Conditions: Acquired Immune Deficiency Syndrome (AIDS) HIV Infections
Keywords: Pediatrics Adolescents HIV HIV-1 Treatment-experienced
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the safety, tolerability and steady-state PK and confirm the dose of EVG/r in HIV-1 infected, antiretroviral treatment-experienced children 4 weeks to \<18 years of age.

The study consists of 2 parts: Part A and Part B. Part A will enroll participants with suppressed viremia (HIV-1 RNA \< 50 copies/mL) or failing a current antiretroviral (ARV) regimen (HIV-1 RNA \> 1,000 copies/mL only for participants in Cohort 2, Part A) to evaluate the steady state PK and confirm the dose of EVG. Part B will enroll participants who are failing a current ARV regimen (HIV-1 RNA \> 1,000 copies/mL) to evaluate the safety, tolerability, and antiviral activity of EVG. The study consists of 4 age cohorts with each cohort including 2 parts (Part A and Part B) with the exception of the adolescent age cohort (Cohort 1: 12 to \< 18 years old) containing Part B only.

Detailed description:

Arms:
arm 1: Part A: No participants will be enrolled in Part A, as PK data is currently available for this age group.

Part B: Participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. arm 2: Part A: Participants with HIV-1 RNA \< 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days. Participants with HIV-1 RNA \> 1,000 copies/mL will receive EVG along with a newly constructed background regimen that includes a Pl/r for 48 weeks. Participants with HIV-1 RNA \> 1,000 copies/mL can continue after Week 48.

Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. Participants who complete the 48-week follow-up in both Part A and Part B will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. arm 3: Part A: Participants with HIV-1 RNA \< 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days.

Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country. arm 4: Part A: Participants with HIV-1 RNA \< 50 copies/mL will receive EVG plus a background regimen that includes a PI/r for 10 days.

Part B: Following confirmation of exposure to EVG and based on safety and PK data assessed in Part A, participants will receive EVG plus a background regimen that includes a PI/r for up to 48 weeks. After Week 48, participants will be given the option to continue EVG therapy until the participant turns 18 and EVG is available for use in adults in the country in which the participant is enrolled, or the age appropriate EVG formulation becomes available for use in the country in which the participant is enrolled, or Gilead Sciences elects to terminate development of EVG in the applicable country.

Interventions: intervention 1: EVG intervention 2: Background regimen
Intervention descriptions: intervention 1: Tablet (s) or tablet (s) for oral suspension (if unable to swallow) will be administered orally once daily intervention 2: Background regimen may consist of the following ritonavir (RTV)-boosted PIs (PI/r): lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. For participants \< 2 months old, only lopinavir/r is allowed. Use of additional antiretrovirals in background therapy may be allowed.

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................................................................... 2 
LIST OF IN-TEXT TABLES ................................................................................................................................. 5 
LIST OF IN-TEXT FIGURES ............................................................................................................................... 5 
PROTOCOL SYNOPSIS ....................................................................................................................................... 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 18 
1. 
INTRODUCTION ....................................................................................................................................... 22 
1.1. 
Background ..................................................................................................................................... 22 
1.2. 
Elvitegravir (EVG, GS-9137) ......................................................................................................... 23 
1.2.1. 
General Information ...................................................................................................... 23 
1.2.2. 
Preclinical Pharmacology and Toxicology .................................................................... 23 
1.2.3. 
Clinical Trials of Elvitegravir ....................................................................................... 25 
1.3. 
Rationale for This Study ................................................................................................................. 37 
1.4. 
Rationale for the Current Dose ....................................................................................................... 38 
1.5. 
Compliance ..................................................................................................................................... 40 
This study will be conducted in compliance with this protocol, Good Clinical ........................................... 40 
2. 
OBJECTIVES .............................................................................................................................................. 41 
3. 
STUDY DESIGN ........................................................................................................................................ 42 
3.1. 
Endpoints ........................................................................................................................................ 42 
3.2. 
Study Design ................................................................................................................................... 42 
3.3. 
Study Treatments ............................................................................................................................ 49 
3.4. 
Duration of Treatment ..................................................................................................................... 50 
3.5. 
Discontinuation Criteria .................................................................................................................. 50 
4. 
SUBJECT POPULATION ........................................................................................................................... 51 
4.1. 
Number of Subjects and Subject Selection ..................................................................................... 51 
4.2. 
Inclusion Criteria ............................................................................................................................ 51 
4.3. 
Exclusion Criteria ........................................................................................................................... 53 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................................... 56 
5.1. 
Randomization, Blinding and Treatment Codes ............................................................................. 56 
5.2. 
Description and Handling of Elvitegravir ....................................................................................... 56 
5.2.1. 
Formulation ................................................................................................................... 56 
5.2.2. 
Packaging and Labeling ................................................................................................ 57 
5.2.3. 
Storage and Handling .................................................................................................... 57 
5.3. 
Dosage and Administration of Elvitegravir .................................................................................... 57 
5.3.1. 
Elvitegravir Powder for Oral Suspension Reconstitution and Dosing .......................... 61 
5.4. 
Prior and Concomitant Medications ................................................................................................ 62 
5.5. 
Accountability for Elvitegravir ....................................................................................................... 65 
5.5.1. 
Investigational Medicinal Product Return or Disposal .................................................. 66 
6. 
STUDY PROCEDURES ............................................................................................................................. 67 
6.1. 
Subject Enrollment and Treatment Assignment .............................................................................. 67 
6.2. 
Pretreatment Assessments ............................................................................................................... 67 
6.2.1. 
Screening Visit .............................................................................................................. 67 
6.2.2. 
Baseline Assessments .................................................................................................... 69 
6.3. 
Treatment Assessments ................................................................................................................... 70 
6.3.1. 
Week 1 (Day 7) and Week 3 Telephone Visits ............................................................. 70 


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6.3.2. 
Day 10 Intensive PK Visit – Part A only ...................................................................... 71 
6.3.3. 
Week 4 – 48 Visits ........................................................................................................ 73 
6.4. 
Post Week 48 Assessments ............................................................................................................. 76 
6.5. 
Assessments for Premature Discontinuation from Study ................................................................ 77 
6.5.1. 
Early Study Drugs Discontinuation (ESDD) ................................................................. 77 
6.6. 
Criteria for Discontinuation of Study Treatment ............................................................................ 79 
6.7. 
End of Study ................................................................................................................................... 79 
6.7.1. 
30-Day Follow-Up Assessments ................................................................................... 79 
6.8. 
Virologic Failure ............................................................................................................................. 81 
6.8.1. 
Management of Suboptimal Virologic Response .......................................................... 81 
6.8.2. 
Management of Virologic Rebound .............................................................................. 83 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ........................................................................ 85 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events .......................... 85 
7.1.1. 
Adverse Events ............................................................................................................. 85 
7.1.2. 
Serious Adverse Events ................................................................................................. 86 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events .............................................................. 86 
7.2. 
Assessment of Adverse Events and Serious Adverse Events .......................................................... 87 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ............................................ 87 
7.2.2. 
Assessment of Severity ................................................................................................. 87 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ................................................................................................................ 87 
7.4. 
Gilead Reporting Requirements ...................................................................................................... 90 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events .............................................................................................................. 91 
7.5.1. 
Grades 1 and 2 Laboratory Abnormality or Clinical Event ........................................... 91 
7.5.2. 
Grade 3 Laboratory Abnormality or Clinical Event ...................................................... 91 
7.5.3. 
Grade 4 Laboratory Abnormality or Clinical Event ...................................................... 92 
7.6. 
Toxicity Management ..................................................................................................................... 92 
7.7. 
Special Situations Reports .............................................................................................................. 93 
7.7.1. 
Definitions of Special Situations ................................................................................... 93 
7.7.2. 
Instructions for Reporting Special Situations ................................................................ 93 
7.8. 
Risks for Females of Childbearing Potential or During Pregnancy ................................................ 94 
7.8.1. 
Definition of Childbearing Potential and Post-Menopausal .......................................... 95 
7.8.2. 
Contraception Requirements for Males and Females of Childbearing 
Potential ........................................................................................................................ 95 
7.8.3. 
Procedures to be Followed in the Event of Pregnancy .................................................. 97 
8. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 98 
8.1. 
Analysis Objectives and Endpoints ................................................................................................. 98 
8.1.1. 
Analysis Objectives ....................................................................................................... 98 
8.1.2. 
Primary Endpoint .......................................................................................................... 98 
8.1.3. 
Secondary Endpoint ...................................................................................................... 98 
8.2. 
Analysis Conventions ..................................................................................................................... 99 
8.2.1. 
Analysis Sets ................................................................................................................. 99 
8.2.2. 
Subject Groups .............................................................................................................. 99 
8.3. 
Data Handling Conventions .......................................................................................................... 100 
8.4. 
Demographic Data and Baseline Characteristics .......................................................................... 100 
8.5. 
Efficacy Analysis .......................................................................................................................... 100 
8.6. 
Safety Analysis ............................................................................................................................. 101 
8.6.1. 
Extent of Exposure ...................................................................................................... 101 
8.6.2. 
Adverse Events ........................................................................................................... 101 
8.6.3. 
Laboratory Evaluations ............................................................................................... 102 


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8.6.4. 
Other Safety Evaluations ............................................................................................. 102 
8.7. 
Pharmacokinetic Analysis ............................................................................................................. 103 
8.8. 
Sample Size and Power ................................................................................................................. 103 
8.9. 
Data Monitoring Committee ......................................................................................................... 104 
9. 
RESPONSIBILITIES ................................................................................................................................ 105 
9.1. 
Investigator Responsibilities ......................................................................................................... 105 
9.1.1. 
Good Clinical Practice ................................................................................................ 105 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Review and Approval ........................................................................................ 105 
9.1.3. 
Informed Consent ........................................................................................................ 106 
9.1.4. 
Confidentiality ............................................................................................................ 106 
9.1.5. 
Study Files and Retention of Records ......................................................................... 106 
9.1.6. 
Case Report Forms ...................................................................................................... 108 
9.1.7. 
Investigational Medicinal Product Accountability and Return ................................... 108 
9.1.8. 
Inspections .................................................................................................................. 109 
9.1.9. 
Protocol Compliance ................................................................................................... 109 
9.2. 
Sponsor Responsibilities ............................................................................................................... 109 
9.2.1. 
Protocol Modifications ................................................................................................ 109 
9.2.2. 
Study Report and Publications .................................................................................... 109 
9.3. 
Joint Investigator/Sponsor Responsibilities .................................................................................. 110 
9.3.1. 
Access to Information for Monitoring ......................................................................... 110 
9.3.2. 
Access to Information for Auditing or Inspections ..................................................... 110 
9.3.3. 
Study Discontinuation ................................................................................................. 110 
10. REFERENCES .......................................................................................................................................... 111 
11. APPENDICES ........................................................................................................................................... 114 
 
Appendix 1. 
Investigator Signature Page ......................................................................................... 115 
Appendix 2. 
Study Procedures Table – Cohorts 1, 2, and 3 ............................................................ 116 
Appendix 3. 
Study Procedures Table – Cohort 4 ............................................................................. 121 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events ........................................... 127 
Appendix 5. 
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities ........................................................................................... 128 
Appendix 6. 
Tanner Stages .............................................................................................................. 151 
Appendix 7. 
Definitions of HIV-1 Related Disease (adapted from CDC 
Guidelines) .................................................................................................................. 152 
 
 


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LIST OF IN-TEXT TABLES 
Table 1-1. 
GS-US-183-0149: EVG Pharmacokinetic Parameters and 
Statistical Comparison following EVG pediatric tablets or EVG 
pediatric suspension versus adult EVG formulation ..................................................... 28 
Table 1-2. 
GS-US-183-0130: Proportions of Subjects with Plasma HIV-1 
RNA < 50 Copies/mL at Study Time Points (Efficacy Analysis 
Set) ................................................................................................................................ 30 
Table 1-3. 
EVG dose (mg) by Weight Range with DRV, fAPV or TPV ....................................... 39 
Table 1-4. 
EVG dose (mg) by Weight Range with ATV, LPV ...................................................... 39 
Table 5-1. 
EVG dose by Weight Range with DRV, fAPV or TPV ................................................ 58 
Table 5-2. 
EVG dose by Weight Range with ATV, LPV ............................................................... 58 
Table 5-3. 
EVG Suspension dose (mL) by Body Weight with DRV, fAPV 
or TPV ........................................................................................................................... 59 
Table 5-4. 
EVG Suspension dose (mL) by Body Weight with ATV, LPV .................................... 60 
Table 7-1. 
Protocol-Recommended Contraceptive Methods .......................................................... 96 
 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1. 
Study Schema ................................................................................................................ 47 
Figure 6-1. 
Suboptimal Virologic Response Schema ...................................................................... 82 
Figure 6-2. 
Virologic Rebound Schema .......................................................................................... 84 
 


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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive  
Foster City, CA 94404 
 
 
Study Title:  
A Phase 2/3 Multicenter, Open-Label, Multicohort, Two-Part 
Study Evaluating the Pharmacokinetics (PK), Safety, and Antiviral 
Activity of Elvitegravir (EVG) Administered with a Background 
Regimen (BR) Containing a Ritonavir-Boosted Protease Inhibitor 
(PI/r) in HIV-1 Infected, Antiretroviral Treatment-Experienced 
Pediatric Subjects 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
072177  
2013-001969-16 
TBD 
Study Centers 
Planned: 
Approximately 50 centers in North America, Europe, Latin 
America, Asia Pacific, and Africa 
Objectives: 
The primary objectives of this study are as follows: 
• To evaluate the steady-state PK and confirm the dose of 
ritonavir-boosted elvitegravir (EVG/r) in HIV-1 infected, 
antiretroviral treatment-experienced subjects 4 weeks to 
<18 years of age 
• To evaluate the safety and tolerability of EVG/r in HIV-1 
infected, antiretroviral treatment-experienced subjects 4 weeks 
to <18 years of age 
The secondary objective of this study is as follows:  
• To evaluate the antiviral activity of EVG/r in HIV-1 infected, 
antiretroviral treatment-experienced subjects 4 weeks to 
<18 years of age who are failing their current HAART regimen 
Study Design: 
Open-label, multicohort, two-part study evaluating the PK, safety, 
and antiviral activity of EVG administered with a BR containing a 
PI/r in HIV-1 infected, antiretroviral treatment-experienced 
pediatric subjects. 
Up to approximately 86 pediatric subjects 4 weeks to <18 years of 
age will be enrolled as follows: 


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Part A  
Approximately 36 subjects either with suppressed viremia (HIV-1 
<50 copies/mL) or failing a current antiretroviral regimen (HIV-1 
RNA >1,000 copies/mL) will be enrolled to evaluate the steady 
state PK and confirm the dose of EVG. Only subjects aged 4 weeks 
to < 12 years old will be enrolled in Part A. 
For subjects with HIV-1 RNA <50 copies/mL at screening, EVG 
will be added to the existing BR that must include a PI/r. The dose 
of EVG will be dependent upon the coadministered PI/r and will be 
based on body weight.  
For subjects with HIV-1 RNA >1,000 copies/mL at screening, 
EVG will be added to a newly constructed BR selected by the 
investigator that is based on the subject’s antiretroviral history and 
screening or historical viral resistance results.  The BR must 
include at least 2 fully-active agents, one of which is a fully-active 
PI/r (fully-active PI/r is defined by genotypic analysis). 
The PI/r contained in the BR must be one of the following: 
lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or 
fosamprenavir/r. For subjects < 2 months old, only lopinavir/r is 
allowed. The BR may contain additional antiretrovirals except for 
the following: saquinavir, indinavir, nelfinavir, double PI 
regimens, efavirenz, nevirapine, delavirdine or an integrase strand 
transfer inhibitor. All PI should be administered according to local 
product label. 
All subjects will take their ritonavir dose based on the dosing 
schedule prescribed for the PI; no additional ritonavir is required to 
be taken with EVG. 
Subjects will be enrolled sequentially by cohort* as follows: 
• Cohort 2: 6 to < 12 years old (n  12) 
• Cohort 3: 2 to < 6 years old (n 12) 
• Cohort 4: 4 weeks to < 2 years old (n 12), which will consist 
of the following age groups – 
— Cohort 4a: 6 months to < 2 years old (n  8) 
— Cohort 4b**: 4 weeks to < 6 months old (n  4) 
   *Cohort 1 subjects are aged 12 to < 18 years old.  No subjects 
will be enrolled in this age group for Part A as EVG PK data are 
already available. 
   **Based on the uncertainty for a dose-exposure relationship in 
subjects < 2 months old, EVG administration will be restricted to 


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coadministration with lopinavir/r, and subjects will be enrolled 
individually and dosed sequentially within the cohort following PK 
analysis and confirmation of the selected dose of the previous 
subject(s). 
Part A will be enrolled sequentially by age cohort. Enrollment will 
be limited to Cohort 2 in Part A until EVG safety and PK through 
Day 10 have been analyzed and determined to be acceptable in 
subjects aged 6 to < 12 years old.  Upon review of safety and PK 
data in Cohort 2, enrollment will then be limited to Cohort 3 until 
EVG safety and PK through Day 10 have been analyzed and 
determined to be acceptable in subjects aged 2 to < 6 years old.  
Upon review of safety and PK data in Cohort 3, enrollment will 
then be limited to Cohort 4a until EVG PK through Day 10 and 
safety through Week 12 have been analyzed and determined to be 
acceptable in subjects aged 6 months to < 2 years old.  
Subsequently, Part A enrollment will open for Cohort 4b.  
Subjects will participate in an intensive PK evaluation on Day 10. 
For Cohorts 2 and 3, samples will be collected at 0 (predose, 
 30 minutes), 1.5, 2.5, 3.5, 5, 8, 10, and 12 hours postdose. For 
Cohort 4, samples will be collected at 0 (predose,  30 minutes), 3, 
3.5, 5, and 8 hours postdose. 
EVG therapeutic dose confirmation will be established if the 90% 
confidence interval (CI) of the geometric mean ratio of EVG AUC 
between the pediatric versus historical EVG exposures are within 
the bounds of 70-143%. If a subject has EVG Ctau levels <44.5 
ng/mL and has documented compliance to study drug, the subject 
will be discontinued. 
Subjects with HIV-1 RNA <50 copies/mL at screening are 
considered to have suppressed viremia and will only participate in 
Part A of the study.  These subjects will discontinue EVG and 
will complete the study following the Day 10 intensive PK visit.   
Subjects with HIV-1 RNA >1,000 copies/mL at screening are 
considered to be failing their antiretroviral regimen and will 
continue to receive EVG following completion of the Day 10 
intensive PK visit for scheduled study visits through Week 48. 
Data from these subjects will be combined with data from Part B 
of the study. 
Part B  
Up to 50 subjects who are failing a current antiretroviral regimen 
(HIV-1 RNA >1,000 copies/mL) will be enrolled in Part B to 
evaluate the safety, tolerability and antiviral activity of EVG. The 
number of additional subjects to be enrolled in Part B will depend 


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on the number of subjects with HIV-1 RNA >1,000 copies/mL 
enrolled in Part A who continue EVG therapy beyond Day 10.  
Overall, a total of 50 subjects in Part A and B combined are 
planned to complete 48 weeks of EVG therapy.  
EVG will be administered for 48 weeks concomitantly with a 
newly constructed BR selected by the investigator that is based on 
the subject’s antiretroviral history and screening viral resistance 
results.  The BR must include at least 2 fully-active agents, 
including one of the following fully active PI/r: lopinavir/r 
(Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r. 
For subjects < 2 months old, only lopinavir/r is allowed. The BR 
may contain additional antiretrovirals except for the following: 
saquinavir, indinavir, nelfinavir, double PI regimens, efavirenz, 
nevirapine, delavirdine or an integrase strand transfer inhibitor. All 
PI should be administered according to local product label. 
All subjects will take their ritonavir dose based on the dosing 
schedule prescribed for the PI; no additional ritonavir is required to 
be taken with EVG.  
For Cohort 1 (12 to < 18 year olds), screening in Part B will 
initiate in parallel with screening in Part A.  For Cohorts 2, 3 and 4 
in Part B, additional subjects will be screened and initiated 
sequentially by each age cohort following confirmation of 
appropriate EVG exposure from the corresponding age cohort in 
Part A.  
 
Subjects will be enrolled sequentially by cohort as follows: 
• Cohort 1: 12 to < 18 years old (n  8) 
• Cohort 2: 6 to < 12 years old (n  8) 
• Cohort 3: 2 to < 6 years old (n  8) 
• Cohort 4***: 4 weeks to < 2 years old (n  4) 
   ***Subjects younger than 6 months will not be allowed to enroll 
in Part B until Part A Cohort 4b data are available indicating 
acceptable EVG safety and PK through Day 10 in this age group. 
Number of Subjects 
Planned: 
Up to 86 subjects  
Part A: Approximately 36 evaluable subjects 
Part B: Between 14 and 50 subjects, depending on the number of 
subjects with HIV-1 RNA >1,000 copies/mL at screening enrolled 
in Part A who continue EVG therapy beyond Day 10. 


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Target Population: 
Part A:  Antiretroviral treatment-experienced, HIV-1 infected 
male and female subjects, ages 4 weeks to < 12 years, either with 
suppressed viremia (HIV-1 RNA <50 copies/mL) or failing a 
current antiretroviral regimen (with HIV-1 RNA 
>1,000 copies/mL)  
Part B:  Antiretroviral treatment-experienced, HIV-1 infected 
male and female subjects, ages 4 weeks to < 18 years failing a 
current antiretroviral regimen (with HIV-1 RNA 
>1,000 copies/mL) 
Duration of 
Treatment: 
10 days for subjects with suppressed viremia   
48 weeks for subjects failing a current antiretroviral regimen  
After Week 48, all subjects receiving EVG will be given the option 
to participate in an extension phase of the study where Gilead will 
provide EVG until: a) the subject turns 18 and EVG is available for 
use in adults in the country in which the subject is enrolled or 
b) the age appropriate EVG formulation becomes available for use 
in the country in which the subject is enrolled or c) Gilead 
Sciences elects to terminate development of EVG in the applicable 
country. 
Diagnosis and Main 
Eligibility Criteria: 
Inclusion Criteria: 
• Antiretroviral treatment-experienced, HIV-1 infected male and 
female subjects 4 weeks (gestational age of at least 44 weeks) 
to < 18 years of age 
• Body weight at screening as follows: 
o Cohort 2 – greater than 15 kg 
o Cohort 3 – greater than 10.6 kg 
o Cohort 4 – greater than 5 kg 
• Part A: Evidence of suppressed viremia or failing a current 
antiretroviral regimen as defined below.  
• Part B: Evidence of failing a current antiretroviral regimen as 
defined below. 
Criteria for subjects with evidence of suppressed viremia (Part A 
only): 
• Plasma HIV-1 RNA concentration (at least 2 consecutive 
measurements) at an undetectable level according to the assay 
being used for at least 3 months prior to screening, and HIV-1 
RNA <50 copies/mL (Roche COBAS TaqMan v2.0) at 
screening.  


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• Stable antiretroviral regimen including one of the following 
PI/r for at least 3 months prior to screening: lopinavir/r 
(Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or 
fosamprenavir/r. Subjects undergoing dose modifications to 
their antiretroviral regimen for growth or switching medication 
formulations are considered to be on a stable antiretroviral 
regimen. 
Criteria for subjects failing a current antiretroviral regimen 
(Parts A and B): 
• HIV-1 RNA >1,000 copies/mL at screening 
(Roche COBAS TaqMan v2.0) 
• Prior treatment for HIV-1 infection, defined as 6 months of 
antiretroviral treatment experience (with the exception of 
Cohort 4 where less than 6 months of treatment experience is 
acceptable) and at least 1 documented resistance mutation as 
defined by current IAS-USA Guidelines. These resistance 
mutations must be documented in a historical genotype 
report(s), or in the genotype report at screening provided by 
Gilead Sciences. 
• Stable antiretroviral regimen (or no antiretroviral regimen) for 
at least 30 days prior to screening. Subjects undergoing dose 
modifications to their antiretroviral regimen for growth or 
switching medication formulations are considered to be on a 
stable antiretroviral regimen. 
• Screening genotype must show full sensitivity to EVG. 
• Ability to construct a BR that must contain one of the 
following fully active PI/r:  lopinavir/r (Kaletra), atazanavir/r, 
darunavir/r, tipranavir/r, or fosamprenavir/r. (Fully active is 
defined by genotypic analysis.) 
• Genotypic sensitivity score (GSS) of at least 2 (including the 
fully active PI/r and EVG). 
• Adequate renal, hematologic, and hepatic function. 
• No opportunistic infection within 30 days of study entry 
Exclusion Criteria: 
• Subjects with the following CD4+ cell counts: 
— For Cohorts 1 and 2: Screening CD4+ cell count 
< 50 cells/mm3 
— For Cohort 3: Screening CD4+ cell count < 75 cells/mm3 
— For Cohort 4: Screening CD4+ cell count < 200 cells/mm3  


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• Evidence of active pulmonary or extra-pulmonary tuberculosis 
disease: 
— Within 3 months of the Screening visit for all subjects 
6 months of age or older 
— At any time for subjects younger than 6 months 
• An ongoing serious infection requiring systemic antibiotic 
therapy at the time of screening 
• An acquired immunodeficiency syndrome (AIDS)-defining 
condition with onset within 30 days prior to screening 
• Life expectancy of < 1 year 
• For subjects with HIV-1 RNA >1,000 copies/mL at screening, 
prior treatment of any duration with an integrase strand transfer 
inhibitor 
Study Procedures/ 
Frequency: 
All Subjects (Parts A and B): 
At the Screening, Baseline/Day 1, and all subsequent in-clinic 
study visits, laboratory analyses (hematology, chemistry and 
urinalysis), HIV-1 RNA (Roche COBAS TaqMan v2.0), CD4+ 
cell count and percentage, vital signs, complete or 
symptom-directed physical examinations, and estimated GFR 
using the Schwartz formula will be performed.  
 
At the Screening visit, Hepatitis B virus (HBV) and Hepatitis C 
virus (HCV) serologies will be analyzed (with the exception of 
Cohorts 3 and 4, where maternal medical history for HBV and 
HCV will be obtained in lieu of laboratory testing) and supine 
ECG will be performed. For subjects failing a current antiretroviral 
regimen (HIV-1 RNA >1,000 copies/mL at screening), HIV-1 
integrase, protease and reverse transcriptase genotype will be 
performed at Screening using the GenoSure PRIme assay. 
Subjects enrolled in Part A will participate in an Intensive PK 
evaluation of EVG on Day 10 (as described below, “Specific 
Procedures in Part A”). A telephone visit wll occur on Week 1 
(Day 7) for safety follow-up assessments. 
Subjects with HIV-1 RNA >1,000 copies/mL at screening are 
considered to be failing a current antiretroviral regimen and will 
return for study visits at Weeks 4, 8, 12, 16, and then every 
8 weeks through Week 48. A telephone visit wll occur on Week 1 
(Day 7) and Week 3 for safety follow-up assessments. 
Metabolic assessments (glucose and lipid panel [total cholesterol, 
HDL, direct LDL, and triglycerides]) will be assessed at Baseline, 


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Week 24, and Week 48 for subjects failing a current antiretroviral 
regimen (HIV-1 RNA >1,000 copies/mL) and weighing at  13 kg 
at the time of the visit. 
Tanner Stage assessments (Appendix 6) will be performed for 
subjects  6 years of age at the time of the visit, at Baseline, 
Weeks 24 and 48 or until subjects reach Tanner Stage 5, at which 
point assessments will no longer be performed. Date of first 
menses will be documented. For subjects with HIV-1 RNA <50 
copies/mL at screening, Tanner Stage assessments will only be 
completed at the Baseline visit. 
Palatability of EVG suspension formulation will be assessed at 
Baseline, Day 10 (Part A only), Week 24, and Week 48, as 
applicable. 
At Weeks 16 and 40, a trough PK sample (20 to 24 hours postdose) 
will be collected. A random single plasma PK sample will be 
collected at all Weeks 4, 8, 12 (except for Cohort 3), and 32, for 
descriptive PK. 
Resistance testing will be performed in subjects who experience 
suboptimal response, virologic rebound, and in subjects at 
Week 48 or Early Study Drug Discontinuation (ESDD) visit if 
HIV-1 RNA is ≥ 400 copies/mL. 
Adverse events (AEs) and concomitant medications will be 
assessed at each visit. Treatment adherence will be assessed at all 
post Baseline visits. 
Subjects who are permanently discontinued from the study before 
Week 48 will be required to complete an ESDD visit within 
72 hours of stopping study drug and return to the clinic 30 days 
after the ESDD visit for a 30-Day Follow-Up Visit. 
After Week 48, all subjects receiving EVG will be given the option 
to participate in an extension phase of the study where Gilead will 
provide EVG until: a) the subject turns 18 and EVG is available for 
use in adults in the country in which the subject is enrolled or b) 
the age appropriate EVG formulation becomes available for use in 
the country in which the subject is enrolled or c) Gilead Sciences 
elects to terminate development of EVG in the applicable country. 
Subjects who are eligible to participate in the study extension must 
demonstrate evidence of response to EVG or show absence of 
resistance to EVG for subjects with HIV-1 RNA > 400 copies/mL 
at Week 48.  


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Specific Procedures in Part A 
Subjects enrolled in Part A will participate in an Intensive PK 
evaluation of EVG on Day 10. For Cohorts 2 and 3, samples will 
be collected at 0 (predose,  30 minutes), 1.5, 2.5, 3.5, 5, 8, 10, and 
12 hours postdose. For Cohort 4, samples will be collected at 0 
(predose,  30 minutes), 3, 3.5, 5, and 8 hours postdose. Subject 
diary cards will be provided to all Part A subjects to record study 
drugs administration on Days 6-9 prior to the Day 10 Intensive PK 
visit.  
• Subjects with HIV-1 RNA <50 copies/mL at screening are 
considered to have suppressed viremia and will only participate 
in Part A of the study.  These subjects will discontinue EVG 
after the Day 10 dose and will return to the clinic 30 days after 
stopping study drug for a 30-Day Follow-Up Visit.  
• Subjects with HIV-1 RNA >1,000 copies/mL at screening will 
continue to receive EVG following completion of the Day 10 
intensive PK visit and return for subsequent study visits as 
described above for all subjects.  
• Subjects who are permanently discontinued from the study 
before Day 10 will be required to complete an ESDD visit 
within 72 hours of stopping study drug. 
Test Product, Dose, 
and Mode of 
Administration: 
EVG 50 mg, 85 mg, and 150 mg tablets or EVG powder for oral 
suspension formulation (5 mg/mL) will be administered orally with 
food in combination with a BR that must include a PI/r (allowed 
and disallowed agents are described above in “Study Design”). 
For subjects weighing  17 kg and receiving darunavir/r, 
tipranavir/r or fosamprenavir/r, the EVG dose will be as follows: 
• 85 mg for subjects  17 kg to < 28 kg 
• 100 mg (2 x 50 mg tablets) for subjects  28 kg to < 34 kg  
• 150 mg for subjects  34 kg 
For subjects weighing  17 kg and receiving atazanavir/r or 
lopinavir/r, the EVG dose will be as follows: 
• 50 mg for subjects  17 kg to < 30 kg 
• 85 mg for subjects  30 kg 
Note: For subjects who are not able to swallow tablets, EVG 
powder for oral suspension formulation (5 mg/mL) may be 
administered to obtain EVG doses of 50 mg, 85 mg, 100 mg, or 
150 mg. 


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For subjects weighing < 17 kg and receiving darunavir/r, 
tipranavir/r or fosamprenavir/r, the EVG dose will be 4 mg/kg, and 
for subjects weighing < 17 kg and receiving lopinavir/r or 
atazanavir/r, the EVG dose will be 2.4 mg/kg, using the EVG 
powder for oral suspension formulation (5 mg/mL) administered as 
an oral suspension. 
Reference Therapy, 
Dose, and Mode of 
Administration: 
None. 
Criteria for 
Evaluation: 
 
Safety: 
Adverse events, clinical laboratory tests, and Tanner Stage 
assessments to evaluate the safety and tolerability of the treatment 
regimen. 
Efficacy: 
The percentage of subjects with HIV-1 RNA <50 copies/mL at 
Weeks 24 (main efficacy endpoint) and 48. 
Pharmacokinetics: 
The following plasma PK parameters will be estimated: Cmax, Tmax, 
Clast, Tlast, Ctau, λz, AUCtau, AUClast, CL/F, Vz/F and T1/2. The effect 
of age, EVG dose, and PI/r BR on the PK of EVG will be explored.
Statistical Methods: 
For analysis purposes, subjects aged 6 months to < 2 years old 
(Cohort 4a) and subjects aged 4 weeks to < 6 months old (Cohort 
4b) will be combined into one age group (Cohort 4) in Part A. 
Plasma concentration and parameter of EVG will be summarized 
using descriptive statistics by age group and overall. EVG 
exposure PK parameters (AUCtau, Ctau, and Cmax) achieved in 
pediatric subjects will be compared to historical data. 
An analysis of variance (ANOVA) using a mixed-effects model 
appropriate for parallel group design will be fitted to 
natural-logarithm transformed AUCtau, Ctau, and Cmax of EVG to 
evaluate whether the exposures of EVG achieved in pediatric 
subjects are similar to the exposure observed in historical control 
subjects. EVG exposures (AUCtau, Ctau, and Cmax) generated from 
population PK modeling will be used as historical control data. 
Two one-sided tests with each performed at an alpha level of 0.05 
and a boundary of 70% to 143% will be used for exposure 
equivalence assessment. 


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The percentage of subjects who achieve HIV-1 RNA 
<50 copies/mL and <400 copies/mL at Weeks 24 and 48 as defined 
by the FDA snapshot analysis algorithm will be summarized by 
age group and overall. The 95% confidence intervals will also be 
presented. The relationship between EVG exposures (AUCtau, Ctau, 
and Cmax) and virologic failure defined by the snapshot analysis 
will be explored.  
The change from baseline in log10 HIV-1 RNA, CD4+ cell count, 
and CD4 percentage will be summarized by visit, age group, and 
overall using descriptive statistics.  
The incidences of treatment-emergent adverse events and 
treatment-emergent laboratory abnormalities will be summarized 
by age group and overall.  
 
Palatability of oral suspension formulation of EVG will be 
summarized using descriptive statistics by appropriate age group 
and overall. 
For each age group and overall, Tanner Stages at Weeks 24 and 48 
will be summarized by baseline Tanner Stage using frequency and 
percentage. Age of first menses will be summarized descriptively. 
A total of 12 pediatric subjects each in Cohorts 2 – 4 compared to 
334 HIV-infected historical control subjects included in the EVG 
population PK modeling will provide at least 90% power to 
conclude exposure equivalence of EVG AUCtau and Cmax in 
pediatric subjects vs. in historical control subjects, assuming the 
expected geometric mean ratio is 1, equivalency boundary is 70% 
to 143%, 2 one-sided tests are each performed at an alpha level of 
0.05, and the standard deviation is 0.36 ng•hr/mL for AUCtau and 
0.28 ng/mL for Cmax (natural log scale, estimated from EVG 
population PK modeling). 
A total of 12 subjects each in Cohorts 2-4 will also provide at least 
80% power to target a 95% confidence interval within 60% and 
140% of the geometric mean estimate of clearance and volume of 
distribution of EVG respectively, assuming a coefficient of 
variation (CV) of 42.3% for clearance and 22.9% for volume of 
distribution (estimated from EVG population PK modeling).  
A total of 50 subjects from Parts A and B combined will provide 
for reasonable assessment of safety through Week 48 in subjects 
< 18 years of age. For the main secondary efficacy endpoint, 
assuming a virologic success rate of 60% (based on Study 
GS-US-183-0145 in adults) in this population of antiretroviral 
treatment-experienced subjects receiving a new class drug, 


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i.e., EVG, a sample size of 50 subjects will result in a 95% 
confidence interval (CI) for the response rate from 46% to 74% 
(i.e., an error margin of 14%). 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP) including archiving of essential documents. 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
° C  
degrees Celsius 
° F 
degrees Fahrenheit 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil counts  
ARV 
Antiretroviral 
ANOVA 
analysis of variance 
AST 
Aspartate aminotransferase 
ATV 
Atazanavir 
ATV/co 
cobisistat-boosted atazanavir 
ATV/r 
ritonavir-boosted atazanavir 
AUC 
area under the plasma/serum/peripheral blood mononuclear cell 
concentration versus time curve 
AUCtau 
the area under the concentration verses time curve over the dosing interval  
AV 
Atrioventricular 
BR 
background regimen 
BMD 
bone mineral density 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CLcr 
creatinine clearance 
Cmax 
the maximum observed serum/plasma/peripheral blood mononuclear 
(PBMC) concentration of drug 
Clast 
the last observed quantifiable concentration of the drug in plasma 
COBI 
cobicistat (GS-9350) 
CNS 
central nervous system 
Ctau 
the observed drug concentration at the end of the dosing interval 
CPI 
comparator protease inhibitor 
CPK 
creatine phosphokinase 
CRO 
contract (or clinical) research organization  
CV 
Coefficient of Variation 
CYP 
cytochrome P450 
DAVG 
average area under the dosing interval 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DRV 
darunavir  
DSPH 
Drug Safety and Public Health 
EC 
Ethics Committee 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
ECG 
Electrocardiogram 
eCRF 
electronic case report form(s) 
EVG 
elvitegravir (GS-9137) 
EVG/co 
cobicistat-boosted elvitegravir 
EVG/COBI/FTC/TDF 
Single tablet regimen of elvitegravir (EVG) 150 mg/ cobicistat (COBI) 
150 mg emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 
300 mg 
EVG/r 
ritonavir-boosted elvitegravir 
Emax 
model predicted maximum efficacy 
FDA 
(United States) Food and Drug Administration 
FTC 
emtricitabine, Emtriva® 
FTC/TDF 
emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg, Truvada® 
GCP 
Good Clinical Practice (Guidelines) 
GFR 
glomerular filtration rate 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practices 
GSI 
Gilead Sciences, Inc. 
GSS 
Genotypic sensitivity score 
GS-9137 
elvitegravir, 6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-
2-yl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 
GS-9350 
cobicistat, 1,3-Thiazol-5-ylmethyl (2R,5R)-(5-(((2S)-2-((methyl((2-(propan-
2-yl)-1,3-thiazol-4-yl(methyl(carbamoyl)amino((-4-(morpholin-4-
yl)butanamido(-1,6-diphenylhexan-2-yl)carbamate 
HAART 
highly active antiretroviral therapy 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
hERG  
human Ether-à-go-go Related Gene 
HIV 
Human Immunodeficiency Virus 
HMG-CoA 
5-hydroxy-3-methylglutaryl-coenzyme A 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IND 
Investigational New Drug (Application) 
INSTI 
integrase strand transfer inhibitor 
IRB 
Institutional Review Board 
IV 
Intravenous 
KS 
kaposi’s sarcoma 
LC/MS/MS  
liquid chromatography – tandem mass spectrometry 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
LLN 
lower limit of the normal range 
LPV 
lopinavir  
MDRD 
modification of diet in renal disease 
MDZ 
Midazolam 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mmHg 
millimeters mercury 
mtDNA 
mitochondrial DNA 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NRTI 
nucleoside/nucleotide reverse transcriptase inhibitor 
NSAID 
non-steroidal anti-inflammatory drug 
OBT 
optimized background therapy 
PI 
protease inhibitor 
PI/r 
ritonovir boosted-protease inhibitor 
PK 
Pharmacokinetic 
PR 
pulse rate 
PPI 
proton pump inhibitor 
PT 
preferred term (in Section 7) 
PT 
prothrombin time (in Appendix 5) 
QD 
once daily  
QTc 
corrected QT 
RAL 
Raltegravir 
RNA 
ribonucleic acid 
RTV 
ritonavir, Norvir®  
SAE 
serious adverse event 
Scr 
serum creatinine 
STR 
Single Tablet Regimen 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T½  
half life 
TDF 
tenofovir disoproxil fumarate, Viread® 
TFV 
Tenofovir 
TLOVR 
time to loss of virologic response 
tmax 
the time (observed time point) of Cmax 
TPR 
tipranavir  
TPV/r  
ritonavir-boosted tipranavir 
Ucr 
urine creatinine 
UGT 
uridine glucuronosyltransferase 
ULN 
upper limit of the normal range 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
US 
United States 
Ȝz 
terminal elimination rate constant, estimated by linear regression of the 
terminal elimination phase of the plasma concentration of drug verses time 
curve  


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1. 
INTRODUCTION 
1.1. 
Background 
HIV-1 infection is a life-threatening and serious disease that is of major public health interest 
around the world. Globally, it was estimated that approximately 33 million people were 
living with HIV-1 in 2009, including 2.5 million children under 15 years of age {16695}.  In 
the European Union (EU), 26,220 newly diagnosed cases of HIV-1 infection were reported in 
2006, a rate of 67.2 per million people {15984}.  In the US there were an estimated 
42,959 diagnoses of HIV-1 infection reported in 2009 and among these an estimated 
2,244 were in children < 19 years of age {17375}, indicating a continuous prevalence of 
HIV-1 infection in US pediatric and adolescent populations. 
The infection, if left untreated or suboptimally treated, is characterized by deterioration in 
immune function, the subsequent occurrence of opportunistic infections and malignancies, 
ultimately resulting in death. Therapeutic strategies for the treatment of HIV-1 disease have 
been significantly advanced by the availability of highly active antiretroviral therapy 
(HAART); the introduction of HAART was associated with a dramatic decrease in acquired 
immune deficiency syndrome (AIDS)-related morbidity and mortality {2537}, {5125}, 
{8284}.  While combination antiretroviral therapy has been largely successful in reducing the 
morbidity and mortality associated with HIV disease, a significant proportion of patients 
eventually experience loss of virologic, immunologic, or clinical benefit from their current 
regimens. 
Suboptimal adherence and subsequent exposure to multiple antiretroviral regimens over time 
often leaves chronically-infected patients with limited options for alternative treatment 
regimens. Developing safe and effective therapies for treatment-experienced patients with 
documented three- or four-class antiretroviral drug resistance remains a priority. Current 
treatment guidelines suggest several approaches to the management of treatment-experienced 
HIV-infected patients {11575}. The evaluation of patients with treatment failure includes 
assessment of virologic, immunologic and clinical status; determination of the cause of 
treatment failure; and review of pharmacokinetic parameters. In addition, resistance testing 
while patients are still taking their failing regimen provides additional information to identify 
active antiretroviral drugs for inclusion in their subsequent treatment regimen {9302}. 
Incomplete adherence to ARV regimens is a critical factor contributing to the development of 
viral resistance and treatment failure and thus is a primary barrier to successful long-term 
treatment. Total pill burden, dosing frequency, and safety concerns are among the greatest 
obstacles to achieving adherence {4266}, {4256}. This is supported by studies in which 
simple, once-daily HAART regimens demonstrate high levels of adherence and treatment 
satisfaction {7034}, {7035}, {7036}. The potential for noncompliance in pediatric patients is 
well known and is recognized in ICH E11. HIV treatment guidelines recommend that unless 
a clinically inappropriate reason is identified, patients ought to be prescribed once-daily 
HAART.  Thus, there remains a need for developing additional, simplified once-daily single 


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tablet regimens that combine potent and sustained efficacy, favorable tolerability, minimal 
long-term toxicity, and practical, convenient dosing. 
Treatment-experienced HIV-infected children failing currently available regimens have 
limited well-tolerated, once-daily treatment options. For these patients, newer treatments 
targeting alternative steps in the viral replication cycle are needed to preserve their immune 
function and prevent clinical progression. In all patients, the ideal goal of therapy remains 
complete suppression of HIV ribonucleic acid (RNA). 
1.2. 
Elvitegravir (EVG, GS-9137)  
Detailed information is available in the current version of the elvitegravir Investigator’s 
Brochure (IB). 
1.2.1. 
General Information 
HIV belongs to the Lentivirus genus of the Retroviridae family that has two copies of an 
approximately 9.5 kb single-stranded RNA genome. Following viral entry and reverse 
transcription of the viral genome, the resulting linear viral deoxyribonucleic acid (DNA) 
migrates into the nucleus and is integrated into the host cell genomic DNA forming a 
provirus. This integration reaction is catalyzed by the viral-encoded enzyme integrase. This 
enzyme is thus an attractive target for selective anti-HIV therapy since there is no known 
functional homologue in human cells. 
Elvitegravir (chemical name: 6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-
2-yl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid) is a low molecular weight 
HIV-1 integrase inhibitor that specifically inhibits integration of viral DNA into the host 
chromosomal DNA in cell culture. Elvitegravir does not inhibit HIV-1 reverse transcriptase 
or protease enzymes, or human topoisomerase I and II. Elvitegravir showed potent anti-HIV 
activity against both laboratory strains and clinical isolates with EC50 values ranging from 
0.02 to 1.7 nM. The EC50 value of elvitegravir in the presence of 50% human serum is 
1.5 nM using HIV-1 IIIb-infected human peripheral blood mononuclear cell cultures. 
Elvitegravir also exhibited potent antiviral activity against virus with resistance to NRTIs, 
NNRTIs and PIs. 
1.2.2. 
Preclinical Pharmacology and Toxicology 
Single and multiple oral dose toxicity studies (13-week mouse; 1-, 3-, and 6-month rat; 
1- and 9-month dog), a 1-month repeated oral dose immunotoxicity study in rats, 
reproductive toxicity (including a 28-day juvenile toxicity evaluation in rats), genotoxicity 
and safety pharmacology studies have been performed with elvitegravir and revealed no 
significant toxicities. In long-term carcinogenicity studies with elvitegravir, no drug-related 
increases in tumor incidence were found in mice at doses up to 2000 mg/kg/day 
(approximately 3 or 5 times the human systemic exposure at the therapeutic dose of 
150 mg/day) or in rats at doses up to 2000 mg/kg/day (approximately 16 to 35 times human 
systemic exposure at the 150 mg/day therapeutic dose). In a mouse study, high-dose 


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elvitegravir (2000 mg/kg/day) was also administered in combination with ritonavir as 
ritonavir substantially increased elvitegravir exposure in mice. No drug-related increases in 
tumor incidence were noted in these animals at exposures approximately 18 times the 
systemic exposure in humans at the maximum therapeutic elvitegravir dose. 
Two bridging toxicity studies conducted with elvitegravir in combination with ritonavir, a 
90-day toxicity study and an embryo-fetal development study in rats, revealed no additional 
toxicities. No effects were seen in studies to investigate potential for inducing 
quinolone-specific toxicity performed because elvitegravir has a quinolone moiety in its 
molecular structure. These included a single oral dose phototoxicity study in mice and a 
single oral dose study of possible synergistic effects (specifically, drug-induced convulsions) 
of elvitegravir and an NSAID (fenbufen) in mice. In the studies of the cardiovascular and 
respiratory systems in conscious Beagle dogs at doses up to 100 mg/kg, elvitegravir did not 
produce adverse effects on blood pressure, heart rate, the electrocardiogram (ECG), 
respiratory rate, or oxygen saturation. Elvitegravir at concentrations of 0.1 and 1 μM had no 
effect on the hERG tail current in vitro. 
There were no significant adverse effects observed in studies where elvitegravir was 
administered in combination with ritonavir. Additionally, no significant adverse events were 
observed in the safety, pharmacology, mutagenicity, reproductive, and immunotoxicity 
studies or special studies to investigate potential quinolone-related toxicity. 
Exposures in the chronic 9-month dog toxicity study were 2- to 3-fold above the estimated 
human exposure at a dose of elvitegravir 150 mg + ritonavir 100 mg; similar or greater safety 
margins were observed in repeat-dose rodent studies. 
Elvitegravir undergoes metabolism primarily by cytochrome (CYP) P450-mediated oxidation 
and glucuronic acid conjugation (glucuronidation). Following elvitegravir/r dosing, 
elvitegravir is the predominant circulating species in plasma (∼ 94%), with low levels of 
metabolites from hydroxylation and/or glucuronidation pathways, including GS-9200 (M4; 
acyl glucuronide metabolite) produced by UDP-glucuronosyltransferase (UGT) 1A1/3 and 
GS-9202 (M1; primary hydroxylated metabolite) produced by CYP3A4, and 
whose formation is inhibited by ritonavir. Mean plasma exposures of the M1 metabolite 
were below the limit of quantitation in all clinical studies. M4 plasma levels relative to parent 
(i.e., mean M4:parent ratio) were less than 10% in all phase 1 studies and 15% to 24% in a 
Phase 2 study. M4 exposures were 4- to 6-fold lower in humans compared to those observed 
during nonclinical toxicology studies. Additionally, the M1 and M4 metabolites are markedly 
less potent (M1: 5- to 18-fold and M4: 10- to 38-fold in antiviral activity assays) than the 
parent drug, thus metabolites are not considered to contribute to the antiviral activity of 
elvitegravir. Urinary elimination of elvitegravir is a minor pathway with ∼ 6.7% of a dose 
excreted in urine. In vitro, incubation of elvitegravir in human microsomes in the presence of 
ketoconazole (a CYP3A4 inhibitor) was able to almost completely inhibit formation of the 
primary oxidative metabolite M1 (70% and 98% at concentrations of 0.2 and 2.0 μM, 
respectively). In vitro data also suggest that elvitegravir may induce its own metabolism as 
well as potentially that of other CYP3A4 substrates (both the impact of CYP3A4 inhibition 


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and potential for induction of its metabolism, when dosed alone, have been confirmed in 
clinical studies). 
Elvitegravir was tested in a standard in vitro assay for specific effects on the synthesis of 
mitochondrial DNA (mtDNA) in HepG2 liver cells. Following 14 days of treatment, 
elvitegravir did not show any specific effect on the content of mtDNA, a result consistent 
with the lack of inhibition of DNA polymerase gamma. 
1.2.3. 
Clinical Trials of Elvitegravir 
As of 16 November 2012, a total of 327 HIV-1 infected subjects and 963 HIV uninfected 
subjects had been dosed with EVG as a single agent in Phase 1 and 2 clinical studies. In 
addition, 354 HIV-1 infected, ARV treatment-experienced subjects have received EVG in an 
ongoing Phase 3 study. 
1.2.3.1. 
Clinical Pharmacokinetics 
Elvitegravir exhibits less than dose-proportional pharmacokinetics over the dose range of 
20 to 300 mg, likely due to decreased absorption likely due to solubility-limited dissolution. 
Coadministration of elvitegravir with low-dose ritonavir (RTV, 100 mg; elvitegravir/r) to 
healthy adults substantially increases the relative oral bioavailability and slows the apparent 
clearance of elvitegravir, resulting in approximately 20-fold improvement in systemic 
exposure (AUC) and high trough (Ctau) concentrations thereby allowing for once-daily 
dosing. A ritonavir dose of 100 mg is sufficient to boost oral elvitegravir; higher doses of 
ritonavir do not result in additional increases in elvitegravir systemic exposure. Once-daily 
elvitegravir administration at a dose of 50 mg + RTV provides Ctau values greater than the 
in vitro protein-adjusted IC95 {9320}. 
1.2.3.1.1. 
Pharmacokinetic (Drug-Drug) Interactions 
A number of healthy adult volunteer studies have been conducted investigating drug-drug 
interaction between elvitegravir and HIV nucleoside/nucleotide analogue reverse 
transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitor (NNRTI) 
etravirine, the human chemokine receptor CCR5 antagonist maraviroc and protease inhibitors 
(PIs). Results from studies with NRTIs including emtricitabine/tenofovir disoproxil fumarate 
(TRUVADA®), zidovudine, didanosine, stavudine and abacavir indicate no clinically 
relevant drug-drug interactions necessitating dose modifications of these agents or 
elvitegravir/r upon their coadministration. These findings are consistent with the differing 
elimination pathways for the NRTIs (predominantly renal and extra-hepatic metabolism, if 
any) versus elvitegravir and ritonavir (cytochrome P450 and Phase 2 metabolism). Further, 
no clinically relevant drug-drug interaction was observed between elvitegravir/r and 
etravirine, allowing coadministration of these agents without dose modification. 
Coadministration of elvitegravir/r, a net CYP3A inhibitor, with maraviroc resulted in no 
clinically relevant change in elvitegravir pharmacokinetics; however, maraviroc exposure 
was 2- to 4-fold higher in the presence of elvitegravir/r. When coadministered with CYP3A4 


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inhibitors (including ritonavir-boosted protease inhibitors [except tipranavir/r]), an 
adjustment of maraviroc dose is recommended. 
Clinical drug-drug interaction studies designed to evaluate the pharmacokinetics of 
elvitegravir when used within the context of ritonavir-boosted PI antiretroviral regimens in 
healthy adults have also been conducted. In these studies elvitegravir + 100 mg RTV was 
compared to elvitegravir in combination with a ritonavir-boosted protease inhibitor, where 
the ritonavir dose/dosing frequency used was the dose/dosing frequency indicated for use 
with the PI under study (elvitegravir + PI/r). 
Results from these studies have shown that coadministration of elvitegravir plus 
ritonavir-boosted tipranavir (TPV/r; 500/200 mg BID), darunavir (DRV/r; 600/100 mg BID), 
or fosamprenavir (FPV/r 700/100 mg BID) did not result in a pharmacokinetic drug 
interaction. Therefore, elvitegravir can be coadministered (added) to TPV/r-, DRV/r-, or 
FPV/r-containing regimens without dose modification. Data from studies examining 
coadministration with lopinavir/r (LPV/r; 400/100 mg BID) or atazanavir/r (ATV/r; 
300/100 mg QD) indicate substantially higher elvitegravir systemic exposures (AUC: 
increased 75% and 100%, respectively) and trough concentrations (Ctau: increased 136% and 
188%, respectively) by these two protease inhibitors. A dose reduction of elvitegravir is 
being used in this study when it is administered with these two boosted PIs to achieve similar 
AUC and maintenance of high trough concentrations. In a multiple dose clinical study in 
healthy adults (GS-US-183-0106), equivalent elvitegravir exposures (Cmax and AUC) were 
observed with 85 mg plus atazanavir/r versus elvitegravir/ritonavir 150/100 mg. Concomitant 
administration of elvitegravir with LPV/r and ATV/r do not significantly affect the 
pharmacokinetics of lopinavir or atazanavir, and no dose modification of these PIs is 
required. 
Elvitegravir/r simultaneously coadministered with antacids can lead to lower elvitegravir 
levels, putatively via complexation with divalent cations present at high concentrations in 
antacids. Separation of elvitegravir/r dosing from antacid by at least 2 hours minimizes the 
impact on elvitegravir absorption. Coadministration with a representative proton pump 
inhibitor (PPI, omeprazole) had no effect on elvitegravir/r exposures, indicating that the 
interaction of elvitegravir with antacids is due to a local effect on drug absorption and not a 
more general effect of gastric pH. 
Coadministration of EVG/r and dose-reduced rifabutin (150 mg every other day) resulted in 
equivalent exposures of EVG and rifabutin, relative to those observed with EVG/r or 
rifabutin (300 mg once daily) administered alone (GS-US-183-0125) {12104}. Plasma 
exposure of the active metabolite of rifabutin, 25-O-desacetylrifabutin, which is equipotent 
with the parent on a molar basis, was increased 5- to 20-fold by EVG/r. The total 
antimycobacterial activity of rifabutin was increased by 50% during coadministration with 
EVG/r. These results are consistent with data from drug interaction studies with other 
RTV-boosted agents. Dose reduction of rifabutin to 150 mg every other day or 3 times 
weekly is recommended during coadministration with EVG/r. Patients receiving EVG/r and 
rifabutin should be closely monitored for AEs associated with rifabutin. 


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Coadministration of ketoconazole (200 mg twice daily) with EVG/r resulted in modest 
increases in both EVG (< 50%) and ketoconazole exposure (as compared with historical 
data) (Study GS-US-183-0146). Overall, the magnitude of the interaction between EVG/r 
and ketoconazole does not necessitate EVG dose reduction in the setting of ketoconazole. 
However, because of the changes in ketoconazole pharmacokinetics, and consistent with 
dosing recommendations with other RTV-boosted agents, a maximum daily ketoconazole 
dose of 200 mg is recommended in the setting of EVG/r. 
Methadone (80 to 120 mg once daily) pharmacokinetics were unaffected by coadministration 
of EVG 150 mg boosted with cobicistat 150 mg once daily (EVG/co). When EVG/co 
(150/150 mg once daily) was coadministered with buprenorphine/naloxone (16/4 to 24/6 mg 
once daily), buprenorphine and norbuprenorphine exposures were modestly higher (35.3% 
and 42.4%, respectively), and naloxone exposure was modestly lower (28.4%) than when 
buprenorphine/naloxone was dosed alone. These changes were not considered clinically 
relevant. No meaningful changes in opioid pharmacodynamics as assessed by subjective and 
objective opiate withdrawal and overdose assessment scales were noted when EVG/co was 
coadministered with methadone or buprenorphine/naloxone (Study GS-US-216-0125). 
Accordingly, no dose adjustments of methadone or buprenorphine/naloxone are required 
when coadministered with EVG/co. In each case, EVG and COBI exposures were consistent 
with historical data obtained following their administration as EVG/co alone, or as 
components of the EVG/COBI/FTC/TDF STR (Stribild™). 
In these Phase 1 clinical studies in adults, mild headache, nausea, and diarrhea were the most 
common side effects. Two serious adverse events were reported: one early-term miscarriage 
with possible attribution to elvitegravir/r and midazolam due to unclear etiology, and one 
congenital abnormality considered not related to elvitegravir (bilateral, fifth-finger 
appendages, most likely skin tags) in an otherwise healthy infant born to a study subject. No 
deaths were reported in these studies. In these Phase 1 clinical studies, healthy volunteers 
received elvitegravir/r once daily at doses ranging from 50/100 to 250/100 mg for up to 
28 days, and elvitegravir/r appeared to be well tolerated. 
1.2.3.2. 
QT/QTC Interval Study 
Results from Study GS-US-183-0128, a Phase 1, randomized, comparative, positive and 
placebo-controlled, parallel group study of the effects of elvitegravir/r on the QT/QTc 
interval in healthy male and female adult subjects, demonstrated that there is no significant 
effect on the QTc interval in either dosing regimen of elvitegravir/r (125/100 mg or 
250/100 mg for 10 days). Both the 125 and 250 mg doses of elvitegravir were well-tolerated 
in this study. The 125 mg dose provided exposures similar to the 150 mg dose under study in 
this protocol. 
1.2.3.3. 
Elvitegravir Pediatric Formulation Pharmacokinetic Study 
In a Phase 1 study in healthy adult volunteers (Study GS-US-183-0149), the 
pharmacokinetics of 2 pediatric EVG formulations were compared to the adult EVG 


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formulation in an open-label, crossover, randomized, multiple cohort, single-center study.  
The plasma EVG concentrations of 150 mg of either the adult EVG formulation (1 × 150 mg 
tablet), the EVG pediatric tablets (3 × 50 mg tablets) and the EVG pediatric suspension 
(30 mL of a 5 mg/mL suspension), each administered as a single dose with 100 mg of 
ritonavir in the fed state, were compared. Preliminary findings show that RTV-boosted EVG 
exposures were comparable across treatments.  Bioequivalent EVG exposures (AUClast, 
AUCinf, and Cmax) were observed following administration of EVG pediatric tablets or EVG 
pediatric suspension, relative to adult EVG formulation (Table 1-1).  All treatments were 
generally well tolerated. 
Table 1-1. 
GS-US-183-0149: EVG Pharmacokinetic Parameters and 
Statistical Comparison following EVG pediatric tablets or EVG 
pediatric suspension versus adult EVG formulation 
EVG PK 
Parameter 
Mean (%CV) 
Geometric Least-
Squares 
Means Ratio (%) 
(90% CI) 
Test 
EVG Pediatric Tablets 
(N = 30) 
Reference 
Adult EVG Formulation 
(N = 30) 
AUCinf 
(ng•h/mL) 
22224.9 (34.5) 
22148.1 (36.2) 
100.07 (93.77,106.78) 
AUClast 
(ng•h/mL) 
21130.9 (31.9) 
20976.2 (29.1) 
99.60 (93.17,106.48) 
Cmax (ng/mL) 
1648.3 (29.8) 
1639.2 (28.5) 
100.02 (93.10,107.45) 
EVG PK 
Parameter 
Mean (%CV) 
Geometric Least-
Squares 
Means Ratio (%) 
(90% CI) 
Test 
EVG Pediatric Suspension 
(N = 26) 
Reference 
Adult EVG Formulation 
(N = 26) 
AUCinf 
(ng•h/mL) 
25005.7 (35.8) 
22827.9 (36.4) 
105.21 (100.00,110.69) 
AUClast 
(ng•h/mL) 
24221.9 (36.3) 
21813.5 (37.2) 
105.15 (99.92,110.65) 
Cmax (ng/mL) 
1800.4 (40.1) 
1650.6 (37.5) 
108.01 (100.91,115.61) 
 
1.2.3.4. 
Clinical Trials in HIV-1 Infected Adult Subjects 
Data from Study GS-US-183-0101 (proof-of-concept), a Phase 1, double-blind, randomized, 
placebo-controlled study in treatment-naive and treatment-experienced HIV-infected 
patients, demonstrated that elvitegravir has potent antiretroviral activity (∼ 2 log10 copies/mL 
reduction) at doses of 400 to 800 mg twice daily or 50 mg once daily when boosted with 
ritonavir 100 mg for 10 days with no clinically significant adverse events or laboratory 
abnormalities {9320}. An Emax dose-response model demonstrated that antiviral activity was 
strongly associated with elvitegravir steady-state Ctau concentrations. 


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Study GS-US-183-0105 was a randomized, partially-blinded, active-controlled, 
dose-ranging, 48-week, Phase 2 study. The study was designed to assess the non-inferiority 
of ritonavir-boosted elvitegravir versus ritonavir-boosted comparator PIs both in combination 
with an optimized background therapy (OBT) in HIV-1 infected treatment-experienced 
subjects. At screening, subjects were to have a plasma HIV RNA load ≥ 1000 copies/mL and 
documented presence of at least one protease gene mutation as defined by the IAS-USA 2006 
Guidelines {9302}. 
A total of 297 patients were randomized (1:1:1:1) to four treatment arms each of which 
included OBT with at least two agents not including a protease inhibitor or a non-nucleoside 
reverse transcriptase inhibitor (randomization was stratified by the use of T-20): 
• Arm 1 – Comparator protease inhibitor boosted with ritonavir (CPI/r) + OBT 
• Arm 2 – Elvitegravir 20 mg/ritonavir 100 mg + OBT 
• Arm 3 – Elvitegravir 50 mg/ritonavir 100 mg + OBT 
• Arm 4 – Elvitegravir 125 mg/ritonavir 100 mg + OBT 
The primary endpoint was the time-weighted mean change from baseline in HIV-1 RNA at 
Week 24 (DAVG24). The DAVG24 of the elvitegravir/r 125 mg treatment arm 
(−1.7 log10 copies/mL) was superior to that of the CPI/r arm (−1.2 log10 copies/mL; 95% CI 
−0.8, −0.05; p = 0.0094). At Week 24, the proportions of patients who received elvitegravir/r 
125 mg with > 1 log10 reduction in HIV-1 RNA from baseline, HIV-1 RNA < 400 copies/mL 
or HIV-1 RNA < 50 copies/mL are non-inferior to the proportions of patients achieving the 
same responses in the CPI/r arm. The magnitude and durability of virologic suppression in 
subjects who received elvitegravir 125 mg correlated with the activity of background 
therapy; for example, 74% of subjects given elvitegravir 125 mg with naive use of T-20 
achieved HIV RNA < 50 copies/mL by Week 16. 
Elvitegravir/r was well-tolerated in this study. The incidences of Grade 3 and 4 adverse 
events, treatment-emergent adverse events leading to study drug discontinuation, serious 
adverse events, and Grade 3 and 4 laboratory abnormalities across the elvitegravir/r treatment 
arms were similar to the incidences in the CPI/r group and were not dose related. Two 
serious adverse events were reported as related/possibly related to elvitegravir/r, including a 
hypersensitivity reaction and syncope. Three subjects treated with elvitegravir/r died during 
the trial. The cause of death was cardiorespiratory failure with underlying cachexia and 
acquired immune deficiency syndrome, pneumocystis infection, and large B-cell lymphoma. 
None of the deaths were assessed as related to elvitegravir/r, but likely due to the subjects' 
underlying HIV infection. 
Study GS-US-183-0130 is an ongoing, Phase 2, open-label, multicenter study of the safety of 
EVG/r administered in combination with a background ARV regimen to HIV-1 infected 
adult and adolescent subjects who had completed a prior EVG/r treatment study without 


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experiencing treatment-limiting toxicity, regardless of whether or not they had received EVG 
in that study, and regardless of their baseline plasma HIV-1 RNA level.  
Data are available from an interim analysis at Week 192, conducted when all adult subjects 
from Study GS-US-183-0105 had completed 192 weeks of treatment. The adolescent 
subjects who rolled-over from Study GS-US-183-0152 (described below) had completed a 
median 32 weeks of treatment.  
A total of 192 subjects were enrolled in the study, 184 adults (95.8%) from Study 
GS-US-183-0105 and 8 adolescents (4.2%) from Study GS-US-183-0152. The interpretation 
of efficacy data in this study is difficult because of the inclusion of subjects who had 
(n = 162) and had not (n = 30) received EVG in their prior study, subjects with baseline 
HIV-1 RNA levels < 50 copies/mL and ≥ 50 copies/mL, a high attrition rate during the study 
for reasons other than lack of efficacy or death (79 of 192 subjects; 41.1%), and the lack of a 
comparator arm. 
Percentages of subjects with a plasma HIV-1 RNA level < 50 copies/mL at different study 
time points are shown in Table 1-2. 
Table 1-2. 
GS-US-183-0130: Proportions of Subjects with Plasma HIV-1 
RNA < 50 Copies/mL at Study Time Points (Efficacy Analysis Set) 
Week 
Baseline HIV-1 RNA 
< 50 Copies/mL (n = 84) 
≥ 50 Copies/mL (n = 107) 
M = Fa 
M = Eb 
M = Fa 
M = Eb 
48 
86.6% 
89.9% 
25.7% 
36.1% 
96 
76.8% 
86.3% 
28.7% 
46.0% 
144 
72.0% 
88.1% 
29.7% 
58.8% 
192 
68.3% 
90.3% 
30.7% 
70.5% 
a 
Missing = Failure. M = F, in which subjects with missing data for a visit were counted as a failure for that visit, was 
used for the primary analysis. Subjects who had missing data for a visit because they had not yet reached the end of the 
analysis window for that visit were excluded from that visit and all subsequent visits. 
b 
Missing = Excluded. M = E analysis, in which subjects with missing data were excluded entirely, was used for 
secondary analysis.  
 
In subjects with baseline HIV-1 RNA < 50 copies/mL, EVG administered in combination 
with a background ARV regimen showed durable efficacy.  
Long-term virologic suppression was achieved in approximately one-third of subjects with 
baseline HIV-1 RNA ≥ 50 copies/mL, most of whom had received EVG uninterrupted from 
their previous study. This low level of efficacy as determined by the missing = failure 
(M = F) analysis in these subjects can be attributed to the inclusion in the study of subjects 
who were treatment-experienced and had received EVG in a prior study (GS-US-183-0105 or 
GS-US-183-0152) and who had virologic failure at the end of that study. Virology data from 


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the previous studies indicated that many subjects who rolled-over into Study 
GS-US-183-0130 did not have an effective background regimen and had developed 
mutations associated with EVG resistance. Additionally, the attrition rate among these 
subjects was high (58 of 107 subjects; 54.2%), and baseline genotyping was not performed, 
meaning that background ARV regimens were not optimized. 
For subjects with baseline HIV-1 RNA < 50 copies/mL (n = 84), HIV-1 RNA levels 
(log10 copies/mL) were maintained over 192 weeks.  For subjects with baseline HIV-1 RNA 
≥ 50 copies/mL (n = 107), HIV-1 RNA levels decreased over 192 weeks. The mean value at 
baseline for these subjects was 3.51 log10 copies/mL. Mean changes from baseline in plasma 
HIV-1 RNA levels at Weeks 48, 96, 144, and 192 were –0.52, –0.44, –0.66, and 
-0.67 log10 copies/mL, respectively.  CD4 cell counts increased over time in both baseline 
plasma HIV-1 RNA level subject groups (< 50 copies/mL and ≥ 50 copies/mL). 
Of the 49 subjects who qualified for resistance testing, 37 subjects (76%) entered the study 
with preexisting INSTI resistance mutations that had developed during their original 
treatment in Study GS-US-183-0105. Among these subjects, 31 gained additional INSTI 
resistance mutations during the 192-week analysis period of the current study. Six of the 
12 subjects tested who had no evidence of INSTI resistance at study entry developed INSTI 
resistance mutations in the current study.  
Within the overall resistance analysis population, E92Q was the most common INSTI 
resistance mutation to develop, consistent with observations from GS-US-183-0105. 
Mutations at position E92 were also the most commonly lost during the current study, 
reflecting the presence of these mutations at study entry and the subsequent evolution of 
INSTI resistance to other patterns of INSTI mutations.   Only 5 of the 84 subjects (6%) who 
entered the study with HIV-1 RNA < 50 copies/mL qualified for resistance testing, 3 of 
whom developed INSTI resistance mutations during the current study.  
EVG/r was well tolerated in Study GS-US-183-0130.  Treatment-emergent AEs reported for 
at least 10% of subjects were upper respiratory tract infection, diarrhea, sinusitis, bronchitis, 
nasopharyngitis, nausea, fatigue, arthralgia, depression, and back pain.  Most treatment-
emergent AEs reported were mild (Grade 1) or moderate (Grade 2) in severity, and most 
were considered by the investigator to be not related to study drug. Among those AEs that 
were considered related to study drug, reported in at least 12.5% of subjects, only pain in 
extremity, peripheral neuropathy, and alopecia (each reported by 2 subjects) occurred with 
greater than single subject incidence. Four subjects (2.1%) experienced a Grade 3 or Grade 4 
AE considered by the investigator to be related to study drug (acute pancreatitis, hepatitis B, 
and peripheral neuropathy [2 subjects]), all of which were Grade 3 in severity.  There were 
11 deaths during the Week 192 analysis period, none of which was considered by the 
investigator to be related to study drug. No AE leading to study drug discontinuation was 
reported for more than 1 subject, none was considered by the investigator to be related to 
study drug, and all but 1 (renal failure) was an SAE.  


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Among the 192 HIV-1 infected subjects enrolled, 72 subjects (37.5%) experienced a 
treatment-emergent SAE during the Week 192 analysis period. Treatment-emergent SAEs 
reported for more than 1 subject included pneumonia (3.1%), cellulitis (2.1%), myocardial 
infarction (1.6%), chest pain (1.6%), gastroenteritis (1.6%), influenza (1.6%), acute renal 
failure (1.6%), anemia (1.0%), congestive cardiomyopathy (1.0%), pyrexia (1.0%), 
esophageal candidiasis (1.0%), Pneumocystis jiroveci pneumonia (1.0%), dehydration 
(1.0%), osteonecrosis (1.0%), depression (1.0%), mental status changes (1.0%), deep vein 
thrombosis (1.0%), and hypotension (1.0%). None of these treatment-emergent SAEs 
reported for more than 1 subject was considered by the investigator to be related to study 
drug. Two subjects had a treatment-emergent SAE that was considered by the investigator to 
be related to study drug (Grade 3 acute pancreatitis and Grade 2 necrotizing retinitis).  
Study GS-US-183-0145 is an ongoing, Phase 3, double-blind, double-dummy, multicenter, 
randomized, active-controlled study to evaluate the safety and efficacy of EVG/r versus 
RAL, each administered with a background regimen (BR), in approximately 700 HIV-1 
infected, ARV treatment-experienced adults with plasma HIV-1 RNA levels 
 1000 copies/mL and documented resistance (as defined by current International Antiviral 
Society-USA guidelines) or at least 6 months experience prior to screening with 2 or more 
different classes of ARV agents. 
A total of 712 subjects were randomized in a 1:1 ratio, stratified by HIV-1 RNA level 
(≤ 100,000 copies/mL or > 100,000 copies/mL) at screening, and the second agent class 
(NRTI/other), to one of the following 2 treatment groups: 
• Treatment Group 1: EVG 150 mg once daily + RAL placebo twice daily + BR (n=354).  
The EVG dose was reduced to 85 mg once daily for subjects taking ATV/r or LPV/r as 
part of their BR because of known PK interactions with these agents.) 
• Treatment Group 2: RAL 400 mg twice daily + EVG placebo once daily + BR (n=358) 
The BR was constructed by the investigator, based on viral resistance testing, to comprise a 
fully active PI/r (which could be ATV/r, DRV/r, FPV/r, LPV/r, or TPV/r) and a second 
agent. At study sites other than those in Spain, the second agent did not need to be fully 
active and could be 1 NRTI or nucleotide reverse transcriptase inhibitor, the NNRTI 
etravirine, the CCR5 receptor inhibitor maraviroc, or the HIV-1 fusion inhibitor enfurvirtide. 
The second agent could not be an integrase inhibitor, the NNRTIs EFV, nevirapine, or 
delavirdine (because of unknown PK interactions with EVG), or the STRs Atripla 
(EFV/FTC/TDF) or Trizivir (ABC/3TC/ZDV). At sites in Spain the second agent was 
required to be fully active. 
If the M184V/I RT mutation was present in the screening genotype, and an NRTI was used 
as the second agent, FTC or 3TC could be added as a third agent in the BR to maintain the 
M184V/I mutation. In this situation only, the STR therapies Combivir (3TC/ZDV), Truvada 
(FTC/TDF), or Epzicom/Kivexa (ABC/3TC) could be used as combined second and third 
agents of the BR. 


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The initial 96-week randomized double-blind period of Study GS-US-183-0145 has been 
completed, and the primary endpoint (the percentage of subjects who achieved and 
maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48) has been analyzed 
{19045}. 
At the time of the data cut-off for the 96-week analysis, 146 of 354 subjects (41.2%) in the 
EVG group and 150 of 358 subjects (41.9%) in the RAL group had discontinued study 
medication and 138 subjects (39.0%) in the EVG group and 135 subjects (37.7%) in the RAL 
group had discontinued the study. Reasons for discontinuation of study medication were 
generally similar in the 2 groups (principally subject noncompliance and lost to follow-up), 
but there were fewer deaths in the EVG group (1 subject; 0.3%) than in the RAL group 
(9 subjects; 2.5%). 
Similar proportions of subjects in each treatment group achieved and maintained confirmed 
HIV-1 RNA < 50 copies/mL at Week 48, the primary efficacy endpoint, using time-to-loss-
of-virologic-response (TLOVR) analysis: 59.0% of subjects in the EVG group and 57.8% of 
subjects in the RAL group were classified as responders. The stratum-weighted difference 
between treatment groups (EVG – RAL) was 1.1% (95% CI: –6.0% to 8.2%). Since the 
lower bound of the 2-sided 95% CI of the stratum-weighted difference in response rate 
(EVG – RAL) was greater than the prespecified noninferiority margin of –10%, EVG was 
determined to be noninferior to RAL. 
Slightly more subjects were never suppressed in the EVG group (7.7%) than in the RAL 
group (5.1%). In contrast, a higher proportion of subjects in the RAL group (16.0%) than in 
the EVG group (11.4%) experienced virologic rebound. Taken together, the proportions of 
subjects with loss of virologic response (due to never having been suppressed or to virologic 
rebound) were similar in the EVG and RAL treatment groups.  
At Week 96, the Kaplan-Meier estimate for the proportion of subjects with loss of virologic 
response was 52% in the EVG group and 55% in the RAL group. The median time to loss of 
virologic response was 617 days in the EVG group and 562 days in the RAL group 
(p = 0.86).  Mean (SD) decreases from baseline in HIV-1 RNA were 
−2.26 (1.078) log10 copies/mL in the EVG group and −2.31 (1.068) log10 copies/mL in the 
RAL group. The difference in least-squares means was 0.05 (95% CI: −0.12 to 0.22).  At 
Week 96, mean (SD) increases from baseline in CD4 cell count were 205 (191.5) cells/mm3 
in the EVG group and 198 (162.2) cells/mm3 in the RAL group. The difference in 
least-squares means was 7 (95% CI: −25 to 39). 
The 95% CIs for treatment differences in the percentages of subjects achieving and 
maintaining confirmed HIV-1 RNA < 50 copies/mL included zero for all subgroups analyzed 
(baseline HIV-1 RNA ≤/> 100,000 copies/mL, class of second agent in BR [NRTI/other], age 
≤/> 45 years, male/female, white/nonwhite, US and Puerto Rico/other geographic area, 
baseline CD4 cell count ≤/> 200 cells/mm3, type of PI in BR [FPV, DRV, or TPV versus 
LPV or ATV], and baseline genotypic sensitivity score ≤/> 1) suggesting no treatment 
difference across subgroups. 


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At screening, all subjects were analyzed for preexisting protease and RT resistance. Overall, 
70% of subjects harbored at least 1 nucleoside-associated mutation, most commonly 
M184V/I, present in 57% of subjects.  A total of 180 subjects met the virologic failure 
criteria during the Week 96 analysis period and were included in the resistance analysis 
population. The proportions of subjects in each of the treatment groups included in the 
resistance analysis population were similar (24.8% of subjects in the EVG group and 26.5% 
of subjects in the RAL group).  INSTI resistance mutations occurred at similarly low 
frequencies in each treatment group (EVG 6.6%, RAL 7.4%). The most frequent INSTI 
resistance mutations observed in the EVG group were T66I/A and E92Q (in 2.3% and 2.0% 
of subjects, respectively), and the most frequent INSTI resistance mutations observed in the 
RAL group were N155H and Q148H (in 4.6% and 2.0% of subjects, respectively). Mutations 
T66I/A, S147G, and Q148R were found exclusively in the EVG group, while Y143R/H/C 
and Q148H were found exclusively in the RAL group. Mutations E92Q/G, T97A, and 
N155H were observed in both treatment groups, confirming their cross-resistant nature. 
Postbaseline phenotypic analysis showed that 91% of subjects that developed INSTI 
resistance mutations while receiving RAL had phenotypic resistance to RAL. Most of these 
subjects exhibited cross-resistance to both RAL and EVG. Seventy percent of subjects 
developing INSTI resistance mutations while receiving EVG had phenotypic resistance to 
EVG. Only 55% of these subjects displayed cross-resistance to both drugs. Overall, the 
presence of genotypic resistance correlated well with the presence of phenotypic resistance, 
with varying degrees of cross-resistance observed depending on the specific resistance 
pattern. 
EVG/r was well-tolerated in this study.  The most frequently reported AEs in the EVG group 
were diarrhea (33.6%), upper respiratory tract infection (18.9%), and headache (13.3%).  
Adverse events were mostly mild or moderate in severity and were reported with similar 
frequencies in both treatment groups except for diarrhea, which was reported more frequently 
in the EVG group. Grade 3 or Grade 4 AEs reported for more than 1% of subjects in either 
treatment group were: pneumonia (EVG: 1.7%, 6 subjects; RAL: 1.4%, 5 subjects); cellulitis 
(EVG: 1.1%, 4 subjects; RAL: 0.3%, 1 subject); blood bilirubin increased, diarrhea, and 
hypercholesterolemia (each reported for EVG: 0.3%, 1 subject; RAL: 1.1%, 4 subjects); and 
liver function test abnormal (EVG: 0 subjects; RAL: 1.4%, 5 subjects). 
Nine subjects died during the Week 96 analysis period, 2 in the EVG group and 7 in the RAL 
group. Neither death in the EVG group (due to acute myocardial infarction and rectal 
hemorrhage) was considered by the investigator to be related to study drug. Three additional 
deaths, 1 in the EVG group (due to chronic hepatic failure as a result of hepatitis C) and 2 in 
the RAL group (due to Stage IV Hodgkin’s lymphoma, and cardiomegaly with mitral valve 
prolapse) were not treatment-emergent in that they occurred > 30 days after the last dose of 
study drugs, and were not considered by the investigator to be related to study drug.  Similar 
proportions of subjects in each treatment group reported SAEs (EVG 20.1%, RAL: 23.5%) 
and SAEs judged by the investigator to be related to study drug (EVG: 1.1%, 4 subjects; 
RAL: 2.0%, 7 subjects) during the Week 96 analysis period. SAEs reported for > 1% of 
subjects in either treatment group were: 


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• EVG group: pneumonia (3.4%, 12 subjects), and cellulitis (1.4%, 5 subjects) 
• RAL group: pneumonia (2.0%, 7 subjects); bronchitis, cellulitis, chest pain, and suicidal 
ideation (each 1.1%, 4 subjects) 
Similar proportions of subjects in each treatment group discontinued study drug due to an AE 
during the Week 96 analysis period (EVG: 3.1%, 11 subjects; RAL 4.2%, 15 subjects). 
Adverse events leading to study drug discontinuation for more than 1 subject were nausea 
(EVG 2 subjects), vomiting (EVG 2 subjects), and hepatitis/acute hepatitis (RAL 3 subjects). 
Adverse events considered related to study drug by the investigator leading to study drug 
discontinuation were reported for 6 subjects (1.7%) in the EVG group and 9 subjects (2.5%) 
in the RAL group. 
In clinical studies in adult HIV-infected subjects completed to date, EVG/r was generally 
well tolerated at all dose levels and with all concomitant treatments studied, as demonstrated 
by the low overall rate of study drug discontinuation due to AEs and the mild/moderate 
severity of most AEs. The most frequently reported AEs for HIV-1 infected subjects 
receiving an EVG-containing regimen were diarrhea, upper respiratory tract infection, and 
headache. 
1.2.3.5. 
Clinical Trials in HIV-1 Infected Pediatric Subjects 
Study GS-US-183-0152 was a Phase 1B, nonrandomized, open-label, multicenter study of 
once-daily administration of EVG plus an ARV BR containing a PI/r that comprised a 10-day 
PK evaluation phase followed by an optional treatment phase through 48 weeks. The PK 
phase evaluated the steady-state pharmacokinetics of EVG; the optional treatment phase 
evaluated safety and efficacy through 48 weeks of treatment. Twenty-five eligible subjects 
ages 12 to < 18 years were assigned to 1 of 2 EVG dose groups (150 mg/day or 85 mg/day) 
according to the PI prescribed for the BR. All subjects received their RTV dose based on the 
dosing schedule prescribed for the PI; no additional RTV was required to be taken with EVG. 
• Group 1: EVG 150 mg plus DRV/r, FPV/r, or TPV/r (n=11) 
• Group 2: EVG 85 mg plus LPV/r or ATV/r (n=14) 
Two subjects (1 in each treatment group) did not complete the study because of AEs during 
the 10-day PK evaluation phase of the study. Eleven of the 23 subjects who completed the 
10-day PK evaluation phase of the study were eligible for enrollment in the optional 
treatment phase; 9/11 eligible subjects enrolled in the optional treatment phase, each of 
whom completed treatment through 48 weeks. Of the 25 enrolled subjects, 13 (52.0%) were 
male, 7 (28.0%) were white, and 18 (72.0%) were African-American. The median age was 
16 years (range 12 to 17 years: 80% 15 to < 18 years; 48% Tanner Stage 5). 
The mean steady-state value for EVG Ctau on Day 10 was higher in the 85-mg treatment 
group (627.0 ng/mL) than in the 150 mg treatment group (324.5 ng/mL), consistent with 
EVG 85-mg versus EVG 150-mg data from adult studies. Protocol-defined statistical 


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comparison indicated that the geometric least squares-means ratio (90% CI) in adolescents 
versus adult healthy subjects for EVG 150 mg AUCtau (93.43 [75.81, 115.14]) was within 
predefined equivalence boundaries. 
Exploratory statistical comparisons of exposure between EVG 150 mg in adolescents and 
EVG 150 mg in adult HIV-1 infected subjects indicated comparable EVG AUCtau and Ctau 
and a modest difference in Cmax. The EVG 85-mg adolescent dose provided modestly higher 
AUCtau and Cmax compared to EVG 150-mg adult data. These differences are not considered 
to be clinically relevant based on the favorable long-term safety profile for EVG in adults at 
doses up to 300 mg once daily (Study GS-US-183-0130). 
Overall, statistical comparisons between HIV-1 infected adolescents and healthy or HIV-1 
infected adults indicated comparable and clinically equivalent EVG exposures. EVG/r mean 
Ctau was 7- to 13-fold above the in vitro protein binding-adjusted IC95 (45 ng/mL). 
At the end of the 10-day PK evaluation phase, all 11 evaluable subjects who had a baseline 
HIV-1 RNA level > 1000 copies/mL at screening had reductions from baseline in HIV-1 
RNA (median -1.84 log10 copies/mL, range –2.41 to –1.39 log10 copies/mL). Nine of 
11 eligible subjects (screening plasma HIV-1 RNA level > 1000 copies/mL) subsequently 
enrolled in, and completed, the 48-week optional treatment phase. All 9 subjects had 
reductions in HIV-1 RNA from baseline to Week 48 (the median change from baseline was 
-1.74 log10 copies/mL, range –2.69 to –0.40), and 2 subjects had HIV-1 RNA < 50 copies/mL 
at Week 48. Increases were observed in CD4 cell counts and percentages; 6/9 subjects had a 
CD4 cell count within or near the normal reference range at Week 48, and 6/9 subjects had 
CD4 cell percentage values within or near the normal reference range at Week 48. 
Four of 9 subjects enrolled in the optional treatment phase through 48 weeks were included 
in the resistance analysis population. Three subjects had preexisting secondary integrase 
mutations at baseline (V72I, L74M, and S119G), and 1 subject developed a secondary 
integrase resistance mutation at or before Week 48 (V72I); however, all 4 subjects lacked 
primary integrase resistance mutations and remained phenotypically susceptible to EVG 
(fold-change < 2.5). 
All 25 enrolled subjects received at least 1 dose of EVG. Twenty-three of 25 subjects 
completed the 10-day PK evaluation phase of the study, including 13/14 subjects in the EVG 
85-mg treatment group and 10/11 subjects in the EVG 150-mg treatment group. The 
9 subjects participating in the optional treatment phase of the study received a median 
48.3 weeks of EVG (range 47.6 weeks to 49.6 weeks). 
During the 10-day PK evaluation phase of the study, treatment-emergent AEs were reported 
for 10/14 subjects (71.4%) in the EVG 85-mg treatment group and 8/11 subjects (72.7%) in 
the EVG 150-mg treatment group. Overall, nausea (6/25 subjects, 24.0%) and dizziness 
(3/25 subjects, 12.0%) were the most frequently reported AEs; all other AEs were reported 
for 2 or fewer subjects in either treatment group. 


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Most AEs were mild or moderate in severity (Grade 1 or 2) and considered by the 
investigator to be not related to study treatment. Grade 3 was the highest severity AE 
reported during the 10-day PK evaluation phase of the study; Grade 3 AEs were reported in 
2/25 subjects, 1 in each treatment group, and included treatment-related nausea, vomiting, 
dizziness and chills. Both of these subjects discontinued EVG because of the AEs. No 
additional subject prematurely discontinued EVG. There were no deaths. There was 1 SAE 
(pneumonia not related to study drug). 
No Grade 3 or 4 AEs and no SAEs were reported for the 9 subjects enrolled in the optional 
treatment phase through 48 weeks. No relationship between AE frequency and EVG dose 
was observed. 
There was no apparent study treatment-related change over time in hematology, clinical 
chemistry, urinalysis, or safety serology results. One subject in the EVG 85-mg treatment 
group (whose background regimen included ATV/r) had Grade 3 hyperbilirubinemia on 
Day 14, during the posttreatment follow-up period. All 9 subjects enrolled in the optional 
treatment phase of the study had treatment-emergent graded laboratory abnormalities at some 
time point through 48 weeks; most of these laboratory abnormalities were Grade 1 or 2. No 
notable change in vital signs, ECGs, or physical findings was observed during the study. No 
pregnancy occurred during the study. 
1.3. 
Rationale for This Study 
Although more than 20 different antiretrovirals in five classes are available for the treatment 
of HIV infection in adults, treatment-experienced pediatric patients who experience virologic 
failure continue to have limited treatment options. Children with longstanding HIV infection 
are in particular need of new classes of drugs that are active against HIV resistant to existing 
classes of agents. Currently, HIV-infected children have very limited options for 
well-tolerated once daily therapy.  No once daily INSTI is currently approved for use in 
HIV-1 infected children. 
Thus, for many children who have experienced and/or failed treatment there is currently 
unmet medical need for effective therapies to be included in second and later-line regimens. 
Elvitegravir is an HIV-1 integrase inhibitor that has demonstrated in vitro activity against 
NNRTI, NRTI or PI drug resistant HIV-1. In clinical studies, elvitegravir has produced 
significant declines in HIV-1 RNA in treatment-experienced patients with documented drug 
resistance. 
The current study is designed to examine the pharmacokinetics, safety and antiviral activity 
of elvitegravir added to a BR containing a ritonavir-boosted PI in HIV-1 infected, 
antiretroviral treatment-experienced pediatric subjects. 


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1.4. 
Rationale for the Current Dose 
Phase 1 and 2 studies have investigated a wide range of doses, dosing intervals, and drug 
exposures, including a > 6-fold range in dose and > 8-fold range in mean trough 
concentrations and indicate that elvitegravir (GS-9137) trough (Cmin) is associated with 
antiviral activity. Analyses of these exposure-response data indicate that the 125 mg boosted 
dose of elvitegravir  provides exposures with substantial and perhaps optimal antiviral 
activity {9320}, {10590}. 
Elvitegravir administered to pediatric subjects within the weight range evaluated in this study 
is planned to provide plasma exposures comparable to the EVG exposures achieved in adults 
when coadministered with a PI/r.  The EVG dose is intended to be adjusted appropriately 
depending on the ritonavir boosted PI being administered. EVG is currently available as 
50 mg, 85 mg and 150 mg tablets, as well as a powder for oral suspension formulation. The 
proposed doses take into account the available dosage forms. The oral suspension 
formulation (150 mg dose) and the pediatric tablets (3 x 50 mg dose) show bioequivalent 
exposures versus the adult tablet formulation. 
The doses of elvitegravir administered to the adolescent population are identical to the doses 
administered in the adult Phase 3 study: EVG 150 mg when coadministered with darunavir/r, 
fosamprenavir/r or tipranavir/r, and EVG 85 mg when coadminstered with atazanavir/r or 
lopinavir/r.  These doses have been demonstrated to result in EVG exposures in HIV-infected 
adolescents that are comparable and clinically equivalent to exposures in healthy or HIV-1 
infected adults (Study GS-US-183-0152). 
EVG dose selection in combination with the ritonavir-boosted protease inhibitors DRV, 
TPV, fAPV, ATV, or LPV entailed considerations of the differing adult EVG dose with these 
agents (EVG 150 mg with DRV, TPV or fAPV; and EVG 85 mg with LPV or ATV) and the 
different PI/r dose across pediatric weight bands that are unique to each PI/r. The proposed 
EVG doses in combination with DRV/r, TPV/r and fAPV/r across the weight bands are listed 
in (Table 1-3). The proposed EVG doses in combination with ATV/r or LPV/r, across the 
weight bands are listed in (Table 1-4).  
For drugs with extensive hepatic metabolism, such as EVG, a prolonged elimination half-life 
is generally observed in neonates compared with older age groups {14699}.  Therefore, these 
drugs, including EVG, should be administered with caution until subjects have reached the 
age of 2 months {10609}. PK data for LPV/r in infants ~ 6 weeks of age as well as fAPV in 
infants < 6 months of age demonstrate lower exposure for the PI in infants of these ages 
compared with older children {21225}, {12272}. Based on the additional uncertainty for a 
dose-exposure relationship in children < 2 months old, EVG administration will be restricted 
to coadministration with LPV/r, and subjects will be enrolled individually and dosed 
sequentially within the cohort following PK analysis and confirmation of the selected dose of 
the previous subject(s). 


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The EVG doses proposed for this study represent a higher dose on a mg/kg basis relative to 
the adult dose, with the magnitude of increase comparable to that of the corresponding PI 
within each weight band. Overall, EVG exposures with the various PIs at the various doses 
are expected to be comparable to those observed in adults and are expected to result in 
efficacious plasma concentrations, i.e. EVG Ctrough maintained above the IC95 (44.5 ng/mL; 
protein-binding adjusted). If suitable EVG exposures are not observed in the PK-lead-in 
phase within an age cohort, alternate EVG dose(s) may be evaluated.  
Table 1-3. 
EVG dose (mg) by Weight Range with DRV, fAPV or TPV  
Weight range  
EVG dose (mg) 
w DRV, fAPV or TPV 
mg/kg 
34 kg 
150 
<4.4 
28 to <34 kg 
100 
2.9-3.6 
17 to <28 kg 
85 
3.0-5.0 
<17 kg 
- a 
4 
a 
For subjects weighing <17 kg, EVG dose will be calculated based on the subject’s actual weight to provide 4 mg/kg. 
 
Table 1-4. 
EVG dose (mg) by Weight Range with ATV, LPV 
Weight range 
EVG dose (mg) 
w ATV, LPV 
mg/kg 
30 kg 
85 
<2.8 
17 to <30 kg 
50 
1.7-2.8 
<17 kg 
-a 
2.4 
a 
For subjects weighing <17 kg, EVG dose will be calculated based on the subject’s actual weight to provide 2.4 mg/kg. 
 
The decision of which ritonavir-boosted PI is selected as part of the BR is strictly at the 
discretion of the investigator in accordance to the local standard of care.  Due to the 
availability of drug-drug interaction data with elvitegravir, the following ritonavir-boosted 
PIs are allowed to be prescribed by the investigator as part of the BR: atazanavir/r, 
darunavir/r, fosamprenavir/r, lopinavir/r (Kaletra), or tipranavir/r (Refer to Section 5.3; no 
other marketed PIs may be taken as part of the BR due to unknown potential 
pharmacokinetic interactions). All subjects who enroll will receive at least two fully-active 
antiretroviral agents one of which must be a fully-active ritonavir-boosted PI. Subjects must 
take the ritonavir dose prescribed for the PI that is part of the BR. No additional ritonavir is 
required to be taken with elvitegravir. Elvitegravir should be administered once daily at the 
same time as a once-daily dose of the ritonavir-boosted PI, or with the first dose of a twice-
daily ritonavir-boosted PI with food at the same time each day. 


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1.5. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 


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2. 
OBJECTIVES 
The primary objectives of this study are: 
• To evaluate the steady-state PK and confirm the dose of EVG/r in HIV-1 infected, 
antiretroviral treatment-experienced subjects 4 weeks to <18 years of age 
• To evaluate the safety and tolerability of EVG/r in HIV-1 infected, antiretroviral 
treatment-experienced subjects 4 weeks to <18 years of age 
The secondary objective of this study is: 
• To evaluate the antiviral activity of EVG/r in HIV-1 infected, antiretroviral 
treatment-experienced subjects 4 weeks to <18 years of age who are failing their current 
HAART regimen 


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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoints of this study are:  
• PK parameters AUCtau and Cmax of EVG 
• The incidence of treatment-emergent AEs and treatment-emergent laboratory 
abnormalities 
The secondary endpoints of this study are: 
• PK parameters Ctau, CL/F, and Vz/F of EVG  
• The percentage of subjects with plasma HIV-1 RNA <50 and <400 copies/mL at 
Weeks 24 and 48 as defined by the FDA snapshot analysis, respectively  
• The change from baseline in plasma log10 HIV-1 RNA (copies/mL), in CD4+ cell count 
(cells/μL), and CD4 percentage at Weeks 24 and 48 
• Tanner Stages at Weeks 24 and 48, and age of first menses.  
• Palatability of oral suspension formulation of EVG in appropriate age group 
• Adherence to EVG 
3.2. 
Study Design 
This protocol describes an open-label, multicohort, two-part study evaluating the PK, safety, 
and antiviral activity of EVG administered with a BR containing a PI/r in HIV-1 infected, 
antiretroviral treatment-experienced pediatric subjects. 
Up to approximately 86 pediatric subjects 4 weeks to <18 years of age will be enrolled to 
receive EVG administered with a BR containing PI/r and other BR components. The study 
will proceed in 2 parts (Part A and Part B), as follows: 
Part A 
Approximately 36 subjects with either suppressed viremia (HIV-1 RNA <50 copies/mL) or 
failing a current antiretroviral regimen (HIV-1 RNA >1,000 copies/mL) will be enrolled to 
evaluate the steady state PK and confirm the dose of EVG. Only subjects aged 4 weeks to 
< 12 years old will be enrolled in this part. 


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Subjects will be enrolled sequentially by cohort* as follows: 
• Cohort 2: 6 to < 12 years old (n  12) 
• Cohort 3: 2 to < 6 years old (n 12) 
• Cohort 4: 4 weeks to < 2 years old (n 12), which will consist of the following age 
subgroups: 
— Cohort 4a: 6 months to < 2 years old (n  8) 
— Cohort 4b**: 4 weeks to < 6 months old (n  4) 
*Cohort 1 subjects are aged 12 to < 18 years old.  No subjects will be enrolled in this age 
group for Part A as EVG PK data are already available. 
**Based on the uncertainty for a dose-exposure relationship in subjects < 2 months old, EVG 
administration will be restricted to coadministration with lopinavir/r, and subjects will be 
enrolled individually and dosed sequentially within the cohort following PK analysis and 
confirmation of the selected dose of the previous subject(s). 
Part A will be enrolled sequentially by age cohort. Enrollment will be limited to Cohort 2 in 
Part A until EVG safety and PK through Day 10 have been analyzed and determined to be 
acceptable in subjects aged 6 to < 12 years old.  Upon review of safety and PK data in Cohort 
2, enrollment will then be limited to Cohort 3 until EVG safety and PK through Day 10 have 
been analyzed and determined to be acceptable in subjects aged 2 to < 6 years old.  Upon 
review of safety and PK data in Cohort 3, enrollment will then be limited to Cohort 4a until 
EVG PK through Day 10 and safety through Week 12 have been analyzed and determined to 
be acceptable in subjects aged 6 months to < 2 years old.  Subsequently, Part A enrollment 
will open for Cohort 4b. 
All subjects enrolled in Part A will participate in an Intensive PK evaluation of EVG on 
Day 10. For Cohorts 2 and 3, samples will be collected at 0 (predose,  30 minutes), 1.5, 2.5, 
3.5, 5, 8, 10, and 12 hours postdose. For Cohort 4, samples will be collected at 0 (predose, 
 30 minutes), 3, 3.5, 5, and 8 hours postdose. Microsampling of intensive PK timepoints 
will be implemented for subjects in Cohort 4. 
Replacement subjects may be enrolled for subjects whose intensive PK data is not evaluable 
or who do not complete all intensive PK procedures in Part A for reasons other than 
discontinuation due to treatment-related adverse events. Replacement subjects will not be 
enrolled in Part A for subjects who discontinue the study due to treatment-related adverse 
events. Subject diary cards will be provided to all Part A subjects and/or parents/guardians to 
record study drugs administration on Days 6-9 prior to the Day 10 Intensive PK visit.  
EVG therapeutic dose confirmation will be established if the 90% CI of the geometric mean 
ratio of EVG AUC between the pediatric versus historical EVG exposures are within the 


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bounds of 70-143%. If a subject has EVG Ctau levels <44.5 ng/mL and has documented 
compliance to study drug, the subject will be discontinued. 
Subjects with HIV-1 RNA <50 copies/mL at screening are considered to have suppressed 
viremia and will discontinue EVG following the Day 10 intensive PK visit. Subjects will be 
required to return to the clinic 30 days after completion of the Day 10 intensive PK visit for a 
30-Day Follow-Up Visit.  
Subjects with HIV-1 RNA >1,000 copies/mL at screening are considered to be failing their 
antiretroviral regimen and will continue to receive EVG following completion of the Day 10 
intensive PK visit and will return for scheduled study visits. Data from these subjects will be 
combined with data from Part B of the study. 
Part B 
Up to 50 subjects who are failing a current antiretroviral regimen (HIV-1 RNA 
>1,000 copies/mL) will be enrolled in Part B to evaluate the safety, tolerability and antiviral 
activity of EVG. The number of additional subjects to be enrolled in Part B will depend on 
the number of subjects with HIV-1 RNA >1,000 copies/mL enrolled in Part A who continue 
EVG therapy beyond Day 10.  Overall, a total of 50 subjects in Part A and B combined are 
planned to complete 48 weeks of EVG therapy. 
For Cohort 1 (12 to <18 year olds), screening in Part B will initiate in parallel with screening 
in Part A.  For Cohorts 2, 3 and 4 in Part B, additional subjects will be screened and initiated 
sequentially by each age cohort following confirmation of appropriate EVG exposure from 
the corresponding age cohort in Part A.   
Subjects will be enrolled sequentially by cohort as follows: 
• Cohort 1: 12 to < 18 years old (n  8) 
• Cohort 2: 6 to < 12 years old (n  8) 
• Cohort 3: 2 to < 6 years old (n  8) 
• Cohort 4***: 4 weeks to < 2 years old (n  4) 
   ***Subjects younger than 6 months will not be allowed to enroll in Part B until Part A 
Cohort 4b data are available indicating acceptable EVG safety and PK through Day 10 in this 
age group. 
For All Subjects (Parts A and B) 
Laboratory analyses (hematology, chemistry, and urinalysis), HIV-1 RNA 
(Roche COBAS TaqMan v2.0), CD4+ cell count and percentage, vital signs, complete or 


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symptom-directed physical examinations and estimated GFR using the Schwartz formula will 
be performed at Screening, Baseline, and all subsequent in-clinic study visits.  
HBV and HCV serologies will be analyzed (with the exception of Cohorts 3 and 4, where 
maternal medical history for HBV and HCV will be obtained in lieu of laboratory testing) 
and supine ECG will be performed at the Screening visit.  
For subjects failing a current antiretroviral regimen (HIV-1 RNA >1,000 copies/mL), HIV-1 
integrase, protease, and reverse transcriptase genotype will be analyzed at Screening using 
the GenoSure PRIme assay (Monogram Biosciences, Inc.).  
Subjects enrolled in Part A with HIV-1 RNA <50 copies/mL at screening (with suppressed 
viremia) will return for the Day 10 Intensive PK evaluation and discontinue the study after 
Day 10. A telephone visit wll occur on Week 1 (Day 7) for safety follow-up assessments.  
Subjects enrolled in Part A who are failing a current antiretroviral regimen (HIV-1 RNA 
>1,000 copies/mL) and all subjects enrolled in Part B will return for study visits at Weeks 4, 
8, 12, 16, and then every 8 weeks through Week 48. A telephone visit wll occur on Week 1 
(Day 7) and Week 3 for safety follow-up assessments. 
Metabolic assessments (glucose and lipid panel [total cholesterol, HDL, direct LDL, and 
triglycerides]) will be assessed at Baseline, Week 24, and Week 48 for subjects failing a 
current antiretroviral regimen (HIV-1 RNA >1,000 copies/mL) and weighing at  13 kg at 
the time of the visit.  
Tanner Stage assessments (Appendix 6) will be performed for subjects  6 years of age at the 
time of the visit, at Baseline, Weeks 24 and 48.  Once a subject is determined to be Tanner 
Stage 5, Tanner Stage assessments will no longer be performed.  
Palatability of EVG suspension formulation will be assessed at Baseline, Day 10 (Part A 
only), Week 24, and Week 48, as applicable. 
At Weeks 16 and 40, a trough PK sample (20 to 24 hours postdose) will be collected. A 
random single plasma PK sample will be collected at Weeks 4, 8, 12 (except for Cohort 3), 
and 32, for descriptive PK. 
Resistance testing will be performed in subjects who experience suboptimal response, 
virologic rebound, and in subjects at Week 48 or ESDD visit if HIV-1 RNA is 
≥ 400 copies/mL. 
Adverse events and concomitant medications will be assessed at each visit. Treatment 
adherence will be assessed at all post Baseline visits. 
Subjects who are permanently discontinued from the study before Week 48 will be required 
to complete an ESDD visit within 72 hours of stopping study drug and return to the clinic 
30 days after the ESDD visit for a 30-Day Follow-Up Visit. 


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After Week 48, all subjects receiving EVG will be given the option to participate in an 
extension phase of the study where Gilead will provide EVG until: a) the subject turns 18 and 
EVG is available for use in adults in the country in which the subject is enrolled or b) the age 
appropriate EVG formulation becomes available for use in the country in which the subject is 
enrolled or c) Gilead Sciences elects to terminate development of EVG in the applicable 
country. Subjects who are eligible to participate in the study extension must demonstrate 
evidence of response to EVG or show absence of resistance to EVG for subjects with HIV-1 
RNA > 400 copies/mL at Week 48.  
Subjects who complete the study through Week 48 and do not wish to participate in the study 
extension will be required to return to the clinic 30 days after completion of the Week 48 
visit for a 30-Day Follow-Up Visit. 
In the extension phase of the study, subjects will return for study visits every 12 weeks for 
laboratory analyses (hematology, chemistry and urinalysis), HIV-1 RNA 
(Roche COBAS TaqMan v2.0), CD4+ cell count and percentage, vital signs, 
symptom-directed physical examinations and estimated GFR using the Schwartz formula.  
Metabolic assessments (glucose and lipid panel [total cholesterol, HDL, direct LDL, and 
triglycerides]) will be assessed every 48 weeks for subjects failing a current antiretroviral 
regimen (HIV-1 RNA >1,000 copies/mL) and weighing at  13 kg at the time of the visit. 
Tanner Stage assessments (Appendix 6) will be performed for subjects  6 years of age at the 
time of the visit, for every 48 weeks in the extension phase.  Once a subject is determined to 
be Tanner Stage 5, Tanner Stage assessments will no longer be performed. A random single 
plasma PK sample will be collected every 12 weeks for descriptive PK. 




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b 
The screening window may be extended to 42 days for subjects who require repeat testing of HIV-1 genotype or if the 
screening visit is divided into multiple visits. 
c 
Screening will initiate after analysis of Day 10 PK and confirmation of EVG exposure in the previous age cohort. 
d 
Subjects with suppressed viremia will discontinue EVG following completion of Day 10 PK and will complete the 
study following the Day 30 follow-up visit. 
e 
Screening for Part A Cohort 4b will initiate only after Day 10 PK and safety through Week 12 have been analyzed 
and determined to be acceptable in Cohort 4a. 
f 
Subjects < 6 months of age will not be allowed to enroll in Part B until Part A Cohort 4b data are available indicating 
acceptable EVG safety and PK through Day 10. 
 


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3.3. 
Study Treatments 
EVG 50 mg, 85 mg, and 150 mg tablets or EVG powder for oral suspension formulation (5 
mg/mL) will be administered orally with food in combination with a BR. Allowed and 
disallowed BR agents are as follows: 
• For subjects with HIV-1 RNA <50 copies/mL at screening, EVG will be added to the 
existing BR that must include a PI/r. The dose of EVG will be dependent upon the 
co-administered PI/r and will be based on body weight.  
• For subjects with HIV-1 RNA >1,000 copies/mL at screening, EVG will be added to a 
newly constructed BR selected by the investigator that is based on the subject’s 
antiretroviral history and screening or historical viral resistance results.  The BR must 
include at least 2 fully-active agents, one of which is a fully-active PI/r (fully-active PI/r 
is defined by genotypic analysis). 
The PI/r contained in the background regimen must be one of the following: lopinavir/r 
(Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or fosamprenavir/r.  For subjects < 2 months 
old, only lopinavir/r is allowed. The BR may contain additional antiretrovirals except for the 
following: saquinavir, indinavir, nelfinavir, double PI regimens, efavirenz, nevirapine, 
delavirdine or an integrase strand transfer inhibitor. All PI should be administered according 
to local product label. 
All subjects must take their ritonavir dose based on the dosing schedule prescribed for the PI; 
no additional ritonavir is required to be taken with EVG. 
For subjects weighing  17 kg and receiving darunavir/r, tipranavir/r or fosamprenavir/r, the 
EVG dose will be as follows: 
• 85 mg for subjects  17 kg to < 28 kg 
• 100 mg for subjects  28 kg to < 34 kg 
• 150 mg for subjects  34 kg 
For subjects weighing  17 kg and receiving atazanavir/r or lopinavir/r, the EVG dose will be 
as follows: 
• 50 mg for subjects  17 kg to < 30 kg 
• 85 mg for subjects  30 kg 
Note: For subjects who are not able to swallow tablets, EVG powder for oral suspension 
formulation (5 mg/mL) may be administered to obtain EVG doses of 50 mg, 85 mg, 100 mg, 
or 150 mg. 


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For subjects weighing < 17 kg and receiving darunavir/r, tipranavir/r or fosamprenavir/r, the 
EVG dose will be 4 mg/kg, and for subjects weighing < 17 kg and receiving lopinavir/r or 
atazanavir/r, the EVG dose will be 2.4 mg/kg, using the EVG powder for oral suspension 
formulation (5 mg/mL) administered as an oral suspension. 
Please refer to Section 5.3, Table 5-1, Table 5-2, Table 5-3, and Table 5-4 for detailed 
information. 
3.4. 
Duration of Treatment 
The screening period will be up to 35 days (42 days if genotype retest is required or if the 
screening visit is divided into multiple visits).  The treatment periods are as follows: 
• Up to 10 days for subjects with HIV-1 RNA <50 copies/mL at screening 
• Up to 48 weeks for subjects with HIV-1 RNA >1,000 copies/mL at screening, and longer 
if subjects elect to participate in an extension phase of the study where Gilead will 
provide EVG until: a) the subject turns 18 and EVG is available for use in adults in the 
country in which the subject is enrolled or b) the age appropriate EVG formulation 
becomes available for use in the country in which the subject is enrolled or c) 
Gilead Sciences elects to terminate development of EVG in the applicable country. 
3.5. 
Discontinuation Criteria 
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, 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 
• Therapeutic failure (ie, virologic failure, see Section 6.8 for details) 
• Subject request to discontinue for any reason 
• Subject noncompliance 
• Pregnancy during the study; refer to Section 7.8 
• Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC) 


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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
Up to 86 pediatric subjects 4 weeks to <18 years of age are planned to be enrolled into this 
study. For Part A, approximately 36 evaluable subjects are planned to be enrolled. For 
Part B, between 14 and 50 subjects, depending on the number of subjects with HIV-1 RNA 
>1,000 copies/mL at screening enrolled in Part A who continue EVG therapy beyond 
Day 10, are planned to be enrolled. 
In Part A, replacement subjects may be enrolled for subjects whose intensive PK data is not 
evaluable or who do not complete all intensive PK procedures for reasons other than 
discontinuation due to treatment-related adverse events. Replacement subjects will not be 
enrolled in Part A for subjects who discontinue the study due to treatment-related adverse 
events. 
4.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. Subjects with screening results that do not meet eligibility criteria will not be 
allowed to rescreen, with the exception of exclusionary screening laboratory results as 
indicated in Section 6.2.1. 
4.2.1. 
HIV-1 infected male and female subjects 4 weeks (gestational age of at least 
44 weeks) to < 18 years of age at the Baseline visit (according to Cohort). 
4.2.2. 
Subjects are able to provide written assent if they have the ability to read and 
write. 
4.2.3. 
Parent or legal guardian able to provide written informed consent prior to any 
screening evaluations and willing to comply with study requirements. 
4.2.4. 
Body weight at screening as follows: 
• Cohort 2 – greater than 15 kg 
• Cohort 3 – greater than 10.6 kg 
• Cohort 4 – greater than 5 kg 
4.2.5. 
Adequate renal function: Estimated Glomerular Filtration Rate (eGFR) 
≥ 90 mL/min/1.73m2 using the Schwartz Formula {23903}: 
Schwartz Formula (mL/min/1.73m2) = k × L/SCr (k is a proportionality 
constant, for pediatric male/female infants to < 2 years old, k = 0.45; ≥ 2 years 
old to < 12 years old, k = 0.55; females ≥ 12 years, k = 0.55 and males 
≥ 12 years, k = 0.70); L is height in centimeters (cm); and SCr is serum 
creatinine (mg/dL) 


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4.2.6. 
Adequate hematologic function defined as: 
• Absolute neutrophil count > 500 cells/mm3 (Note: Subjects with chronic 
neutropenia, defined as having an ANC of < 500/mm3 documented at least 
twice within 6 months of screening, and in whom, according to the 
investigator, there is no evidence of active opportunistic or serious 
infection can enroll in the study contingent upon approval from the 
Gilead Medical Monitor.) 
• Hemoglobin > 8.5 g/dL (9.5 g/dL for infants less than 35 days of age) 
• Platelets > 50,000/mm3 
4.2.7. 
Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN) 
4.2.8. 
Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin 
4.2.10. 
Negative serum β-HCG pregnancy test for female subjects (of childbearing 
potential only, as defined in Section 7.8). 
4.2.11. 
For subjects with evidence of suppressed viremia (Part A only):  
• Plasma HIV-1 RNA concentration (at least 2 consecutive measurements) 
at an undetectable level according to the assay being used for at least 
3 months prior to screening, and HIV-1 RNA <50 copies/mL 
(Roche COBAS TaqMan v2.0) at screening.  
• Stable antiretroviral regimen including one of the following PI/r for at 
least 3 months prior to screening: lopinavir/r (Kaletra), atazanavir/r, 
darunavir/r, tipranavir/r, or fosamprenavir/r. Subjects undergoing dose 
modifications to their antiretroviral regimen for growth or switching 
medication formulations are considered to be on a stable antiretroviral 
regimen. 
4.2.12. 
For subjects failing a current antiretroviral regimen at study entry (Parts A 
and B): 
• HIV-1 RNA >1,000 copies/mL at screening (Roche COBAS TaqMan 
v2.0). 
• Prior treatment for HIV-1 infection, defined as 6 months of antiretroviral 
treatment experience (with the exception of Cohort 4 where less than 
6 months of treatment experience is acceptable) and at least 1 documented 
resistance mutation as defined by current IAS-USA Guidelines. These 
resistance gene mutations must be documented in a historical genotype 
report(s), or in the genotype report at screening provided by 
Gilead Sciences. 


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• Stable antiretroviral regimen (or no antiretroviral regimen) for at least 
30 days prior to screening. Subjects undergoing dose modifications to 
their antiretroviral regimen for growth or switching medication 
formulations are considered to be on a stable antiretroviral regimen. 
• Screening genotype must show full sensitivity to EVG. 
• Ability to construct a BR that must contain one of the following fully 
active PI/r:  lopinavir/r (Kaletra), atazanavir/r, darunavir/r, tipranavir/r, or 
fosamprenavir/r. (Fully active is defined by genotypic analysis.) 
• Genotypic sensitivity score (GSS) of at least 2 (including the fully active 
PI/r and EVG). 
• No opportunistic infection within 30 days of study entry. 
4.2.13. 
Male and female subjects of childbearing potential (as defined in Section 7.8) 
must agree to utilize highly effective contraception methods while on study 
treatment or agree to abstain from heterosexual intercourse throughout the 
study period and for 30 days following the last dose of study drug; highly 
effective methods normally utilize two separate forms of contraception, one of 
which must be an effective barrier contraceptive method. Pre-pubertal females 
(Tanner Stages 1 and 2 are not considered to be of childbearing potential, 
unless onset of menarche has occurred. See Section 7.8 for definition of 
females of childbearing potential). 
• Female subjects who utilize hormonal contraceptive as one of their birth 
control methods must have used the same method for at least three months 
prior to study dosing.  It is recommended that an oral contraceptive 
contain at least 30 μg of ethinyl estradiol if administered with EVG. 
4.2.14. 
Must be willing and able to comply with all study requirements. 
4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
4.3.1. 
Subjects with the following CD4+ cell counts: 
• For Cohorts 1 and 2: Screening CD4+ cell count < 50 cells/mm3 
• For Cohort 3: Screening CD4+ cell count < 75 cells/mm3 
• For Cohort 4: Screening CD4+ cell count < 200 cells/mm3 


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4.3.2. 
An acquired immunodeficiency syndrome (AIDS)-defining condition with 
onset within 30 days prior to screening (refer to Appendix 7) 
4.3.3. 
Life expectancy of < 1 year  
4.3.4. 
For subjects with HIV-1 RNA >1,000 copies/mL at screening, prior treatment 
of any duration with an integrase strand transfer inhibitor. 
4.3.5. 
An ongoing serious infection requiring systemic antibiotic therapy at the time 
of screening. 
4.3.6. 
Evidence of active pulmonary or extra-pulmonary tuberculosis disease: 
• Within 3 months of the Screening visit for all subjects 6 months of age or 
older 
• At any time for subjects younger than 6 months 
4.3.7. 
Anticipated requirement for rifamycin treatment while participating in the 
study.  Note: prophylactic isoniazid therapy for latent TB is allowed. 
4.3.8. 
Have any serious or active medical or psychiatric illness which, in the opinion 
of the Investigator, would interfere with subject treatment, assessment, or 
compliance with the protocol. This would include uncontrolled renal, cardiac, 
hematological, hepatic, pulmonary (including chronic asthma), endocrine 
(e.g., diabetes), central nervous, gastrointestinal (including an ulcer), vascular, 
metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, 
active infection, or malignancy that are clinically significant or requiring 
treatment within 30 days prior to the study dosing. 
4.3.9. 
Subjects experiencing decompensated cirrhosis (eg, ascites, encephalopathy) 
4.3.10. 
A history of or ongoing malignancy other than cutaneous Kaposi’s sarcoma 
(KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous 
carcinoma. Subjects with biopsy-confirmed cutaneous KS are eligible, but 
must not have received any systemic therapy for KS within 30 days of 
Baseline and are not anticipated to require systemic therapy during the study. 
4.3.11. 
Pregnant or lactating subjects. 
4.3.12. 
Current alcohol or substance abuse judged by the Investigator to potentially 
interfere with subject compliance. 
4.3.13. 
Have history of significant drug sensitivity or drug allergy. 
4.3.14. 
Known hypersensitivity to the investigational medicinal product (IMP), the 
metabolites, or formulation excipients. 


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4.3.15. 
Have previously participated in an investigational trial involving 
administration of any investigational agent within 30 days prior to the study 
dosing. 
4.3.16. 
Participation in any other clinical trial without prior approval from sponsor is 
prohibited while participating in this trial. 
4.3.17. 
Subjects receiving ongoing therapy with any medication that is not to be taken 
with EVG or a component of the BR, including drugs not to be used with 
ritonavir (refer to prescribing information for drugs used as part of the BR); 
examples include the following: (Administration of any of the following 
medications must be discontinued at least 30 days prior to the Baseline/Day 1 
visit and for the duration of the study) 
Drug Class 
Agents Disallowed 
Alpha Adrenergic Receptor Antagonists 
Alfuzosin 
Antiarrythmics 
Amiodarone, Flecainide 
Quinidine, Propafenone 
Systemic Lidocaine 
Mexilitine, Disopyramide 
Antibacterials 
Telithromycin 
Anticonvulsants 
Phenobarbital, Phenytoin, Carbamazepine 
Antifungals 
Voriconazole 
Antihistamines 
Astemizole, Terfenadine 
Antimycobacterials 
Rifampin, Rifabutin, Rifapentine 
Calcium Channel Blockers 
Felodipine, Bepridil,  
Nifedipine, Nicardipine,  
Verapamil, Diltiazem 
Ergot Derivatives 
Ergotamine, Ergonovine 
Dihydroergotamine 
Methylergonovine 
Ergometrine 
GI Motility Agents 
Cisapride 
Herbal Supplements 
St. John’s Wort, Echinaccea 
HMG-CoA Reductase Inhibitors 
Simvastatin, Lovastatin, Cerivastatin 
Immunosuppressants 
Cyclosporine, Rapamycin,  
Sirolimus, Tacrolimus 
Immunomodulators 
Interleukin-2 
Neuroleptics 
Pimozide 
Sedatives/Hypnotics 
Midazolam, Triazolam 
Systemic Chemotherapeutic (antineoplastic) Agents 
All agents 


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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Randomization, Blinding and Treatment Codes 
This is an open label study. Randomization, blinding and treatment codes are not applicable. 
Elvitegravir will be provided by Gilead; subjects will be responsible to obtain and take their 
prescribed BR during the study.  
Once eligibility is confirmed, the study site will complete an Eligibility Worksheet for each 
screened subject and submit for Sponsor review. The Sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the study 
site.  
The subject number assignment may be performed up to 7 days prior to the in-clinic baseline 
visit provided that all other screening procedures have been completed and subject eligibility 
has been confirmed. Once a subject number has been assigned, it will not be reassigned to 
any other subject. 
All baseline tests and procedures must be completed and eligibility confirmed prior to 
the administration of the first dose of study drug. 
It is the responsibility of the Investigator to ensure that the subject is eligible for the study 
prior to enrollment. 
5.2. 
Description and Handling of Elvitegravir 
5.2.1. 
Formulation 
5.2.1.1. 
Elvitegravir Tablets – 50 mg, 85 mg, and 150 mg 
Elvitegravir tablets are available in three strengths. Elvitegravir 50 mg, are light-green, 
round, film-coated tablets containing 50 mg of elvitegravir.  Elvitegravir 85 mg, are 
light-green pentagon-shaped, film-coated tablets containing 85 mg of elvitegravir. 
Elvitegravir 150 mg, are light green triangle-shaped, film-coated tablets containing 150 mg 
of elvitegravir. Elvitegravir tablet cores contain croscarmellose sodium, hydroxypropyl 
cellulose, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, and 
magnesium stearate as inactive ingredients and are film-coated with polyvinyl alcohol, 
polyethylene glycol 3350, titanium dioxide, talc, FD&C Blue #2 aluminum lake, and iron 
oxide yellow. The 85 mg and 150 mg tablets are debossed with “GSI” on one side of the 
tablet and “85” and “150”, respectively, on the other side of the tablet.  The 50 mg tablets are 
plain faced on both sides. 


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5.2.1.2. 
Elvitegravir Powder for Oral Suspension – 5 mg/mL  
Elvitegravir powder for oral suspension is an off-white powder blend for constitution with 
112 mL of water to prepare a suspension containing 5 mg/mL of elvitegravir. The powder 
blend contains microcrystalline cellulose, xanthan gum, xylitol, povidone, polysorbate, 
sodium benzoate, citric acid, and silicon dioxide. Each bottle contains approximately 6 grams 
of powder blend. GSI will be providing 10, 20, and 30 mL oral dosing syringes and bottle 
adapter for the elvitegravir suspension formula and be used as appropriate based on the 
suspension dosing volume. 
5.2.2. 
Packaging and Labeling 
Thirty (30) elvitegravir tablets (50 mg, 85 mg or 150 mg) are packaged in white high density 
polyethylene (HDPE) bottles with polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced 
liner. 
Six (6) grams of elvitegravir powder blend for oral suspension are packaged in a natural, high 
density polyethylene (HDPE) bottle. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner. 
All labels for study drug bottles will meet all applicable requirements of the US Food and 
Drug Administration (FDA) and Annex 13 of EU Rules on Good Manufacturing Practices: 
Manufacture of investigational medicinal products (July 2010) and/or other local regulations 
as applicable. 
5.2.3. 
Storage and Handling 
Elvitegravir tablets should be stored at 25 °C (77 °F); excursions are permitted between 
15 °C and 30 °C (59 °F and 86 °F, respectively). Storage conditions for the drug product are 
specified on the label. To ensure the stability of EVG tablets, it is recommended that the drug 
product not be dispensed into a container other than the container in which it is supplied. 
Elvitegravir powder for oral suspension and EVG oral suspension following reconstitution 
should be stored at 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C (59 °F 
and 86 °F, respectively). Exposure of this product to high humidity outside the original 
container for longer than two weeks is not recommended. 
5.3. 
Dosage and Administration of Elvitegravir 
Elvitegravir tablets and powder for oral suspension will be provided by Gilead Sciences and 
will be administered orally, once daily with food at approximately the same time each day. 
Dosage and administration of EVG is outlined below and in Table 5-1, Table 5-2, Table 5-3, 
and Table 5-4. 


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For subjects weighing  17 kg and receiving darunavir/r, tipranavir/r or 
fosamprenavir/r, the EVG dose will be as follows: 
Table 5-1. 
EVG dose by Weight Range with DRV, fAPV or TPV  
Weight range  
EVG tablet dose 
w DRV, fAPV or TPV 
EVG suspension dose 
w DRV, fAPV or TPV 
mg/kg 
34 kg 
150 mg 
30 mL 
<4.4 
28 to <34 kg 
100 mg 
(2 x 50 mg tablets) 
20 mL 
2.9-3.6 
17 to <28 kg 
85 mg 
17 mL 
3.0-5.0 
Note: For subjects who are not able to swallow tablets, EVG powder for oral suspension formulation (5 mg/mL) may be 
administered to obtain EVG doses of 50 mg, 85 mg, 100 mg, or 150 mg. 
 
For subjects weighing  17 kg and receiving atazanavir/r or lopinavir/r, the EVG dose 
will be as follows: 
Table 5-2. 
EVG dose by Weight Range with ATV, LPV 
Weight range  
EVG tablet dose 
w ATV, LPV 
EVG suspension dose             
w ATV, LPV 
mg/kg 
30 kg 
85 mg 
17 mL 
<2.8 
17 to <30 kg 
50 mg 
10 mL 
1.7-2.8 
Note: For subjects who are not able to swallow tablets, EVG powder for oral suspension formulation (5 mg/mL) may be 
administered to obtain EVG doses of 50 mg, 85 mg, 100 mg, or 150 mg. 
 


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For subjects weighing < 17 kg and receiving darunavir/r, tipranavir/r or 
fosamprenavir/r, the EVG dose will be 4 mg/kg, using the EVG powder for oral suspension 
formulation (5 mg/mL) administered as an oral suspension. The EVG dose will be calculated 
based on subject’s actual weight to provide 4 mg/kg, as follows: 
Table 5-3. 
EVG Suspension dose (mL) by Body Weight with DRV, fAPV or 
TPV 
Weight range  
EVG suspension dose w DRV, fAPV or TPV 
16 to <17 kg 
13 mL 
15 to <16 kg 
12 mL 
14 to <15 kg 
12 mL 
13 to <14 kg 
11 mL 
12 to <13 kg 
10 mL 
11 to <12 kg 
9 mL 
10 to <11 kg 
8 mL 
9 to <10kg 
8 mL 
8 to <9 kg 
7 mL 
7 to <8 kg 
6 mL 
6 to <7 kg 
5 mL 
5  to <6 kg 
4 mL 
 


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For subjects weighing < 17 kg and receiving lopinavir/r or atazanavir/r, the EVG dose 
will be 2.4 mg/kg, using the EVG powder for oral suspension formulation (5 mg/mL) 
administered as an oral suspension. The EVG dose will be calculated based on subject’s 
actual weight to provide 2.4 mg/kg, as follows: 
Table 5-4. 
EVG Suspension dose (mL) by Body Weight with ATV, LPV 
Weight range  
EVG suspension dose w ATV, LPV 
16 to <17 kg 
8 mL 
15 to <16 kg 
7.5 mL 
14 to <15 kg 
7 mL 
13 to <14 kg 
6.5 mL 
12 to <13 kg 
6 mL 
11 to <12 kg 
5.5 mL 
10 to <11 kg 
5 mL 
9 to <10kg 
4.5 mL 
8 to <9 kg 
4 mL 
7 to <8 kg 
3.5 mL 
6 to <7 kg 
3 mL 
5  to <6 kg 
2.5 mL 
 
In-clinic dosing will be performed at Baseline/Day 1, Weeks 16 and 40. 
Subjects in Part A will also be administered their dose of study medication in the clinic 
with food during the Day 10 intensive PK visit. In order to allow for ease of PK sampling 
over a 10-hour period, subjects should be instructed to take their dose of elvitegravir together 
with food at the same time every day in the morning (breakfast), during the 9 days leading 
up to intensive PK assessments. Prior to the scheduled PK visit subjects should fast overnight 
(a minimum of 8 hours), except for subjects in Part A Cohort 4. Microsampling of intensive 
PK timepoints will be implemented for subjects in Cohort 4.  
After Week 48, all subjects receiving EVG who complete 48 weeks of study treatment will 
be given the option to participate in an extension phase of the study where Gilead will 
provide EVG until: a) the subject turns 18 and EVG is available for use in adults in the 
country in which the subject is enrolled or b) the age appropriate EVG formulation becomes 
available for use in the country in which the subject is enrolled or c) Gilead Sciences elects to 
terminate development of EVG in the applicable country. 


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Subjects and parents/guardians will be instructed to bring all study medication in the original 
container at each study visit for drug accountability (unless otherwise specified in Section 6). 
Refer to Section 5.5 for information on the Investigator’s responsibilities of IMP. 
5.3.1. 
Elvitegravir Powder for Oral Suspension Reconstitution and Dosing 
Reconstitution Instructions: 
Elvitegravir powder for oral suspension must be reconstituted by the study pharmacist prior 
to dispensation to subjects’ parent/guardian.  
1. Tap the closed bottle several times to loosen the powder. 
2. Measure 112 mL of water in a graduated cylinder. 
3. Unscrew the child-resistant cap from the bottle. 
4. Remove and discard the aluminum seal. 
5. Add half of the water (~60 mL) and shake the closed bottle well for about 15 to 
30 seconds. 
6. Add the rest of the water and shake vigorously for 15 seconds to obtain a uniform 
suspension.   
7. Remove the child-resistant cap and push the bottle adapter into the neck of the bottle. 
8. Tightly close the bottle with the child-resistant cap. This will assure proper seating of the 
bottle adapter in the bottle and child-resistant status of the cap. 
9. Apply a label on the bottle stating the preparation date and an end-of-use date of no more 
than 30 days beyond the preparation date (e.g., compounding date). 
10. Apply “Shake Well Before Use” labels on the bottle. After constitution the bottle will 
contain approximately 120 mL of a suspension of 5 mg/mL elvitegravir suspension.  
Dosing Instructions: 
11. The provided graduated 10, 20, or 30 mL oral dosing syringe will be used to measure the 
appropriate dose volume of elvitegravir oral suspension to the subject.  Refer to 
Table 5-1, Table 5-2, Table 5-3, and Table 5-4 for detailed dosage information.  
12. Insert the syringe into the adapter. 
13. With the syringe, adapter and bottle attached, turn the entire assembly upside down. 
14. Pull the plunger to withdraw the suspension sample for use. 


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15. Administer study drug directly to subject’s mouth via the syringe. 
5.4. 
Prior and Concomitant Medications 
Subjects receiving oral contraceptives or patch contraceptives should consider other methods 
of contraception as concentrations of ethinyl estradiol, norgestimate or norethindrone may 
increase or decrease on coadministration with study drug. Please refer to Section 7.7.2 for 
guidance on the use of contraception methods. 
Concomitant use of some medications and herbal/natural supplements with study drug may 
result in pharmacokinetic interactions resulting in increases or decreases in exposure of study 
drugs or these medications. 
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
the Gilead Sciences Medical Monitor must be consulted prior to initiation of the new 
medication. In instances where an excluded medication is initiated prior to discussion with 
the Sponsor, the Investigator must notify Gilead Sciences as soon as he/she is aware of the 
use of the excluded medication. 
Medications listed in the following table and use of herbal/natural supplements are excluded 
or should be used with caution while subjects are participating in the study: 
Drug Class 
Agents Disallowed 
Use Discouraged and To Be Used 
With Caution 
Alpha Adrenergic Receptor 
Antagonist 
Alfuzosin 
 
Antacids 
 
Subjects may not take antacids 
(e.g., Tums or Rolaids); the ulcer 
medication sucralfate (Carafate); or 
vitamin or mineral supplements 
that contain calcium, iron or zinc 
for a minimum of 2 hours before 
and 2 hours after any dose of 
elvitegravir/r. 
Antiarrythmics 
Amiodarone, Flecainide 
Quinidine, Propafenone 
Systemic Lidocaine 
Mexilitine, Disopyramide 
 
Antibacterials 
Telithromycin 
 
Anticoagulants 
 
Warfarin: Frequent INR 
(International Normalized Ratio) 
monitoring upon initiation of 
ritonavir-boosted elvitegravir 
treatment is recommended. 
Anticonvulsants 
Phenobarbital, Phenytoin, 
Carbamazepine 
 


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Drug Class 
Agents Disallowed 
Use Discouraged and To Be Used 
With Caution 
Antifungals 
Voriconazole 
Ketoconazole and Itraconazole: 
concomitant use with study drug 
may also result in an increase or 
decrease in concentrations. 
Subjects receiving antifungals 
should be monitored for adequate 
clinical response. Daily dose of 
ketoconazole and itraconazole 
should be restricted to 200mg. 
Antigout 
 
Colchicine is a P-gp and CYP3A4 
substrate. Concentrations may 
increase with study drug. Dose 
reductions of colchicine may be 
required. Should not be 
coadministered in patients with 
renal or hepatic impairment. 
Treatment of gout – Colchicine is 
not indicated for treatment of gout 
in pediatric populations.  
Treatment of familial 
Mediterranean fever – 
coadministration of colchicine in 
patients receiving EVG/r: 
Maximum daily dose of 0.6 mg 
(may be given as 0.3 mg twice a 
day). 
Antihistamines 
Astemizole, Terfenadine 
 
Antimycobacterials 
Rifampin, Rifabutin, Rifapentine  
 
Antiretroviral Agents 
Any drug with antiretroviral 
activity not allowed as part of the 
prescribed BR 
 
Calcium Channel Blockers 
Felodipine, Bepridil,  
Nifedipine, Nicardipine,  
Verapamil, Diltiazem 
 
Endothelin Receptor Antagonists 
 
Bosentan:  Coadministration may 
lead to decreased elvitegravir 
exposures and loss of therapeutic 
effect and development of 
resistance.  Alternative endothelin 
receptor antagonists may be 
considered. 
Ergot Derivatives 
Ergotamine, Ergonovine 
Dihydroergotamine 
Methylergonovine 
Ergometrine 
 


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Drug Class 
Agents Disallowed 
Use Discouraged and To Be Used 
With Caution 
GI Motility Agents 
Cisapride 
 
Herbal Supplements 
St. John’s Wort, Echinaccea 
 
HMG-CoA Reductase Inhibitors 
Simvastatin, Lovastatin, 
Cerivastatin 
Atorvastatin, Rosuvastatin, 
Pravastatin: Start with lowest 
possible dose with careful 
monitoring for signs and symptoms 
of muscle weakness or myopathy, 
including rhabdomyolysis. Gradual 
increase in dose may be tailored to 
clinical response. 
Immunosuppressants 
Cyclosporine, Rapamycin,  
Sirolimus, Tacrolimus 
 
Immunomodulators 
Interleukin-2 
 
Neuroleptics 
Pimozide 
 
Opiates 
 
Methadone: Monitoring for signs 
and symptoms of methadone 
withdrawal is recommended. Some 
subjects may require a 
modification of their methadone 
dose. 
Meperidine (Pethidine): Dosage 
increase and long-term use are not 
recommended due to increased 
levels of metabolite normeperidine, 
which has analgesic and CNS 
stimulant (e.g., seizures) activities.  
Buprenorphine: As a substrate of 
CYP3A4, concomitant use of this 
agent with study treatments 
may result in higher or lower 
systemic exposure. Careful 
monitoring for signs and symptoms 
of respiratory and CNS depression, 
and for opiate withdrawal is 
recommended. 
Phosphodiesterase-5 Inhibitors 
 
Sildenafil, Vardenafil, Taladafil: It 
is recommended that a single dose 
of Sildenafil no more than 25 mg 
in 48 hours, Vardenafil no more 
than 2.5 mg in 72 hours, or 
Taladafil no more than 10 mg in 
72 hours be coadministered with 
study treatments. 
Sedatives/Hypnotics 
Midazolam, Triazolam 
 


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Drug Class 
Agents Disallowed 
Use Discouraged and To Be Used 
With Caution 
Systemic Chemotherapeutic 
(antineoplastic) Agents 
All agents 
 
Systemic Corticosteroids 
dexamethasone 
 
Systemic dexamethasone, a 
CYP3A inducer, may significantly 
decrease elvitegravir plasma 
concentrations, which may result in 
loss of therapeutic effect and 
development of resistance. 
Alternative corticosteroids should 
be considered. 
Corticosteroids 
Inhaled/Nasal: 
fluticasone  
 
Use of inhaled or oral 
corticosteroid and study drug may 
increase plasma concentrations of 
fluticasone and is not 
recommended unless the potential 
benefit to the subject outweighs the 
risks. Coadministration of 
fluticasone propionate and 
ritonavir is not recommended 
unless the potential benefit to the 
subject outweighs the risks of 
corticosteroid side effects. 
Alternative corticosteroids should 
be considered, particularly for long 
term use. 
Use of Prednisone as a steroid 
burst (1 week of use) should be 
monitored appropriately. 
 
5.5. 
Accountability for Elvitegravir 
The investigator is responsible for ensuring adequate accountability of all used and unused 
IMP. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All used and unused IMP dispensed to subjects must be returned to the site. 
EVG accountability records will be provided to each study site to: 
• Record the date received and quantity of IMP bottles. 
• Record the date, subject number, subject initials, the IMP bottle number dispensed. 
• Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information. 


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5.5.1. 
Investigational Medicinal Product Return or Disposal 
If applicable, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences 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 investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies. Refer to Section 9.1.7 for more details. 


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6. 
STUDY PROCEDURES 
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and Appendix 3 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the 
sponsor or contract research organization (CRO). 
6.1. 
Subject Enrollment and Treatment Assignment 
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment. 
Please refer to Section 5.1 for details about subject number assignment.  
6.2. 
Pretreatment Assessments 
6.2.1. 
Screening Visit 
Each subject who has the ability to read and write must sign an assent (and parent or legal 
guardian sign an informed consent form) prior to the conduct of any screening procedures. 
Subjects will be assigned a screening number at the time of assent/consent. Screening 
evaluations are used to determine the eligibility of each candidate for study enrollment.  
The following will be performed and documented at screening: 
6.2.1.1. 
Obtain written assent/consent 
6.2.1.2. 
Obtain medical and medication history including history of HIV-1 disease-
related events and any other ongoing medications within 30 days of the 
screening visit. For Cohorts 3 and 4 only, obtain maternal medical history 
for HBV and HCV. 
6.2.1.3. 
Perform a complete physical examination including, vital signs, body weight, 
and height/length (urogenital/anorectal exams will be performed at the 
discretion of the investigator). 
6.2.1.4. 
Obtain urine samples for urinalysis 
6.2.1.5. 
Obtain blood samples for the following laboratory analyses: 
• Serum pregnancy test (females of childbearing potential only). If the test is 
positive, the subject will not be enrolled. 


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• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: complete blood count (CBC) with differential and 
platelet count 
• Estimated glomerular filtration rate (eGFR) using the Schwartz Formula: 
eGFR (mL/min/1.73m2) = k × L/Scr (k is a proportionality constant, refer 
to Section 4.2 for details); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)] 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
• HBV surface antigen serology (HBsAg screening), except for Cohorts 3 
and 4 (see 6.2.1.2). 
• HCV antibody serology (HCVAb screening), except for Cohorts 3 and 4 
(see 6.2.1.2). 
• HIV-1 integrase, reverse transcriptase and protease genotype (only if 
screening HIV-1 RNA is >1,000 copies/mL). The HIV-1 genotype may 
not be performed for subjects that fail to meet other screening laboratory 
criteria. For subjects with HIV-1 RNA <50 copies/mL at screening, 
historical genotypes should be provided, if available. 
6.2.1.6. 
Obtain 12-lead ECG, performed supine 
6.2.1.7. 
Record any adverse events occurring after signing of the consent form. 
From the time of obtaining informed consent through the first administration 
of IMP, record all serious adverse events (SAEs), as well as any non-serious 
adverse events related to protocol-mandated procedures on the adverse events 
case report form (CRF/eCRF).  All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in 
medical history are to be captured on the medical history CRF/eCRF.  See 
Section 7 for additional details. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria 
will return to the clinic within 35 days after the screening visit for the 
Baseline/Day 1 assessments. The screening window may be extended to 42 
days for subjects who require repeat testing of the HIV-1 genotype or if the 
screening visit is divided into multiple visits.  


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Subjects with exclusionary screening laboratory results due to an acute 
clinical condition which resolves can be re-screened within 3 months of initial 
screening. The decision to re-screen the subject will be made in consultation 
with the Medical Monitor, and written notice of eligibility from the Sponsor is 
required before a re-screened subject can be enrolled.  
Complete the Eligibility Worksheet for each screened subject and submit to 
Sponsor for review prior to assignment of subject number. The subject 
number assignment may be performed up to 7 days prior to the in-clinic 
baseline visit provided that all other screening procedures have been 
completed and subject eligibility has been confirmed. 
6.2.2. 
Baseline Assessments 
The following evaluations are to be completed at the Baseline/Day 1 visit. The subject must 
complete all study procedures before being administered the study drug: 
6.2.2.1. 
Perform a complete physical examination including, vital signs, body weight, 
and height/length.  
6.2.2.2. 
Perform Tanner Stage assessment (Appendix 6) for subjects  6 years of age 
at the time of the visit, until Tanner Stage 5 has been reached. Date of first 
menses will be documented. 
6.2.2.3. 
Obtain urine samples for the following procedures: 
• Urinalysis 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive at baseline, study drug will not be dispensed. 
The positive result will be confirmed with a serum pregnancy test. If the 
serum pregnancy test is positive, the subject will not be able to participate 
in the study. 
• Urine sample storage for possible additional testing 
6.2.2.4. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 


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• Metabolic assessments: fasting glucose and lipid panel (total cholesterol, 
HDL, direct LDL, triglycerides) evaluated for subjects failing a current 
antiretroviral regimen (HIV-1 RNA >1,000 copies/mL) only and weighing 
at  13 kg at the time of the visit. If the subject has not fasted prior to the 
visit, the visit may proceed, but the subject must return within 72 hours in 
a fasted state for a re-draw of the metabolic assessments. For Cohorts 2 
and 3 only, direct LDL will be calculated if subjects weigh <15.8 kg at 
the time of the visit. 
• eGFR using the Schwartz Formula (refer to Section 4.2 for details) 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
• For Cohorts 1 and 2 only: plasma storage sample for possible additional 
testing 
6.2.2.5. 
Review of AEs and concomitant medication 
6.2.2.6. 
Study drug dispensation: study drug will be dispensed in an open-label 
fashion 
6.2.2.7. 
Upon completion of the Baseline/Day 1 assessments and procedures, the 
subject will be administered the first dose of EVG + PI/r and other BR 
components per dosing requirements. Review dosing instructions with subject 
and/or parent/guardian. 
6.2.2.8. 
Assess palatability of EVG suspension formulation, as applicable 
6.2.2.9. 
For Part A subjects only: provide subject diary cards 
The Part A intensive PK evaluation is designed to assess the PK and confirm 
the dose of EVG in pediatric subjects. Therefore, all subjects must take their 
QD dose of EVG + PI/r and other BR components with food in the morning 
through Day 9 at approximately the same time every day. 
6.3. 
Treatment Assessments 
6.3.1. 
Week 1 (Day 7) and Week 3 Telephone Visits   
The Week 1 (Day 7) and Week 3 visits should occur within ± 2 days of the protocol-
specified visit date based on the Baseline/Day 1 visit.  
The following evaluations will be reviewed over the telephone with the subject and/or 
parent/guardian: 


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6.3.1.1. 
Review treatment adherence with subject and/or parent/guardian. 
6.3.1.2. 
Review of AEs and concomitant medications. 
6.3.1.3. 
For the Week 1 visit and Part A only:  
• Review subject diary cards 
• Remind subject and/or parent/guardian to come in for the Day 10 intensive 
PK visit without taking their dose of the EVG + PI/r and other BR 
components 
• Remind subject and/or parent/guardian to come in a fasted state for the 
Day 10 intensive PK visit (ie, no food or drink except water at least 
8 hours prior to the Day 10 intensive PK visit). Note: fasting is not 
required for subjects in Part A Cohort 4. 
• Remind subject and/or parent/guardian to bring the drug bottles of the 
EVG + PI/r and other BR components with them for in-clinic dosing and 
drug accountability at the Day 10 intensive PK visit. 
• Remind subject and/or parent/guardian to bring the completed diary cards 
to the Day 10 intensive PK visit.  
6.3.2. 
Day 10 Intensive PK Visit – Part A only 
The Day 10 intensive PK visit should occur on the protocol-specified visit date based on the 
Baseline/Day 1 visit. For the purposes of scheduling, the Day 10 intensive PK visit may 
be performed within + 4 days of the protocol-specified visit date. 
Subjects should come in a fasted state for the Day 10 intensive PK visit (ie, no food or drink 
except water at least 8 hours prior to the Day 10 intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of EVG + PI/r and other BR 
components must not be taken until the evaluations listed below are completed. Note: fasting 
is not required for subjects in Cohort 4. 
If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be instructed to return in a fasted state within 4 days (Days 11, 12, 
13, or 14) for the intensive PK visit. Appropriate study drug re-dispensation must be 
performed in this case. 
If dosing non-compliance not related to AEs is identified on or prior to the Day 10 visit, the 
Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be counseled regarding proper dosing and  be scheduled to return 


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for the Day 10 intensive PK visit no sooner than 3 days following compliant dosing and no 
later than Day 14 (ie, return on Day 13 or Day 14). 
In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the EVG + PI/r and other BR components prior to arriving at the clinic on the day 
of the re-scheduled intensive PK visit. All Day 10 intensive PK assessments listed below 
should be completed when the subject returns. 
If dosing non-compliance due to an AE is identified on or prior to the Day 10 visit, the Day 
10 intensive PK assessments must not be completed. Consultation with the Gilead Medical 
Monitor is required regarding the potential of rescheduling the Day 10 intensive PK visit. 
The following evaluations are to be completed at the Day 10 intensive PK visit: 
6.3.2.1. 
Perform a symptom-directed physical examination as needed. 
6.3.2.2. 
Obtain vital signs and body weight. 
6.3.2.3. 
Obtain urine samples for the following procedures: 
• Urinalysis 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive, EVG therapy will be suspended and intensive 
PK sampling will not be completed. The positive result will be confirmed 
with a serum pregnancy test. If the serum pregnancy test is positive, EVG 
therapy will be discontinued. If pregnancy is not confirmed, consultation 
with the Gilead Medical Monitor is required regarding the potential of 
resuming EVG therapy and completing intensive PK sampling. 
• Urine sample storage for possible additional testing 
6.3.2.4. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 
• eGFR using the Schwartz Formula (refer to Section 4.2 for details) 
• Plasma HIV-1 RNA 


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6.3.2.5. 
Perform intensive PK sampling:  
• Blood samples will be collected at 0 (predose,  30 minutes prior to 
dosing). After collection of the predose sample, subjects will be provided 
a standardized meal. Within 5 minutes after consuming the 
standardized meal, subjects will be dosed with their EVG + PI/r and 
other BR components per dosing requirements. 
• Postdose blood samples will be collected as follows:  
— For Cohorts 2 and 3: at 1.5, 2.5, 3.5, 5, 8, 10, and 12 hours postdose.  
— For Cohort 4: at 3, 3.5, 5, and 8 hours postdose. 
• Subjects will be restricted from food intake until after the 4 hours after 
dosing, except for subjects in Cohort 4. Please also refer to the PK 
manual for details about standardized meals and PK sample processing 
instructions. 
6.3.2.6. 
Assess palatability of EVG suspension formulation, as applicable 
6.3.2.7. 
Review and collect subject diary cards 
6.3.2.8. 
Perform study drug accountability (Note: study drug will not be dispensed at 
this visit). 
6.3.2.9. 
Review treatment adherence with subject and/or parent/guardian. 
6.3.2.10. 
Review of AEs and concomitant medications 
After completing the Day 10 intensive PK visit: 
• Subjects with HIV-1 RNA <50 copies/mL at screening will discontinue 
EVG and return to the clinic for a 30-Day follow-up visit (refer to 
Section 6.3.1).  
• Subjects with HIV-RNA >1,000 copies/mL at screening will continue 
taking study drug and study visits through Week 48 as described in 
Section 6.3.3. 
6.3.3. 
Week 4 – 48 Visits 
Subjects failing a current antiretroviral regimen (HIV-1 RNA >1,000 copies/mL at screening) 
will continue taking their study drugs through Week 48. It is recommended that all subjects 
take their dose of EVG + PI/r and other BR components along with food at approximately the 
same time each day (with the exception of in-clinic dosing at Weeks 16 and 40 visits). 


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The Week 4 visit is to be completed 31 to 33 days from the Baseline visit. The other study 
visits are to be completed within ± 2 days of the protocol-specified visit date based on the 
Baseline visit for Week 8 and completed within ± 4 days of the protocol-specified visit date 
thereafter through Week 48 unless otherwise specified. Regularly scheduled evaluations 
will be completed on all subjects whether or not they continue to receive study drug. 
The following evaluations are to be completed at Weeks 4, 8, 12, 16, 24, 32, 40, and 48 
unless otherwise specified: 
6.3.3.1. 
Perform a complete physical examination (Weeks 24 and 48) or a 
symptom-directed physical examination as needed 
6.3.3.2. 
Obtain vital signs and body weight 
6.3.3.3. 
Obtain height/length. For subjects  1 year of age, obtain measurements at 
Weeks 12, 24, and 48 only. For subjects < 1 year of age, obtain 
measurements at all visits.  
6.3.3.4. 
Perform Tanner Stage assessments (Appendix 6) for subjects  6 years of age 
at the time of the visit, at Weeks 24 and 48, until Tanner Stage 5 has been 
reached. Date of first menses will be documented.  
6.3.3.5. 
Obtain urine samples for the following procedures: 
• Urinalysis (Weeks 4, 12, 24, and 48 only) 
• Urine sample storage for possible additional testing (Weeks 4, 12, 24, and 
48 only) 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive, study drug will not be dispensed. The positive 
result will be confirmed with a serum pregnancy test. If the serum 
pregnancy test is positive, the subject will not be able to continue in the 
study. (all visits) 
6.3.3.6. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 


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• Metabolic assessments: fasting glucose and lipid panel (total cholesterol, 
HDL, direct LDL, triglycerides) evaluated for all subjects weighing at  
13 kg at the time of the visit (Weeks 24 and 48). The subject and/or 
parents/guardians should be reminded to fast prior to the Week 24 and 
48 visits. If the subject has not fasted prior to the visit, the visit may 
proceed, but the subject must return within 72 hours in a fasted state for a 
re-draw of the metabolic assessments. For Cohorts 2 and 3 only, direct 
LDL will be calculated if subjects weigh <15.8 kg at the time of the visit. 
• eGFR using the Schwartz Formula (refer to Section 4.2 for details) 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
• Trough (20 to 24 hours postdose) plasma PK sample at Weeks 16 and 40 
• Random single plasma PK sample for descriptive PK at Weeks 4, 8, 12, 
and 32. For Week 12, obtain sample for Cohorts 1, 2, and 4 only. 
• Plasma storage sample for possible additional testing at Weeks 12, 24 and 
48 for Cohorts 1, 2 and 3 only.  
6.3.3.7. 
Subjects who meet the criteria for Suboptimal Virologic Response will be 
managed according to the Suboptimal Virologic Response Schema 
(Section 6.8.1) 
6.3.3.8. 
Subjects who meet the criteria for Virologic Rebound will be managed 
according to the Virologic Rebound Schema (Section 6.8.2) 
6.3.3.9. 
For Weeks 16 and 40 only: upon completion of the above assessments and 
procedures, the subject will be administered their dose of the EVG + PI/r and 
other BR components along with food 
6.3.3.10. 
Assess palatability of EVG suspension formulation at Weeks 24 and 48, as 
applicable 
6.3.3.11. 
Perform study drug accountability and dispensation.  
6.3.3.12. 
Review treatment adherence with subject and/or parent/guardian. 
6.3.3.13. 
Review of AEs and concomitant medications 


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6.4. 
Post Week 48 Assessments 
Study subjects receiving EVG who complete 48 weeks of study treatment will be given the 
option to participate in an extension phase of the study where Gilead will provide EVG until: 
a) the subject turns 18 and EVG is available for use in adults in the country in which the 
subject is enrolled or b) EVG becomes available for use in children or adolescents in the 
country in which the subject is enrolled or c) Gilead Sciences elects to terminate 
development of EVG in the applicable country. Subjects who are eligible to participate in the 
study extension must demonstrate evidence of response to EVG or show absence of 
resistance to EVG for subjects with HIV-1 RNA > 400 copies/mL at Week 48.  
Subjects who choose to receive EVG will return for study visits every 12 weeks. Study visits 
are to be completed within ± 6 days of the protocol-specified visit date unless otherwise 
specified. 
6.4.1.1. 
Perform a symptom-directed physical examination as needed 
6.4.1.2. 
Obtain vital signs, body weight, and height/length.   
6.4.1.3. 
Perform Tanner Stage assessments (Appendix 6) for subjects  6 years of age 
at the time of the visit, every 48 weeks, until Tanner Stage 5 has been 
reached. Date of first menses will be documented. 
6.4.1.4. 
Obtain urine samples for the following procedures: 
• Urinalysis 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive, study drug will not be dispensed. The positive 
result will be confirmed with a serum pregnancy test. If the serum 
pregnancy test is positive, the subject will not be able to continue in the 
study. 
• Urine sample storage for possible additional testing 
6.4.1.5. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 


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• Metabolic assessments: fasting glucose and lipid panel (total cholesterol, 
HDL, direct LDL, triglycerides) evaluated for all subjects weighing at  
13 kg at the time of the visit (every 48 weeks). The subject and/or 
parents/guardians should be reminded to fast prior to the visits. If the 
subject has not fasted prior to the visit, the visit may proceed, but the 
subject must return within 72 hours in a fasted state for a re-draw of the 
metabolic assessments. For Cohorts 2 and 3 only, direct LDL will be 
calculated if subjects weigh <15.8 kg at the time of the visit. 
• eGFR using the Schwartz Formula (refer to Section 4.2 for details) 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
• Random single plasma PK sample for descriptive PK 
• Plasma storage sample for possible additional testing 
6.4.1.6. 
Subjects who meet the criteria for Virologic Rebound will be managed 
according to the Virologic Rebound Schema (Section 6.8.2) 
6.4.1.7. 
Perform study drug accountability and dispensation.  
6.4.1.8. 
Review treatment adherence with subject and/or parent/guardian. 
6.4.1.9. 
Review of AEs and concomitant medications. 
6.5. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), every attempt 
should be made to keep the subject in the study and continue to perform the required 
study-related follow-up and procedures (see Section 6.3). If this is not possible or acceptable 
to the subject or investigator, the subject may be withdrawn from the study.  
6.5.1. 
Early Study Drugs Discontinuation (ESDD) 
If a Part A subject discontinues study drug prior to Day 10, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for an ESDD visit. 
Subjects with HIV-1 RNA >1,000 copies/mL at screening (failing a current antiretroviral 
regimen) and who discontinue study drugs any time prior to Week 48 will be asked to return 
to the clinic within 72 hours of stopping study drugs for an ESDD visit. Subjects will then be 
asked to continue attending all scheduled study visits. 


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At the ESDD visit, any evaluations showing abnormal results for which there is a 
reasonable possibility of a causal relationship with the study drug should be repeated 
weekly (or as often as deemed prudent by the investigator) until the abnormality is 
resolved, returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at the ESDD visit: 
6.5.1.1. 
Perform a complete physical examination including vital signs, body weight, 
and height/length.   
6.5.1.2. 
Obtain urine samples for the following procedures: 
• Urinalysis 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive, the result will be confirmed with a serum 
pregnancy test.  
• Urine sample storage for possible additional testing 
6.5.1.3. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 
• eGFR using the Schwartz Formula (refer to Section 4.2 for details) 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
• Plasma storage sample for possible additional testing 
6.5.1.4. 
Obtain 12-lead ECG performed supine. 
6.5.1.5. 
Perform study drug accountability. 
6.5.1.6. 
Review of AEs and concomitant medications. 


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6.6. 
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. Following resolution of intercurrent illness, the 
subject may resume study dosing at the discretion of the investigator. 
• Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s 
best interest 
• Therapeutic failure (ie, virologic failure, see Section 6.8 for details) 
• Subject request to discontinue for any reason 
• Subject noncompliance 
• Pregnancy during the study; refer to Section 7.8 
• Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB/IEC 
6.7. 
End of Study 
For Part A subjects with suppressed viremia (HIV-1 RNA <50 copies/mL at screening), the 
end of study is defined as the completion of Day 10 and the 30-Day Follow-up visit. 
For subjects failing a current antiretroviral regimen (HIV-1 RNA >1,000 copies/mL at 
screening), the end of study is defined as the completion of 48 weeks on study drug and the 
30-Day Follow-up visit, or for subjects enrolled in the extension phase, when: a) the subject 
turns 18 and EVG is available for use in adults in the country in which the subject is enrolled 
or b) the age appropriate EVG formulation becomes available for use in the country in which 
the subject is enrolled or c) Gilead Sciences elects to terminate development of EVG in the 
applicable country. 
6.7.1. 
30-Day Follow-Up Assessments 
Part A subjects with suppressed viremia (HIV-1 RNA <50 copies/mL at screening) who 
complete the Day 10 intensive PK visit will discontinue EVG after the Day 10 dose and will 
return to the clinic 30 days after completion of the Day 10 visit for a 30-Day Follow-up visit. 
Subjects failing a current antiretroviral regimen /(HIV-1 RNA >1,000 copies/mL at 
screening) who complete 48 weeks on study drug will be required to return to the clinic 
30 days after completion of the Week 48 visit for a 30-Day Follow-up visit only if they do 
not wish to enroll in the extension phase of the study. 


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Subjects who discontinue study drug and do not wish to continue in the study will be 
required to return to the clinic 30 days after completion of an ESDD visit for a 30-Day 
Follow-Up visit. Those subjects who permanently discontinue study drug and continue in the 
study through at least one subsequent visit after the ESDD visit will not be required to 
complete the 30-Day Follow-Up visit. 
The following evaluations are to be completed at the 30-Day Follow-Up visit: 
6.7.1.1. 
Perform a symptom-directed physical examination as needed 
6.7.1.2. 
Obtain vital signs and body weight.   
6.7.1.3. 
Obtain urine samples for the following procedures: 
• Urinalysis 
• Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive, the result will be confirmed with a serum 
pregnancy test. 
• Urine sample storage for possible additional testing 
6.7.1.4. 
Obtain blood samples for the following laboratory analyses: 
• Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct 
bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, 
creatinine, magnesium, phosphorus, potassium, total protein, sodium, uric 
acid, amylase and lipase 
• Hematology profile: CBC with differential and platelet count 
• Plasma HIV-1 RNA 
• CD4+ cell count and percentage 
6.7.1.5. 
Review of AEs and concomitant medications. 
At the 30-Day Follow-Up Visit, any evaluations showing abnormal results for which there is 
a possible or probable causal relationship with the study drug, should be repeated weekly 
(or as often as deemed prudent by the investigator) until the abnormality is resolved, returns 
to baseline, or is otherwise explained. 


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6.8. 
Virologic Failure 
Resistance testing will be performed in subjects who experience suboptimal virologic 
response, virologic rebound, and at Week 48 or last visit on study at or after Week 8 if HIV-1 
RNA is  400 copies/mL. Subjects who experience either suboptimal virologic response or 
virologic rebound, as defined below (see Sections 6.8.1 and 6.8.2), will be considered to have 
virologic failure. 
6.8.1. 
Management of Suboptimal Virologic Response 
Subjects who meet the criteria listed below will be considered to have suboptimal virologic 
response: 
• HIV-1 RNA < 1 log10 reduction from Baseline and ≥ 400 copies/mL at the Week 8 and 
confirmed at Week 12 or the next unscheduled visit at least 2 weeks after Week 8. 
Following the unconfirmed suboptimal virologic response, HIV-1 RNA levels will be 
monitored at the next scheduled or unscheduled visit, and blood may be drawn for potential 
HIV-1 resistance testing (reverse transcriptase, protease, and integrase) (e.g., the Week 12 
visit for those subjects flagged as having unconfirmed suboptimal virologic response at 
Week 8). 
• Please refer to Figure 6-1 for the management of subjects who meet the criteria for 
Suboptimal Virologic Response. 


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Figure 6-1. 
Suboptimal Virologic Response Schema 
a 
If suboptimal virologic response is not confirmed, the subject will remain on their assigned study drug. 
b 
If suboptimal virologic response is confirmed, the HIV-1 resistance testing (reverse transcriptase, protease, and 
integrase) will be analyzed only if the HIV-1 RNA is ≥ 400 copies/mL. 
c 
If the genotyping/phenotyping assay fails to provide results, an additional specimen will be sent for analysis and a new 
ARV regimen may be configured at the discretion of the Investigator, in consultation with the Medical Monitor.  
d 
Based on the results of the genotype/phenotype assays, the subject's current regimen may be discontinued or altered 
(ie, remain on study drugs, remain on open-label elvitegravir and reconfigure BR, or switch to regimen without open-
label elvitegravir) and the subject will remain in the study through Week 48. 
 


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6.8.2. 
Management of Virologic Rebound 
Subjects who meet any one of the criteria listed below will be considered to be a potential 
virologic failure: 
• At any visit, after achieving HIV-1 RNA < 400 copies/mL, a rebound in HIV-1 RNA to 
≥ 400 copies/mL, which is subsequently confirmed at the following scheduled or 
unscheduled visit at least 2 weeks after date of original test with HIV-1 RNA 
≥ 400 copies/mL 
• At any visit, a > 1 log10 increase of HIV-1 RNA from nadir, which is subsequently 
confirmed at the following scheduled or unscheduled visit at least 2 weeks after date of 
original test with HIV-1 RNA > 1 log10 increase from nadir 
Following the unconfirmed virologic rebound, subjects will be asked to return to the clinic 
for a scheduled or unscheduled HIV-1 RNA and HIV-1 resistance testing (reverse 
transcriptase, protease, and integrase) blood draw. 
Please refer to Figure 6-2 for the management of subjects who meet the criteria for Virologic 
Rebound. 


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Figure 6-2. 
Virologic Rebound Schema 
a 
At least 2 weeks after original elevated HIV-1 RNA test. 
b 
If virologic rebound is not confirmed, the subject will remain on their assigned study drug. 
c 
If virologic rebound is confirmed, HIV-1 resistance testing (reverse transcriptase, protease and integrase) will be 
analyzed only if the HIV-1 RNA is  400 copies/mL. 
d 
If the genotyping/phenotyping assay fails to provide results, an additional specimen will be sent for analysis and a new 
ARV regimen may be configured at the discretion of the Investigator, in consultation with the Medical Monitor.  
e 
Based on the results of the genotype/phenotype assays, the subject's current regimen may be discontinued or altered 
(ie, remain on study drugs, remain on open-label elvitegravir and reconfigure BR, or switch to regimen without 
open-label elvitegravir) and the subject will remain in the study through Week 48. 
 


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7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events 
7.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. AEs may also include pre- or post treatment 
complications that occur as a result of protocol specified procedures, lack of efficacy, 
overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs. 
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae (see Section 7.7.1) 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF. 


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7.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an event that, at any dose, results in the 
following: 
• Death 
• Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.) 
• In-patient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• A medically important event or reaction: such events may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; and development of drug 
dependency or drug abuse. For the avoidance of doubt, infections resulting from 
contaminated medicinal product will be considered a medically important event and 
subject to expedited reporting requirements. 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin). 
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5. 


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7.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event 
information and assessments. 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures 
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations: 
• No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication). 
• Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product. 
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting.  
The relationship to study procedures (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations: 
• No: Evidence exists that the adverse event has an etiology other than the study 
procedure. 
• Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture) 
7.2.2. 
Assessment of Severity 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead 
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-associated procedures performed from 
screening onwards. 
All AEs, regardless of cause or relationship, that occur from initiation of study medication 
until 4 weeks after last administration of study IMP must be reported to the CRF/eCRF 
database as instructed.  


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of 
the last dose of study IMP, regardless of causality, should also be reported.  
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE 
will be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution. 
Investigators are not obligated to actively seek SAEs after the period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH. 
• All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline.  
• At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE 
(eSAE) system. Gilead will notify sites in writing and provide training and account 
information prior to implementing an eSAE system. 
Serious Adverse Event Paper Reporting Process 
• All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of PPD PVG. 




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• If for any reason it is not possible to record the SAE information electronically, ie, the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above. 
• As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper form because the eCRF database has been 
locked, no further action is necessary. 
• For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
• Additional information may be requested to ensure the timely completion of accurate 
safety reports. 
• Any medications necessary for treatment of the SAE must be recorded onto the 
concomitant medication section of the subject’s CRF/eCRF and the event description 
section of the SAE form. 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable.  
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where 
this is required by local regulatory agencies, and in accordance with the local institutional 
policy.  


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7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an 
AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(e.g., electrocardiogram, X-rays, vital signs) that are associated with signs and/or symptoms 
must be recorded as an AE or SAE if they meet the definition of an AE (or SAE). If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (i.e., anemia) 
not the laboratory result (i.e., decreased hemoglobin). 
• Severity should be recorded and graded according to the GSI Grading Scale for Severity 
of Adverse Events and Laboratory Abnormalities. For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity 
in the context of the underlying conditions; this may or may not be in agreement with the 
grading of the laboratory abnormality. Grade 3 and 4 clinically significant laboratory 
abnormalities should be confirmed by repeat testing within 3 calendar days of receipt of 
results and before investigational medicinal product discontinuation, unless such a delay 
is not consistent with good medical practice. 
Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities. 
• When restarting investigational medicinal product following resolution of the adverse 
event, the investigational medicinal product should be restarted at full dose upon 
discussion with the Medical Monitor. 
• Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product. 
• Any questions regarding toxicity management should be directed to the Medical Monitor. 
7.5.1. 
Grades 1 and 2 Laboratory Abnormality or Clinical Event 
Continue investigational medicinal product at the discretion of the Investigator. 
7.5.2. 
Grade 3 Laboratory Abnormality or Clinical Event 
• For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product. 


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• For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to 
≤ Grade 2. 
• If a laboratory abnormality recurs to ≥ Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent 
discontinuation. 
7.5.3. 
Grade 4 Laboratory Abnormality or Clinical Event 
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade. 
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product. 
7.6. 
Toxicity Management  
All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 4. 
• Grade 3 and Grade 4 clinically significant laboratory abnormalities should be confirmed 
by repeat 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. 
Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Gilead Sciences Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 5). 
• When restarting study drug following resolution of the adverse event, the study drug 
should be restarted at full dose or modified dose that is dependent upon discussion with 
the Gilead Sciences Medical Monitor. 


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• 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 the study drug. 
• • Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor. 
7.7. 
Special Situations Reports 
7.7.1. 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack 
of effect reports and pregnancy reports regardless of an associated AE.  Also includes reports 
of adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure. 
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.  
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject. 
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information. 
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s). 
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.   
7.7.2. 
Instructions for Reporting Special Situations 
7.7.2.1. 
Instructions for Reporting Pregnancies 
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the PPD PVG using the pregnancy report 
form within 24 hours of becoming aware of the pregnancy.  


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Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons. 
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term. 
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to PPD PVG. 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD PVG using the pregnancy outcome 
report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477.  
Refer to Section 7.8 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations. 
7.7.2.2. 
Reporting Other Special Situations 
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD PVG within 24 hours of the investigator becoming aware of the situation.  
These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation. 
Refer to Section 7.4 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting. 
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available. 
7.8. 
Risks for Females of Childbearing Potential or During Pregnancy 
The risks of treatment with the study drug during pregnancy have not been evaluated. If 
females are using hormonal agents for contraception, the safety and/or efficacy may be 


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affected by possible drug-drug interactions. The plasma concentration of the hormonal 
contraceptive ethinyl estradiol may be decreased when used concomitantly with EVG in 
combination with ritonavir-boosted protease inhibitors. It is recommended that a non-
hormonal method (or methods) be used concurrently with hormonal contraceptives. If 
females utilize hormonal agents as one of their contraceptive methods, it is required that the 
same hormonal method be used for at least 3 months before study dosing. Please refer to the 
latest version of the Investigator’s Brochure for additional information. 
7.8.1. 
Definition of Childbearing Potential and Post-Menopausal 
A female subject of childbearing potential is a nonmenopausal female who has not had a 
hysterectomy, bilateral oophorectomy, or medically documented ovarian failure. This 
definition includes a young woman who has not yet started menstruating (premenarchal, 
Tanner Stage 3 and below). Pre-pubertal females (Tanner Stages 1 and 2) are not considered 
to be of childbearing potential unless onset of menarche has occurred. 
Menopause can be assumed to have occurred in a woman when there is: 
• Appropriate medical documentation of prior complete bilateral oophorectomy 
(i.e., surgical removal of the ovaries, resulting in “surgical menopause” and occurring at 
the age at which the procedure was performed) 
7.8.2. 
Contraception Requirements for Males and Females of Childbearing 
Potential 
Male subjects and female subjects of childbearing potential must agree to utilize protocol-
recommended methods of contraception from the Screening Visit throughout the study 
period and for 30 days after administration of the last dose of study drug. Female study 
subjects who are not heterosexually active must have periodic confirmation of continued 
abstinence from heterosexual intercourse and regular pregnancy testing while taking EVG. 
The investigator should counsel subjects on the protocol-recommended method(s) for 
avoiding pregnancy in case subject chooses to engage in heterosexual intercourse. These 
methods are recommended due to the low failure rate (ie, less than 1% per year). See 
Table 7-1 for the protocol-recommended methods. 
Females of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test at Baseline/Day 1 prior to receiving the first dose of 
study drug. Lactating females must discontinue nursing before investigational medicinal 
product administration. 


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Table 7-1. 
Protocol-Recommended Contraceptive Methods 
Methods to Use by 
Themselves 
Combination Methods 
Hormone Methods 
(choose one and use with a barrier 
method) 
Barrier Methods 
(use both OR choose one and use 
with a hormone method) 
Intra-uterine devices (IUDs) 
• Copper T 380A IUD 
• LNg 20 IUD 
Estrogen and Progesterone 
• Oral contraceptives 
• Transdermal patch 
• Vaginal ring 
Progesterone 
• Injection 
• Implant 
• 
Diaphragm  
OR 
• 
Cervical cap  
• 
Male condom (without 
spermicide) 
Partner’s vasectomy must be used along with a hormone or barrier method. 
 
Acceptable barrier methods include: diaphragm, cervical cap, and the male condom. Female 
subjects who utilize hormonal contraceptives as one of their birth control methods must have 
used the same method for at least 3 months before study dosing. If females are using 
hormonal agents for contraception, the efficacy may be affected by possible drug-drug 
interaction. The plasma concentration of the hormonal contraceptive ethinyl estradiol may be 
decreased when used concomitantly with EVG in combination with ritonavir-boosted 
protease inhibitors. It is recommended that non-hormonal methods be used concurrently. 
Other contraceptive methods may be acceptable after discussion with the Medical Monitor. 
Male subjects who are sexually active must be willing to use effective barrier contraception 
(e.g., non-lambskin condoms) during heterosexual intercourse from screening through 
completion of the study and continuing for at least 30 days after the last dose of study drug. 
In addition, male subjects must refrain from sperm donation from Day 0 through completion 
of the study and continuing for at least 30 days after administration of the last dose of study 
drug. 
All subjects of child bearing potential must undergo appropriate contraceptive counselling. 
The Investigator should counsel subjects on the most effective method(s) for avoiding 
pregnancy during the study. 
Use of condoms (except for lambskin condoms) should be encouraged for all participants 
with the potential to be sexually active because they have been proven to decrease the risk of 
transmission of HIV and other sexually transmitted diseases.  


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7.8.3. 
Procedures to be Followed in the Event of Pregnancy 
Subjects should be instructed to notify the Investigator if they become pregnant at any time 
during the study, or if they become pregnant within 30 days of last study drug dose. Subjects 
who become pregnant or who suspect that they are pregnant during the study must report the 
information to the Investigator and discontinue study drug immediately. The Investigator 
should report all pregnancies to PPD PVG using the Pregnancy Report form within 24 hours 
of becoming aware of the pregnancy. The Investigator should counsel the subject regarding 
the possible effects of prior study drug exposure on the fetus and the need to inform the study 
site of the outcome of the pregnancy. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary analysis objectives of this study are: 
• To evaluate the steady-state PK and confirm the dose of EVG/r in HIV-1 infected, 
antiretroviral treatment-experienced subjects 4 weeks to <18 years of age 
• To evaluate the safety and tolerability of EVG/r in HIV-1 infected, antiretroviral 
treatment-experienced subjects 4 weeks to <18 years of age  
The secondary analysis objective of this study is: 
• To evaluate the antiviral activity of EVG/r in HIV-1 infected, antiretroviral 
treatment-experienced subjects 4 weeks to <18 years of age who are failing their current 
HAART regimen 
8.1.2. 
Primary Endpoint 
The primary endpoints are PK parameters AUCtau and Cmax of EVG and the incidence of 
treatment-emergent AEs and treatment-emergent laboratory abnormalities.  
8.1.3. 
Secondary Endpoint 
The secondary endpoints include: 
• PK parameters Ctau, CL/F, and Vz/F of EVG  
• The percentage of subjects with plasma HIV-1 RNA < 50 and < 400 copies/mL at 
Weeks 24 and 48 as defined by the FDA snapshot analysis, respectively  
• The change from baseline in plasma log10 HIV-1 RNA (copies/mL) and in CD4+ cell 
count (cells/μL), and CD4 percentage at Weeks 24 and 48 
• Tanner Stages at Weeks 24 and 48, and age of first menses.  
• Palatability of oral suspension formulation of EVG in appropriate age group 
• Adherence to EVG 


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8.2. 
Analysis Conventions 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
Efficacy analysis will be conducted to use the full analysis set (FAS), which will include all 
subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2. 
Safety 
Safety analysis will be conducted to use the safety analysis set, which will include all 
subjects who were enrolled and received at least one dose of study drug.  
All the data collected up to 30 days after subjects permanently discontinue their study 
regimen will be included in the safety summaries. 
8.2.1.3. 
Pharmacokinetics (PK) 
Intensive PK Analysis Set  
The intensive PK analysis set for Part A will include all Part A subjects who were enrolled 
and received at least one dose of study drug and for whom steady-state pharmacokinetic 
profiles of EVG at Intensive PK visit are evaluable. The intensive PK analysis set will be 
used for detailed PK analysis of EVG. 
PK Analysis Set  
The PK analysis set will include all subjects with HIV-1 RNA > 1,000 copies/mL at 
screening and were enrolled and received at least one dose of study drug and for whom at 
least one observed concentration data of EVG is available. The PK analysis set will be used 
for analysis of general PK and trough blood concentrations. 
8.2.2. 
Subject Groups 
Intensive PK Group: includes all Part A subjects. 
Long-Term Safety Group: includes all Part A subjects with HIV-1 RNA >1,000 copies/mL at 
screening and all Part B subjects. 
PK and safety analysis will be conducted by age group and overall for the intensive PK group 
and the long-term safety group. Efficacy analysis will be conducted by age group and overall 
for subjects with HIV-1 RNA < 50 copies/mL at screening and for subjects with HIV-1 RNA 
> 1,000 copies/mL at screening. 


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8.3. 
Data Handling Conventions 
Natural logarithm transformation for key PK parameters, such as Cmax, Ctau and AUCtau, will 
be applied for pharmacokinetic analysis. 
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for 
the determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing and will be excluded in any calculation 
of geometric means or ratios. 
Subjects aged 6 months to < 2 years old (Cohort 4a) and subjects aged 4 weeks to < 6 months 
old (Cohort 4b) in Part A will be combined into one age group (Cohort 4) in Part A for the 
safety analysis, and will be summarized separately and combined for PK evaluation. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for the intensive PK group and the long-term safety group. 
Demographic summaries will include sex, race/ethnicity, randomization stratification group, 
and age. 
Baseline data will include a summary of body weight, height, body mass index, HIV-1 
infection, CD4 counts, and eGFR.  
8.5. 
Efficacy Analysis 
The percentage of subjects with HIV-1 RNA < 50 copies/mL at Week 24 (Windows: Study 
Days 141-196) as defined by the FDA snapshot analysis algorithm will be summarized using 
descriptive statistics. 
Virologic outcome at Week 24 will be defined into the following 3 categories:  
• Virologic Success: this includes subjects who have the last available on study drug HIV-1 
RNA < 50 copies/mL in the Week 24 window;   
• Virologic Failure: this includes (1) subjects who have the last available on study drug 
HIV-1 RNA  50 copies/mL in the Week 24 window, (2) subjects who discontinue prior 
to or in the Week 24 window due to lack of efficacy, or (3) subjects who discontinue 
prior to or in the Week 24 window due to reasons other than AE, death, and lack of 
efficacy and have the last available on study drug HIV-1 RNA  50 copies/mL; 
• No Virologic Data in the Week 24 window due to:  
— Discontinuation of study drug prior to or in the Week 24 window due to AE or death; 
or  


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— Discontinuation of study drug prior to or in the Week 24 window due to reasons other 
than AE, death, or lack of efficacy and the last available on study drug HIV-1 RNA 
< 50 copies/mL; or   
— Missing data in the Week 24 window but on study drug 
Virologic outcomes will be summarized using frequency counts and percentages based on the 
FAS analysis set by age group and overall for subjects with HIV-1 RNA >1,000 copies/mL 
at screening. The 95% confidence intervals for the percentage estimate will be constructed 
using the Exact method. 
The percentage of subjects with HIV-1 RNA < 50 copies/mL at Week 48 (Windows: Study 
Days 309-378) and the percentage of subjects with HIV-1 RNA < 400 copies/mL at 
Weeks 24 and 48 will be summarized in the same manner as described above.  
The relationship between EVG exposures (AUCtau, Cmax, and Ctau) and virologic failures as 
defined by the snapshot algorithm will be explored among subjects who have non-missing 
AUCtau, Cmax, or Ctau for EVG and virologic failure data. 
The changes from baseline in plasma log10 HIV-1 RNA, CD4+ cell count, and CD4 
percentage will be summarized using descriptive statistics by age group and overall for 
subjects with HIV-1 RNA < 50 copies/mL at screening and for subjects with HIV-1 RNA 
>1,000 copies/mL at screening. In addition, the change from baseline in CD4 percentage will 
be summarized by visit for subjects < 5 years of age for subjects with HIV-1 RNA < 50 
copies/mL at screening and for subjects with HIV-1 RNA > 1,000 copies/mL at screening. 
8.6. 
Safety Analysis 
All safety analyses will be performed using the safety analysis set. 
8.6.1. 
Extent of Exposure 
Duration of exposure to study drug will be expressed as the number of weeks between the 
first and last dose of the study regimen, inclusive, regardless of temporary interruptions in 
study regimen administration by age group and overall for subjects with HIV-1 RNA < 50 
copies/mL at screening and for subjects with HIV-1 RNA > 1,000 copies/mL at screening.  
Dosing information for individual subjects will be listed.  
Palatability of oral suspension formulation of EVG will be summarized using descriptive 
statistics by appropriate age group and overall. 
8.6.2. 
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 


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(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will 
be attached to the clinical database. 
Adverse events meeting one of the following criteria are defined as treatment-emergent AEs. 
1. Events with onset dates on or after the start of treatment and up to 30 days after the 
permanent discontinuation of the study medication from each specified study phase, and 
2. The continuing adverse events diagnosed prior to the start of treatment and worsening in 
severity grade, or non-serious adverse events at baseline become serious, or adverse 
events resulting in treatment discontinuation after the start of treatment. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by 
SOC and PT) will be provided by age group and overall for the intensive PK group and the 
long-term safety group. Additional summaries will include summaries for adverse events by 
grade, Investigator’s assessment of relationship to study drug, and effect on study drug 
dosing. 
8.6.3. 
Laboratory Evaluations 
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized by age group and overall 
for the intensive PK group and the long-term safety group . 
Graded laboratory abnormalities will be defined using the grading scheme in Grading of 
Laboratory Abnormalities provided in Appendix 5. 
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at 
least one toxicity grade from baseline at any time post baseline up to and including the date 
of last dose of investigational medicinal product plus 30 days, will be summarized by age 
group and overall for the intensive PK group and the long-term safety group. If baseline data 
are missing, then any graded abnormality (i.e., at least a Grade 1) will be considered 
treatment emergent. The maximum toxicity grade will be summarized by laboratory 
parameter. 
Laboratory abnormalities that occur before the first dose of IMP or after the subject has been 
discontinued from treatment plus 30 days will be included in a data listing. 
8.6.4. 
Other Safety Evaluations 
8.6.4.1. 
Tanner Stage Assessment 
Tanner Stages at Weeks 24 and 48 will be summarized by baseline Tanner Stage using 
frequency and percentage. Age of first menses will be summarized descriptively. 


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8.7. 
Pharmacokinetic Analysis 
For the intensive PK analysis set, the concentration data of EVG over sampling time will be 
listed and summarized. Pharmacokinetic parameters (e.g., AUCtau, AUClast, Cmax, Tmax, Clast, 
Tlast, Ctau, Ȝz, CL/F, Vz/F and T½) will be listed and summarized for EVG using descriptive 
statistics (e.g., sample size, arithmetic mean, geometric mean, coefficient of variation %, 
standard deviation, median, Q1, Q3, minimum, and maximum) by age group and overall. 
Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation, and median (Q1, Q3). 
To evaluate the exposures of EVG achieved in pediatric subjects are similar to the exposures 
observed in historical control subjects, an analysis of variance (ANOVA) will be carried out 
for log-transformed AUCtau and Cmax of EVG as the primary endpoints while Ctau of EVG 
will be explored for the intensive PK analysis set. EVG exposure data from the current study 
will be compared to the integrated historical control data using pharmacokinetic equivalence 
testing with an equivalency boundary of 70% - 143% for the 90% confidence interval. In 
addition, the 95% confidence interval of the geometric mean estimate of CL/F and Vz/F of 
EVG will be provided for the intensive PK analysis set. 
8.8. 
Sample Size and Power 
A total of 12 pediatric subjects in each cohort compared to 334 HIV-infected historical 
control subjects included in the EVG population modeling will provide at least 90% power to 
conclude exposure equivalence of EVG AUCtau and Cmax in pediatric subjects vs. in historical 
control subjects, assuming the expected geometric mean ratio is 1, equivalency boundary is 
70% to 143%, two one-sided tests are each performed at an alpha level of 0.05, and the 
standard deviation is 0.36 ng•hr/mL for AUCtau and 0.28 ng/mL for Cmax (natural log scale, 
estimated from EVG population PK modeling). 
A total of 12 subjects in each cohort will also provide at least 80% power to target a 95% 
confidence interval within 60% and 140% of the geometric mean estimate of clearance and 
volume of distribution of EVG, respectively, assuming a coefficient of variation (CV) of 
42.3% for clearance and 22.9% for volume of distribution (estimated from EVG population 
PK modeling).  
A total of 50 subjects from Parts A and B combined will provide for reasonable assessment 
of safety through Week 48 over the age range 4 weeks to < 18 years. For the main efficacy 
endpoint, assuming a virologic success rate of 60% (based on Study GS-US-183-0145 in 
adults) in this population of antiretroviral treatment-experienced subjects receiving a new 
class drug, i.e., EVG, a sample size of 50 subjects will result in a 95% confidence interval 
(CI) for the response rate from 46% to 74% (i.e., an error margin of 14%). 
Sample size and power calculations were made using the software package nQuery Advisor 
(Version 6.0). 


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8.9. 
Data Monitoring Committee 
An external multidisciplinary data monitoring committee (DMC) will review the progress of 
the study and perform interim reviews of safety and PK data and provide recommendation to 
Gilead about whether the nature, frequency, and severity of adverse effects associated with 
study treatment warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications.  
The DMC’s specific activities will be defined by a mutually agreed charter, which will define 
the DMC’s membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regarding future conduct of the study, 
including possible early study termination, Gilead retains final decision-making authority on 
all aspects of the study. 


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


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9.1.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject’s legally authorized 
representative and the person conducting the consent discussion, and also by an impartial 
witness if required by IRB or IEC local requirements. 
9.1.4. 
Confidentiality 
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
another unique identifier (as allowed by local law) and an identification code will be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. Laboratory specimens must be labeled in such as way as to protect subject 
identity while allowing the results to be recorded to the proper subject. Refer to specific 
laboratory instructions detailed in the study laboratory manual. NOTE: The investigator must 
keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all 
applicable regulations.  
The investigator agrees that all information received from Gilead, including but not limited to 
the investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study 
information, remain the sole and exclusive property of Gilead during the conduct of the study 
and thereafter. This information is not to be disclosed to any third party (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior 
written consent from Gilead. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
9.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms (if 
applicable), 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 should include sequential notes containing at least the following 
information for each subject: 
• Subject identification (name, date of birth, gender); 
• Documentation that subject meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria); 
• Documentation of the reason(s) a consented subject is not enrolled 
• Participation in study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of IMP, including dates of dispensing and 
return; 
• Record of all adverse events and other safety parameters (start and end date, and 
including causality and severity); 
• Concomitant medication (including start and end date, dose if relevant; dose changes); 
• Date of study completion and reason for early discontinuation, if it occurs. 
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Gilead. The investigator must notify Gilead before destroying any clinical 
study records. 
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead must be notified in advance. 
If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Gilead to 
store these records securely away from the site so that they can be returned sealed to the 


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investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site. 
9.1.6. 
Case Report Forms 
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures.  eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system.  Original entries as well as any changes to data 
fields will be stored in the audit trail of the system.  Prior to database lock (or any interim 
time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents.  The eCRF capture the data 
required per the protocol schedule of events and procedures.  System-generated or manual 
queries will be issued to the investigative site staff as data discrepancies are identified by the 
monitor or internal Gilead staff, who routinely review the data for completeness, correctness, 
and consistency.  The site coordinator is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error).  At the conclusion of the 
trial, Gilead will provide the site with a read-only archive copy of the data entered by that 
site.  This archive must be stored in accordance with the records retention requirements 
outlined in Section 9.1.5.  
9.1.7. 
Investigational Medicinal Product Accountability and Return 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s IMP 
disposal procedures and provide appropriate instruction for destruction of unused IMP 
supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead QA, the site may destroy used (empty or partially 
empty) and unused IMP supplies in accordance with that site’s approved SOP. A copy of the 
site’s approved SOP will be obtained for central files.  
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the IMP. Upon study completion, 
copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead. 
The study monitor will review IMP supplies and associated records at periodic intervals. 


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9.1.8. 
Inspections 
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB or IEC, or to regulatory authority or health 
authority inspectors. 
9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
9.2. 
Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead. The investigator must submit all protocol modifications to the 
IRB or IEC in accordance with local requirements and receive documented IRB or IEC 
approval before modifications can be implemented. 
9.2.2. 
Study Report and Publications 
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases.  
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met: 
• the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for at least 2 years 
• The investigator will submit to Gilead any proposed publication or presentation along 
with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation.  
• No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4). 
• The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary. 


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9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. 
Access to Information for Monitoring 
In accordance with regulations and guidelines, the study monitor must have direct access to 
the investigator’s source documentation in order to verify the accuracy of the data recorded 
in the CRF/eCRF. 
The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved. 
9.3.2. 
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. 
REFERENCES 
2537 
Palella FJ, Delaney K, Moorman A, Loveless M, Fuhrer J, Satten G, et al. 
Declining morbidity and mortality among patients with advanced human 
immunodeficiency virus infection N Engl J Med 1998;338 (13):853-60. 
4256 
Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 
2000;30 (Suppl 2):S171-S6. 
4266 
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on 
adherence to HAART [abstract]. 40th Annual Meeting of the Infectious Disease 
Society of America; 2002 Oct 24-27; Chicago, Ill. p. 129. Abstract 486.  
5125 
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. 
Changing patterns of mortality across Europe in patients infected with HIV-1. 
Lancet 1998;352 (9142):1725-30. 
7034 
Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day 
treatment for HIV infection: Final 48-week results. 8th Conference on Retroviruses 
and Opportunistic Infections; 2001 February 4-8; Chicago, IL. Abstract 320. .  
7035 
Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence 
and efficacy with a once-daily efavirenz-based regimen: 48-week results from the 
Daily Antiretroviral Therapy II (DART II) Study [poster 5842]. XV International 
AIDS Conference; 2004 July 11-16; Bangkok, Thailand.  
7036 
Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P, et al. 
Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twice-
daily (BID) antiretroviral therapy (AT), in a large prospective observational cohort 
(CUVA Study) [poster WePeB5780]. XV International AIDS Conference; 2004 
July 11-16; Bangkok, Thailand.  
8284 
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term 
effectiveness of potent antiretroviral therapy in preventing AIDS and death: a 
prospective cohort study. Lancet 2005;366 (9483):378-84. 
9302 
Hammer SM, Saag MS, Schechter M, Montaner JSG, Schooley RT, Jacobsen DM, 
et al. Treatment for adult HIV infection: 2006 recommendations of the 
International AIDS Society-USA panel. JAMA 2006;296 (7):827-43. 
9320 
DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, et al. 
Antiviral activity,pharmacokinetics, and dose response of the HIV-1 integrase 
inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced 
patients. J Acquir Immune Defic Syndr 2006;43 (1):1-5. 


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10590 
Zolopa AR, Mullen M, Berger D, Ruane P, Hawkins T, Zhong L, et al. The HIV 
integrase inhibitor GS-9137 has potent antiretroviral activity in treatment-
experienced patients [oral presentation 143LB]. 14th Conference on Retroviruses 
and Opportunistic Infections; 2007 February 25-28; Los Angeles, Calif, USA.  
10609 
Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on 
paediatric dosing on the basis of developmental physiology and pharmacokinetic 
considerations. Clin Pharmacokinet 2006;45 (11):1077-97. 
11575 
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and 
Adolescents. December 1, 2007. AIDSinfo Web site.  Available at: 
http://AIDSinfo.nih.gov. Accessed 12 December, 2007. 
12104 
German PI, West S, Hui J, Kearney BP. Pharmacokinetic interaction between 
elvitegravir/ritonavir and dose-adjusted rifabutin [poster 19]. 9th International 
Workshop on Clinical Pharmacology of HIV Therapy; 2008 April 7-9; New 
Orleans, LA, USA.  
12272 
LEXIVA® (fosamprenavir calcium) Tablets and Oral Suspension. US Prescribing 
Information. GlaxoSmithKline, Research Triangle Park, NC. Revised: March 
2008.   
13585 
Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A, McKenna MT. 
Revised surveillance case definitions for HIV infection among adults, adolescents, 
and children aged <18 months and for HIV infection and AIDS among children 
aged 18 months to <13 years--United States, 2008. MMWR Recomm Rep 2008;57 
(RR-10):1-12. 
14699 
Ginsberg G, Hattis D, Miller R, Sonawane B. Pediatric pharmacokinetic data: 
implications for environmental risk assessment for children. Pediatrics 2004;113 (4 
Suppl):973-83. 
15984 
EuroHIV. HIV / AIDS Surveillance in Europe End-year report 2006. EuroHIV 
2006;75. 
16695 
Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Report: 
UNAIDS Report on the Global AIDS Epidemic 2010. 2010. Available at 
http://www.unaids.org/globalreport/Global_report.htm.   
17375 
Center for Disease Control and Prevention (CDC). HIV Surveillance Report 
Diagnoses of HIV infection and AIDS in the United States and Dependent Areas, 
2009. 2009;21:1-79. 
Source:http://www.cdc.gov/hiv/topics/surveillance/resources/reports/. 


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19045 
Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, et 
al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in 
treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease 
inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect 
Dis 2012;12:27-35. 
21225 
KALETRA (lopinavir/ritonavir) Tablet, Film Coated for Oral use. KALETRA 
(lopinavir/ritonavir) Solution for Oral use. US Prescribing Information. Abbott 
Laboratories. North Chicago, IL. Revised April 2012.   
23903 
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and 
adolescents. Clin J Am Soc Nephrol 2009;4 (11):1832-43. 
 


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11. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Study Procedures Table – Cohorts 1, 2, and 3 
Appendix 3. 
Study Procedures Table – Cohort 4 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Appendix 5. 
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities 
Appendix 6. 
Tanner Stages 
Appendix 7. 
Definitions of HIV-1 Related Disease (adapted from CDC 
Guidelines) 
 












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j 
Any adverse event or test showing abnormal results that is believed to be possibly/probably related to study drug treatment will be re-evaluated weekly (or as often as deemed 
prudent by the investigator) until the abnormality is resolved, returns to baseline, or is otherwise explained. 
k 
Vital signs include blood pressure, temperature, heart rate, and respiration rate. 
l 
Perform complete physical examinations at Screening, Baseline, Weeks 24, 48 and ESDD visits. 
m 
Tanner Stage assessments (Appendix 6) will be performed for subjects  6 years of age at the time of the visit, until the subject has been documented as Tanner Stage 5. 
Tanner Stage assessments will be performed every 48 weeks in the extension phase of the study or until subjects reach Tanner Stage 5, after which point Tanner assessments 
will no longer be performed. 
n 
Genotypic analysis for reverse transcriptase, protease, and integrase resistance will be done at screening for subjects with HIV-1 RNA >1,000 copies/mL.  The investigator 
must have received the results from the screening genotype before proceeding with the Baseline visit.  Historical genotypes should be obtained for subjects with HIV-1 RNA 
<50 copies/mL at screening.  
o 
CBC with differential and platelet count. 
p 
Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, creatinine, magnesium, phosphorus, 
potassium, total protein, sodium, uric acid, amylase and lipase  
q 
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, and triglycerides) metabolic assessments will be performed for subjects failing a current antiretroviral 
regimen (HIV-1 RNA >1,000 copies/mL) at screening and weighing 13 kg at the time of the visit, for the following visits: Baseline, Weeks 24, 48, ESDD, and every 
48 weeks in the extension phase of the study. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state 
to draw blood for the metabolic assessments. For Cohorts 2 and 3 only, direct LDL will be calculated if subjects weigh <15.8 kg at the time of the visit. 
r 
Plasma storage samples banked for possible future protocol-related testing (virology, PK analysis). For Cohort 3 only, plasma storage samples are collected at Weeks 12, 24, 
48, ESDD, and every 12 weeks in the extension phase of the study. 
s 
eGFR using Schwartz Formula (mL/min/1.73m2) = k × L/Scr [(k is a proportionality constant, refer to Section 4.2 for details); L is height in centimeters (cm); and Scr is 
serum creatinine (mg/dL)]  
t 
Urine storage samples banked for possible future protocol-related testing (Urine chemistry including urine phosphorus and urine creatinine) 
u 
Females of childbearing potential only. 
v 
Palatability of EVG suspension formulation will be assessed at Baseline/Day 1, Day 10 (Part A only), Week 24, and Week 48, as applicable. 
w 
Single PK sampling at Week 12 is only for Cohorts 1 and 2. 
x 
A trough (20 to 24 hours postdose) plasma PK sample will be collected. Subjects must come into the clinic without taking their dose of EVG and the PI/r and other BR 
components. 
y 
Intensive PK sampling will be performed on Day 10 and only applicable for subjects in Part A. Subjects must come into the clinic without taking their dose of EVG and the 
PI/r and other BR components. For Cohorts 2 and 3, samples will be collected at 0 (predose,  30 minutes), 1.5, 2.5, 3.5, 5, 8, 10, and 12 hours postdose. Please refer to the 
PK manual for details. 
z 
All subjects will be given their dose of EVG + PI/r and other BR components with food in the clinic at Baseline, Day 10, Weeks 16 and 40. 
 










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gg 30-Day Follow-up visit to be completed as follows: 30 days after the last dose taken following the Day 10 PK evaluation for subjects with suppressed viremia (HIV-1 RNA 
<50 copies/mL at screening); 30 days after the ESDD visit for subjects who permanently discontinue study drug prior to Day 10; 30 days after the ESDD visit for subjects 
who permanently discontinue study drug during the 48 weeks of dosing and do not wish to continue in the study; 30 days after the Week 48 visit for subjects who complete 
48 weeks on study drug and do not wish to enroll in the extension study. 
hh ESDD visit should occur within 72 hours of last dose of study drug. 
ii 
For subjects weighing < 9.4 kg at each visit, the study visit will be divided into separate visits. The first visit should occur according to the protocol specified visit date, with a 
visit window of ± 2 days up to Week 8 and ± 4 days through Week 48. The second visit should occur up to 7 days from the first visit. Please refer to footnotes KK and LL 
for exceptions to the Baseline/Day 1 and Day 10 visits, respectively. 
jj 
X1 = assessments to be performed at the first visit; X2 = assessments to be performed at the second visit, to be completed up to 7 days from the first visit 
kk The Baseline/Day 1 visit will be divided into a Pre-Baseline visit and a Baseline/Day 1 visit if subjects weigh <9.4 kg at the Screening visit. X0 = assessments to be performed 
at the Pre-Baseline visit, to be completed 3-5 days prior to the Baseline visit; X1 = assessments to be performed at the Baseline visit. 
ll 
The Day 10 intensive PK visit will be divided into 3 visits (Day 7 [instead of a telephone visit], Day 10, and Day 14) if subjects weigh <9.4 kg at the Baseline/Day 1 visit.     
X0 = assessments to be performed at the Day 7 visit; X1 = assessments to be performed at the Day 10 visit; X2 = assessments to be performed at the Day 14 visit. 
mm Maternal medical history for Hepatitis B and C will be obtained in lieu of laboratory testing. 
nn Any adverse event or test showing abnormal results that is believed to be possibly/probably related to study drug treatment will be re-evaluated weekly (or as often as deemed 
prudent by the investigator) until the abnormality is resolved, returns to baseline, or is otherwise explained. 
oo For study visits that are divided into multiple visits, adverse events and concomitant medications will be assessed at every visit. 
pp Vital signs include blood pressure, temperature, heart rate, and respiration rate. 
qq Perform complete physical examinations at Screening, Baseline, Weeks 24, 48 and ESDD visits. 
rr 
For subjects  1 year of age, obtain measurements at Screening, Baseline, Weeks 12, 24, and 48 only. For subjects < 1 year of age, obtain measurements at Screening, 
Baseline, and all visits Weeks 4 through 48. 
ss 
In the extension phase of the study, Tanner Stage assessments (Appendix 6) will be performed for subjects  6 years of age at the time of the visit, every 48 weeks, until 
subjects reach Tanner Stage 5, after which point Tanner assessments will no longer be performed. 
tt 
Genotypic analysis for reverse transcriptase, protease, and integrase resistance will be done at screening for subjects with HIV-1 RNA >1,000 copies/mL.  The investigator 
must have received the results from the screening genotype before proceeding with the Baseline visit.  Historical genotypes should be obtained for subjects with HIV-1 RNA 
<50 copies/mL at screening.  
uu CBC with differential and platelet count. 
vv Chemistry profile: Albumin, alkaline phosphatase, AST, ALT, direct bilirubin, total bilirubin, bicarbonate, BUN, calcium, chloride, CPK, creatinine, magnesium, phosphorus, 
potassium, total protein, sodium, uric acid, amylase and lipase  
ww Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, and triglycerides) metabolic assessments will be performed for subjects failing a current antiretroviral 
regimen (HIV-1 RNA >1,000 copies/mL) at screening and weighing 13 kg at the time of the visit, for the following visits: at Baseline, Weeks 24, 48, ESDD, and every 
48 weeks in the extension phase of the study. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state 
to draw blood for the metabolic assessments. 


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xx Plasma storage samples banked for possible future protocol-related testing (virology, PK analysis) at post-Week 48 visits. 
yy eGFR using Schwartz Formula (mL/min/1.73m2) = k × L/Scr [(k is a proportionality constant, refer to Section 4.2 for details); L is height in centimeters (cm); and Scr is 
serum creatinine (mg/dL)]  
zz 
Urine storage samples banked for possible future protocol-related testing (Urine chemistry including urine phosphorus and urine creatinine) 
aaa Females of childbearing potential only. 
bbb Palatability of EVG suspension formulation will be assessed at Baseline/Day 1, Day 10 (Part A only), Week 24, and Week 48, as applicable. 
ccc A trough (20 to 24 hours postdose) plasma PK sample will be collected. Subjects must come into the clinic without taking their dose of EVG and the PI/r and other BR 
components. 
ddd Intensive PK sampling will be performed on Day 10 and only applicable for subjects in Part A. Subjects must come into the clinic without taking their dose of EVG and the 
PI/r and other BR components. PK samples will be collected at 0 (predose,  30 minutes), 3, 3.5, 5, and 8 hours postdose. Please refer to the PK manual for details. 
eee All subjects will be given their dose of EVG + PI/r and other BR components with food in the clinic at Baseline, Day 10, Weeks 16 and 40. 
 


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Appendix 4. 
Management of Clinical and Laboratory Adverse Events  
 
 
Grade 1 
Grade 4 
Grade 3 
Grade 2 
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 
investigational medicinal products: 
 
1. Withhold investigational medicinal products until ≤ Grade 2 
2. Restart all investigational medicinal products at full dose 
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator 
If confirmed and 
possibly or probably 
related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, discontinue 
all investigational medicinal products dosing permanently 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 


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Appendix 5. 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version: 18 June 2012 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
HIV POSITIVE 
Adult and Pediatric ≥ 57 Days 
 
8.5 to 10.0 g/dL  
85 to 100 g/L 
 
7.5 to < 8.5 g/dL  
75 to < 85 g/L 
 
6.5 to < 7.5 g/dL  
65 to < 75 g/L 
 
< 6.5 g/dL 
< 65 g/L 
HIV NEGATIVE 
Adult and Pediatric ≥ 57 Days  
10.0 to 10.9 g/dL 
100 to 109 g/L 
OR 
Any decrease from Baseline
2.5 to < 3.5 g/dL 
25 to < 35 g/L 
9.0 to < 10.0 g/dL 
90 to < 100 g/L 
OR 
Any decrease from Baseline 
3.5 to < 4.5 g/dL 
35 to < 45 g/L 
7.0 to < 9.0 g/dL 
70 to < 90 g/L 
OR 
Any decrease from Baseline 
≥ 4.5 g/dL 
≥ 45 g/L 
< 7.0 g/dL 
< 70 g/L 
Infant, 36–56 Days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 to 9.4 g/dL 
85 to 94 g/L 
7.0 to < 8.5 g/dL 
70 to < 85 g/L 
6.0 to < 7.0 g/dL 
60 to < 70 g/L 
< 6.0 g/dL 
< 60 g/L 
Infant, 22–35 Days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 to 10.5 g/dL 
95 to 105 g/L 
8.0 to < 9.5 g/dL 
80 to < 95 g/L 
7.0 to < 8.0 g/dL 
70 to < 80 g/L 
< 7.0 g/dL 
< 70 g/L 
Infant, 1–21 Days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 to 13.0 g/dL 
120 to 130 g/L 
10.0 to < 12.0 g/dL 
100 to < 120 g/L 
9.0 to < 10.0 g/dL 
90 to < 100 g/L 
< 9.0 g/dL 
< 90 g/L 
Absolute Neutrophil Count  
(ANC) 
Adult and Pediatric, > 7 Days 
 
1000 to 1300/mm3 
 
750 to < 1000/mm3 
 
500 to < 750/mm3 
 
< 500/mm3 
1.00 to 1.30 GI/L 
0.75 to < 1.00 GI/L 
0.50 to < 0.75 GI/L 
< 0.50 GI/L 


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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infant, 2 – ≤ 7 Days 
1250 to 1500/mm3 
1.25 to 1.50 GI/L 
1000 to < 1250/mm3 
1.00 to < 1.25 GI/L 
750 to < 1000/mm3 
0.75 to < 1.00 GI/L 
< 750/mm3 
< 0.75 GI/L 
Infant, 1 Day 
4000 to 5000/mm3 
4.00 to 5.00 GI/L 
3000 to < 4000/mm3 
3.00 to < 4.00 GI/L 
1500 to < 3000/mm3 
1.50 to < 3.00 GI/L 
< 1500/mm3 
< 1.50 GI/L 
Absolute CD4+ Count 
HIV NEGATIVE ONLY 
Adult and Pediatric 
> 13 Years 
 
 
300 to 400/mm3 
300 to 400/μL 
 
 
200 to < 300/mm3 
200 to < 300/μL 
 
 
100 to < 200/mm3 
100 to < 200/μL 
 
 
< 100/mm3 
< 100/μL 
Absolute Lymphocyte Count 
HIV NEGATIVE ONLY 
Adult and Pediatric 
> 13 Years 
 
 
600 to 650/mm3 
0.60 to 0.65 GI/L 
 
 
500 to < 600/mm3 
0.50 to < 0.60 GI/L 
 
 
350 to < 500/mm3 
0.35 to < 0.50 GI/L 
 
 
< 350/mm3 
< 0.35 GI/L 
Platelets  
100,000 to < 125,000/mm3 
100 to < 125 GI/L 
50,000 to < 100,000/mm3 
50 to < 100 GI/L 
25,000 to < 50,000/mm3 
25 to < 50 GI/L 
< 25,000/mm3 
< 25 GI/L 
WBCs  
2000/mm3 to 2500/mm3 
1,500 to < 2,000/mm3 
1000 to < 1,500/mm3 
< 1000/mm3 
2.00 GI/L to 2.50 GI/L 
1.50 to < 2.00 GI/L 
1.00 to < 1.50 GI/L 
< 1.00 GI/L 
Hypofibrinogenemia 
100 to 200 mg/dL 
75 to < 100 mg/dL 
50 to < 75 mg/dL 
< 50 mg/dL 
1.00 to 2.00 g/L 
0.75 to < 1.00 g/L 
0.50 to < 0.75 g/L 
< 0.50 g/L 
Hyperfibrinogenemia 
> ULN to 600 mg/dL 
> 600 mg/dL 
— 
— 
> ULN  to 6.0 g/L 
> 6.0 g/L 
— 
— 


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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fibrin Split Product  
20 to 40 μg/mL 
> 40 to 50 μg/mL 
> 50 to 60 μg/mL 
> 60 μg/mL 
20 to 40 mg/L 
> 40 to 50 mg/L 
> 50 to 60 mg/L 
> 60 mg/L 
Prothrombin Time (PT) 
> 1.00 to 1.25 × ULN 
> 1.25 to 1.50 × ULN  
> 1.50 to 3.00 × ULN  
> 3.00 × ULN  
International Normalized Ratio 
of prothrombin time (INR) 
1.1 to 1.5 x ULN 
>1.5 to 2.0 x ULN 
>2.0 to 3.0 x ULN 
>3.0 x ULN 
Activated Partial 
Thromboplastin Time (APTT) 
 
> 1.00 to 1.66 × ULN 
 
> 1.66 to 2.33 × ULN 
 
> 2.33 to 3.00 × ULN 
 
> 3.00 × ULN 
Methemoglobin  
5.0 to 10.0% 
> 10.0 to 15.0% 
> 15.0 to 20.0% 
> 20.0%  
 


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia  
130 to <LLN mEq/L 
125 to < 130 mEq/L 
121 to < 125 mEq/L 
< 121 mEq/L 
130 to <LLN mmol/L 
125 to < 130 mmol/L 
121 to < 125 mmol/L 
< 121 mmol/L 
Hypernatremia  
146  to 150 mEq/L 
> 150 to 154 mEq/L 
> 154 to 159 mEq/L 
> 159 mEq/L 
146  to 150 mmol/L 
> 150 to 154 mmol/L 
> 154 to 159 mmol/L 
> 159 mmol/L 
Hypokalemia  
3.0 to 3.4 mEq/L 
2.5 to < 3.0 mEq/L 
2.0 to < 2.5 mEq/L 
< 2.0 mEq/L 
3.0 to 3.4 mmol/L 
2.5 to < 3.0 mmol/L 
2.0 to < 2.5 mmol/L 
< 2.0 mmol/L 
Hyperkalemia  
5.6 to 6.0 mEq/L 
> 6.0 to 6.5 mEq/L 
> 6.5 to 7.0 mEq/L 
> 7.0 mEq/L 
5.6 to 6.0 mmol/L 
> 6.0 to 6.5 mmol/L 
> 6.5 to 7.0 mmol/L 
> 7.0 mmol/L 
Hypoglycemia 
Adult and Pediatric 
≥ 1 Month 
 
55 to 64 mg/dL 
 
40 to < 55 mg/dL 
 
30 to < 40 mg/dL 
 
< 30 mg/dL 
3.03 to 3.58 mmol/L 
2.20 to < 3.03 mmol/L 
1.64 to < 2.20 mmol/L 
< 1.64 mmol/L 
Infant, < 1 Month 
50 to 54 mg/dL 
2.8 to 3.0 mmol/L 
40 to < 50 mg/dL 
2.2 to < 2.8 mmol/L 
30 to < 40 mg/dL 
1.7 to < 2.2 mmol/L 
< 30 mg/dL 
< 1.7 mmol/L 
Hyperglycemia, Nonfasting  
116 to 160 mg/dL 
> 160 to 250 mg/dL 
> 250 to 500 mg/dL 
> 500 mg/dL 
6.42 to 8.91 mmol/L 
> 8.91 to 13.90 mmol/L 
> 13.90 to 27.79 mmol/L 
> 27.79 mmol/L 
Hyperglycemia, Fasting 
110 to 125 mg/dL 
6.08 to 6.96 mmol/L 
>125 to 250 mg/dL 
>6.96 to 13.90 mmol/L 
>250 to 500 mg/dL 
>13.90 to 27.79 mmol/L 
>500 mg/dL 
>27.79 mmol/L 
Hypocalcemia  
(corrected for albumin if 
appropriate*) 
Adult and Pediatric 
≥ 7 Days 
 
7.8 to 8.4  mg/dL 
 
7.0 to < 7.8 mg/dL 
 
6.1 to < 7.0 mg/dL 
 
< 6.1 mg/dL 
1.94 to 2.10 mmol/L 
1.74 to < 1.94 mmol/L 
1.51 to < 1.74 mmol/L 
< 1.51 mmol/L 
Infant, < 7 Days 
6.5 to 7.5 mg/dL 
1.61 to 1.88  mmol/L 
6.0 to < 6.5 mg/dL 
1.49 to < 1.61 mmol/L 
5.5 to < 6.0 mg/dL 
1.36 to < 1.49 mmol/L  
< 5.5 mg/dL 
< 1.36 mmol/L 


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric ≥ 
7 Days 
 
>ULN to 11.5 mg/dL 
 
> 11.5 to 12.5 mg/dL 
 
> 12.5 to 13.5 mg/dL 
 
> 13.5 mg/dL 
>ULN to 2.88 mmol/L 
> 2.88 to 3.13 mmol/L 
> 3.13 to 3.38 mmol/L 
> 3.38 mmol/L 
Infant, < 7 Days 
11.5 to 12.4 mg/dL 
2.86 to 3.10  mmol/L 
> 12.4 to 12.9 mg/dL 
> 3.10 to 3.23  mmol/L 
> 12.9 to 13.5 mg/dL 
> 3.23 to 3.38  mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Hypocalcemia (ionized) 
3.0 mg/dL to < LLN 
2.5 to < 3.0 mg/dL 
2.0 to < 2.5 mg/dL 
< 2.0 mg/dL 
0.74 mmol/L to < LLN 
0.62 to < 0.74 mmol/L 
0.49 to < 0.62 mmol/L 
< 0.49 mmol/L 
Hypercalcemia (ionized) 
> ULN to 6.0 mg/dL 
> 6.0 to 6.5 mg/dL 
> 6.5 to 7.0 mg/dL 
> 7.0 mg/dL 
> ULN to 1.50 mmol/L 
> 1.50 to 1.63 mmol/L 
> 1.63 to 1.75 mmol/L 
> 1.75 mmol/L 
Hypomagnesemia 
1.40 to  <LLN mg/dL 
1.2 to <LLN mEq/L 
1.04 to < 1.40 mg/dL 
0.9 to <  1.2 mEq/L 
0.67 to < 1.04 mg/dL 
0.6 to < 0.9 mEq/L 
< 0.67 mg/dL 
< 0.6 mEq/L 
0.58 to <LLN mmol/L 
0.43 to < 0.58 mmol/L 
0.28 to < 0.43 mmol/L 
< 0.28 mmol/L 
Hypophosphatemia 
Adult and Pediatric 
> 14 Years 
 
2.0 to < LLN mg/dL 
 
1.5 to < 2.0 mg/dL 
 
1.0 to < 1.5 mg/dL 
 
< 1.0 mg/dL 
0.63  to < LLN mmol/L 
0.47 to < 0.63 mmol/L 
0.31 to < 0.47 mmol/L 
< 0.31 mmol/L 
Pediatric 1 Year–14 Years  
3.0 to 3.5 mg/dL 
0.96 to 1.12 mmol/L 
2.5 to < 3.0 mg/dL 
0.80 to < 0.96 mmol/L 
1.5 to < 2.5 mg/dL 
0.47 to < 0.80 mmol/L 
< 1.5 mg/dL 
< 0.47 mmol/L 
Pediatric < 1 Year 
3.5 to 4.5 mg/dL 
1.12 to 1.46 mmol/L 
2.5 to < 3.5 mg/dL 
0.80 to < 1.12 mmol/L 
1.5 to < 2.5 mg/dL 
0.47 to < 0.80 mmol/L 
< 1.5 mg/dL 
< 0.47 mmol/L 
Hyperbilirubinemia  
Adult and Pediatric 
> 14 Days 
 
> 1.0 to 1.5 × ULN  
 
> 1.5 to 2.5 × ULN 
 
> 2.5 to 5.0 × ULN  
 
> 5.0 × ULN  


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infant, ≤ 14 Days 
(non-hemolytic) 
NA 
20.0 to 25.0 mg/dL 
342 to 428 μmol/L 
> 25.0 to 30.0 mg/dL 
> 428 to 513 μmol/L 
> 30.0 mg/dL 
> 513 μmol/L 
Infant, ≤ 14 Days 
(hemolytic) 
NA 
NA 
20.0 to 25.0 mg/dL 
342 to 428 μmol/L 
> 25.0 mg/dL 
> 428 μmol/L 
Blood Urea Nitrogen 
1.25 to 2.50 × ULN  
> 2.50 to 5.00 × ULN  
> 5.00 to 10.00 × ULN  
> 10.00 × ULN 
Hyperuricemia 
>ULN to 10.0 mg/dL  
> 10.0 to 12.0 mg/dL  
> 12.0 to 15.0 mg/dL  
> 15.0 mg/dL 
>ULN to 597 μmol/L 
> 597 to 716 μmol/L 
> 716 to 895 μmol/L 
> 895 μmol/L 
Hypouricemia 
1.5 mg/dL to < LLN 
1.0 to < 1.5 mg/dL 
0.5 to < 1.0 mg/dL 
< 0.5 mg/dL 
87 μmol/L to < LLN 
57 to < 87 μmol/L 
27 to < 57 μmol/L 
< 27 μmol/L 
Creatinine  
> 1.50 to 2.00 mg/dL 
> 2.00 to 3.00 mg/dL 
> 3.00 to 6.00 mg/dL  
> 6.00 mg/dL 
> 133 to 177 μmol/L 
> 177 to 265 μmol/L 
> 265 to 530 μmol/L 
> 530 μmol/L 
Bicarbonate 
16.0 mEq/L to < LLN  
11.0 to < 16.0 mEq/L 
8.0 to < 11.0 mEq/L 
< 8.0 mEq/L 
16.0 mmol/L to < LLN 
11.0 to < 16.0 mmol/L 
8.0 to < 11.0 mmol/L 
< 8.0 mmol/L 
Triglycerides 
(Fasting) 
NA 
500 to 750 mg/dL 
> 750 to 1200 mg/dL 
> 1200 mg/dL 
 
5.64–8.47 mmol/L 
> 8.47–13.55 mmol/L 
> 13.55 mmol/L 
LDL 
(Fasting) 
130 to 160 mg/dL 
>160 to 190 mg/dL 
> 190 mg/dL 
NA 
3.35 to 4.15 mmol/L 
>4.15 to 4.92 mmol/L 
>4.92 mmol/L 
 
Pediatric >2 to <18 years 
110 to 130 mg/dL 
>130 to 190 mg/dL 
> 190 mg/dL 
NA 
2.84 to 3.37 mmol/L 
>3.37 to  4.92 mmol/L 
>4.92 mmol/L 
 


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercholesterolemia 
(Fasting) 
200 to 239 mg/dL 
> 239 to 300 mg/dL 
> 300 mg/dL 
NA 
5.16 to 6.19 mmol/L 
> 6.19 to 7.77 mmol/L 
> 7.77 mmol/L 
 
Pediatric < 18 Years 
170 to 199 mg/dL 
4.39 to 5.15 mmol/L 
> 199 to 300 mg/dL 
> 5.15 to 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 to < 6.0 × ULN 
6.0 to < 10.0 × ULN 
10.0 to < 20.0 × ULN 
≥ 20.0 × ULN 
* 
alcium should be corrected for albumin if albumin is < 4.0 g/dL 
 


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


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


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


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


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


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


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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Dysphagia-Odynophagia  
Symptomatic but able to eat 
usual diet 
Symptoms causing altered 
dietary intake without medical 
intervention indicated 
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated 
Life-threatening reduction in 
oral intake 
Mucositis/Stomatitis  
(clinical exam) 
See also Proctitis, 
Dysphagia-Odynophagia 
Erythema of the mucosa 
Patchy pseudomembranes or 
ulcerations  
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking) 
Nausea  
Transient (< 24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake 
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours 
Persistent nausea resulting in 
minimal oral intake for > 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids) 
Life-threatening consequences 
(eg, hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit) 
Symptomatic AND 
Hospitalization indicated 
(other than ER visit) 
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage) 
Proctitis (functional- 
symptomatic) 
Also see Mucositis/ 
Stomatitis for Clinical 
Exam 
Rectal discomfort AND No 
intervention indicated 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated  
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated  
Life-threatening consequences 
(eg, perforation) 
Vomiting 
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated 
Life-threatening consequences 
(eg, hypotensive shock) 
 


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


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 144 
25 April 2013 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Developmental delay – 
Pediatric ≤ 16 Years 
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting  
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting  
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting  
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Headache  
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Symptoms causing inability to 
perform usual social & 
functional activities 
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function  
Insomnia 
NA 
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities 
Difficulty sleeping causing 
inability to perform usual 
social & functional activities 
Disabling insomnia causing 
inability to perform basic self-
care functions 
Neuromuscular Weakness  
(including myopathy & 
neuropathy)  
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities 
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities 
Muscle weakness causing 
inability to perform usual 
social & functional activities  
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation 
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy) 
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities  
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities  
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities 
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 145 
25 April 2013 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Seizure: (new onset)  
NA 
1 seizure  
2–4 seizures  
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy) 
Seizure: (pre-existing)  
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels 
NA 
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder 
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality)  
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy) 
Seizure  
– Pediatric < 18 Years 
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state 
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with  
< 24 hours post ictal state 
Seizure, generalized onset 
with or without secondary 
generalization, lasting  
> 20 minutes  
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation 
Syncope (not associated 
with a procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities 
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities  
Vertigo causing inability to 
perform usual social & 
functional activities 
Disabling vertigo causing 
inability to perform basic self-
care functions 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 146 
25 April 2013 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
See also Arthritis 
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities 
Joint pain causing greater than 
minimal interference with usual 
social & functional activities 
Joint pain causing inability 
to perform usual social & 
functional activities 
Disabling joint pain causing 
inability to perform basic self-
care functions 
Arthritis 
See also Arthralgia 
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities 
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities 
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities 
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions 
Bone Mineral Loss 
BMD t-score or z-score 
–2.5 to –1.0  
BMD t-score or z-score < –2.5 
Pathological fracture 
(including loss of vertebral 
height) 
Pathologic fracture causing 
life-threatening consequences  
Pediatric < 21 Years 
BMD z-score  
–2.5 to –1.0 
BMD z-score < –2.5 
Pathological fracture 
(including loss of vertebral 
height) 
Pathologic fracture causing 
life-threatening consequences  
Myalgia 
(non-injection site) 
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities 
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities 
Muscle pain causing 
inability to perform usual 
social & functional activities 
Disabling muscle pain causing 
inability to perform basic self-
care functions 
Osteonecrosis 
NA 
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated 
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated 
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 147 
25 April 2013 
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] 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 148 
25 April 2013 
INJECTION SITE REACTION 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Injection Site Pain (pain 
without touching) 
Or Tenderness (pain when 
area is touched)  
Pain/tenderness causing no 
or minimal limitation of use 
of limb 
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities 
Pain/tenderness causing 
inability to perform usual 
social & functional activities 
 
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness 
Injection Site Reaction 
(Localized), > 15 Years 
Erythema OR Induration 
of 5 × 5 cm to 9 × 9 cm (or 
25−81 × cm2) 
Erythema OR Induration OR 
Edema > 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage 
Necrosis (involving dermis and 
deeper tissue) 
Pediatric ≤ 15 Years 
Erythema OR Induration 
OR Edema present but 
≤ 2.5 cm diameter 
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (eg, upper 
arm/thigh) 
Erythema OR Induration 
OR Edema involving 
≥ 50% surface area of the 
extremity segment (eg, 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Necrosis (involving dermis and 
deeper tissue) 
Pruritis Associated with 
Injection  
See also Skin: Pruritis 
(itching—no skin lesions) 
Itching localized to injection 
site AND Relieved 
spontaneously or with 
< 48 h treatment  
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring ≥ 48 h treatment  
Generalized itching causing 
inability to perform usual 
social & functional activities 
NA 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 149 
25 April 2013 
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 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc. 
 
 
Original 
 
 
 
CONFIDENTIAL 
Page 150 
25 April 2013 
GENITOURINARY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Intermenstrual Bleeding 
(IMB) 
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam 
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle 
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle 
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated 
Urinary Tract 
obstruction (eg, stone) 
NA 
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction 
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction 
Obstruction causing life-
threatening consequences 
 
INFECTION 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infection (any other 
than HIV infection) 
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities 
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Life-threatening 
consequences (eg, septic 
shock) 
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. 
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc.  
Original 
 
 
 
CONFIDENTIAL 
Page 151 
25 April 2013 
Appendix 6. 
Tanner Stages 
1. Pubic hair (male and female) 
Tanner I   
no pubic hair at all (prepubertal Dominic state) 
Tanner II   
small amount of long, downy hair with slight pigmentation at the base of the 
penis and scrotum (males) or on the labia majora (females) 
Tanner III   
hair becomes more coarse and curly, and begins to extend laterally 
Tanner IV   
adult-like hair quality, extending across pubis but sparing medial thighs 
Tanner V   
hair extends to medial surface of the thighs 
2. Genitals (male) (One standard deviation around mean age) 
Tanner I   
Testes, scrotum, and penis about same size and proportion as in early childhood 
Tanner II   
Enlargement of scrotum and testes; skin of scrotum reddens and changes in 
texture; little or no enlargement of penis (10.5-12.5) 
Tanner III   
Enlargement of penis, first mainly in length; further growth of testes and scrotum 
(11.5-14) 
Tanner IV   
Increased size of penis with growth in breadth and development of glans; further 
enlargement of testes and scrotum and increased darkening of scrotal skin 
(13.5-15) 
Tanner V  
Genitalia adult in size and shape 
3. Breasts (female) 
Tanner I   
no glandular tissue: areola follows the skin contours of the chest 
Tanner II   
breast bud forms, with small area of surrounding glandular tissue; areola begins 
to widen  
Tanner III   
breast begins to become more elevated, and extends beyond the borders of the 
areola, which continues to widen but remains in contour with surrounding breast  
Tanner IV   
increased breast size and elevation; areola and papilla form a secondary mound 
projecting from the contour of the surrounding breast 
Tanner V  
breast reaches final adult size; areola returns to contour of the surrounding breast, 
with a projecting central papilla.  
 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc.  
Original 
 
 
 
CONFIDENTIAL 
Page 152 
25 April 2013 
Appendix 7. 
Definitions of HIV-1 Related Disease (adapted from CDC 
Guidelines) 
Category B: Symptomatic Conditions in HIV-Infected Subjects 
1. Bacillary angiomatosis 
2. Candidiasis, oropharyngeal (thrush) 
3. Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy 
4. Cervical dysplasia (moderate or severe)/cervical carcinoma in situ 
5. Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting > 1 month 
6. Hairy leukoplakia, oral 
7. Herpes zoster (shingles), involving at least two distinct episodes or more than one 
Dermatome 
8. Idiopathic thrombocytopenic purpura 
9. Listeriosis 
10. Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess 
11. Peripheral neuropathy 
Category C: AIDS-Defining Diagnoses 
12. Candidiasis of bronchi, trachea, or lungs 
13. Candidiasis, esophageal 
14. Cervical cancer, invasive 
15. Coccidioidomycosis, disseminated or extrapulmonary 
16. Cryptococcosis, extrapulmonary 
17. Cryptosporidiosis, chronic intestinal (> 1 month duration) 
18. Cytomegalovirus disease (other than liver, spleen or nodes) 
19. Cytomegalovirus retinitis (with loss of vision) 
20. Encephalopathy, HIV-related 


Elvitegravir 
Protocol GS-US-183-0160 
Final 
Gilead Sciences, Inc.  
Original 
 
 
 
CONFIDENTIAL 
Page 153 
25 April 2013 
21. Herpes simplex: chronic ulcer(s) (> 1 month duration); or bronchitis, pneumonitis or 
esophagitis 
22. Histoplasmosis, disseminated or extrapulmonary 
23. Isosporiasis, chronic intestinal (> 1 month duration) 
24. Kaposi’s sarcoma 
25. Lymphoma, Burkitt’s (or equivalent term) 
26. Lymphoma, immunoblastic (or equivalent term) 
27. Lymphoma, primary, of brain 
28. Mycobacterium avium complex or Myobacterium kansasii, disseminated or 
extrapulmonary 
29. Mycobacterium tuberculosis , pulmonary or extrapulmonary  
30. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary 
31. Pneumocystis jirovecii pneumonia 
32. Pneumonia, recurrent 
33. Progressive multifocal leukoencephalopathy 
34. Salmonella septicemia, recurrent 
35. Toxoplasmosis of brain 
36. Wasting syndrome attributed to HIV infection 
CDC surveillance case definitions for HIV infection and AIDS {13585} 

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