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



Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
Final 
Gilead Sciences, Inc.  
Amendment 2 
 
 
 
CONFIDENTIAL 
Page 2 
08 November 2012 
TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................................................................... 2 
LIST OF IN-TEXT TABLES ................................................................................................................................. 5 
LIST OF IN-TEXT FIGURES ............................................................................................................................... 5 
PROTOCOL SYNOPSIS ....................................................................................................................................... 5 
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 ................................................................. 21 
1.2.3. 
Clinical Trials of Tenofovir DF .................................................................................... 23 
1.3. 
Rationale for the Current Study and Dose Selection ....................................................................... 32 
1.3.1. 
Rationale for Dose Selection ......................................................................................... 33 
1.3.2. 
Rationale for Bone Mineral Density Evaluations .......................................................... 33 
2. 
OBJECTIVES .............................................................................................................................................. 35 
3. 
STUDY DESIGN ........................................................................................................................................ 36 
4. 
SUBJECT POPULATION ........................................................................................................................... 39 
4.1. 
Number of Subjects and Subject Selection ..................................................................................... 39 
4.2. 
Inclusion Criteria ............................................................................................................................ 39 
4.3. 
Exclusion Criteria ........................................................................................................................... 40 
5. 
STUDY DRUGS .......................................................................................................................................... 43 
5.1. 
Randomization, Blinding and Unblinding ...................................................................................... 43 
5.2. 
Description and Handling of Study Drugs – Tenofovir DF Tablet/Oral Powder and 
Matching Placebos .......................................................................................................................... 44 
5.2.1. 
Formulation ................................................................................................................... 44 
5.2.2. 
Packaging and Labeling ................................................................................................ 45 
5.2.3. 
Storage and Handling .................................................................................................... 46 
5.3. 
Dosage and Administration of Study Drugs ................................................................................... 46 
5.3.1. 
Dosing Recommendation – Tenofovir DF or Matching Placebo 
Tablet ............................................................................................................................ 47 
5.3.2. 
Dosing Recommendation - Oral Powder ....................................................................... 47 
5.4. 
Prior and Concomitant Medications ................................................................................................ 48 
5.4.1. 
Prior to Study Entry ...................................................................................................... 48 
5.4.2. 
During the Study ........................................................................................................... 49 
5.5. 
Study Drug Accountability ............................................................................................................. 49 
5.6. 
Study Drug Return or Disposal ....................................................................................................... 50 
6. 
STUDY PROCEDURES ............................................................................................................................. 51 
6.1. 
Subject Enrollment and Treatment Assignment .............................................................................. 51 
6.1.1. 
Screening Visit .............................................................................................................. 51 
6.1.2. 
Baseline Assessments .................................................................................................... 53 
6.2. 
Treatment Assessments ................................................................................................................... 54 
6.2.1. 
Week 4, 8, 16, 24, 32, 40, 56, 64 Assessments ............................................................. 54 
6.2.2. 
Week 48 Assessments ................................................................................................... 56 
6.2.3. 
Week 72 Assessments – End of Blinded Randomized Treatment ................................ 57 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
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Amendment 2 
 
 
 
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6.2.4. 
Assessments for Weeks 80, 88, 96, 108, 120, 132, 144, 156, 168, 180 ........................ 58 
6.2.5. 
Week 192 Assessments/Early Discontinuation ............................................................. 60 
6.3. 
Post-Treatment/Treatment-Free Follow-up Assessments ............................................................... 61 
6.3.1. 
Follow-Up Assessments ................................................................................................ 61 
6.3.2. 
Assessments for Premature Discontinuation from the Study (Early 
Study Drug Discontinuation Visit) ................................................................................ 63 
6.4. 
Bone Mineral Density ..................................................................................................................... 63 
6.5. 
Bone Biochemical Markers ............................................................................................................. 63 
6.6. 
Pharmacokinetic Assessment .......................................................................................................... 64 
6.7. 
Drug Administration and Fasting Criteria for the Pharmacokinectic (PK) Substudy ..................... 65 
6.8. 
Serum and Plasma for Storage ........................................................................................................ 65 
6.10 
 Resistance Surveillance .................................................................................................................. 66 
6. 11 
 Criteria for Discontinuation of Study Treatment ........................................................................... 66 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ........................................................................ 67 
7.1. 
Adverse Events ............................................................................................................................... 67 
7.2. 
Assessment of Adverse Events ....................................................................................................... 68 
7.3. 
Serious Adverse Events .................................................................................................................. 69 
7.3.1. 
Special Situations Report .............................................................................................. 70 
7.4. 
Serious Adverse Event Reporting Requirements ............................................................................ 72 
7.4.1. 
All Serious Adverse Events ........................................................................................... 72 
7.4.2. 
Investigator and Sponsor Reporting Requirements for SAEs ....................................... 73 
7.4.3. 
Post-Study Reporting Requirements ............................................................................. 73 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events .............................................................................................................. 74 
7.6. 
Toxicity Management ..................................................................................................................... 74 
7.6.1. 
Grades 1 and 2 Laboratory Abnormality or Clinical Event ........................................... 75 
7.6.2. 
Grade 3 Laboratory Abnormality or Clinical Event ...................................................... 75 
7.6.3. 
Grade 4 Laboratory Abnormality or Clinical Event ...................................................... 75 
7.6.4. 
Management of Elevated Serum Creatinine and Decreased Creatinine 
Clearance ....................................................................................................................... 76 
7.6.5. 
Special Considerations During Blinded Treatment – Grade 4 ALT 
Management .................................................................................................................. 77 
7.6.6. 
On-Treatment ALT Flare and Post-Treatment Exacerbation of 
Hepatitis Management .................................................................................................. 77 
7.7. 
Risks for Women of Childbearing Potential or During Pregnancy ................................................. 80 
7.7.1. 
Definition of Childbearing Potential ............................................................................. 80 
7.7.2. 
Contraceptive Requirements ......................................................................................... 80 
7.7.3. 
Procedures to be Followed in the Event of Pregnancy .................................................. 81 
8. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 82 
8.1. 
Analysis Objectives......................................................................................................................... 82 
8.2. 
Primary Endpoint ............................................................................................................................ 82 
8.3. 
Key Secondary Endpoint ................................................................................................................ 82 
8.4. 
Secondary Endpoints ....................................................................................................................... 82 
8.5. 
Other Endpoints of Interest ............................................................................................................. 83 
8.6. 
Methods of Analysis ....................................................................................................................... 84 
8.6.1. 
Analysis Sets ................................................................................................................. 84 
8.6.2. 
Data Handling Conventions .......................................................................................... 84 
8.6.3. 
Multiplicity Adjustments............................................................................................... 85 
8.6.4. 
Interim Analysis ............................................................................................................ 85 
8.7. 
Demographic Data and Baseline Characteristics ............................................................................ 85 
8.8. 
Efficacy Analysis ............................................................................................................................ 85 
8.8.1. 
Primary Analysis ........................................................................................................... 85 

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Amendment 2 
 
 
 
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8.8.2. 
Key Secondary Analysis ............................................................................................... 85 
8.8.3. 
Secondary Analyses ...................................................................................................... 86 
8.9. 
Safety Analysis ............................................................................................................................... 86 
8.9.1. 
Extent of Exposure ........................................................................................................ 86 
8.9.2. 
Adverse Events ............................................................................................................. 86 
8.9.3. 
Laboratory Evaluations ................................................................................................. 87 
8.9.4. 
Analyses of Bone Mineral Density and Bone Biochemical Markers ............................ 88 
8.10. 
Pharmacokinetic Analysis ............................................................................................................... 88 
8.11. 
Sample Size ..................................................................................................................................... 88 
8.12. 
Data Monitoring Committee ........................................................................................................... 89 
9. 
RESPONSIBILITIES .................................................................................................................................. 90 
9.1. 
Investigator Responsibilities ........................................................................................................... 90 
9.1.1. 
Good Clinical Practice .................................................................................................. 90 
9.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................... 90 
9.1.3. 
Informed Consent/Assent .............................................................................................. 91 
9.1.4. 
Confidentiality .............................................................................................................. 91 
9.1.5. 
Study Files and Retention of Records ........................................................................... 91 
9.1.6. 
Case Report Forms ........................................................................................................ 93 
9.1.7. 
Drug Accountability ...................................................................................................... 93 
9.1.8. 
Inspections .................................................................................................................... 93 
9.1.9. 
Protocol Compliance ..................................................................................................... 94 
9.2. 
Sponsor Responsibilities ................................................................................................................. 94 
9.2.1. 
Protocol Modifications .................................................................................................. 94 
9.2.2. 
Study Report and Publications ...................................................................................... 94 
9.3. 
Joint Investigator/Sponsor Responsibilities .................................................................................... 95 
9.3.1. 
Access to Information for Monitoring ........................................................................... 95 
9.3.2. 
Access to Information for Auditing or Inspections ....................................................... 95 
9.3.3. 
Study Discontinuation ................................................................................................... 95 
10. REFERENCES ............................................................................................................................................ 96 
11. APPENDICES ........................................................................................................................................... 101 
 
Appendix 1. 
Investigator Signature Page ......................................................................................... 102 
Appendix 2. 
Study Procedures Table ............................................................................................... 103 
Appendix 3. 
Clinical Laboratory Assessments ................................................................................ 108 
Appendix 4. 
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities ........................................................................................... 110 
Appendix 5. 
Management of Clinical and Laboratory Adverse Events ........................................... 130 
Appendix 6. 
Lactic Acidosis Guidelines .......................................................................................... 131 
 
 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
Final 
Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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08 November 2012 
LIST OF IN-TEXT TABLES 
Table 5-1. 
Dosing Recommendations for Pediatric Patients ≥2 Years of Age 
and Weighing ≥17 kg Using VIREAD Tablets ............................................................. 47 
Table 5-2. 
Dosing Recommendations for Pediatric Patients ≥2 Years of Age 
Using VIREAD Oral Powder ........................................................................................ 48 
Table 7-1. 
Protocol-Recommended Contraceptive Methods .......................................................... 81 
 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1. 
Study Schema ................................................................................................................ 38 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
Final 
Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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08 November 2012 
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 72 (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. 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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 
72 weeks 
• Treatment B (n = 33): matching placebo PO once daily for 
72 weeks 
After 72 weeks of blinded randomized treatment, each subject will 
switch to open-label tenofovir DF treatment for an additional 
120 weeks. 
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. 
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 values 

Tenofovir Disoproxil Fumarate 
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Final 
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Amendment 2 
 
 
 
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Study Design: (cont.) 
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 (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 72. Subsequently, ongoing 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 
72 weeks (1.5 years), followed by an additional 120 weeks 
(2.5 years) of open-label tenofovir DF therapy. The duration for a 
given subject is at least 4 years (each subject will receive a total of 
192 weeks of study drug treatment). 

Tenofovir Disoproxil Fumarate 
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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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., Į-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). 

Tenofovir Disoproxil Fumarate 
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Amendment 2 
 
 
 
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Determination of HBV viral genotype (A-H) will be performed at 
baseline for all subjects.  
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) at Weeks 72, 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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Amendment 2 
 
 
 
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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 Week 72. 
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 72. 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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Amendment 2 
 
 
 
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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 72 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, λz, T½, AUC0-last, AUCtau. 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents. 

Tenofovir Disoproxil Fumarate 
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Amendment 2 
 
 
 
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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 
β-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 
FDA 
(U.S.) Food and Drug Administration 
FTC 
emtricitabine, Emtriva™ 

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Amendment 2 
 
 
 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
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 early antibody 
HBeAg 
hepatitis B early 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 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
m2 
square meter(s) 
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 
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 {10952}. Globally, approximately 1 million people die annually of 
complications of chronic hepatitis B ,{10952}. In the United States, an 
estimated 5,000 people die each year of complications of HBV infection {3092}. 
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 {10690}. 
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 {3273}, {10665}. 
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 {10952}. 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 
{2820}. Patients with chronic viral replication are at increased risk of complications and poor 
outcomes {10684}. 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 {17786}. 
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 {3689}, {10644}. 
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 {17786}. 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 {3689},{10678}. 
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) {3653}, with maintained HBeAg seroconversion {10644}. 
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 {10644}. 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 {3653},{10954}. 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 {14352}, {4093}, {7980}. 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) {12336}. 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 {10665}. 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 {11363}, {11362}. 

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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 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). 
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 
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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®{16282}. 
1.2.2. 
Pre-Clinical Pharmacology and Toxicology 
1.2.2.1. 
Mechanism of Action 
Tenofovir disoproxil fumarate (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 {1574}. Tenofovir is efficiently anabolized to TFV-DP in human hepatic 
cells, and has a half-life of 95 hours in primary human hepatocytes {9266}. TFV-DP inhibits 
recombinant HBV polymerase with a Ki of 0.18 μM {9266}. TFV-DP inhibits viral 
polymerases by direct binding competition with the natural deoxyribonucleotide substrate 
(deoxyadenosine triphosphate - dATP) and, after incorporation into DNA, by DNA chain 
termination {1131}. TFV-DP is a very weak inhibitor of mammalian DNA polymerases Į, ȕ, 
and mitochondrial DNA polymerase Ȗ {2516}, {1131}. 
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 μM, 
with CC50 (50% cytotoxicity concentration) values > 100 μM. 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 μM {10}. 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 {9266}. 
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. 

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Using HBV-expressing cell lines (Report Nos. PC-174-2006, PC-164-2004) {6870}, 
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) {6870}. 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) {8176} 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 {8176}. 
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). 
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 {8380}. 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) {9266}. 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 {6868}. In cell-based assays, HBV laboratory strains {6868}, 
{8381}, {8016}, {9266}, as well as those identified in clinical isolates {10916}, {10426}, 

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{7060} 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 {10926}, {9266}, {8016}, 
{7788}. 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 {10926}. 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) {8683}, {10466}, {10804}. 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), {10946}, 
{10916}. 
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 {10425}, {10916}. 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 {8016}. 
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 
 
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 

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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 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) 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%) {13280}. 
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 were eligible to receive emtricitabine plus 
TDF combination therapy. The following describes year-4 (Week 192) data from this 
ongoing trial {16441}, {16437}. 
In Study 102, 315 HBeAg- subjects completed W192 (84% retention). In an ITT analysis 
(ITT), 86% of subjects had HBV DNA <400 copies/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 at W192. Four subjects (3 on TDF 
monotherapy) had HBV DNA 400 copies/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 {6909}, {7346}, and {6852}. 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, 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 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 

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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 ADVíTDF group 
was HBsAgí 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 (74% TDF-TDF; 84% ADV-TDF). In an 
on-treatment analysis 96% (TDF-TDF) and 99% (ADV-TDF) had HBV DNA 
<400 copies/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 at W192. Overall 7 subjects (2 on TDF monotherapy and 5 on FTC/TDF) 
had HBV DNA 400 copies/mL at W192 or after discontinuing between W144 and W192. 
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. 34 subjects added FTC to TDF W192, 83% achieved HBV DNA 
<400 copies/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. 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 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 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. 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 

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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. 
1.2.3.1.2. 
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 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 {16432}. 
1.2.3.1.3. 
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 Jan2008. 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 Hepatology (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. 

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1.2.3.1.4. 
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 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). 
1.2.3.1.5. 
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. 
1.2.3.1.6. 
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 by Week 48 and improved FibroTest fibrosis scores. 

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1.2.3.1.7. 
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. 
1.2.3.1.8. 
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 
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 
1.2.3.1.9. 
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 

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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 {8548}, {9505}. 
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. 
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 

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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 {11526}. 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 {11445}. 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 {10417}. 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. 
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. 

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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. 
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. 

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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 
72 weeks as an appropriate comparator. After 72 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. 
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. 

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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 μM) is similar to the Ki against HBV polymerase (0.18 μM); (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 tenofovir DF experienced decreases in bone mineral density (BMD) {8548}, 
{9505}. 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 

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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 and 72 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 (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 72 (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 72 weeks 
• Treatment B (n = 33): matching placebo PO once daily for 72 weeks 
After 72 weeks of blinded randomized treatment, each subject will switch to open-label 
tenofovir DF treatment for additional 120 weeks (see study schema at end of Section 3. 
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 72. 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. 
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 

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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., α-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) at Weeks 72, 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 
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 

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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 β-HCG pregnancy test (for females of childbearing potential only) 

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• 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; highly effective methods normally 
utilize two separate forms of contraception, one of which must be an effective barrier 
contraceptive method. 
• 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 an 
effective method of contraception during the study. (see Section 7.7. 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 
• α-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) 

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• 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 
• 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) 

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⎯ 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 72 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 72 (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 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 

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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. 
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 
treatement discontinued.  All subjects will be followed until study completion unless consent 
to do so is specifically withdrawn by the subject. 
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 continuing or initiating study 
treatment. 
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, 
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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.  
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 

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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. 
During Weeks 1–96, subjects will be provided with sufficient supplies for 4 to 8 weeks of 
dosing. Thereafter, subjects will be provided with sufficient supplies for 12 weeks of dosing.  
All labels for study drug bottles to be distributed to centers in the US, EU and the rest of the 
regions will meet all applicable requirements of the US Food and Drug Administration 
(FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of investigational 
medicinal products (July 2003) and/or other local regulations as applicable. 
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). 
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). 
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 72 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 
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Treatment B: 
• for subjects  17 kg – matching blinded placebo oral tablet once daily for 72 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 72 weeks. 
After 72 weeks of blinded randomized treatment, each subject will switch to open-label 
tenofovir DF treatment for an additional 120 weeks. 
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: 

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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.   
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. 

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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 
• 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: 

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• 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 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. 
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 
applicable (see above) 
• Medical history, including hepatitis B history, hepatitis B treatement 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 β-HCG test (females of childbearing potential only) 
⎯ Į-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 β-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, 56, 64 Assessments 
The following evaluations will be performed at Weeks 4, 8, 16, 24, 32, 40, 56 and 64, 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) 
⎯ At Week 24 only: bone biochemical markers (refer to Section 6.5. for details) 
⎯ Hepatitis B serology (HBeAg and HBsAg; reflex HBeAb and HBsAb if Ag negative; 
Weeks 16, 32 and 64 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 (Week 24 only; DEXA scan must be performed ± 10 days from Week 24 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, 24, and 56 only: Provide all subjects with a Subject Dosing Diary Card to 
complete the diary for 10 days prior to the next visit. 

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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 
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 β-HCG pregnancy test (females of childbearing potential only) 
⎯ 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 
6.2.3. 
Week 72 Assessments – End of Blinded Randomized Treatment 
Study Visit for Week 72 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 β-HCG pregnancy test (females of childbearing potential only) 

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⎯ 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) 
• 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 72 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 72 weeks of blinded randomized treatment, each subject will switch to open-label 
tenofovir DF treatment for 2.5 additional years. An external independent multidisciplinary 
Data Monitoring Committee will review the progress and safety of this study 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 continuing or initiating 
study treatment. 
Subjects who discontinue the study prior to the Week 72 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. 
6.2.4. 
Assessments for Weeks 80, 88, 96, 108, 120, 132, 144, 156, 168, 180 
After Week 72 through the end of the study (each subject completes Week 192), subjects will 
return for visits at Weeks 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. 

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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 96, 120, 144, 168) 
• 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) 
⎯ 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 80, 96, and then every 12 weeks until the end of the study) 
⎯ Plasma HBV DNA (PCR method) 
⎯ Plasma for determination of tenofovir concentration 
⎯ Resistance surveillance (Week 144 only) 
⎯ 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 96 and 144: Urine bone biochemical markers, including urine bicarbonate, 
urine n-telopeptide, and spot urine creatinine and phosphate 

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• Weeks 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 
6.2.5. 
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 β-HCG pregnancy test (females of childbearing potential only) 
⎯ Resistance surveillance 
⎯ Plasma for determination of tenofovir concentration 

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⎯ 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 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.) 

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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 6.2.5 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. 
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. 

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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. 
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 Week 72.  
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. 

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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  
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 and will return the completed card at the 
next visit for 10 days prior to the next visit.  The Investigator or designee will review the 
diary card to monitor subject compliance with study drug regimen. 

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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. 
Genotypic sequence analysis of the HBV polymerase for resistance mutations will be 
conducted at Baseline for all subjects, and attempted for all viremic subjects (HBV 
DNA ≥ 400 copies/mL) at Weeks 72, 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). 
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 investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and 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. 

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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. 
• 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). 

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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 more severe. 
• 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 pregnancy reports, reports of medication error, abuse, 
misuse, or overdose, and reports of product complaints associated with adverse events.  
A pregnancy report is used to report pregnancies occurring in subjects or their partners 
during the study whether or not maternal or paternal exposure to the product occurred. 
Medication error is any preventable event that can cause or lead to inappropriate medication 
use or patient harm while the medication is in the control of a healthcare professional or 
patient. 
Abuse is defined as persistent, sporadic or intentional excessive use of a medicinal product 
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Misuse is defined as any use of a medicinal product in a way that the product is intentionally 
and inappropriately used not in accordance with the protocol instructions or the local 
prescribing information. 
Product complaint is defined as any written or verbal report arising from potential deviations 
in the manufacture, packaging or distribution of the product. Product complaints associated 
with adverse events should be reported on the Special Situation Report Form. 
An overdose is defined as a dose taken (accidentally or intentionally) exceeding the dose as 
prescribed by the protocol or the maximal recommended daily dose as stated in the Product 
Labeling (as it applies to the daily dose for the subject/patient 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 or subject’s parent(s)/legal guardian(s) 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). 
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 

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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 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): 
 +44 1223-374-102 
For India (KlinEra):  
Email: Safetyreporting@klinera.com 
Fax: 
+91-22-25004588 
Tel: 
+91-22-25004573 or +91-22-25004574, if you have 
 
questions 
 
• For post-study reporting, SAE forms will be reported as outlined in Section 7.4.3 
Post-Study Reporting Requirements. 

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• 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. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC as soon as is practical, of serious events in writing 
where this is required by local regulatory authorities, and in accordance with the local 
institutional policy. 
In accordance with the European Commission Directive 2001/20/EC, Gilead Sciences or 
specified designee will notify worldwide regulatory authorities and the relevant Ethics 
Committees in concerned 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 reported for 
subjects on study through the protocol-required post-treatment follow-up. 
Any SAEs and deaths that occur after the post-treatment follow-up visit but within 30 days of 
the last dose of investigational medicinal product, regardless of causality, should also be 
reported. 

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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. 
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. 

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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. 
• 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. 

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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 

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PT/INR remain elevated or above baseline values. Refer to Appendix 6 for specific 
guidelines for the management of symptomatic and asymptomatic hyperlactatemia. 
• 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. 

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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. 
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. 

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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 
Two Barrier Methods 
• 
Female barrier plus condom  
 
 
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 72 (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 at Week 72. 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 72 (in subjects with baseline HBeAg sero-positivity).  A missing = failure approach 
will be employed for handling missing data. 
8.4. 
Secondary Endpoints 
For Week 72, secondary endpoints to be evaluated in all subjects include: 
• proportion of subjects with normal ALT and normalization of ALT 

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• composite endpoint of proportion of subjects with HBV DNA < 400 copies/mL and 
normal ALT 
• proportion of subjects with HBV DNA < 169 copies/mL 
• proportions of subjects with HBsAg loss and seroconversion 
• genotypic changes from baseline within the HBV polymerase for subjects who were 
viremic (HBV DNA ≥ 400 copies/mL) at Weeks 72, 144, 192 or Early Discontinuation; 
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 72, 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, normal 
ALT and HBeAg loss 
• composite endpoint of proportion of subjects with HBV DNA < 400 copies/mL, normal 
ALT, and HBeAg seroconversion. 
For Week 72, 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 and 
normalized ALT 
For Week 72, 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, 
normalized ALT and HBeAg loss  
• composite endpoint of proportion of subjects with HBV DNA < 400 copies/mL, 
normalized ALT, and HBeAg seroconversion. 

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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, λz, T½, AUC0-last, AUCtau. 
For all categorical secondary endpoints, missing data will be handled using a 
missing = failure approach. 
All endpoints at Week 72 will also be analyzed at Weeks 144 and 192. 
8.6. 
Methods of Analysis  
All summary tables for efficacy endpoints will present data by randomization stratification 
groups (age [2 to < 6 or 6 to < 12] geographical location [North America/Europe and Asia]), 
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 72 will be handled 
using a missing = failure approach, as noted in Section 8.2, 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 
handled using a missing = failure approach, as noted in Section 8.2. 
Sensitivity analyses will be performed if warranted. 

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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. 
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 72. 
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 72. 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.  Missing data will be handled using a missing = failure 
approach. 
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 72. The analysis will evaluate the difference 
between treatment groups in the proportion of subjects achieving the key secondary efficacy 

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endpoint, using a two-sided Fisher’s exact test.  Missing data will be handled using a 
missing = failure approach. 
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. 
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 72 (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: 

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• 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 permanent discontinuation from study, 
• all adverse events that caused change in dose or temporary interruption of study drug, 
• all serious adverse events, and 
• all serious related adverse events. 
Events will be summarized based on the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of 
first dose of study drug. Events that occur prior to the first dose of study drug or after the 
last dose of study drug will be included in data listings. 
A Fisher’s exact test comparing treatment groups may be conducted for each HLT or 
preferred term that occurs with at least 5% incidence in either treatment group. 
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. 

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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.  
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, λz, 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%. 

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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. For studies conducted under a United States 
Investigational New Drug Application (IND), the investigator will ensure that 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, are adhered to. 
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, 
is adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all sub-investigators must 
provide documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the drug being studied. This documentation must be provided before participation 
of the investigator and any subinvestigator. The investigator and sub-investigator agree to 
notify Gilead of any change reportable interests during the study and for one year following 
completion of the study. Study completion is defined as the date that the last subject has 
completed the protocol defined activities. 
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.” 
9.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies 
conducted in the United States) or IEC (for studies conducted outside of the United States). 
Approval from the IRB or IEC must be obtained before starting the study and should be 
documented in a letter to the investigator specifying the protocol number, protocol version, 
protocol date, documents reviewed, and date on which the committee met and granted the 
approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 

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9.1.3. 
Informed Consent/Assent 
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the 
parent/legal guardian and subject of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures. Written assent should be 
obtained from the subject as required by IRB/IEC/local requirements for this age population.  
The investigator must utilize an IRB- or IEC-approved consent/assent form for documenting 
written informed consent/assent. Each informed consent/assent will be appropriately signed 
and dated by the subject or the subject’s parent/legally authorized representative and the 
person obtaining consent/assent. 
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 and 
an identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory. The investigator must keep a subject 
identification log showing codes, names, and addresses for all subjects screened and for all 
subjects enrolled in the trial. 
The investigator agrees that all information received from Gilead, including but not limited to 
the Investigator’s Brochure, this protocol, CRFs, the investigational new drug, and any other 
study information, remain the sole and exclusive property of Gilead during the conduct of the 
study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
9.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB or IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 

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The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject: 
• subject identification (name, date of birth, gender); 
• documentation that subject meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria); 
• participation in trial (including trial number); 
• trial 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 trial medication (preferably drug 
dispensing and return should be documented as well); 
• record of all adverse events and other safety parameters (start and end date, and 
preferably including causality and intensity); 
• concomitant medication (including start and end date, dose if relevant; dose changes 
should be motivated); 
• date of trial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated 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 required by applicable 
regulatory requirements or 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 guarantee 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 in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the 

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continued care of the subject, appropriate copies should be made for storage outside of the 
site. 
Biological samples at the conclusion of this study may be retained in storage by the Sponsor 
for a period up to 15 years for purposes of this study. 
9.1.6. 
Case Report Forms 
For each subject enrolled, a CRF must be completed and signed by the principal investigator 
or subinvestigator within a reasonable time period after data collection. This also applies to 
records for those subjects who fail to complete the study (even during a prerandomization 
screening period if a CRF was initiated). If a subject withdraws from the study, the reason 
must be noted on the CRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome. 
9.1.7. 
Drug Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of receipt of 
each shipment of study product (quantity and condition) and subject dispensing records and 
returned or destroyed study product. Dispensing records will document quantities received 
from Gilead and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction in order to ensure that it complies with Gilead requirements. Drug 
may be returned or destroyed on an ongoing basis during the study if appropriate. At the end 
of the study, following final drug inventory reconciliation by the monitor, the study site will 
dispose of and/or destroy all unused study drug supplies, including empty containers, 
according these procedures. If the site cannot meet Gilead’s requirements for disposal, 
arrangements will be made between the site and Gilead or its representative for destruction or 
return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study. 
9.1.8. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 

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9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
9.2. 
Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead. All protocol modifications must be submitted to the IRB or 
IEC in accordance with local requirements. Approval must be obtained before changes can 
be implemented. 
9.2.2. 
Study Report and Publications 
A clinical study report 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. 
After conclusion of the study and without prior written approval from Gilead, 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. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4). 
The investigator will submit 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. 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. 

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9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the CRFs for consistency. 
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
9.3.2. 
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. 
9.3.3. 
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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10 
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Cherrington JM, Allen SJW, Bischofberger N, Chen MS. Kinetic interaction of the 
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Kramata P, Birkus G, Otmar M, Votruba I, Holy A. Structural features of acyclic 
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3273 
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Hadziyannis SJ, Tassopoulos N, Heathcote EJ, Chang T-T, Kitis G, Rizzetto M, et 
al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic 
hepatitis B. N Engl J Med 2003;348 (9):800-7. 
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Piketty C, Pellegrin I, Katiama C, Rozenbaum W, Neau D, Le Teuff G, et al. 
Efficacy of Tenofovir Disoproxil Fumarate (TDF) in Hepatitis B Virus in HIV-1 
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Retroviruses and Opportunistic Infections; 2004 February 8-11; San Francisco, 
CA.  
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Delaney WE, IV, Yang H, Sabogal A, Qi X, Miller M, Xiong S. Generation of 
novel stable cell lines for cross-resistance testing of anti-HBV compounds by real-
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Antiviral Research; 2004 May 2-6; Tuscon, AZ, USA.  
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Delaney WE, IV, Yang H, Miller MD, Gibbs CS, Xiong S. Combinations of 
adefovir with nucleoside analogs produce additive antiviral effects against hepatitis 
B virus in vitro. Antimicrob Agents Chemother 2004;48 (10):3702-10. 
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Lada O, Benhamou Y, Cahour A, Katlama C, Poynard T, Thibault V. In vitro 
susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. 
Antivir Ther 2004;9 (3):353-63. 
7346 
Arimilli MN, Jones RJ, Prisbe EJ. Nucleotide analogs. US Patent 5,717,095. 1998 
February 10.   
7788 
Qi X, Zhu Y, Curtis M, Yang H, Currie G, Miller MD, et al. In vitro cross-
resistance analysis of the HBV polymerase mutation A181V [poster]. 40th Annual 
Meeting of the European Association for the Study of the Liver; 2005 April 13-17; 
Paris, France. Poster Number P-1295.  
7980 
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang T-T, Kitis G, Rizzetto M, 
et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic 
hepatitis B. N Engl J Med 2005;352 (26):2673-81. 
8016 
Brunelle M-N, Jacquard A-C, Pichoud C, Durantel D, Carrouée-Durantel S, 
Villeneuve J-P, et al. Susceptibility to Antivirals of a Human HBV Strain With 
Mutations Conferring Resistance to Both Lamivudine and Adefovir. Hepatology 
2005;41 (6):1391-8. 

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8176 
Menne S, Cote PJ, Korba BE, Butler SD, George AL, Tochkov IA, et al. Antiviral 
effect of oral administration of tenofovir disoproxil fumarate in woodchucks with 
chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 
2005;49 (7):2720-8. 
8380 
Sheldon J, Camino N, Rodes B, Bartholomeusz A, Kuiper M, Tacke F, et al. 
Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients 
treated with tenofovir. Antivir Ther 2005;10 (6):727-34. 
8381 
Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE, IV. Cross-resistance 
testing of next-generation nucleoside and nucleotide analogues against lamivudine-
resistant HBV. Antivir Ther 2005;10 (5):625-33. 
8548 
Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir 
disoproxil fumarate and an optimized background regimen of antiretroviral agents 
as salvage therapy for pediatric HIV infection. Pediatrics 2005;116 (6):e846-54. 
8683 
Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al. 
Clinical emergence of entecavir-resistant hepatitis B virus requires additional 
substitutions in virus already resistant to Lamivudine. Antimicrob Agents 
Chemother 2004;48 (9):3498-507. 
9266 
Delaney WE, IV, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular 
metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob 
Agents Chemother 2006;50 (7):2471-7. 
9505 
Gafni RI, Hazra R, Reynolds JC, Maldarelli F, Tullio AN, DeCarlo E, et al. 
Tenofovir disoproxil fumarate and an optimized background regimen of 
antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-
infected children. Pediatrics 2006;118 (3):e711-8. 
10417 
Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Vigano A. A 12-
month treatment with tenofovir does not impair bone mineral accrual in HIV-
infected children. J Acquir Immune Defic Syndr 2005;40 (4):448-50. 
10425 
Villet S, Pichoud C, Villeneuve JP, Trepo C, Zoulim F. Selection of a multiple 
drug-resistant hepatitis B virus strain in a liver-transplanted patient. 
Gastroenterology 2006;131 (4):1253-61. 
10426 
Lacombe K, Ollivet A, Gozlan J, Durantel S, Tran N, Girard PM, et al. A novel 
hepatitis B virus mutation with resistance to adefovir but not to tenofovir in an 
HIV-hepatitis B virus-co-infected patient. AIDS 2006;20 (17):2229-31. 
10466 
Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, et al. 
Entecavir resistance is rare in nucleoside naive patients with hepatitis B. 
Hepatology 2006;44 (6):1656-65. 

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10644 
Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol 
Nutr 2006;43 Suppl 1:S56-60. 
10665 
Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45 (2):507-39. 
10678 
Bortolotti F. Treatment of chronic hepatitis B in children. J Hepatol 2003;39 Suppl 
1:S200-5. 
10684 
Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular 
carcinoma across a biological gradient of serum hepatitis B virus DNA level. 
JAMA 2006;295 (1):65-73. 
10690 
Disease Burden from Hepatitis A, B, and C in the United States. 
www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/disease_burden.pdf. 
Accessed April 12, 2007. 
10804 
Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, et al. 
Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B 
virus patients reveals different clinical outcomes depending on the resistance 
substitutions present. Antimicrob Agents Chemother 2007;51 (3):902-11. 
10916 
Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, et al. In Vitro 
Activity of 2,4-Diamino-6-[2-(Phosphonomethoxy)Ethoxy]-Pyrimidine against 
Multidrug-Resistant Hepatitis B Virus Mutants. Antimicrob Agents Chemother 
2007;51 (6):2240-3. 
10926 
Qi X, Xiong S, Yang H, Miller M, Delaney WE, IV. In vitro susceptibility of 
adefovir-associated hepatitis B virus polymerase mutations to other antiviral 
agents. Antivir Ther 2007;12 (3):355-62. 
10946 
Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo C, et al. Stepwise 
process for the development of entecavir resistance in a chronic hepatitis B virus 
infected patient. J Hepatol 2007;46 (3):531-8. 
10952 
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 
2006;101:6. 
10954 
Sokal E, Kelly D, Mizerski J, Badia I, Areias J, Schwarz K, et al. Long-term 
Lamivudine therapy for children with HBeAg-positive chronic hepatits B. 
Hepatology 2006;43 (2):8. 
11362 
Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A 
Randomized, Double-Blind Comparison of Tenofovir DF (TDF) Versus Adefovir 
Dipivoxil (ADV) for the Treatment of HBEAG-Positive Chronic Hepatitis B 
(CHB): Study GS-US-174-0103 [AASLD Abstracts]. Hepatology 2007;46 (4 
Supp1):861A. 

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11363 
Marcellin P, Buti M, Kraslev Z, Germanidis G, Kaita K, Kotzev I, et al. A 
Randomized, Double-Blind Comparison of Tenofovir DF (TDF) Versus Adefovir 
Dipivoxil (ADV) for the Treatment of HBEAG-Negative Chronic Hepatitis B 
(CHB): Study GS-US-174-0102 [AASLD Abstracts]. Hepatology 2007;46 (4 
Suppl 1):290A-1A. 
11445 
Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. 
Renal safety of tenofovir in HIV-infected children: a prospective, 96-week 
longitudinal study. Clin Drug Invest 2007;27 (8):573-81. 
11526 
Vigano A, Brambilla P, Cafarelli L, Giacomet V, Borgonovo S, Zamproni I, et al. 
Normalization of fat accrual in lipoatrophic, HIV-infected children switched from 
stavudine to tenofovir and from protease inhibitor to efavirenz. Antivir Ther 
2007;12 (3):297-302. 
12336 
Jonas MM, Kelly D, Pollack H, Mizerski J, Sorbel J, Frederick D, et al. Safety, 
efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents 
(age 2 to <18 years) with chronic hepatitis B. Hepatology 2008;47 (6):1863-71. 
13280 
Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus 
adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359 (23):2442-55. 
14352 
Hepsera® (adefovir dipivoxil) Tablets. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. October 2009.   
16282 
VIREAD® (tenofovir disoproxil fumarate) tablets. US Prescribing Information. 
Gilead Sciences, Inc. Foster City, CA. Revised October 2010.   
16432 
Berg T, Marcellin P, Zoulim F, Moller B, Trinh H, Chan S, et al. Tenofovir is 
effective alone or with emtricitabine in adefovir-treated patients with chronic-
hepatitis B virus infection. Gastroenterology 2010;139 (4):1207-17. 
16437 
Heathcote EJ, Gane EJ, deMan RA, Chao S, George J, Tsai NC. Long Term (4 
Year) Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Treatment in 
HBEAG-Positive Patients (HBEAG+) with Chronic Hepatitis B (Study 103): 
Prelininary Analysis [Abstract 477]. Hepatology 2010;52 (4 (Suppl)):556-7A. 
16441 
Marcellin P, Buti M, Kraslev Z, Guerel S, DiBisceglie AM. Continued Efficacy 
and Safety Through 4 Years of Tenofovir Disoproxil Fumarate (TDF) Treatment in 
HBEAG-Negative Patients with Chronic Hepatitis B (Study 102): Preliminary 
Anslysis. Hepatology 2010;52 (4 (Suppl)):555A-6A. 
17786 
Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, et al. 
Treatment of children with chronic hepatitis B virus infection in the United States: 
patient selection and therapeutic options Hepatology 2010;52 (6):2192-205. 

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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 

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Appendix 2. 
Study Procedures Table 
Study Procedures 
Screeninga 
Baseline 
Study Week 
4 
8 
16 
24 
32 
40 
48 
56 
64 
72 
Written Informed Consent, Subject Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination (including 
Tanner Staging starting at Baseline) 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
Symptom-Directed Physical Examination 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Vitals Signs, Height, Weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1, HAV, HCV, HDV, Į-fetoprotein 
X 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA Levels (PCR-Based Assay) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV Serologyg 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
HBV Genotyping, Resistance Surveillanceh 
 
X 
 
 
 
 
 
 
 
 
 
X 
Hematology Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry and Liver Testsi 
X 
X 
X 
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 
X 
X 
X 
Pregnancy Testk 
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 

Tenofovir Disoproxil Fumarate 
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Study Procedures 
Screeninga 
Baseline 
Study Week 
4 
8 
16 
24 
32 
40 
48 
56 
64 
72 
Serum and Plasma for Storagel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA Scan – Spine and Whole-Bodym 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
Bone Biochemical Markersn 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
Blood sample storage for genomic testings o 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
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 
Subject Dosing Diary Card 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Study Drug Dispensing/Returnp 
 
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 
 

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Appendix 2. 
Study Procedures Table (continued) 
Study Procedures 
Study Week 
Early 
DCc 
FUd 
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 
 
Symptom-Directed Physical Examination 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Vital Signs, Height, Weightf 
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 
HBV Serologyg 
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 
 
HBV Resistance Surveillanceh 
 
 
 
  
  
 
X 
  
  
 
X 
X 
 
Serum Chemistry and Liver Testsi 
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 
 
Pregnancy Testk 
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 
 
Serum and Plasma for Storagel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA Scan – Spine and Whole-Bodym 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
 
Bone Biochemical Markersn 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
 
Concomitant Medications 
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 

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Amendment 2 
 
 
 
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Study Procedures 
Study Week 
Early 
DCc 
FUd 
80 
88 
96b 
108 
120 
132 
144 
156 
168 
180 
192 
Study Drug Dispensing/Returnp 
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 
 
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) at Weeks 72, 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 ȕ-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 longterm 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. 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
Final 
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Amendment 2 
 
 
 
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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. 
 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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) 
Į-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 ȕ-
HCG if positive) 
Electrolytes: 
Sodium 
Potassium 
Bicarbonate 
Phosphorus+ 
Calcium 
Magnesium 
Chloride 
HBV Serology: 
HBsAg, HBeAg (reflex HBsAb and HBeAb). 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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 β-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 
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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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Appendix 4. 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version: 21 September 2011 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin  
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 
Absolute Neutrophil Count  
(ANC) 
1000 to 1300/mm3 
750 to < 1000/mm3 
500 to < 750/mm3 
< 500/mm3 
1.00 to 1.30 GI/L 
0.75 to < 1.00 GI/L 
0.50 to < 0.75 GI/L 
< 0.50 GI/L 
Absolute CD4+ Count 
300 to 400/mm3 
300 to 400/ȝL 
200 to < 300/mm3 
200 to < 300/ȝL 
100 to < 200/mm3 
100 to < 200/ȝL 
< 100/mm3 
< 100/ȝL 
Absolute Lymphocyte Count 
600 to 650/mm3 
0.60 to 0.65 GI/L 
500 to < 600/mm3 
0.50 to < 0.60 GI/L 
350 to < 500/mm3 
0.35 to < 0.50 GI/L 
< 350/mm3 
< 0.35 GI/L 
Platelets  
100,000 to < 125,000/mm3 
100 to < 125 GI/L 
50,000 to < 100,000/mm3 
50 to < 100 GI/L 
25,000 to < 50,000/mm3 
25 to < 50 GI/L 
< 25,000/mm3 
< 25 GI/L 
WBCs  
2000/mm3 to 2500/mm3 
1,500 to < 2,000/mm3 
1000 to < 1,500/mm3 
< 1000/mm3 
2.00 GI/L to 2.50 GI/L 
1.50 to < 2.00 GI/L 
1.00 to < 1.50 GI/L 
< 1.00 GI/L 
Hypofibrinogenemia 
100 to 200 mg/dL 
75 to < 100 mg/dL 
50 to < 75 mg/dL 
< 50 mg/dL 
1.00 to 2.00 g/L 
0.75 to < 1.00 g/L 
0.50 to < 0.75 g/L 
< 0.50 g/L 

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Gilead Sciences, Inc.  
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperfibrinogenemia 
> ULN to 600 mg/dL 
> 600 mg/dL 
— 
— 
> ULN  to 6.0 g/L 
> 6.0 g/L 
— 
— 
Fibrin Split Product  
20 to 40 ȝg/mL 
> 40 to 50 ȝg/mL 
> 50 to 60 ȝg/mL 
> 60 ȝg/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 (APPT) 
> 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%  
 

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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia  
130 to 135 mEq/L 
125 to < 130 mEq/L 
121 to < 125 mEq/L 
< 121 mEq/L 
130 to 135 mmol/L 
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 
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 
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) 
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 
Hypercalcemia 
(corrected for albumin) 
10.6 to 11.5 mg/dL 
> 11.5 to 12.5 mg/dL 
> 12.5 to 13.5 mg/dL 
> 13.5 mg/dL 
2.64 to 2.88 mmol/L 
> 2.88 to 3.13 mmol/L 
> 3.13 to 3.38 mmol/L 
> 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 

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Protocol GS-US-174-0144 
Final 
Gilead Sciences, Inc.  
Amendment 2 
 
 
 
CONFIDENTIAL 
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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypomagnesemia 
1.40 to  1.76mg/dL 
1.2 to 1.4 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 0.72 mmol/L 
0.43 to < 0.58 mmol/L 
0.28 to < 0.43 mmol/L 
< 0.28 mmol/L 
Hypophosphatemia 
2.5 mg/dL to < LLN 
2.0 to < 2.5 mg/dL 
1.0 to < 2.0 mg/dL 
< 1.0 mg/dL 
0.80 mmol/L to < LLN 
0.63 to < 0.80 mmol/L 
0.31 to < 0.63 mmol/L 
< 0.31 mmol/L 
Hyperbilirubinemia  
> 1.0 to 1.5 × ULN  
> 1.5 to 2.5 × ULN 
> 2.5 to 5.0 × ULN  
> 5.0 × ULN  
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 ȝmol/L 
> 597 to 716 ȝmol/L 
> 716 to 895 ȝmol/L 
> 895 ȝmol/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 ȝmol/L to < LLN 
57 to < 87 ȝmol/L 
27 to < 57 ȝmol/L 
< 27 ȝmol/L 
Creatinine  
> 1.50 to 2.00 mg/dL 
> 2.00 to 3.00 mg/dL 
> 3.00 to 6.00 mg/dL  
> 6.00 mg/dL 
> 133 to 177 ȝmol/L 
> 177 to 265 ȝmol/L 
> 265 to 530 ȝmol/L 
> 530 ȝmol/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 
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 
 
Creatine Kinase 
3.0 to < 6.0 × ULN 
6.0 to < 10.0 × ULN 
10.0 to < 20.0 × ULN 
≥ 20.0 × ULN 
 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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 
30 g/L to < LLN 
2.0 to < 3.0 g/dL 
20 to < 30 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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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 
6–10 RBC/HPF 
> 10-75 RBC/HPF 
> 75 RBC/HPF 
NA 
Proteinuria (Dipstick) 
1+ 
2–3+ 
4+ 
NA 
Proteinuria, 24 Hour Collection 
200 to <1000 mg/24 h 
1000 to <2000 mg/24 h 
2000 to 3500 mg/24 h 
> 3500 mg/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. 
 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Arrhythmia (general) 
(By ECG or physical exam) 
Asymptomatic AND No 
intervention indicated 
Asymptomatic AND Non-
urgent medical intervention 
indicated 
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated  
Life-threatening arrhythmia 
OR Urgent intervention 
indicated 
Cardiac-ischemia/Infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia  
Unstable angina OR Acute 
myocardial infarction 
Hemorrhage (significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND 
Transfusion of ≤ 2 units 
packed RBCs (for children 
≤ 10 cc/kg) indicated  
Life-threatening hypotension 
OR Transfusion of > 2 units 
packed RBCs indicated (for 
children ≤ 10 cc/kg) indicated 
Hypertension (with repeat 
testing at same visit) 
140–159 mmHg systolic  
OR  
90–99 mmHg diastolic 
> 159–179 mmHg systolic  
OR  
> 99–109 mmHg diastolic 
> 179 mmHg systolic  
OR  
> 109 mmHg diastolic 
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated 
Hypotension 
NA 
Symptomatic, corrected with 
oral fluid replacement 
Symptomatic, IV fluids 
indicated 
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure 
Pericardial Effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, moderate or 
larger effusion requiring no 
intervention 
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated 
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated 
Prolonged PR Interval 
PR interval  
0.21 to 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree AV 
block OR Ventricular pause 
> 3.0 sec 
Complete AV block  

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Gilead Sciences, Inc.  
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CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prolonged QTc 
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval < 0.03 sec above 
baseline 
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline 
Asymptomatic, QTc interval 
≥ 0.50 sec OR Increase in 
interval ≥ 0.06 sec above 
baseline 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia 
Thrombosis/Embolism 
NA 
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)  
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)  
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus)  
Vasovagal Episode (associated 
with a procedure of any kind) 
Present without loss of 
consciousness  
Present with transient loss of 
consciousness 
NA  
NA 
Ventricular Dysfunction 
(congestive heart failure, 
CHF) 
NA 
Asymptomatic diagnostic 
finding AND intervention 
indicated 
New onset with symptoms 
OR Worsening symptomatic 
CHF 
Life-threatening CHF 
 

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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Bronchospasm (acute) 
FEV1 or peak flow reduced to 
70% to 80% 
FEV1 or peak flow 50% to 69% 
FEV1 or peak flow 25% to 
49%  
Cyanosis OR FEV1 or peak flow 
< 25% OR Intubation 
Dyspnea or Respiratory 
Distress 
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities  
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities  
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated 
 
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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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alopecia 
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults) 
Thinning or patchy hair loss 
detectable by health care 
provider 
Complete hair loss 
NA 
Cutaneous Reaction – Rash 
Localized macular rash  
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions  
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized  
Marked or generalized 
NA 
NA 
Pruritis (itching – no skin 
lesions)  
(See also Injection Site 
Reactions: Pruritis associated 
with injection) 
Itching causing no or 
minimal interference with 
usual social & functional 
activities 
Itching causing greater than 
minimal interference with 
usual social & functional 
activities 
Itching causing inability to 
perform usual social & 
functional activities  
NA 
 

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Protocol GS-US-174-0144 
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Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anorexia 
Loss of appetite without 
decreased oral intake 
Loss of appetite associated with 
decreased oral intake without 
significant weight loss  
Loss of appetite associated 
with significant weight loss  
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition] 
Ascites 
Asymptomatic 
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis) 
Symptomatic despite 
intervention 
Life-threatening consequences 
Cholecystitis 
NA 
Symptomatic AND Medical 
intervention indicated 
Radiologic, endoscopic, or 
operative intervention 
indicated 
Life-threatening consequences 
(eg, sepsis or perforation)  
Constipation  
NA 
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas  
Obstipation with manual 
evacuation indicated 
Life-threatening consequences 
(eg, obstruction) 
Diarrhea  
Transient or intermittent 
episodes of unformed stools 
OR Increase of ≤ 3 stools 
over baseline/24 hr 
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs.  
Bloody diarrhea OR Increase 
of ≥ 7 stools per 24-hour 
period OR IV fluid 
replacement indicated 
Life-threatening consequences 
(eg, hypotensive shock) 
Dysphagia-Odynophagia  
Symptomatic but able to eat 
usual diet 
Symptoms causing altered 
dietary intake without medical 
intervention indicated 
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated 
Life-threatening reduction in 
oral intake 
Mucositis/Stomatitis  
(clinical exam) 
See also Proctitis, 
Dysphagia-Odynophagia 
Erythema of the mucosa 
Patchy pseudomembranes or 
ulcerations  
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking) 

Tenofovir Disoproxil Fumarate 
Protocol GS-US-174-0144 
Final 
Gilead Sciences, Inc.  
Amendment 2 
 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea  
Transient (< 24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake 
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours 
Persistent nausea resulting in 
minimal oral intake for > 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids) 
Life-threatening consequences 
(eg, hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit) 
Symptomatic AND 
Hospitalization indicated 
(other than ER visit) 
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage) 
Proctitis (functional- 
symptomatic) 
Also see Mucositis/ 
Stomatitis for Clinical 
Exam 
Rectal discomfort AND No 
intervention indicated 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated  
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated  
Life-threatening consequences 
(eg, perforation) 
Vomiting 
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated 
Life-threatening consequences 
(eg, hypotensive shock) 
 

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

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NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Headache  
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Symptoms causing inability to 
perform usual social & 
functional activities 
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function  
Insomnia 
NA 
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities 
Difficulty sleeping causing 
inability to perform usual 
social & functional activities 
Disabling insomnia causing 
inability to perform basic self-
care functions 
Neuromuscular Weakness  
(including myopathy & 
neuropathy)  
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities 
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities 
Muscle weakness causing 
inability to perform usual 
social & functional activities  
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation 
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy) 
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities  
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities  
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities 
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions 
Seizure: (new onset)  
NA 
1 seizure  
2–4 seizures  
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy) 

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NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Seizure: (pre-existing)  
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels 
NA 
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder 
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality)  
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy) 
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  
Myalgia 
(non-injection site) 
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities 
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities 
Muscle pain causing 
inability to perform usual 
social & functional activities 
Disabling muscle pain causing 
inability to perform basic self-
care functions 
Osteonecrosis 
NA 
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated 
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated 
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions 
 

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

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INJECTION SITE REACTION 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Injection Site Pain (pain 
without touching) 
Or Tenderness (pain when 
area is touched)  
Pain/tenderness causing no 
or minimal limitation of use 
of limb 
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities 
Pain/tenderness causing 
inability to perform usual 
social & functional activities 
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness 
Injection Site Reaction 
(Localized) 
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) 
Pruritis Associated with 
Injection  
See also Skin: Pruritis 
(itching—no skin lesions) 
Itching localized to injection 
site AND Relieved 
spontaneously or with 
< 48 h treatment  
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring ≥ 48 h treatment  
Generalized itching causing 
inability to perform usual 
social & functional activities 
NA 
 

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

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

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Appendix 5. 
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 and the 
patient. 

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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). 
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. 

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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.