the ULN as outlined above.
Section B.
Asymptomatic Hyperlactatemia
In ASYMPTOMATIC subjects, lactic acidosis will be defined as hyperlactatemia greater than 
four times the ULN. Any patient with a lactate level more than two times the ULN but less than 
or equal to four times the ULN, should be questioned closely for symptoms (described above) 
and have a repeat venous sample obtained in 1 week, and, if confirmed, subsequently at monthly 
intervals.
If the patient fulfills the definition for ASYMPTOMATIC hyperlactatemia, repeat venous lactate 
should be obtained within a week with confirmation of a more than 4-fold venous elevation in 
lactate by arterial lactate measurement and arterial blood gas (pH, PO2, PCO2, bicarbonate, 
oxygen saturation) within 48 hours. If confirmed, the patient should be discontinued from the 
study and alternative therapy instituted. Hyperlactatemia should be followed until levels return to 
below two times the ULN.
Section C.
Specimen Collection
Venous lactate levels are highly dependent on collection techniques. It is therefore recommended 
that the instructions below be followed closely. High lactate levels should be repeated for 
verification. If carefully collected, venous lactate level is equivalent to an arterial collection in 
most clinical situations. If it is not possible to collect the specimen without hand clenching or 
prolonged tourniquet time, an arterial lactate should be considered, as this will help exclude 
falsely elevated lactate levels.
1. Have subject sit, relaxed for 5 minutes prior to venipuncture.
2. Instruct subject to not clench the fist before or during the procedure and to relax the hand as 
much as possible.
3. If possible, do not use a tourniquet. If a tourniquet is necessary, then apply tourniquet lightly 
and draw lactate first before the other samples with the tourniquet still in place.
4. Collect the blood in a chilled gray-top (sodium fluoride-potassium oxalate) tube.
5. Place the specimen immediately on ice and send to the laboratory for immediate processing, 
preferably within 30 minutes of collection.
6. If random lactate is elevated, then repeat as above with the following additional patient 
instructions: no alcohol within 24 hours, no exercise within 8 hours, and no food or drink 
except water within 4 hours of the draw.