Conditions: HIV
Keywords: Pediatric
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 160
Healthy volunteers: no

Brief summary:
The purpose of this study is to describe the safety, efficacy, and pharmacokinetics of a regimen of atazanavir powder boosted with ritonavir and an optimized dual nucleoside reverse transcriptase inhibitor in pediatric patients aged ≥3 months to \<11 years.

Detailed description:

Arms:
arm 1: Participants received atazanavir powder orally (dosed by weight: 5 to \<10 kg=150 mg, 5 to \<10 kg=200 mg, 10 to \<15 kg=200 mg, 15 to \<25 kg=250 mg, 25 to \<35 kg=300 mg) once daily for 24 to 48 weeks or a weight ≥35 kg. Participants also received ritonavir once daily for 24 to 48 weeks or weight ≥35 kg in the form of 80-mg/mL solution, orally (dosed by weight 5 to \<25 kg=80 mg, 25 to \<35 kg=100 mg); 100-mg capsule, orally (dosed by weight 25 to \<35 kg=100 mg); or 100-mg tablet, orally (dosed by weight 25 to \<35 kg=100 mg)

Interventions: intervention 1: Atazanavir Sulphate intervention 2: Ritonavir
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
AI424451
IND Number:
56,897
Ex-US
Non-IND
EUDRACT Number
2010-024537-23
Date:
08-Feb-2011
Revised Date:
15-Apr-2014
Clinical Protocol AI424451
A Prospective Single Arm, Open-Label, International, Multicenter Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of Atazanavir (ATV) Powder boosted with Ritonavir (RTV) with 
an Optimized NRTI Background Therapy, in HIV Infected, Antiretroviral, Naive and 
Experienced Pediatric Subjects from 3 Months to Less Than 11 Years. (Pediatric Atazanavir 
International Clinical Evaluation: the PRINCE II study)
Revised Protocol Number: 05
Incorporates amendment(s) 08, Administrative letter 02
Study Director / Central Medical Monitor
Daniela Cambilargiu, MD
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
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Date: 15-Apr-2014
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (e.g., amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved.
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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SYNOPSIS
Clinical Protocol AI424451
Title of Study: Protocol AI424451: A Prospective Single Arm, Open-Label, International, Multicenter Study to 
Evaluate the Safety, Efficacy and Pharmacokinetics of Atazanavir (ATV) Powder boosted with Ritonavir (RTV) 
with an Optimized NRTI Background Therapy, in HIV Infected, Antiretroviral, Naive and Experienced Pediatric 
Subjects from 3 Months to Less Than 11 Years. (Pediatric Atazanavir International Clinical Evaluation: the 
PRINCE II study)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): ATV oral powder with RTV liquid (or RTV capsules/tablets for 25 to < 35 kg weight band only) at 
doses recommended per protocol. 
Subjects will receive ATV powder with RTV liquid (or RTV capsules/tablets for 25 to < 35 kg weight band only) 
once a day with food. 
Duration of treatment is dependent on a subject’s age, weight, and the timing with which a country receives 
approval and has availability for the pediatric indication of a formulation whose requirements are met by the subject.
ATV/RTV should be taken orally with food at approximately the same time of each day.
Two NRTIs must be locally approved for pediatric use and should be dosed as per the local country label. Study 
physicians will prescribe NRTIs based on viral resistance results, the local guidelines for ARV treatment and 
subject’s treatment history. Tenofovir is prohibited. 
Study Phase: 3b
Research Hypothesis: Regimens consisting of ATV powder boosted with RTV with an optimized dual-NRTI 
backbone are safe and well tolerated in pediatric subjects 3 months to yrs who are 5 kg to < 35 kg.
Primary Objective: To describe the safety of ATV powder formulation boosted with RTV based HAART regimens 
in pediatric subjects dosed through a minimum of 24 weeks, as measured by the frequency of deaths, serious adverse 
events and discontinuation due to AEs.
Secondary Objectives:
1)
To describe efficacy as measured by proportions of subjects with a virologic response as defined by HIV RNA 
levels < 50 copies/mL and < 400 copies/mL by Roche AmplicorHIV-1 RNA Assay (version 1.5), or Abbott 
RealTime HIV-1 assay after the Roche Amplicor assay is discontinued, at Week 24 and Week 48 of ATV 
powder formulation
2)
To describe the pharmacokinetic profile of ATV powder formulation boosted with RTV in pediatric subjects 
weighing 25 to < 35 kg and/or who are 6 to years of age, and for subjects enrolling in the new 5 -
<10 kg cohort (200mg ATV and 80 mg RTV) in terms of ATV Cmax, Cmin and AUC.
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Study Design: 
Enter Stage 2.
Transition to capsules.**
Stage 2
Maximum time: until subject reaches 18 years of age or Pediatric Indication is locally approved and subject meets 
requirements to receive appropriate formulation
Age 12 years or  
Weight > 35 kg? *
Powder
Yes
Availability of Locally-
Approved, appropriate Pediatric 
Indication?
Age 18 years or Availability of 
Locally-Approved, appropriate 
Pediatric Indication
Transition out of Stage 2; begin dosing with powder or capsule according 
to local guidelines. Subject may qualify for PSDP
* Subjects are required to switch to capsules when they reach 35 kg and/or 12 years of age. However, subjects who reach a weight of 25 kg and/or 6 years of 
age during Stage 2 may, at the discretion of the investigator and caregiver, choose to attempt switch to the solid dosage forms of ATV/RTV. Careful 
consideration should be given to the time of switch as subjects who are unable to swallow capsule after an 8-week transition period must be discontinue from 
Stage 2.
** Subjects who are unable to swallow the capsule formulation after an 8 week transition period must be discontinued from thestudy.
Weight > 35 kg?
Complete 48 weeks.
Enter Stage 2 on powder.
Stage 1
Maximum time: up to 48 weeks of powder dosing
No
Yes
Age > 3 months to < 11 years: Minimum 56 subjects treated with  ATV powder formulation for 24 
weeks
Body Weight     (kg)
Target # of 
Subjects
ATV Dose 
(mg)
RTV Dose (mg)
5 to less than 10
Minimum of 5
Minimum of 6
150
200
80
80
+ approved NRTI backbone 
(tenofovir is prohibited)
10 to less than 15
Minimum of 10
200
80
15 to less than 25
Minimum of 10
250
80
25 to less than 35
No Minimum
300
100
The study will commit to enroll a minimum of 30 A RV experienced patients treated with A TV powder for  a minimum of 24 weeks.
Complete Final Stage 1 Status  
Evaluation and Enter Stage 2
Stage 1: Subject did not have 
opportunity to reach Week 48 by 
the time the last treated subject 
reaches Week 24?
Transition to capsule; 
remain in Stage 2.**
Capsule
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Study Population: 
Key Inclusion Criteria:

Confirmed HIV 1 infection diagnosed by protocol criteria

5kg  to < 35kg, and 3 months to 11 years of age at the time of first treatment

Antiretroviral naive or treatment-experienced. Treatment experienced subjects are defined by a previous 
exposure to antiretroviral drugs (ARVs) through either prior treatment for their HIV disease or through a post-
natal treatment with 1 ARVs for the prevention of mother to child transmission (PMTCT). For the purposes of 
this study, subjects exposed to ARVs in utero or intra-partum are eligible for the study, but will be considered 
‘treatment naive’.

Screening HIV RNA 1000 copies/mL by Roche Amplicor HIV-RNA Assay (version 1.5), or Abbott
RealTime HIV-1 assay after the Roche Amplicor assay is discontinued.

Antiretroviral naive subjects must have genotypic sensitivity at screening to ATV and at least 2 NRTIs 
(excluding TDF). NRTIs must be approved for pediatric use at the local country level. 

Antiretroviral experienced subjects (as defined above) must have documented genotypic and phenotypic 
sensitivity at screening to ATV (Fold Change in susceptibility < 2.2) and at least 2 NRTIs (excluding TDF). 
NRTIs must be approved for pediatric use at the local country level. 
Key Exclusion Criteria:

Experienced subjects who received ATV or ATV/RTV at any time prior to study enrollment or who have prior 
history of 2 or more PI failures

Antiretroviral-naive or experienced HIV-1 infected subjects with contraindication to study medications

Documented cardiac conduction abnormality(ies) or significant cardiac dysfunction, or a history of syncope

Family history of QTc interval syndrome, Brugada syndrome or right ventricular dysplasia or with a corrected 
QTc interval at screening of > 440 ms

One of the following cardiac rhythm abnormalities documented on the screening ECG: First degree 
atrioventricular (AV) block 

Type I second degree AV block while awake, type II second degree AV block at any time, complete AV block 
at any time, or age-adjusted heart rate < 2nd percentile) 

Need for Tenofovir

Coinfection with either HBV or HCV
Study Assessments and Primary Endpoint:  Safety assessments include vital signs and physical measurements, 
deaths, adverse events, serious and non-serious, including Centers for Disease Control (CDC) Class C AIDS events, 
concomitant medication, laboratory measurements, and ECGs. Efficacy assessments include HIV RNA and CD4 
cell counts. Intensive pharmacokinetic assessment in subjects weighing 25 kg to < 35 kg or 6 to years old, 
and subjects enrolling in the new 5 - <10 kg cohort (200mg ATV and 80 mg RTV) receiving the ATV powder 
formulation will be conducted. Palatability assessments includes a palatability survey for all subjects and Facial 
Hedonic Scale (only for subjects who are years old in Stage 2 on ATV powder formulation and switching to new 
4.2% aspartame ATV powder formulation).
Statistical Methods:  Values after transition from ATV powder to ATV capsules (i.e. Stage 2) will be excluded 
from all analyses through week 48 (Stage 1). Efficacy, safety and PK will be summarized by weight band on ATV 
powder through a minimum of 24 weeks for treated subjects. 
The primary safety endpoints are the frequency of deaths, SAEs and AEs leading to discontinuation of study 
therapy. 
The principal efficacy endpoints are the proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL at 
Week 24 and Week 48. 
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For intensive PK, ATV and RTV PK parameters (e.g. Cmax, Cmin, AUC, etc.) will be summarized for subjects 
weighing 25 - <35 kg and/or aged 6 - to 11 years receiving the powder ATV formulation and for subjects 
enrolling in the new 5 - <10 kg cohort (200mg ATV and 80 mg RTV). Trough PK of ATV and RTV will be 
summarized over time
There will be an independent data monitoring committee (DMC) for this study.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objective .............................................................................. 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Study Design ............................................................................................ 
3.1.2 Study Duration ......................................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Restrictions ..................................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.5.1 Premature Termination ............................................................................ 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Noninvestigational Product ..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Dosing Instructions .................................................................................. 
4.3.2 Specific Dosing Instructions on Days of Pharmacokinetic Assessments . 
4.3.3 Dose Modifications .................................................................................. 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
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4.5.1 Guidelines for the Management of Subjects with Rebound HIV RNA 
Levels Greater Than or Equal to 50 copies/mL .......................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
4.7 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Vital Signs and Physical Examinations ................................................... 
5.3.2 Adverse Events ......................................................................................... 
5.3.3 Concomitant Medication Assessment ...................................................... 
5.3.4 Electrocardiograms ................................................................................. 
5.3.5 Physical Measurements ........................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Intensive Pharmacokinetic Assessment .................................................... 
5.5.1.1 Data Collection (Intensive PK- only for subjects weighing  25 - 
< 35 kg  and/or aged  6 to < 11 years; subjects enrolling in a new  5 
- <10 kg cohort with 200mg ATV and 80 mg RTV ) ............................. 
5.5.2 Trough Plasma Concentration (for all subjects) ..................................... 
5.5.2.1 Data Collection (Trough PK - for all subjects) .............................. 
5.5.3 Blood Collection and Processing (Intensive and Trough Samples) ........ 
5.5.3.1 Collection Instructions .................................................................... 
5.5.4 Labeling and Shipping of Biological Samples (Intensive and Trough 
Samples) ...................................................................................................... 
5.6 Pharmacodynamics Assessments ...................................................................... 
5.7 Pharmacogenomic/Pharmacogenetic Assessments ........................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.9.1 Palatability Assessments .......................................................................... 
5.9.2 Laboratory Test Assessments ................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Abnormalities ......................................................................... 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Toxicity Management ............................................................................... 
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6.7.1.1 Management of Hyperbilirubinemia ............................................... 
6.7.1.2 Criteria for Treatment Interruption ................................................ 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoint Definitions ......................................................................................... 
8.3.1 Safety Endpoints....................................................................................... 
8.3.2 Efficacy Endpoints ................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Pharmacodynamic Analyses .................................................................... 
8.4.6 Pharmacogenomic Analyses .................................................................... 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.4.8.1 Palatability ...................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Publications ....................................................................................................... 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 LISTINGS OF PROHIBITED AND PRECAUTIONARY 
THERAPIES DURING THE STUDY ................................................................... 
APPENDIX 2 DAIDS TOXICITY GRADES .............................................................. 
APPENDIX 3 AIDS-DEFINING DIAGNOSES.......................................................... 
APPENDIX 4 SPECIFIC RECOMMENDATION FOR MANAGEMENT OF 
OTHER TOXICITIES ............................................................................................ 
APPENDIX 5 RECOMMENDATIONS FOR GRADING ACUTE AND SUBACUTE 
TOXIC EFFECTS (WHO) ..................................................................................... 
 
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1.3
Objectives
1.3.1
Primary Objectives
To describe the safety of ATV powder formulation boosted with RTV based HAART regimens 
in pediatric subjects dosed through a minimum of 24 weeks, as measured by the frequency of 
deaths, serious adverse events and discontinuation due to AEs.
1.3.2
Secondary Objectives
1) To describe efficacy as measured by proportions of subjects with a virologic response as 
defined by HIV RNA levels < 50 copies/mL and < 400 copies/mL by Roche Amplicor
HIV-1 RNA Assay (version 1.5), or Abbott RealTime HIV-1 assay after the Roche Amplicor 
assay is discontinued, at Week 24 and Week 48 of ATV powder formulation.
2) To describe the pharmacokinetic profile of ATV powder formulation with RTV in pediatric 
subjects weighing 25 - < 35 kg and/or 6 to < 11 years of age and for new 5 - < 10 kg 
cohort (200 mg ATV and 80 mg RTV) in terms of ATV Cmax, Cmin and AUC.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
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2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling, information to be provided to subjects and any updates. 
The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
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The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. The explicit wish of a minor 
who is capable of forming an opinion and assessing this information to refuse participation in, or 
to be withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
3.1.1
Study Design
This study is a prospective, international, multicenter, non-randomized study of a cohort of HIV 
infected pediatric subjects 3 months to years of age and weight 5 kg to < 35 kg, treated 
with ATV powder and RTV optimized regimens. 
Subjects can be antiretroviral naive or experienced (without prior exposure to ATV). Treatment 
experienced subjects are defined by a previous exposure to antiretroviral drugs (ARVs) through 
either prior treatment for their HIV disease or through a post natal treatment with 1 ARVs as 
part of a prevention of mother to child transmission (PMTCT) program (in accordance with 
multiple guidelines: WHO, DHHS and South Africa PMTCT guidelines). For the purposes of 
this trial, subjects exposed to ARVs intra-uterine or peri-partum will not be considered treatment 
experienced (but are still eligible for the study). 
Nucleoside backbone therapy will be determined by the investigator on the basis of the viral 
resistance profile and local guidelines according to the subject’s treatment history. It will consist 
of 2 NRTIs approved for pediatric use and dosed as per the local country label (tenofovir will be 
excluded). Background NRTIs should remain unchanged through the duration of the study unless 
changes are required for treatment-limiting NRTI toxicity. 
The choice of the switched NRTI backbone has to be locally approved for pediatric use and 
dosed as per the local country label and will be determined by the investigator on the basis of the 
viral resistance profile of the subject, susceptibility profile of the NRTIs being considered, and 
local guidelines for treatment of HIV infected children.
A total of approximately 95 subjects will be treated with the ATV powder formulation boosted 
with RTV oral solution (or RTV capsules/tablets for 25 to < 35 kg weight band only) in order to 
have a minimum number of 56 treated subjects with at least 24 weeks follow-up on ATV powder 
formulation. In the event that the minimum number of subjects (overall and/or per weight band) 
with at least 24 weeks follow-up is projected not to be met due to higher than projected early 
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discontinuation rate, then enrollment target will be re-adjusted during enrollment period or 
enrollment re-opened during the study to replace these subjects.
The study consists of two stages (see Figure 3.1.1-1):
STAGE 1
In-clinic study visits in Stage 1 will be at Day 1, Week 2, Week 4, then every 4 weeks through 
Week 16, then every 8 weeks through a minimum of 24 weeks or a maximum of 48 weeks. A 
“visit” done via the telephone is conducted after the first week of study participation, primarily to 
check in with the caregiver to ask how the subject is tolerating the study drug regimen.
Important assessments done during Stage 1 include but are not limited to:

A Week 2 Intensive 24 hour PK samples will be collected only for subjects in Stage 1 who 
either enter the study weighing 25 - < 35 kg and/or 6 to 11 years of age or those who 
grow into that weight or age range during Stage 1, or for subjects enrolling in a new 5 -
< 10 kg cohort with 200 mg ATV and 80 mg RTV dose, (see Section 5.5.1)

Malfunctions to the venous catheter, poor venous access, or other difficulties which 
would cause time point sample delays may be cause for the reschedule of the Intensive 
PK visit;

A PK Trough sample (Ctrough) will be collected for all subjects for ATV and RTV (see 
Section 5.5.2) at each scheduled visit from Week 4 through a minimum of 24 weeks up 
through Week 48,

ECGs will be collected at each scheduled in-clinic visit for all subjects, and during the 
Intensive PK portion at Week 2 (pre-dose, 2.5, 4 hours post-dose) for subjects weighing 
25 - < 35 kg and/or 6 to < 11 years of age or those who grow into that weight or age 
range during Stage 1, or for subjects enrolling in a new 5 - < 10 kg cohort with 200 mg 
ATV and 80 mg RTV dose. 
It is important to note that all visits in Stage 1 (with the exception of Week 2 and Transition 
Visits) include a PK trough assessment, so it is of critical importance to instruct the caregivers 
that study medication should NOT be administered on the day of a study visit, rather at the clinic 
after the blood draw has been completed.  An elapsed time from the previous dose of study 
medication to the draw of the blood for PK must be within a 20-28-hour window.
Dosing of ATV in Stage 1 is performed only with the powder formulation, dosed according to 
weight, as outlined in Table 3.1.1-1. When dosing with ATV powder, RTV oral solution is dosed 
at 80 mg for subjects weighing 5 to < 25 kg, and 100 mg RTV oral solution or 100 mg RTV 
tablets/capsules for subjects weighing 25 to < 35 kg. 
Once a subject has qualified by weight to move to a higher weight band/higher dose, they will 
remain at that new dose regardless of any subsequent weight loss.
BMS will require extra monitoring of subjects each time they transition to a higher weight 
band/higher dose of ATV. If a subject is moved to a higher weight band during Stage 1 on or 
after Week 16 (beyond which study visits occur every 8 weeks), the subject will be required to 
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return to the clinic for a weight band transition visit 4 weeks later. If they moved to the 25 to 
< 35 weight range or reach 6 years of age during Stage 1, a 24-hr intensive PK will be taken 
2 weeks after the dose change for the new weight band. If the subject becomes 6 years of age but 
without a dose change then the intensive PK visit can occur at the next regular Stage 1 visit.
Intensive PK collection for the age range (6 to 11 years), but not fulfilling the 25 to < 35 
weight range, will be stopped when PK samples from approximately 10 subjects have been 
collected. All subjects from the weight cohorts (25 - < 35 kg, 5 - < 10kg on 200 mg ATV and 
80 mg RTV dose) will be evaluated for Intensive PK.
Subjects who reach the weight 35kg during Stage 1: Subjects must immediately enter Stage 2 
and be switched to the capsule formulation of ATV and the corresponding capsule/tablet 
formulation of RTV.
Subjects who do not reach the weight 35kg during Stage 1: Subjects continue on the powder 
formulation of ATV through the end of the 48-week period of Stage 1 and then move into Stage 
2 while remaining on the powder formulation.
Subjects who did not have the opportunity to reach Week 48 or weight 35kg during Stage 1 by 
the time the last treated subject reaches Week 24 will have a final Stage 1 status assessment 
performed and will immediately move into Stage 2 while remaining on ATV powder. These 
subjects will follow then the assessments and in-clinic study visits specified in Stage 2.
STAGE 2
In-clinic study visits in Stage 2 will be conducted every 12 weeks through the end of study 
participation. 
Dosing of ATV in Stage 2 may include subjects taking ATV powder and subjects taking ATV 
capsules, dosed according to weight, as outlined in Table 3.1.1-1 and Table 3.1.1-2, respectively. 
When dosing with ATV powder, RTV oral solution is dosed at 80mg if weight < 25 kg and is 
dosed at 100 mg RTV oral solution or 100 mg RTV tablets/capsules when weight is 25 -
< 35 kg. When dosing with ATV capsules, RTV (capsules/tablets) is dosed at 100mg.
Once a subject has qualified by weight to move to a higher weight band/higher dose, they will 
remain at that new dose regardless of any subsequent weight loss.
BMS will require extra monitoring of subjects each time they transition to a higher weight 
band/higher dose of powder and capsules. If a subject is moved to a higher powder or capsule 
weight band during Stage 2, the subject will be required to return to the clinic for a weight band 
transition visit 4 weeks later.
10% aspartame ATV powder to 4.2% aspartame ATV Powder Transition:
Subjects who remain on ATV powder formulation in Stage 2 must be switched to the new 4.2% 
aspartame ATV oral powder formulation at their next regularly scheduled visit that occurs after 
the IRB/IEC approval of the amended protocol and informed consent has been received. Dose 
recommendation of new 4.2% aspartame ATV powder is the same as for the 10% aspartame 
ATV powder and will be determined by weight according to Table 3.1.1-1.
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Subjects who reach the age of 12 years or weight of 35kg during Stage 2: Subject must be 
switched from the powder formulation of ATV to the capsule formulation of ATV.
ATV Powder-to-Capsule Transition:
Subjects who are transitioning from powder to capsules, either at entry to Stage 2 or at any point 
during Stage 2, will be required to return to the clinic for two subsequent powder-to-capsule 
transition visits 4 weeks and 8 weeks after the switch is initiated.

Dose of the ATV capsule will be determined by weight, according to Table 3.1.1-2; RTV is 
dosed at 100mg (capsules or tablets) when dosing with the ATV capsule;

Subjects who are unable to swallow the ATV and RTV capsules/tablets by the end of the 
8-week transition period will be required to be discontinued from the study;

Subjects who complete a successful transition to ATV and RTV capsules/tablets will 
continue in Stage 2 and will be dosed according to the recommendations provided in Table 
3.1.1-2. 

Subjects are required to switch to capsules in Stage 2 when they reach 35 kg and/or 12 years 
of age. However, subjects who reach a weight of 25 kg and/or 6 years of age during Stage 2 
may, at the discretion of the investigator and caregiver, choose to attempt switch to the solid 
dosage forms of ATV/RTV. Careful consideration should be given to the time of switch as 
subjects who are unable to swallow capsules after an 8-week transition period must be 
discontinued from Stage 2.
Stage 2 participation ends when:

A subject reaches the age of 18 years

A subject’s country has an approved and available pediatric indication whose requirements 
are met by the subject; the subject will then transition off of the study and will be dosed 
according to those local guidelines.

If an approved pediatric indication for ATV capsules becomes available for a subject who 
is dosing with the powder formulation, the powder-to-capsule transition will occur within 
the study within an 8-week timeframe as described above.  After the 8-week transition 
period, the subject will be discontinued from the study, regardless of tolerability of the 
capsule.

Subjects who are medically stable may be eligible for a post-study drug program to 
ensure continuity of care (for greater detail regarding the post-study drug program, please 
see Section 3.2).
Table 3.1.1-1:
ATV Powder/RTV Oral Solution Dosing Table
Body Weight (kg)
Target # Subjects with at 
least 24 weeks Follow-up
ATV Dose (mg)a
RTV Dose (mg)
5 to less than 10
Minimum of 5
150
80 
5 to less than 10
Minimum of 6
200b
80
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Table 3.1.1-1:
ATV Powder/RTV Oral Solution Dosing Table
Body Weight (kg)
Target # Subjects with at 
least 24 weeks Follow-up
ATV Dose (mg)a
RTV Dose (mg)
10 to less than 15
Minimum of 10
200
80
15 to less than 25
Minimum of 10
250
80
25 to less than 35c
No Minimum
300
100d
a ATV powder will be dosed in 50 mg sachet packets.
b After reviewing the AI424397 interim intensive PK report19, a new cohort for the 5 to < 10 kg weight band will 
be added to assess if exposures could potentially be enhanced with a higher dose (200mg ATV powder, 80 mg 
RTV) in this weight band.
c Subjects in a lower weight band who transition to the 25 - < 35 kg weight band during Stage 1 will have a Week 2 
Intensive PK assessment completed.
d RTV oral solution, capsules or tablets is allowed for the 25 - < 35 kg weight band.
Table 3.1.1-2:
Dosage for Pediatric Patients (12a to less than 18 years of age) 
for REYATAZ Capsules with Ritonavir Capsules or Tablets
Body Weight
REYATAZ Doseb
(mg)
Ritonavir Dose
(mg)
(kg)
(lbs)
15 to less than 20
33 to less than 44
150
100
20 to less than 40
44 to less than 88
200
100
at least 40
at least 88
300
100
a Subject who reach 6 years of age during Stage 2 may, at the discretion of the investigator and caregiver, choose to 
attempt to switch to the solid dosage forms of ATV/RTV. 
b The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule 
strengths. NOTE: The capsule dose of ATV is lower than the highest powder dose for subjects 25 to < 35 kg 
because of the lower bioavailability of the ATV powder as compared with ATV capsules.
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Figure 3.1.1-1:
Study Schematic
Enter Stage 2.
Transition to capsules.**
Stage 2
Maximum time: until subject reaches 18 years of age or Pediatric Indication is locally approved and subject meets 
requirements to receive appropriate formulation
Age 12 years or  
Weight > 35 kg? *
Powder
Yes
Availability of Locally-
Approved, appropriate Pediatric 
Indication?
Age 18 years or Availability of 
Locally-Approved, appropriate 
Pediatric Indication
Transition out of Stage 2; begin dosing with powder or capsule according 
to local guidelines. Subject may qualify for PSDP
* Subjects are required to switch to capsules when they reach 35 kg and/or 12 years of age. However, subjects who reach a weight of 25 kg and/or 6 years of 
age during Stage 2 may, at the discretion of the investigator and caregiver, choose to attempt switch to the solid dosage forms of ATV/RTV. Careful 
consideration should be given to the time of switch as subjects who are unable to swallow capsule after an 8-week transition period must be discontinue from 
Stage 2.
** Subjects who are unable to swallow the capsule formulation after an 8 week transition period must be discontinued from thestudy.
Weight > 35 kg?
Complete 48 weeks.
Enter Stage 2 on powder.
Stage 1
Maximum time: up to 48 weeks of powder dosing
No
Yes
Age > 3 months to < 11 years: Minimum 56 subjects treated with  ATV powder formulation for 24 
weeks
Body Weight     (kg)
Target # of 
Subjects
ATV Dose 
(mg)
RTV Dose (mg)
5 to less than 10
Minimum of 5
Minimum of 6
150
200
80
80
+ approved NRTI backbone 
(tenofovir is prohibited)
10 to less than 15
Minimum of 10
200
80
15 to less than 25
Minimum of 10
250
80
25 to less than 35
No Minimum
300
100
The study will commit to enroll a minimum of 30 A RV experienced patients treated with A TV powder for  a minimum of 24 weeks.
Complete Final Stage 1 Status  
Evaluation and Enter Stage 2
Stage 1: Subject did not have 
opportunity to reach Week 48 by 
the time the last treated subject 
reaches Week 24?
Transition to capsule; 
remain in Stage 2.**
Capsule
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3.1.2
Study Duration
STAGE 1  
Duration of study participation in Stage 1 is dependent on weight milestone:

Subjects who do not reach a weight of 35kg while in Stage 1 will complete the full 
48 weeks of dosing with ATV powder, at which point they will transition to Stage 2 and 
continue on ATV powder.

Subjects reaching the weight of 35kg at any point during Stage 1 will immediately 
transition to Stage 2 and begin the transition to the ATV capsule formulation.
Subjects who did not have the opportunity to reach Week 48 by the time the last treated subject 
reaches Week 24 will have a final Stage 1 status assessment performed and will immediately 
move into Stage 2 while remaining on ATV powder. These subjects will then follow the 
assessments and in-clinic study visits specified in Stage 2.
STAGE 2
Duration of study participation in Stage 2 is dependent on an age milestone, or by the timing of 
approval of a local pediatric indication (whichever is first):

Subjects will end study participation in Stage 2 when they reach the age of 18 years, or when 
there is approval and availability of a locally-approved pediatric indication whose 
requirements are met by the subject.
The sponsor reserves the right to terminate Stage 2 if any of the following occur: a) the 
marketing application is rejected by responsible health authority; b) the study is terminated due 
to safety concerns; c) the subject can obtain medication from a government sponsored or private 
health program; or d) therapeutic alternatives become available in the local market. 
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who complete the study and continue to demonstrate 
clinical benefit will be eligible to receive study drug. In countries where the study drug is not 
approved and available, study drug will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of the sponsor. The sponsor reserves the right to terminate access to 
study drug if any of the following occur: a) the marketing application is rejected by responsible 
health authority; b) the study is terminated due to safety concerns; c) the subject can obtain 
medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
In countries where the regimen is approved and available, subjects who are not able to receive 
drug reimbursement through a private or government sponsored health program and are in 
financial need may be eligible to continue to receive medication they received on study through 
the BMS Post Study Drug Program. This program will provide only medicines that 1) were used 
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in the subject’s regimen in this trial and 2) are locally marketed. The drugs provided to a subject 
will be limited to drugs made available in the clinical trial in which the subject was treated. If a 
newer formulation of marketed product is not available, an earlier formulation may be provided. 
Safety monitoring and evaluation will be the sole responsibility of the investigator. 
3.3
Study Population
HIV infected pediatric subjects 3 months to < 11 years of age and 5 kg to < 35 kg.  Subjects 
can be antiretroviral naive or experienced (without prior exposure to ATV). Treatment 
experienced subjects are defined by a previous exposure to antiretroviral drugs (ARVs) through 
either prior treatment for their HIV disease or through a post natal treatment with ≥ 1 ARVs for 
the prevention of MTCT (in accordance with multiple guidelines: WHO, DHHS and South 
Africa PMTCT guidelines). For the purposes of this study, subjects exposed to ARVs in utero or 
intra-partum may be included in the study but will be considered ‘treatment naive’. 
A total of 30 ARV experienced subjects treated with ATV powder for a minimum of 24 weeks 
will be enrolled in this study. Study enrollment will remain open until a minimum of 30 ARV 
experienced subjects treated with ATV powder for a minimum of 24 weeks are enrolled.  Weight 
designation will be based upon the child’s weight at the time of first treatment (Day 1 Visit). 
Subjects 2 months and < 3 months are eligible to be screened as long the date of first treatment 
does not occur until reaching the age of 3 months AND 5 kg in weight. 
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Informed consent from a parent/legal guardian must be obtained prior to screening. 
Minors who are judged to be of an age of reason must also give their written assent (see 
Section 2.3).
2) Target Population
Confirmed HIV-1 infection diagnosed by positive virologic test results on 2 separate 
occasions by any of the following: 
a) HIV DNA PCR.
b) HIV RNA with values 1,000 copies/mL will be considered evidence of infection.
c) Positive HIV ELISA at 18 months of age, with confirmatory Western blot or indirect 
immunoflourescence antibody.
Note: At least one diagnostic result may have been prior to the Screening visit.
3) Age and Sex
a) Infants and children of either gender, 3 months to 11 years of age at the time of first 
treatment. 
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4) Other Inclusion Criteria
a) Antiretroviral naive or treatment-experienced subjects. Treatment experienced subjects 
are defined by a previous exposure to antiretroviral drugs (ARVs) through either prior 
treatment for their HIV disease or through a post-natal treatment with 1 ARVs for the 
prevention of mother to child transmission (PMTCT). For the purposes of this study, 
subjects exposed to ARVs in utero or intra-partum are eligible for the study, but will be 
considered ‘treatment naive’.
b) Antiretroviral naive subjects must have genotypic sensitivity at screening to ATV and at 
least 2 NRTIs (excluding tenofovir). NRTIs must be approved for pediatric use at the 
local country level.
c) Antiretroviral experienced subjects (as defined above) must have documented genotypic 
and phenotypic sensitivity at screening to ATV (Fold Change in susceptibility < 2.2) and 
to at least 2 NRTIs (excluding TDF). NRTIs must be approved for pediatric use at the 
local country level. 
3.3.2
Exclusion Criteria
1) Target Disease Exceptions  
a) Experienced subjects who received ATV or ATV/RTV at any time prior to study 
enrollment or who have prior history of 2 or more PI failures will not be allowed in the 
study. 
b) Antiretroviral-naïve or experienced HIV-1 infected subjects with contraindication to 
study medications.
c) Subjects with genotypic resistance at screening to ATV or either component of the local 
NRTI backbone based upon the following criteria:
i)
Any Major Mutations: I50L, I84V, N88S.
ii) 2 of the following minor or cross resistant mutations:
(1) M46I/L, G48V, I54L/V/M/T/A, V82A/T/FI, L90M, V32I
d) The use of any investigational agent within 30 days of enrollment.
e) History of psychiatric or cognitive/developmental impairment that could compromise 
subject safety or the ability of the subject to comply with the protocol.
f)
Premature infants (less than 37 weeks gestation at birth) will not be eligible to enter the 
study until they are over 6 months of age.
g) The need for Tenofovir.
2) Medical History and Concurrent Diseases
a) Any active CDC Category C clinical condition.
b) Not applicable as per protocol amendment 04.
c) Coinfection with either HBV or HCV
i)
Coinfection with HBV as documented* by the presence of HBsAg and/or HBV DNA 
by a PCR assay in infants < 18 months and HBsAg for children ≥ 18 months of age
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ii) Coinfection with HCV as documented* by the presence of HCV RNA by a PCR 
assay in infants < 18 months and HCV ELISA positive for children ≥ 18 months of 
age
iii) HBV or HCV infection in mothers for children in whom HBV or HCV infection can 
not be excluded.
*: HBV and HCV serologies for all ages and PCR for infants < 18 months are to be
performed locally.
d) Documented cardiac conduction abnormality(ies) or significant cardiac dysfunction, or a 
history of syncope.
e) Family history of QTc interval syndrome, Brugada syndrome or right ventricular 
dysplasia or with a corrected QTc interval at screening of > 440 ms.
f)
One of the following cardiac rhythm abnormalities documented on the screening ECG: 
First degree atrioventricular (AV) block; type I second degree AV block while awake, 
type II second degree AV block at any time, complete AV block at any time, or age-
adjusted heart rate < 2nd percentile).
g) History of pancreatitis, peripheral neuropathy, malignancy that requires systemic therapy, 
or any medical condition which, in the opinion of the investigator, adds undue risk to trial 
participation. 
h) Malabsorption syndrome.
i)
Presence of a newly diagnosed HIV-related opportunistic infection or any medical 
condition requiring acute therapy at the time of enrollment.
3) Physical and Laboratory Test Findings
a) Weight < 5 or 35 kg at date of first dose (Day 1)
b) > Grade 2 transaminase (AST, ALT) abnormalities.
4) Allergies and Adverse Drug Reaction
a) Hypersensitivity to any component of the study medication formulations (ATV/RTV, or a 
locally prescribed NRTI with a pediatric indication).
5) Sex and Reproductive Status
a) Infants and children of either gender, < 3 months or 11 years at the time of first 
treatment.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: 
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
Amenorrhea ≥ 12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL or 

Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or
NOTE: FSH level testing is not required for women 62 years old with amenorrhea 
of 1 year

Women on hormone replacement therapy (HRT)
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin 
patches, or implanted or injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are 
practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be 
of childbearing potential.
 
 
 
 
 
 
 
 
 
 
 
3.4.2
Other Restrictions and Precautions
3.4.2.1
Restrictions
Grapefruit Juice: Due to the known interaction of grapefruit juice with the cytochrome P450 
isoform CYP3A4 (the metabolizing enzyme for atazanavir), it is suggested that subjects not 
consume grapefruit or grapefruit juice for the duration of the study.
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Subject requires a medication prohibited by the protocol as outlined in Sections 3.4.1 and 
3.4.2.

Virologic failure or disease progression which, in the investigator’s opinion, precludes the 
subject’s continued participation in the study or meets any of the following criteria:

Subjects with an incomplete virologic response defined as  less than a 1 log10 drop from 
baseline in plasma HIV RNA level by Week 16  (using the Amplicorv1.5 PCR assay 
for measuring HIV RNA), confirmed by a second plasma HIV RNA level redrawn within 
2 and 4 weeks from original sample; or

Subjects with a confirmed HIV RNA of ≥ 1000 copies/mL (after Week 24); or

Subjects with a confirmed HIV RNA of ≥ 400 copies/mL and showing Genotypic and / 
or Phenotypic resistance to ATV/RTV and/or one or more assigned NRTI study drugs

Non-compliance by the subject with the requirements of the protocol, treatment or 
monitoring.

Inability to swallow capsule after an 8-weeks transition period from powder to capsule in 
Stage 2.

Any of the following cardiac findings:

Clinical symptoms potentially related to heart block,

QTc interval > 440 msec seen on EKG,

Third degree AV heart block.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
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3.5.1
Premature Termination
With the exception of subjects who did not have the opportunity to reach 48 weeks of treatment 
by the time that the last treated subject reaches week 24, premature termination is defined as 
discontinuing the study prior to 48 weeks of treatment.

If premature termination is due to toxicity or occurs while the subject is experiencing 
Grade 3 toxicities, these should be followed with appropriate clinical and/or laboratory 
monitoring until resolved to Grade 2.

Subjects who fail to comply with the study requirements (in taking study medications or in 
showing up for scheduled visits) may be terminated by the investigator.

Subjects who discontinue the study early for reasons other than withdrawn consent will be 
asked to participate in an early discontinuation study visit. 

Subjects who discontinue study medications due to virologic failure, and subjects who 
discontinue study treatment for any other reason except withdrawal of consent, will be asked
to provide a sample for HIV genotypic and phenotypic resistance testing at their early 
discontinuation study visit. If a subject withdraws consent to participate, no additional study 
blood draws will be performed. 

When a subject is “lost to follow-up”, eg, does not return for clinic visits, a reasonable effort 
should be made (and documented) to have the subject return for end-of-treatment evaluation.

Subjects unable to tolerate 2 NRTIs in addition to ATV/RTV will be terminated from the 
study.
Subjects who did not have the opportunity to reach week 48 by the time the last patient reaches 
week 24, they will be considered to have completed Stage 1.
4
TREATMENTS
All protocol-specified investigational and non-investigational products are considered study 
drug. 
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4.1
Study Treatments
Table 4.1-1:
Product Description: AI424451 Study Medication
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Atazanavir (ATV) 
powdera for oral use
50 mg/sachet
1.5 g sachet/open label 
with text and symbols 
printed directly on 
sachet and cross-
referencing to outer 
carton
Outer carton containing 
30 sachets/open label 
booklet label cross-
referencing to the 
sachet label
Sachet: aluminum foil 
with text and symbols 
printed directly on the 
sachet
Outer carton: white 
cardboard with booklet 
label attached
15° - 25C (59° - 77F)
Norvir (RTV) Oral 
Solution
80 mg/ml
90 ml (EU-sourced) or 
240 ml (US-sourced) 
bottle/open label 
booklet label
NA
A practically clear, 
orange solution in 
amber-colored, multi-
dose bottles
Store below 25C 
(77F); Do not 
refrigerate or freeze. 
Store in a tightly closed 
container. Protect from 
excessive heat.
Atazanavir Capsule
150 mg
60 capsules per 
bottle/open label
NA
Blue cap and powder 
blue body with “BMS 
150 mg” and “3624” 
markings.
Store at 25C (77°F); 
excursions permitted to 
15°- 30°C (59°- 86°F)
Atazanavir Capsule
200 mg
60 capsules per 
bottle/open label
NA
Blue cap and blue body 
with “BMS 200 mg” 
and “3631” markings.
Store at 25°C (77°F); 
excursions permitted to 
15°- 30°C (59°- 86°F)
Atazanavir Capsule
300 mg
30 capsules per 
bottle/open label
NA
Red cap and blue body 
with “BMS 300 mg” 
and “3622” markings.
Store at 25°C (77°F); 
excursions permitted to 
15°- 30°C (59°- 86°F)
Ritonavir Capsule
100 mg
30 capsules (US 
sourced) or 84 capsules 
(EU-sourced) per 
bottle/open label
NA
White soft gelatin 
capsules imprinted with 
the Abbott corporate 
logo and “100”, and 
“DS” markings.
Store at 2° - 8°C 
(36° - 46°F); protect 
from light. 
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Table 4.1-1:
Product Description: AI424451 Study Medication
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Ritonavir Tablet
100 mg
30 tablets (US sourced) 
or 30 or 60 tablets (EU-
sourced)/open label
NA
White film-coated 
ovaloid tablets 
debossed with the 
corporate logo and
the Abbo-Code NK 
providing 100 mg 
ritonavir.
Store at 20°- 25°C 
(68°- 77°F); excursions
permitted to 15°- 30°C 
(59°- 86°F).  Storage in 
original container. 
Protect from moisture.
a ATV powder for oral use containing 10% aspartame is used in stage 1 and 2. Subjects remaining on ATV powder in stage 2 will be switched to the new 4.2% 
aspartame ATV powder for oral use after the amendment 07 has been approved by the IRB/IEC of the subject’s site.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: Atazanavir, and Ritonavir. Both will be 
provided as part of the study. Please refer to Table 4.1-1 for details regarding these 
2 medications.
4.1.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as noninvestigational products. 
In this protocol, noninvestigational product(s) is/are: Any antiretroviral medication from the 
NRTI class. NRTIs must be approved for pediatric use and should be dosed as per the local 
country label. Study physicians will prescribe NRTIs based on viral resistance results and 
subject’s treatment history. In cases where NRTI backbone therapy is not covered by private 
insurance, government programs, etc, Bristol-Myers Squibb will provide treatment or reimburse 
for the cost of prescription therapy.
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
4.2
Method of Assigning Subject Identification
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System (IVRS) designated by the Sponsor to enroll the subject and 
to obtain a subject/patient identification number (PID), which must be recorded on the Case 
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Report Form (CRF). This unique subject number must be used on all further documentation and 
correspondence referring to this particular subject.
For subjects who meet the protocol eligibility criteria, the investigative staff will call the IVRS 
on Day 1 and subjects will be assigned to a dose of ATV/RTV appropriate to weight. It is the 
responsibility of the principal investigator to ensure that the subject is eligible for the study prior 
to a second call to the assignment center for confirmation of the appropriate dosage. It is 
important that the investigative staff reconfirm the subject’s willingness to continue in the trial 
prior to treatment administration. Once the dosage has been confirmed, study medication should 
be initiated within 3 days, with the first dose being given in the clinic at the Day 1 visit. Note: if, 
in order to allow for timely provisioning of study medication by the site investigational 
pharmacy, it is necessary to call IVRS in advance of the subject’s Day 1 visit (within 1 day 
prior), this is acceptable and will not be considered a protocol deviation. All efforts should be 
made to call IVRS on Day 1, however, to limit the possibility of enrolling subjects that do not 
start treatment. If a subject is enrolled but does not receive study medication, the study team 
must be notified immediately.
A minimum of 56 treated subjects on ATV powder with at least 24 weeks of follow-up are 
needed with a minimum number of subjects with at least 24 weeks of follow-up from the 
following weight bands: 

Minimum 5 subjects (on 150 mg ATV powder and 80 mg RTV) between 5 - < 10 kg,

Minimum 6 subjects (on 200 mg ATV powder and 80 mg RTV) between 5 - < 10 kg,

Minimum 10 subjects between 10 - < 15 kg,

Minimum 10 subjects between 15 - < 25 kg,
In the event that the minimum number of subjects in any one weight band has been met while the 
other 3 weight bands remain substantially under-enrolled, further enrollment in the fully enrolled 
weight band may be temporarily put on hold. Enrollment will continue for the under-enrolled 
groups until the minimum number of treated subjects has been achieved (except for 25 - < 35kg 
weight band). After this point, enrollment will continue for all weight bands until at least a total 
of 95 subjects started treatment in order to have a minimum number of 56 treated subjects with a 
minimum of 24 weeks follow-up. In the event that the minimum number of subjects (overall 
and/or per weight band) with a minimum of 24 weeks follow-up is projected not to be met due to 
higher than projected early discontinuation rate, then enrollment target will be re-adjusted during 
enrollment period or enrollment re-opened during the study to replace these subjects.
Subjects in a lower weight band who transition to the 25 - < 35 kg weight band during Stage 1 
will have a Week 2 Intensive PK assessment completed.
A total of 30 ARV experienced subjects treated with ATV powder for minimum of 24 weeks will 
be enrolled in this study, which will be tracked through the IVRS. Treatment experienced 
subjects are defined by a previous exposure to antiretroviral drugs (ARVs) through either prior 
treatment for their HIV disease or through a post natal treatment with ≥ 1 ARVs for prevention 
of MTCT. In the event that the minimum number of ARV experienced subjects remains 
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substantially under-enrolled, then further enrollment of ARV-naive subjects may be temporarily 
put on hold until the target of 30 ARV experienced is met. After this point, enrollment will 
continue for both ARV naive and experienced subjects. Enrollment will remain open until a 
minimum of 30 ARV experienced subjects are enrolled (regardless of weight band) and treated 
with ATV powder for minimum of 24 weeks.
4.3
Selection and Timing of Dose for Each Subject
Dosing information for RTV oral solution and ATV powder is provided in Table 3.1.1-1; dosing 
information for RTV and ATV capsules is provided in Table 3.1.1-2.
Initial dose will be determined by the subject’s weight on the day of the first on-treatment study 
visit (Day 1).
Dosing changes are driven by weight band thresholds provided in Table 3.1.1-1 and Table 3.1.1-
2.
Transitioning from the powder to the capsule formulation of ATV is driven by reaching the age 
of 12 or weight of 35 kg.
Please refer to Section 3.1.1 Study Design for specific details of dosing changes.
4.3.1
Dosing Instructions
The prescriber should instruct the caregiver to tap the sachet to settle the contents. Use scissors 
to cut open the sachet on the dotted line.
The powder may be mixed with a small amount of food or beverage (eg, water, milk, chocolate 
milk, liquid infant formula, applesauce or yogurt). If water is used, the mixture must be taken 
with food. The entire contents of the mixture must be consumed to obtain the full dose. The 
mixture should be consumed within one hour and may be stored at room temperature 20° - 25C 
(68° - 77F) during this time.
Ritonavir oral solution should be taken immediately after the ATV powder preparation.
ATV capsules should be ingested with food and stored at 25°C (77°F); excursions permitted to 
15° - 30°C (59° - 86°F).
Ritonavir capsules should be ingested with food immediately before or after ATV intake.
Ritonavir tablets should be ingested with food immediately before or after ATV intake. The 
tablets should be swallowed whole and not chewed, broken or crushed.
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4.3.2
Specific Dosing Instructions on Days of Pharmacokinetic Assessments
Intensive PK 
Intensive 24 hour PK samples will be collected in Stage 1 only on subjects who:

Enter the study weighing 25 - < 35 kg and/or 6 to 11 years of age at scheduled Week 2 
visit or 

Subjects moving into the 25 - < 35 kg weight range or becoming 6 years old during Stage 
1, the intensive PK visit will occur two weeks after the dose change for the new weight band. 
If the subject becomes 6 years of age but without a dose change then the intensive PK visit 
can occur at the next regular Stage 1 visit. 

Subjects enrolling a new 5 - <10 kg cohort with 200mg ATV and 80 mg RTV dose.
Intensive PK collection for the age range (6 to 11 years), but not fulfilling the 25 to < 35 
weight range, will be stopped when PK samples from approximately 10 subjects have been 
collected. All subjects from the weight cohorts (25 - < 35 kg, 5 - < 10kg on 200 mg ATV and 
80 mg RTV dose) will be evaluated for Intensive PK.

Subjects must be instructed to take their dose of study medication such that the last dose 
(dose on the day prior to the PK visits) of ATV/RTV is approximately 24 hours prior to the 
pre-dose sample collection.

Subjects must be instructed not to take any dose of study medication prior to the study visit 
on the day of the PK assessment. 

The investigative site should ensure that the atazanavir powder is administered either mixed 
with a food substance or water and taken with a light meal and should ensure the NRTIs are 
dosed according to the local label, but after the pre-dose sample collection.
ATV/RTV Trough PK (All subjects at scheduled visits Week 4 through a minimum of 
24 weeks and up through 48 weeks, except transition visits)
Trough PK will be collected at scheduled study visits through a minimum of 24 weeks and up to 
a maximum of 48 weeks. Trough PK collection will be stopped for ongoing subjects in Stage 1 
when the last treated subject reaches Week 24.

Subjects must be instructed to take their dose of study medication such that the last dose of 
ATV/RTV is approximately 24 hours prior to the trough sample collection. Subjects must be 
able to provide the date and time of the meal and dose prior to the trough sample collection.

Subjects must be instructed not to take their dose of study medication prior to the study visit 
on the day of the trough PK assessment, and must not take their dose prior to the trough 
sample collection. Subjects may take their dose at the investigative site after the trough 
sample collection.
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4.3.3
Dose Modifications
There will be no dose modifications for toxicity or PK. Dose modifications will be made to 
ATV/RTV or the NRTI backbone as needed to compensate for weight gain only (see Table 
3.1.1-1 and Table 3.1.1-2). 
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Subject adherence to the treatment regimen will be critical in the conduct of this study. Subjects 
will be required to complete study medication diaries through Stage 1 of the study. Caregivers 
should be provided with the medication diary at the Day 1 visit, instructed on its completion, 
including the importance of making daily entries and bringing the diary at each visit throughout 
Stage 1. Where feasible, the study coordinator should make a telephone call to the caregiver in 
the interim period (eg, at Week 1) to provide further adherence support. Adherence will be 
evaluated by the investigative staff at every treatment visit through direct interviews with the 
subject’s caregivers, a sachet count and the review of a diary. In addition, periodic contact with 
the caregivers between study visits is strongly encouraged in order to confirm compliance with 
the study regimen. The caregiver should be instructed to bring all unused study medication back 
in the original container to each visit. Use of the study medication diaries; will be used for all 
subjects.
Subjects remaining on ATV powder in Stage 2 are encouraged to continue using the study 
medication diaries. After the switch from the 10% aspartame ATV powder to the new 4.2% 
aspartame ATV powder in Stage 2, study medication diaries will be used as long as the subject is 
on the new 4.2% aspartame ATV powder or maximum duration of one year, whichever comes 
first. The caregiver should be instructed to continue bringing the diary at each visit.
4.5.1
Guidelines for the Management of Subjects with Rebound HIV RNA 
Levels Greater Than or Equal to 50 copies/mL
This section provides clinical guidance for the management of subjects with virologic failure 
during the study. Laboratory results must be confirmed with repeated testing before a final 
assessment of virologic treatment failure is made.
Virologic failure occurs as an incomplete virologic response to therapy or as a viral rebound after 
virologic suppression is achieved.
Incomplete virologic response to therapy is defined as:

Less than a 1 log10 drop from baseline in plasma HIV RNA level by Week 16 (using the 
Amplicorv1.5 PCR assay, or Abbott RealTime HIV-1 assay after the Roche Amplicor 
assay is discontinued, for measuring HIV RNA), confirmed by a second plasma HIV RNA 
level redrawn within 2 and 4 weeks from original sample; or
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
A plasma HIV RNA level > 200 copies/mL after Week 24, confirmed by a second plasma 
HIV RNA level redrawn within 2 and 4 weeks from original sample; or 

Repeated plasma HIV RNA level 50 copies/mL (using the Amplicorv1.5 PCR assay, or 
Abbott RealTime HIV-1 assay after the Roche Amplicor assay is discontinued, for measuring 
HIV RNA) after Week 48.
Viral rebound is defined as:

A plasma HIV RNA level 400 copies/mL (using the Amplicorv1.5 PCR assay, or Abbott 
RealTime HIV-1 assay after the Roche Amplicor assay is discontinued, for measuring HIV 
RNA) confirmed by a second plasma HIV RNA level of 400 copies/mL redrawn within 2 
and 4 weeks from original sample) at any time in a subject who had previously achieved a 
plasma HIV RNA level < 50 copies/mL.

Subjects with a plasma HIV RNA level 50 copies/mL and < 1000 copies/mL (using the 
Amplicorv1.5 PCR assay, or Abbott RealTime HIV-1 assay after the Roche Amplicor 
assay is discontinued, for measuring HIV RNA) followed by return to virologic suppression 
will be considered a viral blip and not a viral rebound. 
The subjects meeting the criteria for viral rebound or virologic failure at any time during the study 
will be managed as follows:

Those with a confirmed HIV RNA of < 400 copies/mL may continue on their assigned 
treatment and must have a repeat confirmatory HIV RNA checked every study visit.

Those with a confirmed HIV RNA of 400 copies/mL and < 1000 copies/mL may remain on 
assigned treatment at the discretion of the investigator, in consultation with the BMS Medical 
Monitor. 

A viral resistance test will be conducted automatically and the result forwarded to the site 
investigator.

Subjects with Genotypic and / or Phenotypic resistance to ATV/RTV and/or one or more 
assigned NRTI study drugs must be discontinued. 

Further management will be at the discretion of the investigator in consultation with the 
BMS Medical Monitor.

Those with a confirmed HIV RNA of 1000 copies/mL must be discontinued from the 
study.

Those subjects with an incomplete virologic response defined as less than a 1 log10 drop 
from baseline in plasma HIV RNA level by Week 16 (using the Amplicorv1.5 PCR assay, 
or Abbott RealTime HIV-1 assay after the Roche Amplicor assay is discontinued, for 
measuring HIV RNA), confirmed by a second plasma HIV RNA level redrawn within 2 and 
4 weeks from original sample, must be discontinued from the study.
Plasma samples for resistance testing will be collected at screening and at, or immediately after, 
a rebound or virologic failure. Samples will be submitted for immediate testing and the results 
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conveyed to the investigator. Only samples with a confirmed HIV RNA level 400 copies/mL 
will be tested for genotypic and phenotypic resistance. Investigators may also send an ATV 
trough PK sample for subjects with virologic rebound. See Table 5.1-2 and Section 5.5.2.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. The unused study drugs can only be destroyed after being inspected and 
reconciled by the responsible BMS Study Monitor.
4.6.2
Return of Study Drug
Study drug will not be returned. All unused and/or partially used study drug may be destroyed on 
site providing the site has an applicable standard operating procedure on file.
4.7
Retained Samples for Bioavailability / Bioequivalence
Not applicable
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (AI424451)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Demography
X
Informed Consent
X
Eligibility(Inclusion/Exclusion 
Criteria)
X
Medical History
X
Safety Assessments
Full Physical Examination
X
Vital Signs
X
Medication Review (Prior ARV 
Treatment)
X
Physical Measurements
X
ECG
X
Assessment of Pre-Treatment Events
X
AIDS Defining Pre-Treatment Events
X
Clinical Laboratory
HIV RNA
1 mL
Viral Resistance
2 mL
For treatment-experienced subjects, a sample for genotype and phenotype will be collected at 
Screening. Treatment-naive subjects will only have a sample collected at Screening for genotype 
testing.
Hematology
1 mL
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Table 5.1-1:
Screening Procedural Outline (AI424451)
Procedure
Screening
Visit
Notes
Serum Chemistry
1 mL
Up to 4ml additional blood volume will be collected in the event that HBV and HCV serologies for 
all ages and PCR for infants < 18 months is unknown and testing will be performed locally. 
Urinalysis
X
Total Blood Volumes
5 mL
Blood Volumes do not exceed NIH Clinical Center Guidelines of 3 mL/Kg at a single draw (ie, 
15 mL for a 5 Kg infant, the smallest weight that would be enrolled in the study) or 7 mL/Kg over 
6 weeks (ie, 35 mL for a 5 kg infant). These volumes represent SOC for HIV infected pediatric 
subjects except for the PK sampling.
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Table 5.1-2:
Treatment Phase (Stage 1) Procedural Outline (AI424451)
Procedure
Start of 
Treatment
Day 1
(Baseline)a
Week 1b
Week 2 
(also  
Intensive 
PK Visitc
for some 
subjects)
Day 14
(+4 days)
Weeks 4, 8, 
12, 16, 32, 
and 40d
(5 days)
Week 24 and 
48 (final    
Stage 1 Visit)d
(5 days)
Transition 
Visit for 
Weight Band 
changee
(5 days)
Notes
Eligibility Assessments
Eligibility (Inclusion/Exclusion 
Criteria)
X
Safety Assessments
Drug Tolerability Assessment
X
X
X
X
X
Full Physical Examination 
X
Targeted Physical Examination
X
X
X
X
Vital Signs
X
X
X
X
X
Concomitant Medication 
Assessment
X
X
X
X
X
Physical Measurements
X
X
X
X
ECG
X
X
X
X
X
Recorded 3 times at intensive PK 
visit (pre-dose, 2.5 hrs, and 4 hrs 
(Cmax)
Adverse Events Assessment
X
X
X
X
X
AIDS Defining Adverse Events
X
X
X
X
X
X
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Table 5.1-2:
Treatment Phase (Stage 1) Procedural Outline (AI424451)
Procedure
Start of 
Treatment
Day 1
(Baseline)a
Week 1b
Week 2 
(also  
Intensive 
PK Visitc
for some 
subjects)
Day 14
(+4 days)
Weeks 4, 8, 
12, 16, 32, 
and 40d
(5 days)
Week 24 and 
48 (final    
Stage 1 Visit)d
(5 days)
Transition 
Visit for 
Weight Band 
changee
(5 days)
Notes
Central Laboratory
HIV RNA
1 mL
1-2 mL
1-2 mL
1-2 mL
Up to 2mL of blood will be 
required when Abbott RealTime 
HIV RNA-1 assay will be used 
after Roche Amplicor HIV-1 
assay (1mL) will be discontinued. 
If a VL 400 c/mL is reported, a 
confirmation sample is to be 
taken between 2-4 weeks of the 
original sample date.
CD4 Count and Percent
1 mL
1 mL
1 mL
Viral Resistance
Additional 2 ml samples for both 
genotype and phenotype 
resistance testing will be collected 
in the instance of virologic failure 
or rebound.
Intensive ATV 
Pharmacokinetics
11.7 mL
only for subjects weighing 25 -
< 35 kg and/or aged 6 to 11
years or enrolling in a new 5 -
< 10 kg cohort with 200 mg ATV
powder and 80 mg RTV
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Table 5.1-2:
Treatment Phase (Stage 1) Procedural Outline (AI424451)
Procedure
Start of 
Treatment
Day 1
(Baseline)a
Week 1b
Week 2 
(also  
Intensive 
PK Visitc
for some 
subjects)
Day 14
(+4 days)
Weeks 4, 8, 
12, 16, 32, 
and 40d
(5 days)
Week 24 and 
48 (final    
Stage 1 Visit)d
(5 days)
Transition 
Visit for 
Weight Band 
changee
(5 days)
Notes
ATV PK Plasma Troughf
1 mL
1 mL
To be collected pre-dose. ATV 
should be administered following 
the PK plasma trough sample 
collection. Will not require a 
fasting state except when fasting 
lipids are drawn. Will only be 
collected for a minimum of 24 
weeks up through the Week 48 
visit.
Hematology
1 mL
1 mL
1mL
Serum Chemistry
1 mL
1 mL
1mL
1mL
Lipids
X
X
Fasting for subjects 3 years of 
age (ie, NPO except for water and 
medications for at least 12 hours). 
Subjects < 3 years of age may be 
non-fasting.
Urinalysis
X
Conducted yearly after the 
Screening visit.
Clinical Drug Supplies
Register Study Treatment
X
X
X
Dispense Study Treatment
X
X
X
ATV powder, RTV oral solution
or RTV capsules/Tablets (when 
weight is 25 - < 35 kg, NRTIs)
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Table 5.1-2:
Treatment Phase (Stage 1) Procedural Outline (AI424451)
Procedure
Start of 
Treatment
Day 1
(Baseline)a
Week 1b
Week 2 
(also  
Intensive 
PK Visitc
for some 
subjects)
Day 14
(+4 days)
Weeks 4, 8, 
12, 16, 32, 
and 40d
(5 days)
Week 24 and 
48 (final    
Stage 1 Visit)d
(5 days)
Transition 
Visit for 
Weight Band 
changee
(5 days)
Notes
Education of Study Treatment
X
Record Study Medication 
Compliance
X
X
X
X
Adherence/Tolerability
Dispense/Review Subject Diary
X
X
X
X
X
X
Conduct Dosing Assessment
X
X
X
X
X
Total Blood Volumes
4 mL
11.7 mL
5-6 mL
5-6 mL
2-3 mL
Blood Volumes do not exceed 
NIH Clinical Center Guidelines 
of 3 mL/Kg at a single drawn (ie, 
15 mL for a 5 Kg infant, the 
smallest weight that would be 
enrolled in the study) or 7 mL/Kg 
over 6 weeks (ie, 35 mL for a 
5 kg infant). These volumes 
represent SOC for HIV infected 
pediatric subjects except for the 
PK sampling. To avoid sample 
dilution, when PK sampling 
through an IV catheter, 
approximately an additional 1 mL 
(blood and saline mix) should be 
withdrawn and discarded prior to 
collecting the 0.8 mL for the 
blood PK sample (ie, to discard 
the catheter saline flush).
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a The Baseline visit must be within 30 days of the screening visit. In cases where the test or re-test results are not available after 30 days, the timeline to the 
Baseline visit (Day 1) may be extended to 50 days. The IVRS can be called up to 72 hours prior to the Baseline (Day 1) visit. The first dose must be taken in 
the clinic at the Baseline (Day 1) visit.
b Telephone call or brief clinic visit to ensure that subject is tolerating the study medication.
c All subjects will have a week 2 visit. Only subjects weighing 25 - < 35 kg and/or aged 6 to 11 years or subjects enrolling in a new 5 - < 10 kg cohort 
(with 200mg ATV and 80 mg RTV) will have Intensive PK performed at this visit. Intensive PK visit may take place from Day 14 - Day 18 following the first 
study dose of ATV. Subjects who move into the 25 - < 35 kg weight range or becoming 6 years old during Stage 1, will also have the Intensive PK 
performed (approximately 2 weeks or 14 - 18 days) after switching to the new doses. If the subject becomes 6 years of age but without a dose change then the 
intensive PK visit can occur at the next regular Stage 1 visit. Intensive PK collection for the age range (6 to 11 years), but not fulfilling the 25 to < 35 
weight range, will be stopped when PK samples from approximately 10 subjects have been collected. All subjects from the weight cohorts (25 - < 35 kg, 5 
- < 10kg on 200 mg ATV and 80 mg RTV dose) will be evaluated for Intensive PK.
d Subjects who did not have the opportunity to reach Week 48 by the time the last treated subject reaches Week 24 will have a final Stage 1 status assessment 
performed and will immediately move into Stage 2.
e If a subject moved to a higher weight band during Stage 1 on or after  Week 16  (beyond which study visits occur every 8 weeks), a transition visit will be 
scheduled 4 weeks following the change in dose. Study visits will then follow per the regular schedule.
f Trough ATV levels may be sent for analysis at the discretion of the investigator as a component of a clinical evaluation of subjects with virologic rebound, or 
failure to achieve virologic suppression in the timeframe expected by the investigator.
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Table 5.1-3:
Treatment Phase (Stage 2) Procedural Outline (AI424451)
Procedure
Visit every 3 
months until Early 
D/C or local ATV 
pediatric approval
(5 days)
Transition Visit 
for powder-to-
capsule switcha
(5 days)
Transition Visit 
for Weight Band 
changeb
(5 days)
Notes
Safety Assessments
Full Physical Examination
X
A full physical exam must be performed with 
vital signs for Final and Early D/C visits.
Targeted Physical Exam
X
X
Vital Signs
X
X
X
Concomitant Medication Assessment
X
X
X
Physical Measurements
X
Adverse Events Assessment
X
X
X
AIDS Defining Adverse Events
X
X
X
ECG
X
X
Central Laboratory 
HIV RNA
1-2 mL
1-2 mL
1-2 mL
Up to 2mL of blood will be required when 
Abbott RealTime HIV RNA-1 assay will be used 
after Roche Amplicor HIV-1 assay (1 mL) will 
be discontinued. If a VL 400 c/mL is reported, 
a confirmation sample is to be taken between 2-4 
weeks of the original sample date.
CD4 Count and Percent
1 mL
Viral resistance
Additional 2 ml samples for both genotype and 
phenotype resistance testing will be collected in 
the instance of virologic failure or rebound.
Hematology
1 mL
Serum Chemistry
1 mL
1 mL
1 mL
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Table 5.1-3:
Treatment Phase (Stage 2) Procedural Outline (AI424451)
Procedure
Visit every 3 
months until Early 
D/C or local ATV 
pediatric approval
(5 days)
Transition Visit 
for powder-to-
capsule switcha
(5 days)
Transition Visit 
for Weight Band 
changeb
(5 days)
Notes
Lipids
X
Fasting for subjects 3 years of age (ie, NPO 
except for water and medications for at least 
12 hours). Subjects < 3 years of age may be non-
fasting.
Urinalysis
X
Conducted yearly after the Screening visit.
Pregnancyc
X
Local urine pregnancy testing is preferred. In 
case of doubt, serum pregnancy testing will be 
done.
Clinical Drug Supplies
Dispense Study Treatment
X
X
Unless final or Early Discontinuation visit.
Record Study Medication Compliance
X
X
X
Adherence/Tolerability
Dispense/Review Subject Diary
X
X
X
Only for subjects on ATV powder and switching 
to new 4.2% aspartame ATV powder. At time of 
switch and each visit after as long as the subject 
is on the new ATV powder formulation or 
maximum duration of one year, whichever comes 
first.
Conduct Dosing Assessment
X
X
X
Only for subjects on ATV powder and switching 
to new 4.2% aspartame ATV powder. Assessed 
at time of switch and each visit after as long as 
the subject is on the new ATV powder 
formulation or maximum duration of one year, 
whichever comes first
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Table 5.1-3:
Treatment Phase (Stage 2) Procedural Outline (AI424451)
Procedure
Visit every 3 
months until Early 
D/C or local ATV 
pediatric approval
(5 days)
Transition Visit 
for powder-to-
capsule switcha
(5 days)
Transition Visit 
for Weight Band 
changeb
(5 days)
Notes
Facial Hedonic Scale
X
X
X
5-point scale only to be completed by subjects 
3 years of age on ATV powder and switching 
to new 4.2% aspartame ATV powder. At time of 
switch and after as long as the subject is on the 
new ATV powder formulation or maximum 
duration of one year, whichever comes first.
Total Blood Volumes
4-5 mL
2-3 mL
2-3 mL
Blood Volumes do not exceed NIH Clinical 
Center Guidelines of 3 mL/Kg at a single drawn 
(ie, 15 mL for a 5 Kg infant, the smallest weight 
that would be enrolled in the study) or 7 mL/Kg 
over 6 weeks (ie, 35 mL for a 5 kg infant). These 
volumes represent SOC for HIV infected 
pediatric subjects except for the PK sampling.
a For those subjects switching to the ATV capsule formulation, follow-up visits will be scheduled at 4 and 8 weeks following the indication to switch. Study 
visits will then follow 4 weeks later, then every 12 weeks until local pediatric ATV approval or until 18 years of age. Subjects who are not able to swallow the 
capsule after an 8-week transition period will have to discontinue from the study.
b When a subject moves to a higher powder or capsule weight band, a follow-up visit will be scheduled 4 weeks following the change in dose. Study visits will 
then follow per the regular schedule
c Started when applicable and more frequent testing can be done if required per local guidelines.
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Table 5.1-4:
Safety Follow-Up Procedural Outline for Subjects who discontinue the study for any reason, and have 
hyperbilirubinemia and/or jaundice or ocular icterus at the time of discontinuation
Procedure
Safety Follow-up
Visit every 2 Weeksa
Notes
Safety Assessments
Targeted Physical Examination
X
Concomitant Medication Assessment
X
Adverse Events Assessment
X
AIDS Defining Adverse Events
X
Central Laboratory 
Serum Chemistry
1 mL
Total Blood Volumes
1 mL
Blood Volumes do not exceed NIH Clinical Center Guidelines of 3 mL/Kg at a 
single draw (ie, 15 mL for a 5 kg infant, the smallest weight that would be enrolled 
in the study) or 7 mL/kg over 6 weeks (ie, 35 mL for a 5 kg infant). These volumes 
represent SOC for HIV infected pediatric subjects except for the PK sampling.
a Additional visits every 2 weeks until bilirubin levels are back to Grade 0 or until in the opinion of the investigator, the hyperbilirubinemia is no longer an 
effect of study medication (eg, it is attributable to other medication or concomitant illness). (See Section 6.7.1.1)
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5.2
Study Materials
The sponsor will provide each investigative site with the following:

ATV (BMS-232632) IB and any relevant safety addenda

Protocol and any Amendments to the Protocol

Instructions for completing case report forms (CRFs)

Investigator Manual from the central laboratory

Instructions for processing and shipping PK and resistance samples

SAE and pregnancy forms

Worksheets for calling the IVRS Assignment Center to enroll, register study treatment, and 
discontinue subjects

Investigational Product inventory and assignment logs

Subject Medication Diary

Facial Hedonic Scale
5.3
Safety Assessments
Safety assessments include vital signs, physical measurements, deaths, adverse events (serious 
and non-serious), including Centers for Disease Control (CDC) Class C AIDS events, 
concomitant medication, laboratory measurements, and ECGs.
Toxicities will be graded according to the Division of AIDS (DAIDS) of the US National 
Institutes of Health, Toxicity Tables for Grading Severity of Adult and Pediatric (> 3 months of 
age) Adverse Experiences [December 2004; clarification August 2009] (Appendix 2). The 
modified WHO grades will be used if DAIDS grading are not available (Appendix 5). Harriet 
Lane laboratory normals will be used to grade toxicities when laboratory normal ranges are not 
available.29 Electrocardiogram (ECG) changes and symptoms related to cardiac conduction 
abnormalities will be monitored as per protocol (see Section 5.1 for a schedule of ECGs).
5.3.1
Vital Signs and Physical Examinations
The schedule of vital signs, physical examinations, and targeted physical examinations is 
provided in Section 5.1 (Flow Chart/Time and Events Schedule). Vital signs (blood pressure, 
heart rate, respiration rate, and temperature) should be measured after the subject has been 
sitting/resting for at least 5 minutes. Targeted physical examinations will include an examination 
of the heart, lungs, skin, abdomen, any symptomatic organ system, and general appearance.
5.3.2
Adverse Events
Subjects will be closely monitored throughout the study for any new or ongoing HIV-related 
diagnoses (Appendix 3) and/or adverse events. Events that occur from the Screening Visit 
through Day 1 (prior to dosing) will be recorded as Pre-treatment Events. All events that occur 
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after dosing on Day 1 will be recorded on the appropriate Adverse Event eCRF. Additional 
information on Adverse Events is provided in Section 6.
 
 
5.3.4
Electrocardiograms
The schedule of electrocardiograms (ECGs) is provided in Section 5.1 (Flow Chart/Time and 
Events Schedule). ECGs will be read by a central vendor to monitor for evidence of arrhythmias, 
ischemia, or AVB at Screening to determine eligibility, including PR prolongation, QTc 
increase, QRS widening and any other abnormalities occurring on treatment. A complete report 
will be generated for each ECG, including all standard measurements and an interpretation.
5.3.5
Physical Measurements
Physical measurements (measured without shoes, without diapers, and wearing minimal 
clothing) include height, weight, head circumference (for subjects < 3 years of age at the visit), 
and BSA.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
All efficacy assessments address secondary study objectives.
5.4.2
Secondary Efficacy Assessments
Efficacy analysis will include: proportions of subjects with HIV RNA < 50 c/mL and 
< 400 c/mL at each scheduled visit through Week 24 and up to Week 48; (see Section 8.3 for 
further detail). 

Change from baseline in HIV RNA, CD4 cell count and CD4 percentage will be assessed.

Results from Stage 2: Efficacy will be assessed only to ensure subjects maintain virologic 
and immunologic control.
Subjects who did not have the opportunity to reach Week 48 by the time the last treated subject 
reaches Week 24 will have a final Stage 1 status assessment performed and will immediately 
move into Stage 2 while remaining on ATV powder.
5.5
Pharmacokinetic Assessments
5.5.1
Intensive Pharmacokinetic Assessment 
Intensive 24 hour PK samples will be collected in Stage 1 only for subjects who:
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
Enter the study weighing 25 - < 35 kg and/or 6 to 11 years of age at scheduled Week 2 
visit or 

Subjects moving into the 25 - < 35 kg weight range or becoming 6 years old during Stage 
1, the intensive PK visit will occur two weeks after the dose change for the new weight band. 
If the subject becomes 6 years of age but without a dose change then the intensive PK visit 
can occur at the next regular Stage 1 visit. 

Subjects enrolling a new 5 - < 10 kg cohort with 200mg ATV and 80 mg RTV dose
An intensive PK assessment will be conducted at Week 2 (Day 14). Serial plasma concentrations 
will be collected over a 24-hour period in order to assess the steady state PK of ATV and RTV. 
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of PK over a 24 hour 
period at Week 2. For subjects moving into the 25 to < 35 kg weight range or becoming 
6 years old during Stage 1, the intensive PK visit will occur 2 weeks after the dose change for the 
new weight band. If the subject becomes 6 years of age but without a dose change then the 
intensive PK visit can occur at the next regular Stage 1 visit. 
Intensive PK collection for the age range (6 to 11 years), but not fulfilling the 25 to < 35 
weight range, will be stopped when PK samples from approximately 10 subjects have been 
collected. All subjects from the weight cohorts (25 - < 35 kg, 5 - < 10 kg on 200 mg ATV 
and 80 mg RTV dose) will be evaluated for Intensive PK.
Table 5.5.1-1:
Intensive PK Sample Schedule
Sample Collection Time
Time 
(Relative To Dosing)
hours:min
PK Blood Sample for 
ATV/RTV
Study Week
Time (Event)
Week 2
0 h (pre-dose)a
00:00 (pre-dose)
X
1.5 h (post-dose)
01:30
X
2.5 h (post-dose)
02:30
X
4 h (post-dose)
04:00
X
6 h (post-dose)
06:00
X
8 h (post-dose)
08:00
X
12 h (post-dose)
12:00
X
24 h(post-dose)
24:00
X
a Samples to be obtained prior to study drug(s) administration
Steady state PK parameters to be assessed include ATV and RTV Cmax, Tmax, AUC(TAU), 
Cmin, apparent oral clearance from plasma (CLT/F) and apparent oral clearance from plasma 
adjusted for body weight (CLT/F/kg).
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5.5.1.1
Data Collection (Intensive PK- only for subjects weighing 25 - < 35 kg  
and/or aged 6 to 11 years; subjects enrolling in a new 5 - <10 kg 
cohort with 200mg ATV and 80 mg RTV )
There are several important dates and times to record relative to the Intensive PK visit at Week 2, 
not only on the day of the actual visit, but also on the day prior to the visit, as well as the day 
after the visit is initiated.
PK data is viable only if the time elapsed between the dose taken prior to the sampling (taken on 
the day before the sampling) and the actual start of the Intensive PK blood sampling (the 0-hr 
blood draw) is between 20 - 28 hours.  In order to determine adherence to this window, data 
points collected on the CRF and on the laboratory requisition are analyzed to calculate the 
elapsed time. 
Important Lab Requisition data points 
1. Date and Time* of Blood Sampling on the day of the Intensive PK visit
Important CRF data points
1. Date and Time* of Dose PRIOR TO the 0-hr PK blood draw 
a) This date and time should be the day prior to the visit (20 - 28 hours before the PK blood 
sampling is started).  If the subject was mistakenly dosed on THE DAY OF the Intensive 
PK visit before they came to the clinic, then the 20 - 28-hour window cannot be applied 
and the Intensive PK visit should be rescheduled to occur as quickly as possible. 
(Immediately notify your BMS Site Manager.)
2. Date and Time* of Dose and light Meal AFTER the 0-hr PK blood draw
a) This is the date and time of the dose on THE DAY OF the Intensive PK visit. This dose 
must not be taken at home, rather AT the clinic visit and AFTER the 0-hr blood draw is 
taken.
3. All concomitant medication taken by the subject within 24 hours of the 0-hr PK blood draw
4. Date and Time* of Dose AFTER the 24-hr PK blood draw
a) This is the date and time on the day AFTER the PK sampling began. Once the 24-hr PK 
sample has been drawn, the subject may be administered the dose for the day.
* Time will be captured in the 24-hour clock format.
5.5.2
Trough Plasma Concentration (for all subjects)
Trough PK will be evaluated at each scheduled visit from Week 4 through a minimum of 24 
weeks up to a maximum of 48 weeks. Trough PK collection will be stopped for ongoing subjects 
in Stage 1 when the last subject reaches week 24. These samples will be collected at 24 hours 
after the last dose for ATV and RTV (acceptable window from prior ATV dose: 20 - 28 hours).
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Trough ATV levels may be sent for analysis at the discretion of the investigator as a component 
of a clinical evaluation of subjects with virologic rebound, or failure to achieve virologic 
suppression in the timeframe expected by the investigator.
5.5.2.1
Data Collection (Trough PK - for all subjects)
There are several important dates and times to record relative to all of the Trough PK visits, not 
only on the day of the actual visit, but also on the day prior to the visit. Trough PK collection 
will be stopped for ongoing subjects in Stage 1 when the last subject reaches week 24.
PK data is viable only if the time elapsed between the dose taken prior to the sampling (taken on 
the day before the sampling) and the actual time of the Trough PK blood sampling is between 
20 - 28 hours. In order to determine adherence to this window, data points collected on the CRF 
and on the laboratory requisition are analyzed to calculate the elapsed time. 
Important Lab Requisition data points 
1. Date and Time* of Blood Sampling on the day of the Trough PK visit
Important CRF data points:
1. Date and Time* of Dose and light Meal PRIOR TO the Trough PK blood draw 
a) This date and time should be the day prior to the visit (20 - 28 hours before the PK blood 
draw).  If the subject was mistakenly dosed on THE DAY OF the Trough PK visit before 
they came to the clinic, then the 20 - 28-hour window cannot be applied and the sample 
should not be drawn.  Depending on the visit, it may be possible to reschedule the Trough 
PK visit. (Immediately notify your BMS Site Manager.)
2. All concomitant medication taken by the subject within 24 hours of the Trough PK blood 
draw.
* Time will be captured in the 24-hour clock format.
5.5.3
Blood Collection and Processing (Intensive and Trough Samples)
Blood samples will be collected from an indwelling catheter or by direct venipuncture. If a 
catheter is used for blood collection then approximately 1 mL of blood/saline should be 
withdrawn initially and discarded. Malfunctions to the venous catheter, poor venous access, or 
other difficulties which would cause time point sample delays may be cause for the reschedule of 
the intensive PK visit. Note: 1 sample tube is collected as ATV/RTV is assayed simultaneously.
5.5.3.1
Collection Instructions
One (1) Polyethylene Terephthalate (PET) tube of 0.8 mL of blood for ATV/RTV will be 
collected from an indwelling catheter or by direct venipuncture. The blood samples will be 
collected into an evacuated collection tube containing EDTA (K2EDTA) as the anticoagulant. 
Immediately after collection, each blood sample will be gently inverted a few times for complete 
mixing with the anticoagulant (K2EDTA) and then placed on chipped ice. Within 60 minutes of 
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collection, each blood sample will be centrifuged (using a refrigerated centrifuge) for 10 minutes 
at approximately 1000 x g at about 5C to separate the cellular elements from plasma. The 
separated plasma will be transferred within 30 minutes to a labeled screw-capped polypropylene 
cryotube and stored at -20C until shipped to the analytical laboratory for analysis. At a 
minimum, times of sample collection, centrifugation, plasma harvest, and sample storage should 
be recorded on a sample harvest log. Each blood sample will be labeled appropriately and the 
date for each sample will be entered on the blood collection requisition form for the central
laboratory. The status of sample collection for each PK time point (yes or no) will be entered on 
the blood collection eCRF page.
Alternatively, if there is no refrigerated centrifuge available at the clinical site, samples should be 
centrifuged as follows. After collection, samples should be gently inverted a few times for 
mixing with the anticoagulant and placed on chipped ice or in a refrigerator for 20 minutes prior 
to centrifugation. The centrifuge tube buckets(s) should be placed on chipped ice or in a 
refrigerator for 15 - 20 minutes prior to blood sample centrifugation. Each sample will then be 
centrifuged for 10 - 15 minutes at approximately 1000 x g to separate cellular elements from 
plasma. The separated plasma should be transferred within 60 minutes of collection to a 
polypropylene cryotube and stored at - 20C until shipped to the central laboratory. At a 
minimum, times of sample collection, centrifugation, plasma harvest, and sample storage should 
be recorded on a sample harvest log. Each blood sample will be labeled appropriately and the 
actual, precise time and date for each sample will be entered on the blood collection requisition 
form for the central laboratory. The status of sample collection for each PK time point (yes or 
no) will be entered on the blood collection eCRF page. Samples should not be batched and 
should be shipped as soon as possible to the central laboratory. 
5.5.4
Labeling and Shipping of Biological Samples (Intensive and Trough 
Samples)
Pre printed computer labels will be supplied along with sample collection kits for each 
pharmacokinetic sample.
All tubes will be clearly and indelibly labeled with the following information:

Study

Subject Number

Study Week/Study Hour

Period

Sample Type

Label Type

Barcode
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For plasma pharmacokinetic samples, the sampling time is written as Week(W) hour(h) 
minute(m). For example, the Week 2, 1.5 hour post-dose sample will be written as 2W 1h 30m; 
and the Week 2, 4 hour post-dose sample will be written as W2 4h 0m.
The samples should be shipped to the designated Central Laboratory by overnight air express 
using insulated containers with enough dry ice to maintain the samples in a frozen state until they 
are received at the analytical site. The shipment of biospecimens (human samples) must comply 
with the appropriate regulations as specified by the carrier. At a minimum, all samples must be 
packaged within 2 containers with absorbent material between containers to control any spill or 
leakage. The outer container must be puncture resistant (eg, cardboard mail tube, corrugated 
cardboard box). In addition to the name and address of the person responsible for receiving the 
samples, a fluorescent, orange-red BIOHAZARD label with the appropriate symbol must be 
affixed to the inner container.
The arrangements for shipping are to be made by the Study Coordinator. The Coordinator should 
contact the Central Laboratory (contact name to be provided) by telephone and/or fax at least 
1 day prior to the sample shipment to ensure proper receipt.
SAMPLES SHOULD NOT BE SHIPPED TO ARRIVE OVER WEEKENDS OR HOLIDAYS.
5.6
Pharmacodynamics Assessments
Not applicable.
5.7
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable.
5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
5.9.1
Palatability Assessments
Subjects who are still on ATV powder formulation in Stage 2 will be switched to the new 4.2% 
aspartame ATV powder at their next regular study visit. The palatability assessment will be 
conducted by completion of a palatability survey and 5-point Facial Hedonic Scale.30,31,32,33 The 
5-point Facial Hedonic Scale will be completed by subjects 3 years of age on ATV powder and 
switching to the new ATV powder formulation. Subjects that cannot complete the assessment 
will be exempted from the Facial Hedonic Scale palatability assessment. Specific instructions for 
the Facial Hedonic Scale assessment tool and source documents will be provided to the sites.
The palatability assessments should be completed at the time of switch to the new 4.2% 
aspartame ATV powder formulation and after as long as the subject is on the new 4.2% 
aspartame ATV powder formulation or maximum duration of one year, whichever comes first.
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The first dose on the new 4.2% aspartame ATV powder should be administered at the clinic and 
immediately followed by first 5-point Facial Hedonic Scale assessment. Subjects are encouraged 
not to take their dose of new study medication prior to the study visit as long as subject is on new 
ATV powder and Facial hedonic Scale palatability will be assessed. Subjects will take their dose 
at the clinic followed by Facial Hedonic Scale administration.
5.9.2
Laboratory Test Assessments
Please refer to Section 5.1 as to when these tests are required.
The tests will be performed by a central laboratory that is licensed and meets Clinical Laboratory 
Improvement Amendments (CLIA) regulations or equivalent by country. A copy of the current 
laboratory license and CLIA certification or equivalent must be kept on file at the study site. 
Laboratory test kits and a manual will be provided by the central laboratory.
Fasting lipids for subjects 3 years of age (ie, NPO except for water and medications for at least 
12 hours). Subjects < 3 years of age may be non-fasting.

Hematology will consist of CBC, cell differential (including absolute neutrophils + absolute 
bands), and platelet count, CD4 cell count, and percentage.

Serum Chemistry will consist of sodium, potassium, chloride, bicarbonate, calcium, glucose, 
BUN, creatinine, urate (uric acid), total protein, albumin, LDH, ALT, AST, alkaline 
phosphatase, total bilirubin, direct bilirubin, amylase, and lipase. 

Fasting lipids - The following analytes will be evaluated: total cholesterol, HDL, LDL, and 
triglycerides. Subjects in 3 years of age will be NPO for 12 hours prior to draw except for 
water and medication. Subjects in < 3 years may have samples for these laboratory tests 
drawn non-fasting.

Record the time of the most recent meal on the CRF.

Urinalysis will comprise pH, specific gravity, protein, glucose, ketones, blood, and 
microscopy. 

HIV-1 RNA PCR by Roche AmplicorAssay (version 1.5), or Abbott RealTime HIV-1 
assay after the Roche Amplicor assay is discontinued.

Pregnancy test (when applicable in stage 2). Urine pregnancy testing is preferred. In case of 
doubt, serum pregnancy testing (FSH, hCG) can be done.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product.
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.)
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs for data 
transmission purposes (See Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
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
medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing. The investigator should report any SAE 
occurring after these time periods that is believed to be related to study drug or protocol-
specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs must be recorded on the BMS SAE Report Form; pregnancies on a BMS Pregnancy 
Surveillance Form. These original BMS Forms are to remain on site. SAEs, whether related or 
not related to study drug, and pregnancies must be reported to BMS (or designee) within 24 
hours via confirmed facsimile (fax) transmission, or scanned and reported via electronic mail to:
SAE Email Address: Worldwide.Safety@BMS.com
SAE Facsimile Number: See Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
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6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Abnormalities
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted

Any laboratory abnormality that required the subject to receive specific corrective therapy.
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
Females who may become sexually active women of childbearing potential (WOCBP) must use 
an effective method of birth control during the course of the study, in a manner such that risk of 
failure is minimized. The definition of WOCBP is addressed in protocol Section 3.3.3. 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.
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The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
Specific Information Related to ATV and Pregnancy
Atazanavir is classified by the US FDA as Pregnancy “Category B” (Animal reproduction 
studies have failed to demonstrate a risk to the fetus and there are no adequate and well-
controlled studies in pregnant women.)
At maternal doses producing the systemic drug exposure levels equal to (in rabbits) or 2 times (in 
rats) those at the human clinical dose (400 mg once daily), ATV did not produce teratogenic 
effects. In the pre- and post-natal development assessment in rats, ATV, at maternally toxic drug 
exposure levels 2 times those at the human clinical dose, caused body weight loss or weight gain 
suppression in the offspring. Offspring were unaffected at a lower dose that produced maternal 
exposure equivalent to that observed in humans given 400 mg once daily. ATV had no effect on 
reproductive performance of the offspring. In conclusion, ATV demonstrated no selective 
developmental toxicity and no effects on reproductive function or fertility in rats and/or rabbits at 
exposures that were at least equal to or slightly greater than that observed in humans given 400 
mg once daily.
Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. 
In clinical trial AI424-182, ATV/RTV (300/100 mg or 400/100 mg) in combination with 
zidovudine/lamivudine was administered to 41 HIV-infected adult pregnant women during the 
second or third trimester. The study also assessed 40 infants who received antiretroviral 
prophylactic treatment (which did not include ATV) and were negative for HIV-1 DNA at the 
time of delivery and/or during the first 6 months postpartum.  PK and safety results were 
evaluated and detailed information is available in the U.S. Package insert for Reyataz and in the 
Summary of Medicinal Product Characteristics in the EU.  Available human and animal data 
suggest that atazanavir does not increase the risk of major birth defects overall compared to the 
background rate. However, because the existing studies in humans cannot rule out the possibility 
of harm, atazanavir should be used during pregnancy only if the potential benefit justifies the 
potential risk. There are no studies and adequate clinical data in pregnant teenager females. 
The CDC recommend that HIV-infected mothers not breast-feed their infants to avoid risking 
postnatal transmission of HIV. Studies in lactating rats have demonstrated that ATV is secreted 
in milk. It is not known whether ATV is secreted in human milk. Because of both the potential 
for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers 
should be instructed not to breast-feed if they are receiving ATV.
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Pregnancy testing must also be performed throughout the study as specified in Section 5.1 (see 
flow chart/time and events schedule) and the results of all pregnancy tests (positive or negative) 
recorded on the CRF or transferred electronically.
In addition, all WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any time during study 
participation.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1. for reporting details).
Potential drug induced liver injury is defined as 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase),  
AND 
3..No 
other 
immediately 
apparent 
possible 
causes 
of 
AT 
elevation 
and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
6.7.1
Toxicity Management
There will be no dose reductions for study drug toxicities. Additionally, there will be no 
substitutions for ATV/RTV. On-study substitutions of nucleoside analog therapy with one or 
more other nucleoside analogs approved for use by infants/children will be permitted for toxicity 
at the discretion of the investigator. The BMS medical monitor or designee should be contacted 
prior to the substitution, if possible. 
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The cost of “alternative” NRTI agents not provided per protocol will be defrayed by the sponsor. 
Alternative nucleoside analogs, if used, must be administered according to labeled dosing 
recommendations. Subjects must receive 2 nucleoside analogs in addition to ATV/RTV 
throughout the study. 
If it becomes necessary to temporarily interrupt any study medication for toxicity, all 
antiretrovirals must be stopped and restarted at the same time (on the same day), at full dose. If 
either NRTI is replaced with an alternative nucleoside analog all, new drugs should be started on 
the same day with ATV/RTV; sequential restarting of study medications is not allowed.
Symptomatic therapy for toxicity (eg, analgesics, anti-emetics, anti-diarrhea agents, or other 
medications) is permitted as long as it is not an exclusionary medication, but must be recorded in 
the CRF.
The Division of AIDS (DAIDS) standardized toxicity table for grading severity of pediatric 
adverse experiences (Appendix 2) will be used for grading toxicities. The supplemental toxicity 
tables supersede the DAIDS toxicity table when grading skin rash, triglyceride, and cholesterol 
toxicities.
In general, for abnormal treatment-related, or possibly treatment-related, clinical or laboratory 
observations of:

Grade 1 severity - Continue study medications; routine monitoring.

Grade 2 severity - Continue study medications; monitor closely with more frequent visits; 
work-up to exclude other causes.

Grade 3 severity (with the exception of hyperbilirubinemia)- Repeat observation within 
72 hours for confirmation. Subjects should continue taking study medications pending receipt 
of the confirmatory laboratory tests. However, the clinician has the option of immediately 
interrupting the study medications if a repeat confirmatory laboratory test cannot be
performed within 72 hours, or if the clinician determines that the continuation of study 
medications is unsafe while awaiting test results. For all confirmed Grade 3 toxicities, stop 
all study medications until toxicity resolves to Grade 2. Subjects will be allowed to 
interrupt study treatment for up to 14 days. If toxicity persists at Grade 3 for more than 
14 days or recurs on re-challenge, study medications generally should be discontinued 
permanently. 

Grade 4 severity* (with the exception of hyperbilirubinemia) - Hold study medications and 
notify the BMS medical monitor or designee. Obtain confirmatory laboratory results within 
72 hours and notify the BMS medical monitor or designee of those results. For all confirmed 
Grade 4 toxicities, stop all study medications until toxicity resolves to < Grade 2. Subjects 
will be allowed to interrupt study treatment for up to 14 days. If toxicity persists at 
Grade 4 for more than 14 days or recurs on re-challenge, discontinue study medications 
permanently.
*Note: For all Grade 4 toxicities (with the exception of hyperbilirubinemia)-, telephone the BMS 
medical monitor or designee within 24 hours of the event.
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Specific 
recommendations 
for 
management 
of 
pancreatitis, 
hyperlipasemia, 
hyperamylasemia, abnormal liver enzymes, CNS symptoms, lipid abnormalities, 
hyperglycemia, and rash are outlined in Appendix 4. 
6.7.1.1
Management of Hyperbilirubinemia
Many subjects taking ATV experience asymptomatic elevations in indirect (unconjugated) 
bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase 
elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. Dose 
modification of ATV is not permitted. Subjects who experience unacceptable jaundice/ocular 
icterus should be discussed with the BMS Medical Monitor to determine if subjects are to be 
discontinued from study.
The investigator must contact the BMS Medical Monitor prior to discontinuing any subject due 
to hyperbilirubinemia.
A post-study follow up will be required for the following discontinued subjects: 

Subjects who discontinue for hyperbilirubinemia and/or jaundice or ocular icterus (regardless 
of the grade of either) 

Subjects who discontinue for other reasons unrelated to hyperbilirubinemia or jaundice or 
ocular icterus but have a total bilirubin of Grade 2 at the time of discontinuation 
The post-study follow up will consist of additional visits every 2 weeks until the 
hyperbilirubinemia decreases back to Grade 0 or until in the opinion of the investigator the 
hyperbilirubinemia is no longer an effect of study medication (eg, it is attributable to other 
medication or concomitant illness). 
Follow-up visit procedures will include laboratory evaluation of liver function, assessments of 
concomitant medications and adverse events (and jaundice or ocular icterus resolution if 
applicable), and a targeted physical exam as needed (see Table 5.1-4).
6.7.1.2
Criteria for Treatment Interruption
Study medications may be interrupted either for medication toxicity, as detailed previously, or 
for an intercurrent illness, for up to 14 days. Therapy or prophylaxis for opportunistic infections 
requiring use of concomitant medications not allowed in the protocol should be discussed with
the BMS medical monitor or designee.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
There will be an independent data monitoring committee (DMC) for this study. The DMC shall 
have access to data on at least an annual basis, including but not limited to following: the 
frequency and spectrum of serious adverse events; Grades 3 to 4 laboratory abnormalities; 
occurrence of malignancies; and other select adverse events of interest. The DMC shall act as an 
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advisor to the sponsor and have responsibility for safeguarding the subjects’ interests. The DMC 
shall bring any safety concerns to the attention of the sponsor so that the sponsor can review the 
data and prepare appropriate communications to the Regulatory Authorities. A separate charter 
shall be developed for the DMC; this will describe the membership and activities of the DMC.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Sample size is not based on power calculations. A total of approximately 95 subjects are planned 
for this study in order to treat approximately 10 - 15 subjects in the new 5 - < 10 kg (200 mg 
ATV and 80 mg RTV) cohort and have a minimum number of 56 treated subjects with 48 weeks 
follow-up on ATV powder based on an expected drop-out rate of approximately 30%. This study 
plans to enroll approximately 160 subjects, which will result in approximately 95 treated subjects 
due to an expected screen failure rate of 40%.
A target sample size of 95 treated subjects can detect with 80% probability, a safety event that 
occurs at a per subject incident rate of 1.7%.
A target sample size of 95 treated subjects can produce an exact binomial 95% confidence 
intervals (CI) within 10.5% for a response rate of 50.5% for modified intent-to-treat (ITT) 
analysis.
8.2
Populations for Analyses

Enrolled subjects are those whose informed consent form were signed by a parent/legally 
acceptable representative and were assigned a subject identification number (PID).

Treated subjects are enrolled subjects who received at least 1 dose of study therapy (ATV).
8.3
Endpoint Definitions
8.3.1
Safety Endpoints
Primary safety endpoints are: 

the number of subjects who died (regardless of onset)

frequency of SAEs in Stage 1 through Week 48 on ATV powder

frequency of AE leading to discontinuation in Stage 1 through Week 48 on ATV powder.
All safety data in Stage 1 through Week 48 on ATV powder will be included in the safety 
analysis.
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8.3.2
Efficacy Endpoints
All efficacy endpoints are secondary. The principal efficacy endpoints are the proportions of 
subjects with HIV RNA < 50 c/mL and HIV RNA < 400 c/mL at Week 24 and Week 48 of ATV 
powder formulation.
The efficacy analysis at Week 48 of ATV powder formulation will include only those subjects 
who had the opportunity to reach week 48 by the time that the last treated subjects reaches week 
24.
8.4
Analyses
When summarizing Stage 1 data, values after transitioning from powder to capsules will be excluded. 
Categorical variables are summarized with counts and percents or with proportions (number with 
event divided by number evaluable) and percents, depending on the endpoint. Continuous 
variables are summarized with univariate statistics (e.g., n, mean, median, standard error). 
Efficacy and safety parameters are assessed on ATV powder in Stage 1 through Week 48 (i.e., 
values after the first dose of ATV capsule are excluded), unless specified otherwise.
Analyses of HIV RNA use pre-defined analysis week windows based on both regulatory 
correspondence and the study visit schedule, while analyses of other parameters (e.g., laboratory 
tests, ECGs) use pre-defined visit week windows based on the study visit schedule. 
Laboratory parameters are assessed using US values and units. 
Efficacy is presented by baseline weight band (5 - < 10 (ATV 150 mg), 5 - < 10 (ATV 200 mg), 
10 - < 15 kg, 15 - < 25 kg, 25 - < 35 kg), prior ARV use (naive, experienced) and total (pooled). 
All other summaries are presented by baseline weight and total. All summaries are presented for 
treated subjects unless otherwise noted. 
8.4.1
Demographics and Baseline Characteristics
The following will be summarized for treated subjects: 

Demographics: age, race, ethnicity, gender, geographic region; 

Disease characteristics at baseline: HIV RNA, CD4 cell count, CD4 percentage, prior ARV 
use (naive, experienced);

Vital signs and physical measurements at baseline; 

Laboratory tests at baseline; 

Pre-treatment CDC Class C AIDS events; 

Prior medications.
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8.4.2
Efficacy Analyses
The following efficacy endpoints will be summarized on treatment:

Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL at Week 24:

Modified intent-to-treat (ITT): The numerator is based on subjects with HIV RNA < 50 
(400) c/mL at Week 24. The denominator is based on treated subjects.

Observed values: Similar to modified ITT, the numerator is based on subjects with HIV 
RNA < 50 (400) c/mL at Week 24. However, the denominator is based on subjects with 
HIV RNA at Week 24.

Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL at Week 48:

Modified intent-to-treat (ITT): The numerator is based on subjects with HIV RNA < 50 
(400) c/mL at Week 48. The denominator is based on treated subjects who had the 
opportunity to be assessed at Week 48.

Observed values: Similar to modified ITT, the numerator is based on subjects with HIV 
RNA < 50 (400) c/mL at Week 48. However, the denominator is based on subjects with 
HIV RNA at Week 48.
Response rates will be presented with exact binomial 95% CIs using modified ITT and observed 
values.

HIV RNA log10 values and changes from baseline at each analysis week in Stage 1 through 
Week 48 on ATV powder;

CD4 cell count and CD4 percentage: values and changes from baseline at each visit week in 
Stage 1 through Week 48 on ATV powder;

Resistance in Stage 1 through Week 48 on ATV powder for virologic failures (defined in 
Section 4.5.1): 

Newly-emergent genotypic substitutions, i.e., on-treatment substitutions that were not 
detected at baseline;

Newly-emergent phenotypic resistance, i.e., baseline fold change ≤ the cut-off for 
reduced susceptibility and an on-treatment fold change > the cut-off for reduced 
susceptibility.
Stage 2 data will be summarized at each visit week through the end of the study. 
8.4.3
Safety Analyses
The investigators will determine the intensity and relationship of adverse events to study therapy. 
The investigators’ terms will be coded and grouped by system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA) in production at BMS. 
Adverse events will be presented by system organ class and preferred term. Summaries will 
include both non-serious and serious adverse events, unless specified otherwise. If a subject had 
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an adverse event with different intensities over time, then only the greatest intensity will be 
reported on treatment. 
Deaths will be listed for enrolled subjects without regard to onset.
The frequencies of the following safety endpoints will be summarized on treatment in Stage 1 
through Week 48 on ATV powder:

Serious adverse events;

Adverse events leading to discontinuation of study therapy;

Adverse events by intensity;

CDC Class C AIDS events;

Laboratory abnormalities by toxicity grade and overall. The highest toxicity grade on 
treatment will be reported for each test.

ECG categories at each visit week;

Physical measurements (age-adjusted percentiles and age-adjusted Z scores for height and 
weight): values and changes from baseline at each visit week. 
Stage 2 data will be summarized using freq of SAEs, AEs leading to disc, grade 3 to 4 AEs, 
grade 3 to 4 laboratory abnormalities.
8.4.4
Pharmacokinetic Analyses
Intensive PK (only for subjects weighing 25 - < 35 kg and/or aged 6 to < 11 years and 
subjects enrolling in the new 5 - < 10 kg cohort (200mg ATV and 80mg RTV).
An intensive PK assessment for ATV and RTV will be conducted. Serial plasma concentrations 
will be collected over a 24-hour period at Week 2 in order to assess the steady state PK of ATV 
and RTV. For subjects moving into the 25 to < 35 kg weight range or becoming 6 years old 
during Stage 1, the intensive PK visit will occur two weeks after the dose change for the new 
weight band. If the subject becomes 6 years of age but without a dose change then the intensive 
PK visit can occur at the next regular Stage 1 visit. Pharmacokinetic parameters of ATV and 
RTV will be derived from plasma concentration versus time data by a non-compartmental 
method using a validated pharmacokinetic program. Steady state parameters to be assessed 
include: 

Cmax: Maximum observed concentration;

Tmax: Time of maximum observed concentration; 

Cmin: Plasma concentration 24 hours post observed dose; 

AUC (TAU): Area under the concentration-time curve, in 1 dosing interval from time 0 to 24 
hours post observed dose;

IQ: Ratio of Cmin at Week 2 to Protein Binding Adjusted EC90 derived from individual 
subject clinical isolates at baseline (ATV only);
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
CLT/F: apparent oral clearance from plasma

CLT/F/kg: apparent oral clearance from plasma adjusted for body weight.
Summary statistics for all the relevant PK parameters of ATV will be presented by weight bands. 
Additional summaries may be presented by age group. In addition, geometric means and 
coefficients of variation (CV) will be presented for Cmax, AUC (TAU), Cmin, and IQ. Medians, 
minima, and maxima will be reported for Tmax.
Similar analyses will be performed for RTV.
Trough Concentrations (for all subjects, Weeks 4 through a minimum of 24 weeks and up 
through 48 weeks in Stage 1, except transition visits)
Trough plasma concentrations (Ctrough) of ATV and RTV and IQ of ATV will be summarized 
by visit week.
8.4.5
Pharmacodynamic Analyses
The relationship between ATV PK parameters and efficacy and/or safety endpoints and ATV 
composite trough concentration and IQ versus efficacy endpoints following administration of the 
powder formulation will be explored graphically. Efficacy endpoints may include proportion of 
subjects with HIV RNA < 50 c/mL, proportion with HIV RNA < 400 c/mL, HIV RNA changes 
from baseline, CD4 cell count changes from baseline, and CD4 percentage changes from 
baseline. Safety endpoints may include selected AEs and changes from baseline in laboratory 
tests.  
8.4.6
Pharmacogenomic Analyses
Not applicable.
8.4.7
Outcomes Research Analyses
Not applicable.
8.4.8
Other Analyses 
8.4.8.1
Palatability
For ATV 10% aspartame powder formulation, proportions of subjects in each category of each 
question on the palatability survey will be tabulated at each visit when they are taking this 
formulation by weight band.
For the new ATV 4.2% aspartame powder formulation, proportions of subjects in each category 
of each question on the palatability survey will be tabulated by weight band at each visit since 
they switch to the new formulation in Stage 2. In addition, Facial Hedonic Scale will be 
summarized at each visit for subjects who take it (i.e. ≥ 3 years old in Stage 2 on ATV powder 
formulation).
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8.5
Interim Analyses

The primary analysis will be conducted when Week 24 data of all treated subjects are 
available (Stage 1). 

The final analysis will be conducted when Stage 2 data of all treated subjects are available. 

Additional safety updates and summaries of efficacy may be conducted at unscheduled 
intervals to support regulatory questions/interactions; and at the request of the DMC.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

Bristol-Myers Squibb

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
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In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact BMS prior to 
destroying any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor) and the following noninvestigational 
product(s): all NRTI backbone therapy, is maintained at each study site where study drug is 
inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label ID number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to the sponsor
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
retain samples for bioavailability/bioequivalence, if applicable 

dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
(IP) 
dispensing/accountability, as per the Delegation of Authority Form.
The sponsor will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data reported on the CRF that are derived from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the SAE form and Pregnancy Surveillance form, respectively. Spaces may be left blank only in 
those circumstances permitted by study-specific CRF completion guidelines provided by the 
sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly reviewed, 
signed, and dated by a qualified physician who is an investigator or sub-investigator. For 
electronic CRFs, review and approval/signature is completed electronically through the BMS 
electronic data capture tool. The investigator must retain a copy of the CRFs including records of 
the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by the sponsor. User accounts are not to be shared or reassigned to other individuals.
9.3
Publications
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as set forth 
in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the sponsor at the 
earliest practicable time for review, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
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confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the 
investigator or the sponsor as related to the 
investigational product
Expedited Safety Report
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product)
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11
LIST OF ABBREVIATIONS
Term
Definition
3TC
lamivudine/Epivir
AE
adverse event
ALT
alanine transaminase (SGPT)
ARV
Antiretroviral
AST
aspartate transaminase (SGOT)
ATV
Atazanavir
AUC
area under the curve
AUC(TAU)
area under the curve (over the dosing interval)
AV
Atrioventricular
BSA
body surface area
c/mL
copies per milliliter
CBC
complete blood count
CD4
antigenic marker of helper/inducer T cells
CDC
Centers for Disease Control and Prevention
CI
Confidence Interval
CLT/F
Apparent oral clearance from plasma
CLT/F/kg
Apparent oral clearance from plasma adjusted for body weight
Cmax
maximum concentration of drug
Cmin
minimum concentration of drug
CRF
case report form, paper or electronic
CSR
Clinical Study Report
DAIDS
Division of AIDS
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
eCRF
electronic CRF
EDC
electronic data capture
FDA
Food and Drug Administration
GCP
good clinical practice
h
Hour
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Term
Definition
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high density lipoprotein
HIV RNA
human immunodeficiency virus ribonucleic acid
ICH
International Council on Harmonization (of technical requirements 
for registration of pharmaceuticals for human use)
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent To Treat
IVRS
Interactive voice response system
Kg
Kilogram
L
Liter
LDL
low density lipoprotein
LPV
Lopinavir
mL
milliliter 
NRTI
nucleoside reverse transcriptase inhibitor
NPO
nothing by mouth
PD
Pharmacodynamic
PI
protease inhibitor
PK
Pharmacokinetic
PMTCT
Prevention of mother to child transmission
PPK
Population pharmacokinetics
PSDP
Post Study Drug Program
QD
Once daily
RNA
ribonucleic acid
RTV
Ritonavir
SAE
serious adverse event
SOC
Standard of care
TAO
trial access online, the BMS implementation of an EDC capability
TDF
Tenofovir
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Term
Definition
ULN
upper limit of normal
VR
Virologic response
WOCBP
women of child-bearing potential
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APPENDIX 1
LISTINGS OF PROHIBITED AND PRECAUTIONARY
THERAPIES DURING THE STUDY
General Notes: 

Guidelines for the use of drugs with established or other potentially significant drug 
interactions listed in the Package Inserts of the marketed ARV agents used by subjects 
participating in this study (Reyataz, Norvir) should be followed. 

Medications listed in the Package Inserts as contra-indicated with the other marketed ARV 
agents used by subjects participating in this study are not permitted. 

Prophylaxis for Pneumocystis carinii pneumonia (PCP) is strongly recommended for subjects 
who may develop during the study an absolute CD4 cell count 200 cells/mm3 or who have 
had a prior episode of PCP.

Guidelines regarding immunization:

Subjects on study and treated for > 12 weeks: Any immunizations deemed appropriate by 
the subject’s physician are permitted provided that the immunization is given ≥ 4 weeks 
from any HIV RNA measurement; i.e. immunization should be given immediately after 
the HIV RNA sample is collected for purpose of the study visit

Subjects ≤ week 12 visit: The immunization program can be performed while keeping the 
visits schedule.

For bone-marrow suppression emerging on study, the use of erythropoietin and/or G CSF 
and/or blood transfusions are allowed.

A subject may not be co-enrolled in a concomitant trial prior to randomization.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Drugs that may prolong the QT Interval and/or induce Torsades de Pointes:
amiodarone
mesoridazine
arsenic trioxide
mexiletine 
chlorpheniramine
moexipril/HCTZ 
chlorpromazine
moxifloxacin
clarithromycin
naratriptan
disopyramide
nicardipine
dofetilide
octreotide
dolasetron
paroxetine
droperidol
procainamide
erythromycin
quetiapine
felbamate
risperidone
fluoxetine
salmeterol
foscarnet
sertraline
fosphenytoin
sotalol
gatifloxacin
sparfloxacin
halofantrine
sumatriptan
haloperidol
tamoxifen
ibutilide
thioridazine
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indapamide
tizanidine
isradipine
venlafaxine
levofloxacin
ziprasidone
levomethadyl
zolmitriptan
lidocaine (systemic) 
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APPENDIX 2
DAIDS TOXICITY GRADES
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APPENDIX 3
AIDS-DEFINING DIAGNOSES
I.
PARASITIC INFECTIONS
Pneumocystis carinii (PC)
1011
PC pneumonia histologically proven.
1012
PC pneumonia, clinical diagnosis by the following specifications and confirmed HIV 
infection:
A history of dyspnea on exertion or non-productive cough of recent onset (within the past 
3 months).
AND
Chest X-ray evidence of diffuse bilateral interstitial or gallium scan evidence of diffuse 
bilateral pulmonary disease;
AND
Arterial blood gas analysis showing an arterial pO2 of < 70 mmHg or a low respiratory 
diffusing capacity (< 80% of predicted values) or an increase in the alveolar-arterial 
oxygen tension gradient;
AND
Successful response to appropriate therapy and no evidence of pneumonias of other 
etiologies.
1013
Pneumocystis carinii, histologically proven, at a site other than lungs.
Toxoplasmosis (in patients > 1 month old)
1021
Toxoplasmosis, clinical diagnosis (of brain only) by the following specifications and 
confirmed HIV infection:
Recent onset of a neurologic disease consistent with toxoplasmosis;
AND
Brain imaging evidence of a mass lesion (on computed tomography, nuclear magnetic 
resonance of radiography enhanced by injection of contrast medium);
AND
Serum antibody to toxoplasmosis and successful response to therapy for toxoplasmosis.
1022
Toxoplasmosis, of brain or internal organs other than liver, spleen or lymph nodes. 
Proven by microscopy.
Isosporiasis
1031
Isosporiasis causing chronic diarrhea of > 1 month. Proven by microscopy.
Cryptosporidiosis
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1041
Cryptosporidiosis causing chronic diarrhea of > 1 month. Proven by microscopy.
II.
FUNGAL INFECTIONS
Candidiasis
2011
Candidiasis, Esophageal, definitive diagnosis by the following specifications:
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
2012
Candidiasis, Esophageal, presumptive diagnosis by the following specifications and 
confirmed HIV infection:
Recent onset of retrosternal pain on swallowing:
AND
Oral candidiasis diagnosed by the gross appearance of white patches or plaques on an 
erythematous base OR by the microscopic appearance of fungal mycelial filaments in an 
uncultured specimen scraped from the oral mucosa;
AND
Response to appropriate therapy.
2013
Candidiasis, Bronchial/Pulmonary, definitive diagnosis by the following specifications; 
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
Cryptococcosis
2022
Cryptococcosis, Extra-pulmonary, proven by microscopy (histology or cytology), culture 
or detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
Histoplasmosis
2031
Histoplasmosis, Disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes), proven by microscopy (histology or cytology), culture or detection of 
antigen in a specimen obtained directly from the tissues affected or a fluid from those 
tissues.
Coccidioidomycosis
2041
Coccidioidoidomycosis, Disseminated (at a site other than or in addition to lungs or 
cervical or hilar lymph nodes), proven by microscopy (histology or cytology), culture or 
detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
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2042
Coccidioidomycosis, clear reactivation of prior infection, proven by microscopy 
(histology or cytology), culture or detection of antigen in a specimen obtained directly 
from the tissues affected or a fluid from those tissues.
III.
BACTERIAL INFECTIONS
Mycobacterium
3001
Mycobacterium (unidentified species). Presumptive diagnosis, by the following 
specifications and confirmed HIV infection.
Acid fast bacilli (AFB) positive stain of specimen obtained from endoscopic biopsy or 
from a normal sterile site other than lungs, skin or cervical or hilar lymph nodes. Species 
NOT identified by culture.
Mycobacterium tuberculosis
3011
Mycobacterium tuberculosis, Pulmonary, definitive diagnosis proven by culture, without 
evidence of upper respiratory infection symptoms of Mycobacterium tuberculosis that 
could account for the positive culture.
3012
Mycobacterium tuberculosis, definitive diagnosis proven by culture, of at least one extra 
pulmonary site regardless of concurrent pulmonary involvement.
3013
Mycobacterium tuberculosis, Disseminated, definitive diagnosis proven by culture.
Mycobacterium avium intracellulare
3022
MAI in Blood, proven by culture.
3023
MAI Colitis, proven by histology and culture. (This does not include MAI of the stool 
alone).
3024
MAI, Disseminated, at a site other than or in addition to lungs or cervical or hilar lymph 
nodes, proven by culture.
Mycobacterium Kansasii, Mycobacterium Scrofulaceum and Other Atypical 
Mycobacterium
3032
M. Kansasii, in Blood, proven by culture.
3033
M. Kansasii Colitis, proven by histology and culture. (NOT including positive M. 
Kansasii of stool alone).
3034
M. Kansasii, Disseminated, at a site other than or in addition to lungs, or cervical or hilar 
lymph nodes, proven by culture.
3035
M. Scrofulaceum or other Atypical Mycobacterium, proven by culture.
Salmonella
3041
Salmonella, recurrent Bacteremia (non-typhoid), proven by culture.
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IV.
VIRAL INFECTIONS
Cytomegalovirus
4011
CMV, Pneumonitis, pathologically or histologically confirmed. Serum antibody titer and 
culture alone is not sufficient for the diagnosis.
4012
CMV, Esophagitis, as diagnosed by histology, pathology or culture of an esophageal 
lesion. Serum antibody titer and culture of other than esophageal tissue is not sufficient 
for the diagnosis.
4013
CMV, Retinitis as evidenced by a characteristic appearance on serial ophthalmoscopic 
examinations (eg, discrete patches of retinal whitening with distinct borders, spreading in 
a centrifugal manner, following blood vessels, progressing over several months, 
frequently associated with retinal vasculitis, hemorrhage, and necrosis). Resolution of 
active disease leaves retinal scarring and atrophy with retinal pigment epithelial mottling.
4014
CMV, Colitis, as diagnosed by histology, pathology or culture of a colonic lesion. Serum 
antibody titer and culture of other than colonic tissue is not sufficient for the diagnosis.
4015
CMV, Encephalitis, as diagnosed by histology, pathology or culture of brain tissue or 
CSF. Serum antibody titer and culture of other than brain tissue or CSF is not sufficient 
for the diagnosis.
Herpes Simplex (in patients > 1 month old).
4021
HSV, Disseminated (but not encephalitis alone), proven by microscopy (histology or 
cytology), culture or detection of antigen in a specimen obtained directly from affected 
tissues.
4022
HSV, Esophagitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4023
HSV, Bronchitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4024
HSV, Pneumonitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for diagnosis.
4025
HSV, GI, other than mouth, throat, or peri-rectal, as diagnosed by microscopy (histology 
or cytology), culture or detection of antigen in a biopsy specimen obtained directly from 
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affected tissue. Serological measurement and culture from other than the affected tissue is 
not sufficient for diagnosis.
4026
HSV, Mucocutaneous, ulcers persisting for 1 month despite appropriate therapy, as 
diagnosed by microscopy (histology or cytology), culture or detection of antigen in a 
biopsy specimen obtained directly from affected tissue. Serological measurement and 
culture from other than the affected tissue is not sufficient for the diagnosis.
Progressive Multifocal Leukoencephalopathy
4041
Progressive Multifocal Leukoencephalopathy, proven by microscopy.
VI.
NEOPLASTIC DISEASES
Kaposi’s Sarcoma
6011
Kaposi’s sarcoma, Mucocutaneous, proven by microscopy.
6012
Kaposi’s sarcoma. Mucocutaneous, presumptive diagnosis with characteristic gross 
appearance and confirmed HIV infection.
6013
Kaposi’s sarcoma, Visceral.
6014
Kaposi’s sarcoma, other than above.
Lymphoma of the Brain
6021
Primary Lymphoma of the brain at any age, proven by microscopy.
Non-Hodgkins Lymphoma
6031
Small Non-cleaved lymphoma (either Burkitt or non-Burkitt type).
6032
Immunoblastic sarcoma, equivalent to any of the following, although not necessarily all 
in combination: Immunoblastic lymphoma, large-cell lymphoma, diffuse histocytic 
lymphoma.
Cervical Carcinoma
6041
Histologically proven invasive carcinoma of the cervix.
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7011
HIV Dementia, clinical findings of disabling cognitive and/or motor dysfunction 
interfering with occupation or activities of daily living progressing over weeks to months, 
in the absence of a concurrent illness or condition other than HIV infection that could 
explain the findings. Method to rule out such concurrent illnesses and conditions must 
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include cerebrospinal fluid examination and either brain imaging (computed tomography 
or magnetic resonance) or autopsy.
Slim Disease or HIV Wasting Syndrome
7021
HIV Wasting Syndrome, findings of profound involuntary weight loss > 10% of baseline 
body weight plus either chronic diarrhea (at least two loose stools per day for 30 days) 
or chronic weakness and documented fever (for 30 days, intermittent to constant) in the 
absence of a concurrent illness or condition other than HIV infection that could explain 
the findings (eg, cancer, tuberculosis, cryptosporidiosis, or other specific enteritis).
7061
Recurrent pneumonia, acute onset within 12 months of most recent episode.
Pediatric patients only:
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7012
Loss of Developmental Milestone, loss of behavioral development milestones affecting a
child.
7013
Progressive Symmetrical Motor Defects.
Slim Disease or HIV Wasting Syndrome
7022
Failure to Thrive.
Lymphoid Interstitial Pneumonitis
7031
Lymphoid 
Interstitial 
Pneumonitis, 
characterized 
by 
diffuse 
interstitial 
and 
peribronchiolar infiltration of lymphocytes and plasma cells and without identifiable 
pathogens to appropriate antimicrobial therapy.
OR
Chronic Pneumonitis, characterized by bilateral reticulonodular intestinal infiltrates with 
or without hilar lymphadenopathy unresponsive to therapy.
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APPENDIX 4
SPECIFIC RECOMMENDATION FOR MANAGEMENT OF 
OTHER TOXICITIES
1
CLINICAL PANCREATITIS
If a subject develops nausea, vomiting, or abdominal pain of any grade associated with any 
elevation of serum fractionated pancreatic amylase or lipase, or develops a clinical syndrome that 
in the opinion of the subject's clinician is classified as pancreatitis, study medications should be 
permanently discontinued. Future consideration should be given to avoiding ddI or other drugs 
potentially affecting the pancreas. Notify BMS medical monitor or designee immediately. 
2
HYPERLIPASEMIA
For elevations of lipase in blood, follow this algorithm:

For Grade 2 hyperlipasemia (> 1.5 ULN), consider holding all study drugs, Notify BMS 
medical monitor or designee immediately, schedule follow-up visits every two weeks if 
necessary until toxicity resolves to Grade 1.

For any Grade 3 hyperlipasemia (> 2.5 ULN), hold all study drugs until both lipase and 
amylase are Grade 1. Notify BMS medical monitor or designee immediately.

For Grade 4 hyperlipasemia (> 5.0 ULN), all study drugs should be held and may be 
permanently discontinued. If study drugs are not permanently discontinued, do not restart 
until both lipase and amylase are Grade 1. Notify BMS medical monitor or designee 
immediately to determine course of action. If hyperlipasemia recurs, discontinue all study 
drugs.
3
HYPERAMYLASEMIA
For Grade 3 or 4 hyperamylasemia, the amylase should be fractionated and the pancreatic 
fraction should then be used for toxicity management. A lipase should also be obtained and the 
following algorithm applies:

If there is an elevation in lipase, hold all study drugs until both amylase and lipase are 
Grade 1. Notify BMS medical monitor or designee immediately. 

Pending the results of the fractionated amylase evaluation if the lipase is normal, study 
medications may be continued. Notify BMS medical monitor or designee.

Once available, fractionated pancreatic amylase elevations should be managed in 
consultation to with the BMS Medical Monitor or designee.
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4
INCREASE IN VALUES FOR THE LIVER FUNCTION TESTS (LFTS):
The following algorithm for management of this toxicity should be observed:

For all Grade 2 LFTs, monitor subject every two weeks until values return to Grade 1. Notify 
BMS medical monitor or designee

In general all Grade 2 LFTs or higher, should be reported to the team every other week.

Elevations in LFTs should be managed as per Section 6.7.1 depending on the toxicity grade.
5
CNS SYMPTOMS
For grading CNS symptoms follow Appendix 2 “Division of AIDS (DAIDS) Toxicity Table for 
Grading Severity of Adult and Pediatric (> 3 months of age) Adverse Experiences [December 
2004; clarification August 2009].” 
For management of CNS toxicities follow Section 6.7.1. Contact the BMS medical monitor or 
designee if you have any doubts on how to proceed after observing specific CNS symptoms.
6
CHOLESTEROL AND TRIGLYCERIDES
Initiation of HAART therapy, with and without PIs and/or NNRTIs has been associated with 
elevations in cholesterol and triglyceride levels. (See Appendix 2 “the Division of AIDS 
(DAIDS) Table for Grading Severity of Adult and Pediatric (> 3 Months of Age) Adverse 
Experiences [December 2004; clarification August 2009]”).
If triglycerides 750mg/dL (Grade 2 or greater), obtain fasting triglycerides, as well as amylase 
and lipase (follow Section 6.7.1 for toxicity management if elevated); if fasting triglycerides < 
749mg/dL, continue study drugs; if fasting triglycerides 750mg/dL (Grade 2), notify BMS 
medical monitor or designee immediately to determine course of action. After a subject has had a 
Grade 2 or Grade 3 triglycerides in non-fasting state, all future triglycerides must be obtained in 
fasting state.
7
HYPERGLYCEMIA/GLYCOSURIA
If non-fasting blood glucose > 200 or urinary dipstick > 2+ positive, obtain fasting blood 
glucose. If the fasting blood glucose is 150mg/dL or greater, notify BMS medical monitor or 
designee immediately. Consult with an endocrinologist regarding possible new onset diabetes, 
and relay this information to the BMS medical monitor or designee.
8
SKIN RASH
Rashes which meet the criteria for Grade 2 or higher AE (using the Division of AIDS (DAIDS) 
Toxicity Table for Grading Severity of Adult and Pediatric (> 3 months of age) Adverse 
Experiences [December 2004; clarification August 2009]), (Appendix 2) must be reported 
immediately to the BMS medical monitor or designee. 
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Study drugs may be continued for Grade 2 (A or B) skin rash following consultation with the 
BMS medical monitor or designee. All study drugs must be permanently discontinued for any 
Grade 3 or 4 rash.
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APPENDIX 5
RECOMMENDATIONS FOR GRADING ACUTE AND SUBACUTE 
TOXIC EFFECTS (WHO)
ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
HEMATOLOGY
HEMATOCRIT
28.5 to < 31.5%
24 to < 28.5%
19.5 to < 24%
< 19.5%
HEMOGLOBIN
9.5 - 11.0 g/dL
8.0 - 9.4 g/dL
6.5 - 7.9 g/dL
< 6.5 g/dL
WHITE BLOOD 
CELLS
2500 to 
< 4000/mm3
1000 to < 
2500/mm3
800 to 
< 1000/mm3
< 800/mm3
ABSOLUTE 
NEUTROPHIL COUNT
1000 to 
< 1500/mm3
750 to < 
1000/mm3
500 to < 
750/mm3
< 500/mm3
PLATELETS
75,000 -
99,000/mm3
50,000 -
74,999/mm3
20,000 -
49,999/mm3
< 20,000/mm3 or 
diffuse petechiae
PT
1.01 - 1.25 X upper 
normal
1.26 - 1.5 X upper 
normal
1.51 - 3.0 X upper 
normal
> 3 X upper normal
PTT
1.01 - 1.66 X upper 
normal
1.67 - 2.33 X upper 
normal
2.34 - 3 X upper 
normal
> 3 X upper normal
FIBRINOGEN
0.99 - 0.75 X lower 
normal
0.74 - 0.50 X lower 
normal 
0.49 - 0.25 X lower 
normal
< 0.25 X lower 
normal
FIBRIN SPLIT 
PRODUCT
20 - 40 g/mL 
41 - 50 g/mL 
51 - 60 g/mL 
> 60 g/mL 
METHEMOGLOBIN
5 - 9.9% 
10.0 - 14.9%
15.0 - 19.9%
20%
CHEMISTRIES 
HYPONATREMIA
130 - 132 meq/L
123 - 129 meq/L
116 - 122 meq/L
115 meq/L and less 
or mental status 
changes or seizures
HYPERNATREMIA
148 - 150 meq/L
151 - 157 meq/L
158 - 165 meq/L
> 165 meq/L OR 
mental status 
changes/seizures
HYPOKALEMIA
3.0 - 3.4 meq/L
2.5 - 2.9 meq/L or 
replacement Rx req
2.0 - 2.4 meq/L or 
intensive 
replacement Rx 
Reg or hosp
< 2.0 meq/L or 
paresis or ileus or 
life - threatening 
arrhythmias
HYPERKALEMIA
5.6 - 6.0 meq/L
6.1 - 6.5 meq/L
6.6 - 7.0 meq/L
> 7.0 OR paresis or 
ileus or 
life - threatening 
arrhythmias
HYPOGLYCEMIA
55 - 64 mg/dL
40 - 54 mg/dL
30 - 39 mg/dL
< 30 mg/dL or 
mental status 
changes or coma
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
HYPERGLYCEMIA
116 - 160 mg/dL
161 - 250 mg/dL
251 - 500 mg/dL
> 500 mg/dL or 
ketoacidosis or 
seizures
HYPERTRIGLYCER –
IDEMIA
250 - 400 mg/dL
401 - 750 mg/dL
751 - 1250 mg/dL
> 1250 mg/dL
HYPERURICEMIA
13 - 18 yrs
> 18 yrs
9.1 - 12.0 mg/dL
9.6 - 9.9 mg/dL
12.1 - 14.0 mg/dL
10.0 - 12.0 mg/dL
14.1 - 17.0 mg/dL
12.1 - 15.0 mg/dL
> 17.0 mg/dL
> 15.0 mg/dL
HYPOCALCEMIA 
corrected for albumin
8.4 - 7.8 mg/dL
7.7 - 7.0 mg/dL
6.9 - 6.1 mg/dL
< 6.1 mg/dL or 
life - threatening 
arrhythmia or 
tetany
HYPERCALCEMIA 
corrected for albumin
10.6 - 11.5 mg/dL
11.6 - 12.5 mg/dL
12.6 - 13.5 mg/dL
> 13.5 mg/dL or 
coma or cardiac 
arrhythmias
HYPOMAGNESEMIA 0.8 - 1.0 meq/L
0.5 - 0.7 meq/L or 
replacement Rx req.
0.3 - 0.4 meq/L or 
intensive Rx req. 
hospitalization
< 0.3 meq/L or 
life - threatening 
arrhythmias
HYPOPHOSPHATEMI
A
2.0 - 2.4 mg/dL
1.5 - 1.9 mg/dL or 
replacement Rx req.
1.0 - 1.4 mg/dL 
intensive Rx req. 
hospitalization
< 1.0 mg/dL 
life - threatening 
arrhythmias or CHF
BUN
1.25 - 2.5 X upper 
normal
2.6 - 5.0 X upper 
normal
5.1 - 10 X upper 
normal
> 10 X upper 
normal
CREATININE
1.1 - 1.5 X upper 
normal
1.6 - 3.0 X upper 
normal
3.1 - 6 X upper 
normal
> 6 X upper normal 
or requires dialysis
HYPOCARBIA
(BICARBONATE)
19 - 21 meq/L
15 - 18 meq/L
10 - 14 meq/L
< 10 meq/L
HYPERCARBIA
(BICARBONATE)
33 - 36 meq/L
37 - 40 meq/L
41 - 45 meq/L
> 45 meq/L
HYPOCHLOREMIA
90 - 93 meq/L
85 - 89 meq/L
80 - 84 meq/L
< 80 meq/L
HYPERCHLOREMIA
113 - 116 meq/L
117 - 120 meq/L 
121 - 125 meq/L
> 125 meq/L
ENZYMES
BILIRUBIN
1.1 - 1.5 x upper 
normal
1.6 - 2.5 X upper 
normal
2.6 - 5 X upper 
normal
> 5 X upper normal
AST/SGOT
1.25 - 2.5 X upper 
normal
2.6 - 5 X upper 
normal
5.1 - 10 X upper 
normal
> 10 X upper 
normal
ALT/SGPT
1.25 - 2.5 X upper 
normal
2.6 - 5 X upper 
normal
5.1 - 10 X upper 
normal
> 10 X upper 
normal
GGT
1.25 - 2.5 X upper 
normal
2.6 - 5 X upper 
normal
5.1 - 10 X upper 
normal
> 10 X upper 
normal
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
ALKALINE 
PHOSPHATASE
1.25 - 2.5 X upper 
normal
2.6 - 5 X upper 
normal
5.1 - 10 X upper 
normal
> 10 X upper 
normal
AMYLASE
1.10 - 1.39 X upper 
normal
1.40 - 2.09 X upper 
normal
2.10 - 5.0 X upper 
normal, mild 
clinical pancreatitis
> 5.0 X upper 
normal or severe 
clinical pancreatitis
LIPASE
1.10 - 1.39 X upper 
normal
1.40 - 2.09 X upper 
normal
2.10 - 5 X upper 
normal or mild 
clinical pancreatitis
5.0 X upper normal 
or severe clinical 
pancreatitis
CPK
2 - 3.0 X upper 
normal
3.1 - 5.0 X upper 
normal,
mild myalgia
5.1 - 10.0 X upper 
normal 
moderate/severe 
myalgia requiring 
non - steroidals
> 10 X upper 
normal severe 
myalgia requiring 
narcotics
LDH
1.10 - 1.39 X upper 
normal
1.40 - 2.09 X upper 
normal
2.1 - 5.0 X upper 
normal
> 5 X upper normal
URINALYSIS
PROTEINURIA
1+ or 1g loss/day 2 - 3 + or> 1 - 2 g 
loss/day
4+ or > 2 - 3.5 g 
loss/day
nephrotic syndrome 
or > 3.5 g loss/day
HEMATURIA
microscopic only, 
10
gross, no clots, 
11 - 100
gross + clots, 101 obstructive or 
requires 
catheterization
CARDIAC
CARDIAC RHYTHM
asymptomatic, 
transient signs, no 
Rx required
recurrent/persistent 
no Rx required
requires treatment
HYPERTENSION
transient inc. 
> 20mm, no Rx
recurrent, chronic 
> 20mm, Rx req.
requires outpt. 
acute Rx
hospitalization
HYPOTENSION
transient orthostatic 
hypotension, No Rx
symptoms 
correctable with 
oral fluid Rx
requires IV fluids 
no hosp. required
requires 
hospitalization
PERICARDITIS
minimal effusion
mild/mod. asymp. 
effusion no Rx
symptomatic 
effusion, pain, EKG 
changes
tamponade; 
pericardio - centesis 
or surgery req.
HEMORRHAGE, 
BLOOD LOSS
microscopic/occult mild, no transfusion gross blood loss, 1 -
2 units transfused
massive blood loss, 
> 3 units transfused
RESPIRATORY
COUGH 
transient - no Rx
local non - narcotic 
Rx
narcotic Rx 
required
uncontrolled
SHORTNESS OF 
BREATH
mild, does not 
interfere with 
routine activities
moderate, interferes 
with routine 
activities req. 
intermittent Rx
moderate, 
debilitating 
requiring nasal 
oxygen
severe, requiring 
ventilatory 
assistance
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
BRONCHOSPASM 
ACUTE
transient, no Rx, 
FEV1, or peak flow 
of > 70% NL
req. Rx, normalize 
w/ broncho -
dilator; FEV1, or 
peak flow 50%
no normalization 
w/bronchodilator, 
FEV1, or peak flow 
25 - 50%; 
retractions
cyanosis; FEV1, or 
peak flow < 25%; 
intubated
GASTROINTESTINAL
STOMATITIS
mild discomfort, no 
limits on activity
some limits on 
eating/talking
eating/talking very 
limited
unable to drink 
fluids; req. IV 
fluids
NAUSEA
mild discomfort, 
maintains 
reasonable intake
mod. discomfort, 
sign. dec of intake, 
some limit of 
activity
severe discomfort; 
no significant food 
intake activities 
limited
minimal fluid 
intake;
VOMITING
transient emesis
occ/moderate 
vomiting
orthostatic 
hypotension or IV 
fluid Rx req.
hypotensive shock 
hospitalization IV 
fluid therapy
CONSTIPATION
mild
moderate; Rx 
required
severe; Rx required; 
vomiting
distention with 
vomiting;
DIARRHEA
transient or 3 - 4 
loose stools/day
5 - 7 loose 
stools/day and/or 
nocturnal loose 
stools. Rx required
orthostatic 
hypotension 
of > 7 loose 
stools/day or req. 
IV fluid Rx
hypotensive shock 
or hospitalization 
for IV fluid therapy
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
NEURO/PSYCHOLOGICAL
LEVEL OF 
CONSCIOUSNESS
Mildly inattentive 
to outside stimuli
Drowsy, but readily 
responds to verbal 
or uncomfortable 
stimuli
Stuporous. Able to 
be aroused by 
vigorous stimuli but 
verbal responses 
are slow or absent; 
able to make some 
effort to avoid 
painful stimuli
Comatose. Cannot 
be aroused by 
vigorous stimuli 
and makes no 
purposeful attempt 
to avoid painful 
stimuli
CONFUSION
Oriented to person, 
place and time, but 
has difficulty 
performing tasks 
requiring logic, 
math or spatial 
organization
Oriented to person 
and place, not time. 
Unable to perform 
complex tasks 
requiring logic, 
math
Oriented to person 
only. Unable to 
focus attention or 
care for bodily 
needs.
Delirious; not 
oriented to person, 
place or time; 
agitated
NEURO CEREBELLAR slight 
incoordination 
Dysdiadochokinesi
as
intention tremor, 
dysmetria, slurred 
speech; nystagmus
locomotor ataxia
incapacitated
MOOD
mild anxiety or 
depression
mod. anxiety or 
depression and 
therapy required
severe anxiety or 
depression or 
manic; (needs 
assistance)
acute psychosis; 
incapacitated 
requires 
hospitalization
NEUROMUSCULAR
MUSCLE STRENGTH subjective 
weakness; no 
objective 
symptoms/signs
mild objective weak 
- ness; no decrease 
in function 
objective weakness; 
function limited
paralysis
PAINFUL 
NEUROPATHY
mild discomfort; no 
therapy required
moderate 
discomfort 
persisting for > 72 
hrs; analgesia 
required
severe discomfort, 
marked antalgic 
gait. Narcotic 
analgesia required, 
with symptomatic 
improvement 
incapacitating, 
intolerable 
discomfort. Not 
improved or unable 
to walk despite 
narcotic analgesics
“PINS & NEEDLES”
mild; does not 
interfere with 
routine activities
moderate; interferes 
with some ADL, 
but responds to 
symptomatic 
therapy
severe; significantly 
impairs ability to 
perform ADL 
despite 
symptomatic 
therapy; interferes 
with patient's sleep
Very severe; 
incapacitates 
patient
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
NUMBNESS
mild decrease in 
sensation reported 
by patient, but 
pinprick and 
vibration exams are 
normal; does not 
interfere with ADL
moderate decrease 
in sensation 
reported by patient; 
reduced pinprick 
and vibratory 
sensation on exam; 
interferes with some 
ADL, but responds 
to symptomatic 
therapy
severely impaired 
sensation with 
inability to perceive 
pinprick or 
vibration; 
significantly 
impairs ability to 
perform ADL 
despite 
symptomatic 
therapy
Total lack of 
sensation on 
examination; 
incapacitates 
patient despite 
symptomatic 
therapy
MYALGIAS
Mild discomfort; 
no Rx required
Moderate 
discomfort 
persisting for > 72 
hrs; analgesia 
required
severe discomfort; 
narcotic analgesia 
required with 
symptomatic 
improvement
severe discomfort 
not relieved by 
narcotic analgesic
NEUROMUSCULAR (continued)
MYOSITIS
minimal findings
Patients must have 
some measures of 
myositis (positive 
EMG or muscle 
biopsy) and one of 
the following:
Patients must have 
some measures of 
myositis (positive 
EMG or muscle 
biopsy) and one of 
the following:
Patients must have 
some measures of 
myositis (positive 
EMG or muscle 
biopsy) and one of 
the following:
1) mild to moderate 
myalgias, > 4 weeks 
requiring 
non - steroidal 
anti - inflammatory 
agents.
1) moderate/severe 
myalgias or muscle 
tenderness 
> 4 weeks requiring 
non - steroidal 
anti - inflammatory 
agents
1) severe muscle 
pain (myalgias) not 
related to exercise, 
requiring narcotics.
2) difficulty 
climbing stairs or 
rising from a sitting 
position but able to 
ambulate without 
assistance
2) requires some 
assistance with 
ambulation or 
general activities
2) muscle weakness 
resulting in 
inability to 
ambulate, requiring 
special care and 
assistance with 
mobilization.
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ITEM
GRADE 1 
TOXICITY
GRADE 2 
TOXICITY
GRADE 3 
TOXICITY
GRADE 4 
TOXICITY
3) acute 
rhabdomyolysis 
with muscle 
necrosis and edema, 
moderate to severe 
muscle weakness 
with inability to
ambulate or 
mobilize self 
without assistance.
4) acute 
rhabdomyolysis 
associated with 
electrolyte 
imbalance or renal 
failure.
OTHER PARAMETERS
FEVER; oral, W/O 
infection, > 12 hrs.
37.7 - 38.5C or 
100.0 - 101.5F
38.6 - 39.5C or 
101.6 - 102.9F
39.6 - 40.5C or 
103 - 105F
> 40.5C
> 105F
HEADACHE
mild, no Rx therapy transient, mod.; Rx 
req/
severe, responds to 
initial narcotic 
therapy
intractable, req. 
repeated narcotic 
therapy
FATIGUE
no dec. in daily 
activities
normal activity dec. 
25 - 49%
normal activity dec. 
50%, can't work
unable to care for 
self
ALLERGIC 
REACTION
pruritus w/o rash
localized urticaria, 
angioedema
generalized 
urticaria 
angioedema
anaphylaxis
LOCAL REACTION
tenderness or 
erythema
induration < 10cm 
or phlebitis or 
inflammation;
induration> 10cm 
or ulceration
necrosis
MUCOCUTANEOUS
erythema, pruritus
diffuse, mac. pap. 
rash dry 
desquamation
vesiculation, moist 
desquam, ulceration
exfoliative 
dermatitis, mucous 
membrane 
involvement 
suspected, Stevens 
Johnson or 
erythema 
multiforme, 
necrosis requiring 
surgery
FOR TOXICITIES NOT LISTED ABOVE, GRADE AS FOLLOWS:
Intensity Grades: 1 =
Mild = does not interfere with routine activity.
2 =
Moderate = interferes with performance of some activities of daily living (ADL), but 
responds to symptomatic therapy or rest.
3 =
Severe = significantly limits ability to perform ADL despite symptomatic therapy.
4 =
Very severe = incapacitates patient despite symptomatic therapy; hospitalization
Revised Protocol No.: 05
Date: 15-Apr-2014
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Official Title of Study:  A PROSPECTIVE SINGLE ARM OPEN-LABEL, INTERNATIONAL, 
MULTICENTER STUDY TO EVALUATE THE SAFETY, EFFICACY AND 
PHARMACOKINETICS OF ATAZANAVIR (ATV) POWDER BOOSTED 
WITH RITONAVIR (RTV) WITH AN OPTIMIZED NRTI BACKGROUND 
THERAPY, IN HIV INFECTED, ANTIRETROVIRAL, NAIVE AND 
EXPERIENCED PEDIATRIC SUBJECTS FROM 3 MONTHS TO LESS 
THAN 11 YEARS. (PEDIATRIC ATAZANAVIR INTERNATIONAL 
CLINICAL EVALUATION: THE PRINCE II STUDY) 
 
NCT Number:  NCT01335698 
 
Document Date:  November 2, 2017 


STATISTICAL ANALYSIS PLAN
A PROSPECTIVE SINGLE ARM OPEN-LABEL, INTERNATIONAL, 
MULTICENTER STUDY TO EVALUATE THE SAFETY, EFFICACY AND 
PHARMACOKINETICS OF ATAZANAVIR (ATV) POWDER BOOSTED 
WITH RITONAVIR (RTV) WITH AN OPTIMIZED NRTI BACKGROUND 
THERAPY, IN HIV INFECTED, ANTIRETROVIRAL, NAIVE AND 
EXPERIENCED PEDIATRIC SUBJECTS FROM 3 MONTHS TO LESS 
THAN 11 YEARS. (PEDIATRIC ATAZANAVIR INTERNATIONAL 
CLINICAL EVALUATION: THE PRINCE II STUDY)
PROTOCOL AI424451
VERSION 2.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN................................................................................................1
TABLE OF CONTENTS.................................................................................................................2
1
BACKGROUND AND RATIONALE.........................................................................5
2
STUDY DESCRIPTION..............................................................................................6
2.1
Study Design.................................................................................................................6
2.2
Treatment Assignment..................................................................................................8
2.3
Blinding and Unblinding ..............................................................................................9
2.4
Protocol Amendments ..................................................................................................9
3
OBJECTIVES.............................................................................................................10
3.1
Primary .......................................................................................................................10
3.2
Secondary ...................................................................................................................11
3.3
Exploratory .................................................................................................................11
4
ENDPOINTS ..............................................................................................................11
4.1
Primary Endpoint........................................................................................................11
4.2
Secondary Endpoints ..................................................................................................11
5
SAMPLE SIZE AND POWER ..................................................................................11
6
STUDY PERIODS, TREATMENT REGIMEN AND POPULATIONS FOR 
ANALYSES ...............................................................................................................12
6.1
Study Periods..............................................................................................................12
6.1.1
Pre-Treatment Period.................................................................................................12
6.1.2
On-Treatment Period..................................................................................................12
6.1.3
Off-Treatment Follow-up Period................................................................................13
6.2
Treatment Regimen ....................................................................................................13
6.3
Populations for Analyses ............................................................................................13
7
STATISTICAL ANALYSES.....................................................................................13
7.1
General Methods.........................................................................................................13
7.2
Study Conduct ............................................................................................................14
7.3
Study Population.........................................................................................................15
7.3.1
Disposition of Subjects ...............................................................................................15
7.3.1.1
Pre-Treatment Subject Status and Accrual.................................................................15
7.3.1.2
End of Stage 1 Treatment Subject Status....................................................................15
7.3.1.3
End of Stage 2 Treatment Subject Status....................................................................15
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7.3.1.4
End of Study Subject Status ........................................................................................15
7.3.2
Demographic and Other Baseline Characteristics.....................................................15
7.3.2.1
Demographics.............................................................................................................16
7.3.2.2
Baseline Disease Characteristics ...............................................................................16
7.3.2.3
Other Baseline Characteristics...................................................................................16
7.4
Extent of Exposure .....................................................................................................17
7.4.1
Study Therapy.............................................................................................................17
7.4.2
Discontinuation of Study Therapy ..............................................................................17
7.4.3
Interruption or Delay of Study Therapy .....................................................................17
7.4.4
Measures of Treatment Compliance...........................................................................17
7.4.5
Concomitant Therapy .................................................................................................17
7.5
Efficacy.......................................................................................................................17
7.5.1
HIV RNA < 50 c/mL and < 400 c/mL Over Time.......................................................18
7.5.2
HIV RNA Changes from Baseline...............................................................................19
7.5.3
CD4 Changes from Baseline ......................................................................................19
7.5.4
Resistance Profiles......................................................................................................19
7.6
Safety..........................................................................................................................20
7.6.1
Deaths.........................................................................................................................21
7.6.2
Other Serious Adverse Events ....................................................................................21
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy ..................................22
7.6.4
Other Significant Adverse Events ...............................................................................22
7.6.4.1
Renal Toxicity.............................................................................................................22
7.6.4.2
Cardiac Disorders ......................................................................................................22
7.6.4.3
Rash ............................................................................................................................23
7.6.4.4
CDC Class C AIDS Events .........................................................................................23
7.6.4.5
Lipodystrophy-Related Adverse Events......................................................................23
7.6.4.6
Lactic Acidosis Syndrome (LAS) or Symptomatic Hyperlactatemia (SHL)................23
7.6.4.7
Hyperbilirubinemia-Related Adverse Events .............................................................24
7.6.4.8
Cholelithiasis..............................................................................................................24
7.6.4.9
Nephrolithiasis............................................................................................................24
7.6.5
Overall Adverse Events...............................................................................................24
7.6.6
Clinical Laboratory Evaluations................................................................................25
7.6.6.1
Laboratory Abnormalities by Toxicity Grade.............................................................25
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7.6.6.2
Drug Induced Liver Injury (DILI) ..............................................................................25
7.6.7
Electrocardiograms ....................................................................................................25
7.6.7.1
ECG over Time ...........................................................................................................25
7.6.8
Physical Measurements ..............................................................................................26
7.7
Pharmacokinetics........................................................................................................26
7.7.1
PK Parameters in Stage 1...........................................................................................27
7.7.2
Trough Concentrations in Stage 1..............................................................................27
7.8
Pharmacodynamics.....................................................................................................28
7.9
Taste Assessment........................................................................................................28
8
CONVENTIONS........................................................................................................29
8.1
Windows for Analysis Weeks and Visit Weeks.........................................................29
8.2
Domain Derivations....................................................................................................31
8.2.1
Exposure .....................................................................................................................31
8.2.1.1
Study Therapy.............................................................................................................31
8.2.1.2
Interruption or Delay of Study Therapy .....................................................................32
8.2.2
Laboratory Tests.........................................................................................................32
8.2.3
Physical Measurements ..............................................................................................32
8.2.4
Viral Genotyping and Phenotyping ............................................................................32
8.2.5
Virology ......................................................................................................................33
8.2.6
Adverse Events............................................................................................................33
9
CONTENT OF REPORTS.........................................................................................34
9.1
Planned Analyses........................................................................................................34
9.2
Listings .......................................................................................................................34
10
REFERENCES ...........................................................................................................36
APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS...............................................37
APPENDIX 2
SNAPSHOT ALGORITHM......................................................................38
APPENDIX 3
GENOTYPIC AND PHENOTYPIC RESISTANCE................................40
DOCUMENT HISTORY...............................................................................................................44
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
 
 
 
 
 
 
Research Hypothesis:  
Regimens consisting of ATV powder boosted with RTV with an optimized dual-NRTI backbone 
are safe and well tolerated in pediatric subjects 3 months to < 11 years who are ≥ 5 kg to < 35 
kg.
Schedule of Analyses:
The primary analysis will be conducted when Week 24 data of all treated subjects are available
(in Stage 1) to confirm the safety of ATV powder with RTV in pediatric patients. The final 
analysis will be conducted after the last subject in Stage 2 completes the study. Other analyses 
may be conducted if needed for submission to health authorities and at the request of the DMC.
2
STUDY DESCRIPTION
2.1
Study Design
This study is a Phase 3b prospective, international, multicenter, non-randomized study of a 
cohort of HIV infected pediatric subjects 3 months to < 11 years of age and weight 5 kg to < 
35 kg, treated with ATV powder and RTV optimized regimens. 
The study consists of two stages: 
Stage1 
Subjects must be 3 months to < 11 years of age at the time of first treatment. In-clinic study 
visits in Stage 1 will be at Day 1, Week 2, Week 4, then every 4 weeks through Week 16, then 
every 8 weeks through a minimum of 24 weeks or a maximum of 48 weeks.
Dosing of ATV in Stage 1 is performed only with the powder formulation, dosed according to 
weight, as outlined in Protocol Table 3.1.1-1. When dosing with ATV powder, RTV oral 
solution is dosed at 80 mg for body weight less than 25 kg, and RTV oral solution or RTV 
capsules or tablets 100 mg for body weight 25 kg to less than 35 kg. 
Subjects who reach the weight of 35 kg during Stage 1 must immediately enter Stage 2 and be 
switched to the capsule formulation of ATV and the corresponding capsule/tablet formulation of 
RTV. 
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Subjects who do not reach the weight of 35 kg during Stage 1 continue on the powder 
formulation of ATV through the end of the 48-week period of Stage 1 and then move into Stage 
2 while remaining on the powder formulation.
Subjects who did not have the opportunity to reach Week 48 during Stage 1 by the time the last 
treated subjects reaches Week 24 will have a final Stage 1 status assessment performed and will 
immediately move in Stage 2 while remaining on ATV powder. These subjects will follow the 
assessment and in-clinic study visits specified in Stage 2.
Stage 2
In-clinic study visits in Stage 2 will be conducted every 12 weeks through the end of study 
participation. 
Dosing of ATV in Stage 2 may include subjects taking ATV powder and subjects taking ATV 
capsules, dosed according to weight, as outlined in Protocol Tables 3.1.1-1 and 3.1.1-2, 
respectively. When dosing with ATV powder, RTV oral solution is dosed at 80 mg for body 
weight less than 25 kg and is dosed at 100 mg RTV oral solution or tablets/capsules for body 
weight 25 kg to less than 35 kg; when dosing with ATV capsules, RTV (capsules/tablets) is 
dosed at 100 mg. 
10% aspartame ATV powder to 4.2% aspartame ATV powder transition:
Subjects who remain on ATV powder formulation in Stage 2 must be switched to the new 4.2% 
aspartame ATV oral powder formulation at their next regular visit provided that IRB/IEC 
approval of the amended protocol has been received. Dose recommendation of new 4.2% 
aspartame ATV powder is the same as for the 10% aspartame ATV powder and will be 
determined by weight.
Subjects who reach the age of 12 years or weight of 35kg during Stage 2 must be switched 
from the powder formulation of ATV to the capsule formulation of ATV. 
Powder-to-Capsule Transition: 
Subjects who are transitioning from powder to capsule, either at entry to Stage 2 or at any point 
during Stage 2, will be required to return to the clinic for two subsequent powder-to-capsule 
transition visits 4 weeks and 8 weeks after the switch is initiated. 

Dose of the ATV capsule will be determined by weight, according to Protocol Table 3.1.1-2; 
RTV is dosed at 100 mg (capsules or tablets) when dosing with the ATV capsule; 

Subjects who are unable to swallow the capsule by the end of the 8-week transition period 
will be required to be discontinued from the study; 

Subjects who complete a successful transition to capsules will continue in Stage 2 and will be 
dosed according to the recommendations provided in Protocol Table 3.1.1-2.
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
Subjects are required to switch to capsule in Stage 2 when they reach 35 kg or 12 years of 
age. However, subjects who reach a weight of 25 kg or 6 years of age during Stage 2 may, at 
the discretion of the investigator and caregiver, choose to attempt switch to the solid dosage 
forms of ATV/RTV.
Stage 2 participation ends when: 

a subject reaches the age of 18 years, or

a subject’s country has an approved and available pediatric indication whose requirements 
are met by the subject; the subject will then transition off of the study and will be dosed 
according to those local guidelines. 
If an approved pediatric indication for ATV capsule becomes available for a subject who is 
dosing with the powder formulation, the powder-to-capsule transition will occur within the study 
within an 8-week timeframe as described above. After the 8-week transition period, the subject 
will be discontinued from the study, regardless of tolerability of the capsule.
2.2
Treatment Assignment
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System (IVRS) designated by the Sponsor to enroll the subject and 
to obtain a subject/patient identification number (PID), which must be recorded on the Case 
Report Form (CRF). This unique subject number must be used on all further documentation and 
correspondence referring to this particular subject.
A minimum of 56 treated subjects on ATV powder with at least 24 weeks of follow-up are 
needed with a minimum number of subjects with at least 24 weeks of follow-up from the
following weight bands: 

Minimum 5 subjects (on 150 mg ATV powder and 80 mg RTV) between 5 - < 10 kg,

Minimum 6 subjects (on 200 mg ATV powder and 80 mg RTV) between 5 - < 10 kg,

Minimum 10 subjects between 10 - < 15 kg,

Minimum 10 subjects between 15 - < 25 kg,
In the event that the minimum number of subjects in any one weight band has been met while the 
other weight bands remain substantially under-enrolled, further enrollment in the fully enrolled 
weight band may be temporarily put on hold. Enrollment will continue for the under-enrolled 
groups until the minimum number of treated subjects has been achieved (except for 25 - < 35kg 
weight band). After this point, enrollment will continue for all weight bands until at least a total 
of 95 subjects started treatment in order to have a minimum number of 56 treated subjects with a 
minimum 24 weeks follow-up. In the event that the minimum number of subjects (overall and/or 
per weight band) with a minimum 24 weeks follow-up is projected not to be met due to higher 
than projected early discontinuation rate, then enrollment target will be re-adjusted during 
enrollment period or enrollment re-opened during the study to replace these subjects.
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Subjects in a lower weight band who transition to the 25 - < 35 kg weight band during Stage 1 
will have a Week 2 Intensive PK assessment completed.
A total of 30 ARV experienced subjects treated with ATV powder for minimum 24 weeks will 
be enrolled in this study, which will be tracked through the IVRS. Treatment experienced 
subjects are defined by a previous exposure to antiretroviral drugs (ARVs) through either prior 
treatment for their HIV disease or through a post natal treatment with ≥ 1 ARVs for prevention 
of MTCT. In the event that the minimum number of ARV experienced subjects remains 
substantially under-enrolled, then further enrollment of ARV-naive subjects may be temporarily 
put on hold until the target of 30 ARV experienced is met. After this point, enrollment will 
continue for both ARV naive and experienced subjects. and) and treated with ATV powder for 
minimum 24 weeks.
2.3
Blinding and Unblinding
Not applicable (This study is open label).
2.4
Protocol Amendments
This section describes protocol amendments that affect statistical analyses.
Amendment 2 allowed use of both brand and generic locally approved and available NRTIs by 
removing statements not intended to have been in protocol section 6.7.1.
Amendment 4 included the following changes:

Allowed that also the Ritonavir Trough plasma concentration at each scheduled visit from 
Week 4 through Week 48 will be evaluated from the sample tube collected for the ATV 
Trough plasma concentration assessment as ATV/RTV can be assessed simultaneously.

Clarified objective and aligned with the primary objective measurements used in the 
AI424397 sister study. The frequency of AEs and lab abnormalities will be summarized but 
is not part of the primary study objective analysis

 
 
 

Updated Section 8.0 to be aligned with the Statistical Analysis Plan.
Amendment 5 included the following changes:

To change the whole treatment regimen, including ATV, in patients with confirmed virologic 
failure or virologic rebound above 1000 copies/mL based on the resistance profile at failure 
in accordance with the recommendations from guidelines as per FDA comments on sister 
study AI424397 amendment 05.

To modify the definition of virologic failure in accordance with the updated 2011 DHHS 
pediatric guidelines and clarified the virologic failure criteria to discontinue a subject in the 
study.
Amendment 7 included the following changes:
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
To increase the inclusion upper age limit to < 11 years of age and updated title, research 
hypothesis and objectives accordingly.

Added palatability/taste as exploratory objective.

Following the AI424-397 intensive PK analysis, added new 5 - < 10kg cohort with higher 
ATV dose (200 mg ATV and 80 mg RTV)

Increased the sample size from 75 to 95 subjects in order to complete new cohort and have a 
minimum of 56 subjects with 48 weeks of follow-up on ATV powder overall and minimum 
number of subjects required per weight band.

To switch all subjects in stage 2, who are still on the current atazanavir oral powder 
formulation (10% aspartame), to the new 4.2% aspartame atazanavir oral powder formulation 
and to collect palatability/acceptability data at the time of switch and after the switch.

Clarified that subjects with a confirmed HIV RNA of ≥1000 copies/mL (after Week 24) 
should be discontinued.

Added that subject diaries should be used for subjects switching to the new 4.2% aspartame 
ATV powder formulation in stage 2 and as long as the subject is on the new ATV powder or 
maximum duration of one year, whichever comes first.

Added Adherence/Tolerability assessment procedures and note that the assessments only 
apply to subjects remaining on ATV powder in Stage 2 in Time and Event Table and 
described the palatability assessment and analyses.

To allow use of RTV capsules or Tablets for subjects enrolled in the 25 - < 35 kg weight 
band.

Added new assay (Abbott RealTime HIV-1 RNA) to be used when Roche Amplicor HIV 
RNA is discontinued.

Updated the list of intensive PK steady state parameters in PK analyses.

Removed upper age criterion as milestone from maximum study duration in stage 1 and 
changed the maximum age for powder to capsule transition from 8 to 12 years old.
Amendment 8 included the following changes:

To remove the minimum number of 6 subjects required for the 25 - < 35kg weight band with 
48 weeks of ATV powder.

To modify primary endpoint study duration from 48 weeks to a minimum of 24 weeks and to 
modify key secondary objectives by adding Week 24 efficacy endpoint.

To increase the blood volume collection from 1 up to 2 mL for HIV RNA testing when 
switching to the new Abbott RealTime HIV-1 assay after the Roche Amplicor assay is 
discontinued.
3
OBJECTIVES
3.1
Primary
To describe the safety of ATV powder formulation boosted with RTV based HAART regimens 
in pediatric subjects dosed through a minimum 24 weeks, as measured by the frequency of 
deaths, serious adverse events and discontinuation due to AEs.
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3.2
Secondary

To describe efficacy as measured by proportion of subjects with a virologic response as 
defined by HIV RNA levels < 50 copies/mL and < 400 copies/mL by Roche Amplicor
HIV-1 RNA Assay (version 1.5), or Abbott RealTime HIV-1 assay after the Roche Amplicor 
assay is discontinued, at Week 24 and Week 48 of ATV powder formulation.

To describe the pharmacokinetic profile of ATV powder formulation with RTV in pediatric 
subjects weighing 25 - < 35 kg and/or 6 - < 11 years of age and for new 5 - <10 kg cohort 
(200mg ATV and 80 mg RTV) in terms of ATV Cmax, Cmin and AUC.
 
 
 
 
 
4
ENDPOINTS
4.1
Primary Endpoint

Safety, as measured by the frequencies of deaths, SAEs through Week 48 on ATV powder, 
and discontinuations due to AEs through Week 48 on ATV powder.
All safety data up through Week 48 on ATV powder regardless of stage will be included in the 
safety analysis. 
4.2
Secondary Endpoints

Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL at Week 24 and  Week 48
of ATV powder formulation;

Summary statistics for PK parameters (Cmax, Cmin and AUC) of ATV powder.
5
SAMPLE SIZE AND POWER
Sample size is not based on power calculations. A total of Approximately 95 subjects are 
planned for this study in order to treat approximately 10-15 subjects in the new 5 - < 10 kg 
(200mg ATV and 80 mg RTV) cohort and have a minimum number of 56 treated subjects with 
minimum 24 weeks follow-up on ATV powder based on an expected drop-out rate of 
approximately 30%. This study plans to enroll approximately 160 subjects, which will result in 
approximately 95 treated subjects due to an expected screen failure rate of 40%.
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A target sample size of 95 treated subjects can detect with 80% probability, a safety event that 
occurs at a per subject incident rate of 1.7%.
A target sample size of 95 treated subjects can produce an exact binomial 95% confidence 
interval (CI) within ± 10.5% for a response rate of 50.5% for the modified intent-to-treat (ITT) 
analysis.
6
STUDY PERIODS, TREATMENT REGIMEN AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Pre-Treatment Period
The pre-treatment period begins at the first visit until initiation of active study therapy (ie, ATV).
Measurements taken before Day 1 (ie, the first dose of active study therapy) are considered pre-
treatment for all data domains. In addition, measurements taken on Day 1 are considered pre-
treatment for the following data domains: demography, disease history, ECG, laboratory test 
results, medical history, physical examination, physical measurements, subject status, viral 
genotyping, viral phenotyping, virology and vital signs.
6.1.2
On-Treatment Period
The on-treatment period begins after Day 1 and ends on the last dose of study therapy. In 
addition, measurements taken on Day 1 are considered on-treatment for the following data 
domains: AEs, drug dispensation, exposure, inclusion/exclusion, non-study medications, sample 
collection, sample inform consent and sample reference.
For Stage 1, the on-treatment period ends on the visit date entered on the end of Stage 1 
treatment subject status CRF. For Stage 2, the Stage 2 on-treatment period begins on the visit 
date plus 1 day.
Analyses of the following select endpoints extend the on-treatment period to include 
measurements through a specified number of days after the last dose of study therapy: 

Efficacy (HIV RNA and CD4; Sections 7.5.1 through 7.5.3): 4 days after the last dose of 
study therapy. The 4-day cut-off reflects the point at which minimal antiviral activity related 
to ATV is present. It is also expected that minimal drug exposure and undetectable drug
levels will be present beyond 4 days post-dose.

Resistance (viral genotyping and phenotyping; Section 7.5.4): 10 days after the last dose of 
study therapy. The 10-day cut-off reflects the point at which the virus reverts rapidly to wild 
type and resistant variants become minor variants that cannot be detected reliably.

Safety (AEs, ECGs, vital signs and laboratory tests; Section 7.6): 30 days after the last dose 
of study therapy to account for safety reporting per protocol.
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6.1.3
Off-Treatment Follow-up Period
The off-treatment follow-up period begins after the last dose of study therapy and ends at the last 
follow-up visit. 
Measurements taken after the last dose of study therapy are considered follow-up.
6.2
Treatment Regimen
The treatment regimen is ATV powder with RTV liquid (or RTV capsules/tablets for 25 - < 35 
kg weight band only) for subjects enrolled in this study. The dose will be determined by the 
subject’s weight on the date of first dose (Day 1). Refer to Protocol Section 3.1 for the dosing 
guidelines. Subjects must be dose adjusted once they exceed the upper limit of their current 
weight band. Subjects reaching their 12th birthday or reaching a weight ≥35 kg should be 
transitioned to the capsule formulation of ATV.
6.3
Populations for Analyses
Populations consist of enrolled and treated subjects grouped according to baseline weight band:

Enrolled subjects are those who signed an informed consent form and were assigned a Patient 
Identification number (PID). This cohort is used to assess subject status and deaths.

Treated subjects are enrolled subjects who received at least 1 dose of active study therapy
(ATV). This cohort is used to assess all data domains.

Week 24 ATV Powder Cohort consists of treated subjects who did not switch to ATV 
capsule before analysis Week 24 or before their HIV RNA Week 24 assessment (see Section 
8.1). This cohort is used to assess efficacy of ATV powder through Week 24.

Eligible Week 48 ATV Powder Cohort: Subjects who initiated study therapy at least 48 
weeks prior to LPLV date and did not switch to ATV capsule before analysis Week 48 or 
before their HIV RNA Week 48 assessment.  This cohort is used to assess efficacy of ATV 
powder through Week 48.
7
STATISTICAL ANALYSES
Statistical analyses are performed using the version of UNIX SAS or S-Plus in production at 
BMS, unless specified otherwise.
Summaries are presented by baseline weight band (and ATV initial dose for 5 - < 10 kg) (5 - <
10 kg (ATV 150mg), 5- < 10 kg (ATV 200mg), 10 - < 15 kg, 15 - < 25 kg, 25 - < 35 kg) and 
total for treated subjects, unless specified otherwise.
7.1
General Methods
Categorical variables are summarized with counts and percents or with proportions (number with 
event divided by number evaluable) and percents, depending on the endpoint. 
Continuous variables are summarized with univariate statistics (eg, n, mean, median, minimum, 
maximum, quartiles, standard deviation [SD]). Changes from baseline in continuous variables 
are summarized with univariate statistics (eg, n, mean, standard error [SE], median, interquartile 
range [IQR]).
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Longitudinal summaries of efficacy and safety parameters use pre-defined visit week windows
(see Section 8.1). In addition, analyses of HIV RNA use pre-defined analysis week windows (see 
Section 8.1).
Subjects must have a baseline measurement and at least 1 on-study measurement (ie, after the 
first dose of study therapy) to be evaluable for change from baseline analyses for observed 
values. In addition, subjects must have a baseline measurement to be evaluable for longitudinal 
summaries of parameter values and changes from baseline based on observed values. 
Summaries of relevant protocol deviations, non-study medications, AEs (except multiple AEs in 
Section 8.2.6), and laboratory abnormalities present incidence rates, i.e., numbers of subjects 
with unique events. Thus, multiple occurrences of the same event are counted only once per 
subject.
By-subject listings sorted by baseline weight band and PID are provided for select endpoints (see 
Section 9.2). Listings display all events regardless of study period unless specified otherwise, 
and identify ATV formulation (powder or capsule).
For non-study medications, imputed start and end dates are used only for classification of 
medications into study periods for summary reporting purposes (ie, prior, concomitant, and post-
treatment). The actual dates entered on the CRF are reported in by-subject listings. 
For AEs, imputed onset dates are used only for classification of AEs into study periods for 
summary reporting purposes (ie, pre-treatment, on treatment and follow-up) and to calculate 
duration of events. The actual dates entered on the CRF are reported in by-subject listings.
Subjects who move to another investigative site during the study are classified according to 
original investigative site, country and region.
Formats of tables, listings and graphs are described in the AI424451 Data Presentation Plan.
7.2
Study Conduct
Relevant protocol deviations are summarized. Relevant protocol deviations are those that could 
potentially affect the interpretability of the study results, which is related, but not limited to: 

Some inclusion or exclusion criteria

Subject management, such as:

Incorrect dosing or study treatment assignment;

Use of prohibited concomitant medications;

Subjects not withdrawn from treatment or study despite having met specified criteria for 
withdrawal.
A subject is considered to have a deviation of an inclusion or exclusion criterion only if all pre-
treatment measurements fail the criterion. Appendix 1 describes the relevant protocol deviations 
that can be programmed from the database.
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7.3
Study Population
7.3.1
Disposition of Subjects 
7.3.1.1
Pre-Treatment Subject Status and Accrual 
Pre-treatment subject status is summarized. This presents the number of subjects enrolled, treated 
and not treated. Reasons for not treated are also included (eg, AE, death, lost to follow-up).
Enrollment at each investigative site by country is summarized for enrolled subjects and treated 
subjects pooled across baseline weight band.
7.3.1.2
End of Stage 1 Treatment Subject Status 
End of Stage 1 treatment subject status is summarized. This presents the number of subjects 
treated, completed the Stage 1 treatment period, not completed the Stage 1 treatment period, 
continuing in the study, and not continuing in the study. Reasons for not completing the Stage 1
treatment period are also included (eg, lack of efficacy, AE, death, lost to follow-up). For 
subjects continuing in the study, the next phase entered is also shown (ie, Stage 2 transition to 
capsule; Stage 2; safety follow-up).
See Section 7.4.2 for indentifying subjects who discontinued ATV powder. 
7.3.1.3
End of Stage 2 Treatment Subject Status 
End of Stage 2 treatment subject status is summarized for treated subjects who entered Stage 2. 
This presents the number of subjects who entered Stage 2, completed the Stage 2 treatment 
period, not completed the Stage treatment period, continuing in the study to safety follow-up, 
and not continuing in the study. Reasons for not completing the Stage 2 treatment period are also 
included (eg, lack of efficacy, AE, death, lost to follow-up).
7.3.1.4
End of Study Subject Status 
End of study subject status is summarized for treated subjects who entered safety follow-up. This 
presents the number of subjects who entered safety follow-up, completed the study, and not 
completed the study. Reasons for not completing the study are also included (ie, subject 
withdrew consent, death, lost to follow-up, other). Percentages are based on subjects with end of 
study subject status CRFs.
7.3.2
Demographic and Other Baseline Characteristics 
Summaries identify the number and percent of subjects with missing measurements as ‘NOT 
REPORTED’. 
Baseline is the last value measured pre-treatment (see Section 6.1.1).
Demographics and baseline disease characteristics are also summarized by prior ARV use (ARV 
naive, ARV experienced).
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7.3.2.1
Demographics 
The following demographics are summarized: age at consent (months), age at first dose of study 
therapy (months), gender, race, ethnicity (Hispanic/Latino, not Hispanic/Latino), geographic 
region and country.
7.3.2.2
Baseline Disease Characteristics 
The following baseline HIV disease characteristics are summarized: 

HIV RNA (log10 c/mL), HIV RNA categories (< 30,000, 30,000 - 100,000, > 100,000 
c/mL);

CD4 (cells/mm3), CD4 categories (< 50, 50 - < 200, 200 - < 350, 350 - < 500, 500 - <
750, 750 - < 1000, 1000 - < 1500, 1500 - < 2000 and 2000 cells/mm3);

CD4 percent (%) and CD4 percent categories (< 15, 15 - < 25, 25). 

Prior ARV use (ARV naive, ARV experienced).
7.3.2.3
Other Baseline Characteristics 
Laboratory Tests at Baseline
Laboratory tests at baseline are summarized by toxicity grade (normal; grade 1, 2, 3, 4; see 
Section 7.6.6.1).
ECG at Baseline
See Section 7.6.7.
Physical Measurements at Baseline
Physical measurements are summarized: height (cm), weight (kg), body mass index (BMI; 
kg/m2), body surface area (BSA; m2), head circumference (cm). See also Section 7.6.8.
Vital Signs at Baseline
Vital signs are summarized: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
heart rate (bpm).
Pre-Treatment Events
All grades pre-treatment events are summarized within system organ class.
Pre-Treatment CDC Class C AIDS Events
Pre-treatment acquired immunodeficiency syndrome (AIDS) events are
summarized. 
Documented clinical diagnoses are used to define AIDS (see Protocol Appendix 3). 
Prior Treatments
Prior medications are summarized. Prior medications are those taken before the first dose of 
study therapy. Medications are presented alphabetically by anatomic class, therapeutic class and 
generic name using the World Health Organization (WHO) dictionary.
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7.4
Extent of Exposure
Extent of exposure is presented for treated subjects. 
7.4.1
Study Therapy
Time on therapy is summarized for each study drug formulation (ATV powder, ATV capsule, 
RTV oral solution, RTV capsule, lamivudine oral solution, zidovudine tablets, etc.). Time on 
therapy is defined as the number of days between the first dose date and last dose date of the 
drug formulation. 
Average daily dose is summarized for each study drug formulation. Average daily dose is the 
total amount of drug formulation in dose units divided by time on therapy. 
7.4.2
Discontinuation of Study Therapy 
Time on ATV powder is described by a Kaplan-Meier curve and life table. Discontinuations of 
ATV powder are considered events in this analysis, and are identified by subjects with (a) non-
missing first dose date of ATV capsule, or (b) missing first dose date of ATV capsule and non-
missing last dose date of study therapy. For subjects who have not discontinued ATV powder, 
time on ATV powder is censored at the last dose date of ATV powder.
See Section 8.2.1.1 for additional conventions.
7.4.3
Interruption or Delay of Study Therapy 
Interruptions of ATV and RTV (ATV powder, ATV capsule, RTV oral solution, RTV capsule) 
greater than 3 consecutive days are summarized. Reasons for interruption are also identified (ie, 
AE, dosing error, other).
See Section 8.2.1.2 for additional conventions.
7.4.4
Measures of Treatment Compliance
See Section 7.9 for the palatability survey and Appendix 1 for relevant protocol deviations that 
address treatment compliance.
 
 
 
 
 
 
7.5
Efficacy
All efficacy endpoints are secondary and focus on the ATV powder formulation using the 
extended on-treatment period (see Section 6.1.2). Values after the first dose date of ATV capsule 
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are excluded. HIV RNA viral loads are based on results by Roche AmplicorHIV-1 RNA Assay 
(version 1.5), or Abbott RealTime HIV-1 assay after the Roche Amplicor assay is discontinued.
Longitudinal summaries are presented through Week 48 on ATV powder for the primary
analysis and through stages combined for the final analysis.
Efficacy endpoints are also summarized by prior ARV use (ARV naive, ARV experienced).
7.5.1
HIV RNA < 50 c/mL and < 400 c/mL Over Time
Secondary endpoints are the proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL 
at each scheduled analysis week on ATV powder over time. Response rates are presented with 
exact binomial 95% CIs.1
Response rates are assessed using following approaches with the snapshot algorithm, which uses 
the last HIV RNA in the pre-defined analysis week window to determine response:
Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL through Week 24 (Week 24 
ATV Powder Cohort):

Modified intent-to-treat (ITT): The numerator is based on subjects meeting the response 
criteria, ie, on-treatment HIV RNA < 50 (< 400) c/mL at the analysis week through Week 24. 
The denominator is based on all treated subjects in the Week 24 ATV Powder Cohort.
Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL through Week 48 (Eligible 
Week 48 ATV Powder Cohort):

Modified intent-to-treat (ITT): The numerator is based on subjects meeting the response 
criteria, ie, on-treatment HIV RNA < 50 (< 400) c/mL at the analysis week through Week 48. 
The denominator is based on all treated subjects in the Eligible Week 48 ATV Powder
Cohort.
Proportions of subjects with HIV RNA < 50 c/mL and < 400 c/mL through Week 48 (Treated 
Subjects):

Observed values: Similar to modified ITT, the numerator is based on subjects meeting the 
response criteria. However, the denominator is based on treated subjects with on-treatment 
HIV RNA at the analysis week.
Response rates and CIs are presented at baseline and each analysis week over time on ATV 
powder as follows:

Through Week 24 for the Week 24 ATV Powder Cohort using modified ITT and observed 
values;

Through Week 48 for the Eligible Week 48 ATV Powder Cohort using modified ITT and 
observed values;Through Week 48 for treated subjects using observed values.

Through stages combined for treated subjects using observed values.
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Longitudinal plots displays response rates using modified ITT versus analysis week through 
Week 48 by baseline weight band with error bars representing CIs of the reported statistic for the
Week 48 ATV powder cohort.
Outcomes
Outcomes for HIV RNA < 50 c/mL and < 400 c/mL are summarized using the snapshot 
algorithm on modified ITT as follows:

At Week 24 for the Week 24 ATV Powder Cohort;

At Week 48 for the Eligible Week 48 ATV Powder Cohort.
Outcomes, other than virologic successes, are based on the primary reason for treatment failure 
at the analysis week. 
Outcome categories are virologic success, virologic failure (HIV RNA ≥ 50 [400] c/mL;
discontinued due to virologic failure; discontinued due to other reasons and HIV RNA ≥ 50 
[400] c/mL at time of discontinuation; OBT changed), no virologic data in analysis week 
window (discontinued due to AE or death; discontinued due to other reasons and HIV RNA < 50 
[400] c/mL at time of discontinuation; missing data in window but on treatment). See Appendix
2 for more details about the snapshot algorithm. 
7.5.2
HIV RNA Changes from Baseline 
HIV RNA log10 observed values and changes from baseline are summarized at baseline and each 
analysis week on ATV powder through Week 48 and stages combined. The last HIV RNA in the 
pre-defined analysis week window is used.
Longitudinal plots display mean value versus analysis week and mean change from baseline 
versus analysis week through Week 48 by baseline weight band with error bars representing 1 
SE of the reported statistic.
7.5.3
CD4 Changes from Baseline 
Observed values and changes from baseline in CD4 cell counts and percents are summarized at 
baseline and each visit week on ATV powder through Week 48 and stages combined. 
Longitudinal plots display CD4 cell count median value versus visit week and median change
from baseline versus week on ATV powder through Week 48 by baseline weight band with error 
bars representing 1 SE of the reported statistic.
CD4 cell counts and changes from baseline are also summarized using last observation carried
forward (LOCF) and baseline observation carried forward (BOCF) methods on ATV powder
through Week 48. For LOCF, missing values are replaced with the last on-treatment value in the 
previous visit window; if a subject did not have any on-treatment value, then the baseline value 
is carried forward. For BOCF, missing values are replaced with the baseline value.
7.5.4
Resistance Profiles 
Viral genotypic and phenotypic resistance profiles are assessed for virologic failures. Virologic 
failures are subjects who meet the criteria for resistance testing per Protocol Section 4.5.1. Only 
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samples with a confirmed HIV RNA level ≥ 400 c/mL will be tested for genotypic and 
phenotypic resistance. Note that the threshold of 400 c/mL reflects the limitations of resistance 
tests used in this study. 
HIV isolates are tested for phenotypic resistance to selected protease inhibitors (PIs), nucleoside 
reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors 
(NNRTIs) using the PhenoSense™ HIV assay (Monogram Biosciences, Inc., CA). HIV 
substitutions in the reverse transcriptase and protease genomes are determined using the 
GeneSeqTM HIV assay (Monogram Biosciences, Inc., CA).
Genotypic substitutions at baseline are summarized for virologic failures. This presents subjects 
with genotypable isolates, those with PI substitutions from genotypable isolates, and those with 
selected RT substitutions from genotypable isolates using the most current version of the 
International AIDS Society-USA (IAS-USA) list and Stanford HIV Drug Resistance Database 
(see Appendix 3). 
Newly emergent genotypic substitutions are summarized analogously for virologic failures
without baseline phenotypic resistance to ATV or RTV, using all on-treatment isolates. Newly 
emergent substitutions are on-treatment substitutions that were not detected at baseline. 
Phenotypic resistance at baseline is summarized for virologic failures. This presents subjects 
with phenotypable isolates and those with phenotypic resistance. Resistance to a drug is defined 
as a fold change (ie, ratio of the 50% inhibitory concentration [IC50] of the clinical isolate to the 
IC50 of the reference strain) > the cut-off for reduced susceptibility (see Appendix 3). Cut-offs 
may change based on the availability of clinical data
Newly emergent phenotypic resistance is summarized analogously for virologic failures using all 
on-treatment isolates. This presents subjects with phenotypable isolates and those with 
phenotypic resistance. Newly emergent phenotypic resistance to a drug is defined as a baseline 
fold change ≤the cut-off for reduced susceptibility, and an on-treatment fold change > the cut-
off for reduced susceptibility.
7.6
Safety
Safety endpoints are assessed using the extended on-treatment period (see Section 6.1.2), unless 
specified regardless of onset.
For the primary analysis, key on-treatment summaries are presented for treated subjects on ATV 
powder through Week 48 (ie, ≤54 weeks, the mid-point between Stage 1 Week 48 and Stage 2 
Week 12; see Section 8.1). In addition, the following on-treatment summaries are also presented 
for treated subjects on ATV powder through Stages 1 and 2 combined: SAEs; AEs leading to 
discontinuation of study therapy; all grades AEs; grade 2 - 4 related AEs; grade 2 - 4 related AEs 
occurring with overall incidence ≥ 5%; grade 3 - 4 laboratory abnormalities.
For the final analysis, key on-treatment summaries are presented for treated subjects on ATV 
powder through Stages 1 and 2 combined. 
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In summaries, values are excluded after the first dose date of ATV capsule (for AEs, values on 
the first dose date of ATV capsule are also excluded) unless specified otherwise.
Longitudinal summaries are presented through Week 48 on ATV powder for the primary 
analysis and through stages combined for the final analysis.
The investigators determine the intensity of AEs and the relationship of AEs to study therapy. 
The investigators’ terms are coded and grouped by system organ class using the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA) in production at BMS.
In order to account for AEs with multiple occurrences in the same subject, AE records are 
collapsed for each subject and preferred term when records have the same onset date, or when 
records are contiguous or overlapping (see Section 8.2.6). All AE presentations are based on 
collapsed records.
AEs are presented by system organ class and preferred term, both in descending order of 
incidence of total, unless specified otherwise.
Summaries of AEs include both non-serious and SAEs as defined in the protocol, unless 
specified otherwise. AEs with missing intensity are included only in summaries of all grades 
(related or regardless of relationship to study therapy). If a subject had an AE with different 
intensities during the treatment period, then only the greatest intensity is reported. If relationship 
to study therapy is missing, the AE is included in summaries of AEs related to study therapy.
Select MedDRA preferred terms in Section 7.6.4 may change according to the current version of 
MedDRA in production at BMS and review from a BMS physician prior to database lock.
7.6.1
Deaths
Deaths are listed for enrolled subjects regardless of onset. The death listing contains date of 
death, study days to death, source of information, and cause of death. Deaths from multiple 
sources of information are listed (ie, Status or AE/SAE CRF).
Deaths are identified from the following sources: 

Status data: study discontinuation reason of death.

AE/SAE data: MedDRA higher level, lower level or preferred term contains ‘death’; SAE 
outcome of death; SAE category of death; death date.
7.6.2
Other Serious Adverse Events
SAEs are summarized within system organ class for the following:

Regardless of onset for enrolled subjects;

ATV powder through Week 48;

ATV powder through stages combined. 
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7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs that led to discontinuation of study therapy are summarized within system organ class for 
the following:

Regardless of onset;

ATV powder through Week 48;

ATV powder through stages combined. 
7.6.4
Other Significant Adverse Events
Other significant AEs are assessed as described in Sections 7.6.4.1 through 7.6.4.9.
7.6.4.1
Renal Toxicity
Renal toxicity AEs (all grades) are summarized within system organ class on ATV powder 
through Week 48 and stages combined. Renal toxicity AEs are identified from the following 
MedDRA preferred terms: acute prerenal failure, albuminuria, anuria, azotaemia, continuous 
haemodiafiltration, costovertebral angle tenderness, creatinine renal clearance abnormal, 
creatinine renal clearance decreased, crystalluria, crystal nephropathy, cylindruria, diabetic 
cystopathy, diabetic end stage renal disease, diabetic nephropathy, dialysis, dysuria, Fanconi 
syndrome, Fanconi syndrome acquired, fluid retention, focal glomerulosclerosis, glomerular 
filtration 
rate 
abnormal, 
glomerular 
filtration 
rate 
decreased, 
glomerulonephritis, 
glomerulonephritis 
acute, 
glomerulonephritis 
chronic, 
glomerulonephritis 
membranoproliferative, glomerulonephritis membranous, glomerulonephritis minimal lesion, 
glomerulonephritis proliferative, glomerulonephritis rapidly progressive, glomerulonephropathy, 
glomerulosclerosis, glycosuria, haematuria, haemodialysis, hypercreatininaemia, hyperkaliuria, 
hyperphosphaturia, hypophosphataemia, intercapillary glomerulosclerosis, ketonuria, kidney 
enlargement, kidney fibrosis, kidney small, leukocyturia, lipiduria, microalbuminuria, neonatal 
anuria, nephritic syndrome, nephritis, nephritis allergic, nephritis autoimmune, nephritis 
haemorrhagic, 
nephritis 
interstitial, 
nephrocalcinosis, 
nephrogenic 
diabetes 
insipidus, 
nephrolithiasis, nephropathy, nephropathy toxic, nephrosclerosis, nephrotic syndrome, oliguria, 
peritoneal dialysis, polyuria, proteinuria, renal colic, renal disorder, renal failure, renal failure 
acute, renal failure chronic, renal failure neonatal, renal glycosuria, renal impairment, renal 
impairment neonatal, renal osteodystrophy, renal pain, renal tubular acidosis, renal tubular 
atrophy, renal tubular disorder, renal tubular necrosis, tubulointerstitial nephritis, urea renal 
clearance decreased and urine abnormality. 
7.6.4.2
Cardiac Disorders
Cardiac disorder AEs (all grades) are summarized within system organ class on ATV powder 
through Week 48 and stages combined. Cardiac disorders are identified from the following 
MedDRA preferred terms: angina pectoris, arrhythmia, atrial fibrillation, atrioventricular block,
atrioventricular block first degree, atrioventricular block complete, atrioventricular block second 
degree, bradycardia, bundle branch block left, bundle branch block right, cardiac failure 
congestive, cardiomegaly, cor pulmonale, electrocardiogram abnormal, electrocardiogram PR 
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prolongation, electrocardiogram QRS complex prolonged, electrocardiogram QT prolonged, 
long QT syndrome, sinus bradycardia, tachycardia, cardiac function test abnormal, ventricular 
dysfunction, and cardiomyopathy. 
7.6.4.3
Rash
Rash AEs (all grades; grade 2 - 4 related) are summarized within system organ class on ATV 
powder through Week 48 and stages combined. Rash is identified from the following MedDRA 
preferred terms: dermatitis allergic, dermatitis atopic, dermatitis exfoliative, drug eruption, drug 
rash with eosinophilia and systemic symptoms,  erythema, erythema multiforme, exfoliative 
rash, prurigo, pruritus allergic, psoriasis, rash, rash erythematous, rash follicular, rash 
generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, 
rosacea, skin exfoliation, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, urticaria 
and urticaria papular. 
Time to first rash and duration of first rash are summarized for all grades and grade 2 - 4 related 
rash separately. The duration of rash is measured from the onset date to the resolution date (the 
last contact date is used if the resolution date is ‘continuing’; the onset date is used if the 
resolution date is missing). The last contact date is the death date (if it exists), or the latest of the 
following: adverse event onset dates; adverse event resolution dates; last contact date if study 
discontinuation reason is lost to follow-up; HIV RNA draw dates; laboratory test dates; visit 
dates.
7.6.4.4
CDC Class C AIDS Events
CDC Class C AIDS AEs (all grades) are summarized within system organ class on ATV powder 
through Week 48 and stages combined. Documented clinical AIDS diagnoses are used to define 
AIDS (see Protocol Appendix 3).
7.6.4.5
Lipodystrophy-Related Adverse Events
Lipodystrophy-related AEs (all grades) are summarized within system organ class on ATV 
powder through Week 48 and stages combined. Lipodystrophy-related AEs are identified from 
the following MedDRA preferred terms: atrophy, breast enlargement, central obesity, congenital 
generalized lipodystrophy, facial wasting, fat atrophy, fat redistribution, gynaecomastia, 
lipoatrophy, lipodystrophy acquired, lipohypertrophy, lipomatosis, partial lipodystrophy and 
waist circumference increased. 
7.6.4.6
Lactic Acidosis Syndrome (LAS) or Symptomatic Hyperlactatemia 
(SHL)
Potential cases of LAS/SHL are listed regardless of onset. Potential cases of LAS/SHL are 
identified from the following MedDRA preferred terms: acidosis, blood lactic acid increased, 
coma hepatic, cytolytic hepatitis, hepatic encephalopathy, hepatic failure, hepatic necrosis, 
hepatic steatosis, hepatitis, hepatitis acute, hepatitis chronic active, hepatitis chronic persistent, 
hepatitis fulminant, hepatitis toxic, hepatocellular damage, hepatomegaly, hepatotoxicity, 
hyperlactacidemia, lactic acidosis, metabolic acidosis and mitochondrial toxicity. 
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All terms are further reviewed for case definitions of LAS/SHL or hepatic steatosis by a BMS 
safety physician to validate the cases. In addition, subjects are included if supporting evidence of 
LAS or SHL was available (ie, hospital records, SAE comments, etc), which may not have been 
reflected in the AEs.
7.6.4.7
Hyperbilirubinemia-Related Adverse Events
Hyperbilirubinemia-related AEs (all grades; grade 2 - 4 related) are summarized within system 
organ class on ATV powder through Week 48 and stages combined. Hyperbilirubinemia-related 
AEs are identified by the following combination of MedDRA preferred terms: 
hyperbilirubinaemia combined (blood bilirubin abnormal, blood bilirubin conjugated increased, 
blood bilirubin increased, blood bilirubin unconjugated, blood bilirubin unconjugated increased, 
hyperbilirubinaemia), jaundice combined (jaundice or yellow skin) and ocular icterus. The 
summary also presents subjects who have at least 2 or more of hyperbilirubinaemia combined, 
jaundice combined or ocular icterus.
7.6.4.8
Cholelithiasis
Cholelithiasis AEs (all grades) are summarized within system organ class on ATV powder 
through Week 48 and stages combined. Cholelithiasis is identified from the following MedDRA 
preferred terms:  bile duct stone, biliary colic, biliary dilatation, cholangitis, cholecystitis, 
cholecystitis acute, cholecystitis chronic, cholelithiasis, cholelithiasis obstructive, gallbladder 
disorder and hydrocholecystis.
7.6.4.9
Nephrolithiasis
Nephrolithiasis AEs (all grades) are summarized within system organ class on ATV powder 
through Week 48 and stages combined. Nephrolithiasis is identified from the following 
MedDRA preferred terms: calculus bladder, calculus ureteric, calculus urinary, crystalluria, 
crystal urine, nephrocalcinosis, nephrolithiasis and renal colic.
7.6.5
Overall Adverse Events
AEs are summarized within system organ class by intensity on ATV powder through Week 48 
and stages combined: all grades; all grades related; grade 2 - 4 related; grade 3 - 4. 
Grade 2 - 4 related AEs occurring with overall incidence ≥ 5% are also summarized on ATV 
powder through Week 48 and stages combined.
Non-serious AEs (all grades) occurring with overall incidence 5% are also summarized 
analogously on ATV powder through Week 48 and stages combined.
Multiple AEs (all grades) occurring with overall incidence > 5% are also summarized on ATV 
powder through Week 48 and stages combined, presenting the numbers of events and exposure-
adjusted incidence rates (see Section 8.2.6).
Generic medication names are also summarized by preferred term for AEs that require treatment 
with concomitant medications on ATV powder through Week 48 and stages combined (see also 
Section 7.4.5).
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All grades AEs on ATV powder through Week 48 and stages combined may be summarized for 
new onset AEs and AEs that are exacerbation of a pre-treatment event separately depending on 
data availability.
7.6.6
Clinical Laboratory Evaluations
Summaries are based on subjects with at least 1 laboratory measurement during the study period.
Values are excluded after the first dose date of ATV capsule.
7.6.6.1
Laboratory Abnormalities by Toxicity Grade
Laboratory abnormalities (normal; grade 1 - 4; grade 3 - 4) are summarized on ATV powder 
through Week 48 and stages combined for the following tests: 

Hematology: hematocrit, hemoglobin, platelets, WBC and neutrophils + bands (absolute).

Liver function tests: ALT, AST, alkaline phosphatase, total bilirubin and albumin.

Enzymes: amylase (total, total pancreatic or total salivary) and lipase (colorimetric or 
turbidimetric assay).

Renal function tests: BUN/urea (BUN or urea), creatinine, creatinine clearance, and uric acid.

Electrolytes (low and high): bicarbonate (low only), calcium, chloride, potassium and 
sodium.

Lipids (fasting): total cholesterol, LDL cholesterol and triglycerides.

Glucose (low, fasting high and non-fasting high).
Laboratory abnormalities are further summarized by baseline toxicity grade (normal; grade 1 - 4; 
grade 3 - 4).
Laboratory test results are graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, unless specified otherwise (see Protocol 
Appendix 2). Hematocrit, amylase, BUN/urea and chloride are graded using modified WHO 
criteria (see Protocol Appendix 5). 
The highest toxicity grade on treatment is reported for each test. 
7.6.6.2
Drug Induced Liver Injury (DILI)
Potential cases of DILI are listed on treatment regardless of ATV formulation. Potential DILI is 
defined as AT (ALT or AST) > 3 x upper limit of normal (ULN) concurrent with total bilirubin > 
2 x ULN. Concurrent is defined as within ± 30 days.
All cases are further reviewed by a BMS safety physician to validate the cases.
7.6.7
Electrocardiograms 
7.6.7.1
ECG over Time
Longitudinal summaries of ECG parameters (HR, QTcB, QTcF, PR) present observed values 
and changes from baseline at baseline and each visit week on ATV powder through Week 48.
Categories of ECG parameters are summarized at baseline and each scheduled visit week on 
ATV powder through Week 48 using observed values: 
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1. QTcB and QTcF intervals ≤ 450, > 450 - 480, > 480 - 500, > 500 msec;
2. PR interval ≤ 98th percentile, borderline, prolonged (see table below).
Subject’s Age
98th Percentile for PR 
Interval (msec)
Borderline Range 
(msec)
Prolonged  Range 
(msec)
3 - < 6 months
150
151 - 187
> 187
6 months - < 1 year
160
161 - 200
> 200
1 - < 3 years
150
151 - 187
> 187
3 - < 5 years
160
161 - 200
> 200
5 - < 8 years
160
161 - 200
> 200
8 - < 12 years
170
171 - 212
> 212
12 - < 13 years
180
181 - 225
> 225
13 years
200a
201 - 250
> 250
a Not the 98th percentile for PR interval, but the upper limit of normal for the PR interval in this age group
Source: Protocol PACTG 1020-A Version 6.0
The QT interval corrected for heart rate by the Bazett’s formula, QTcB, is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds.
Three ECG measurements are taken at Week 2 visit for subjects who have intensive PK taken at 
that visit. The worst (highest) value of these 3 measurements at Week 2 is used for those subjects 
in the analysis.
7.6.8
Physical Measurements
Longitudinal summaries of physical measurements (height, weight, age-adjusted percentiles and 
age-adjusted Z scores for height and weight) present observed values and changes from baseline 
at baseline and each visit week on ATV powder through Week 48 and stages combined. 
7.7
Pharmacokinetics
The lower limit of quantification (LLOQ) for each analyte is determined by analytical 
laboratories and is subject to change:

ATV:10 ng/mL;

RTV: 5 ng/mL.
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Analyses are based on ATV powder and RTV. Values are excluded after the first dose date of 
ATV capsule.
7.7.1
PK Parameters in Stage 1
In Stage 1, intensive PK samples are taken for subjects weighing 25 - <35 kg and/or ≥ 6 to < 11
years of age and for subjects in the new 5 - < 10 kg cohort with 200 mg ATV and 80 mg RTV 
dose. The following steady state PK parameters of ATV and RTV are derived from plasma 
concentration versus time data at Week 2 by non-compartmental methods using a validated PK 
program: 

Cmax: Maximum observed concentration;

Tmax: Time of maximum observed concentration;

Cmin: Plasma concentration 24 hours post observed dose. Pre-observed dose concentration is 
used as an estimate of Cmin if sample 24 hours post dose is not collected;

AUC(TAU): Area under the concentration-time curve, in 1 dosing interval from time 0 to 24
hours post observed dose. This is calculated by log- and linear-trapezoidal summations using 
a mixed log-linear method. Pre-observed dose concentration is used as an estimate of 
concentration 24 hours post observed dose if sample is not collected. 

IQ: Ratio of Cmin at Week 2 to Protein Binding Adjusted EC90 derived from individual 
subject clinical isolates at screening (ATV only, For ARV naive subjects, a population mean 
protein binding adjusted EC90 for wild-type virus (14 ng/mL) may be used if individual 
EC90 was not collected).

CLT/F: apparent oral clearance from plasma

CLT/F/kg: apparent oral clearance from plasma adjusted for body weight
PK parameters of ATV and RTV at Week 2 are summarized (eg, n, mean, SD, geometric mean, 
coefficient of variation [CV], median, quartiles, minimum, maximum) by baseline weight bands.
IQ is a PK/PD parameter that will be reported separately in a combined PK/PD analysis of data 
from AI424397 and AI424451. 
7.7.2
Trough Concentrations in Stage 1
Analyses are based on trough concentrations that meet the following criteria: complete sampling 
and dosing times; collected within 20-28 hours (inclusive) of the previous day’s dose; collected 
before the next dose;  concentrations < LLOQ imputed as LLOQ/2.
ATV trough concentrations are collected pre-dose at each scheduled visit week on treatment
through a minimum 24 weeks and up to a maximum of 48 weeks and are summarized (eg, n, 
mean, SD, geometric mean, CV, median, quartiles, minimum, maximum). ATV IQ, defined as 
the ratio of Cmin at the visit week to Protein Binding Adjusted EC90 derived from individual 
subject clinical isolates at baseline, is summarized analogously.
ATV composite trough concentration, defined as the geometric mean of a subject’s ATV trough 
concentrations through a minimum 24 weeks and up to a maximum of 48 weeks, is summarized. 
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ATV composite IQ, defined as the geometric mean of a subject’s ATV IQ through a minimum 
24 weeks and up to a maximum of 48 weeks, is also summarized.
RTV trough concentrations are collected similarly.  RTV trough concentration and RTV 
composite trough are assessed analogously.
Trough concentration data will be included in a separate report and combined with data from 
study AI424397 for PK/PD analyses.
7.8
Pharmacodynamics 
The relationship between endpoints of safety or efficacy and ATV trough and composite trough 
concentration (see Section 7.7.2) may be summarized and/or explored graphically, depending on 
the observed safety and efficacy profiles:

Efficacy on ATV powder using the Week 24 ATV Powder Cohort and Eligible Week 48 
ATV Powder Cohort

Selected physiological and adverse events (eg, jaundice) on ATV powder through Week 48

Selected laboratory parameters (eg, total bilirubin) on ATV powder through Week 48
Additional statistical methods may be used if appropriate.
Data will be combined with study AI424397 to perform PK/PD analyses in a separate report.
Analyses are described in the Data Presentation Plan (DPP).
7.9
Taste Assessment
Palatability surveys are administered at each on treatment study visit in Stage 1 from Week 2 
through Week 48 when a subject takes ATV 10% aspartame powder formulation. In Stage 2, the 
survey will be administrated for subjects on ATV powder who switches to the new ATV 4.2% 
aspartame powder formulation. Assessment will be carried out at time of switch and after switch 
as long as the subject is on the new ATV powder formulation or maximum duration of one year, 
whichever comes first. The following are presented at each visit week while subjects are on ATV 
10% aspartame powder formulation through Week 48 by weight band based on current weight:

Proportions of subjects mixing ATV powder with food: milk, water, other, not reported.

Proportion of subjects generally having trouble completing the dose of ATV. For those who 
have trouble completing, reasons are also included: does not generally like medicines or 
food; does not like the taste of ATV; child generally regurgitates (spits up) after meals; other; 
not reported.

Proportion of subjects generally having trouble completing the dose of RTV. For those who 
have trouble completing, reasons are also included: does not generally like medicines or 
food; does not like the taste of RTV; child generally regurgitates (spits up) after meals; other; 
not reported.
Proportions are based on the number of subjects with at least 1 survey response at the visit week.
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For the new ATV 4.2% aspartame powder formulation, proportions of subjects in each category 
of each question on the palatability survey will be tabulated similarly at each visit since they 
switch to the new formulation in Stage 2. In addition, 5-point Facial Hedonic Scale will be 
summarized at each visit for subjects who take it (i.e. ≥ 3 years old in Stage 2 on ATV powder 
formulation) since they switch to the new formulation in Stage 2. The visit windows on ATV 
4.2% aspartame powder formulation (4.2% POU) are provided in section 8.1.
8
CONVENTIONS
Presentations follow BMS general global standards for all data domains.2 This document is 
available upon request.
8.1
Windows for Analysis Weeks and Visit Weeks
Time is measured from the first dose of study therapy. For longitudinal presentations of data, 
windows around planned measurement times are based on the midpoint between planned study 
visits. 
Analysis week windows for HIV RNA are defined at baseline and on ATV powder through 
Stages 1 and 2 consistent with FDA correspondence about the snapshot algorithm (see table 
below). First, values are included through the extended on-treatment period (see Section 6.1.2), 
and are excluded after the first dose date of ATV capsule. Analysis week windows are created 
after value selection. Longitudinal summaries use the last value in the analysis week window.
Week
Label
Analysis Week Window on ATV Powder
-1
SCREENING
≤ 1 day not at baseline
0
BASELINE
≤ 1 day at baseline
4
WEEK 4
Day 2 - < 6
8
WEEK 8
6 - < 10
12
WEEK 12
10 - < 14
16
WEEK 16
14 - < 18
24
WEEK 24
18 - < 30
32
WEEK 32
30 - < 36
40
WEEK 40
36 - < 42
48
WEEK 48
42 - < 54
60
WEEK 60
54 - < 66
72
WEEK 72
66 - < 78
84
WEEK 84
78 - < 90
96
WEEK 96
90 - < 102
108
WEEK 108
102 - < 114
120
WEEK 120
114 - < 126
X
WEEK X
(X - 6) - < (X + 6)
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Visit windows are defined in the following table for study periods. The on-treatment period is
split into Stage 1 and 2. Visit labels appear in listings and in raw datasets.
  Study Period
Label
Visit Label
Target Day from Start of 
Study Period
Visit Windows
PRE-TREAT
PRE-TREAT
1
< 1 daya
ON-TRT ST1
DAY 1
1
1 - 4 daysb
WEEK 2
14
> Day 4 - 3 weeks
WEEK 4
28
> 3 - 6 weeks
WEEK 8
56
> 6 - 10 weeks
WEEK 12
84
> 10 - 14 weeks
WEEK 16
112
> 14 - 20 weeks
WEEK 24
168
> 20 - 28 weeks
WEEK 32
224
> 28 - 36 weeks
WEEK 40
280
> 36 - 44 weeks
WEEK 48
336
> 44 - 54 weeksc
ON-TRT ST2
WEEK 12 ST2
84
18 weeks
WEEK 24 ST2
168
> 18 - 30 weeks
WEEK 36 ST2
252
> 30 - 42 weeks
WEEK 48 ST2
336
> 42 - 54 weeks
WEEK 60 ST2
420
> 54 - 66 weeks
WEEK 72 ST2
504
> 66 weeks - 78 weeks
WEEK X ST2
X * 7
> (X - 6) weeks - (X + 6) weeks
FOLLOW-UP
F/U WEEK 2
10
> Day 4 - 3 weeks
F/U WEEK 4
24
> 3 - 5 weeks
F/U WEEK 6
38
> 5 - 7 weeks
F/U WEEK 8
52
> 7 - 9 weeks
...
F/U WEEK 48
332
> 47 - 49 weeks
a See Section 6.1 for classification of measurements on Day 1 (first dose of active study therapy) as pre-treatment 
or on-treatment depending on the data domain.
b See Section 6.1.2.
c For primary analysis, Week 48 visit window in Stage 1 may include data from Stage 2.
Weeks are study days divided by 7.
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Visit windows are rederived for longitudinal analyses of CD4, ECG, physical measurements and 
taste assessment. First, values are included through the extended on-treatment efficacy/safety 
period (see Section 6.1.2), and are excluded after the first dose date of ATV capsule. Visit week 
windows are created after value selection. Longitudinal summaries use the value closest to the 
target day of the visit week window, except for ECG at Week 2, which uses the worst (highest) 
value of the 3 measurements for subjects who have intensive PK at Week 2. The visit windows 
on ATV 4.2% aspartame powder formulation (4.2% POU) are provided in the table below.
   Study Period 
Label
Visit Label
Target Day from 
Start of 4.2% 
POU ATV
Visit Windows
ON-TRT 4.2% POU
WEEK 12-4.2% POU
84
18 weeks
WEEK 24 4.2% POU
168
> 18 - 30 weeks
WEEK 36 4.2% POU
252
> 30 - 42 weeks
WEEK 48 4.2% POU
336
> 42 - 54 weeks
WEEK 60 4.2% POU
420
> 54 - 66 weeks
WEEK 72 4.2% POU
504
> 66 weeks - 78 weeks
WEEK X 4.2% POU
X * 7
> (X - 6) weeks - (X + 6) weeks
8.2
Domain Derivations
Refer to BMS internal documents for additional conventions on date imputation and derivation 
of parameters across study periods for standard data domains: AEs, demography, ECGs, human 
genotyping, laboratory test results, non-study medications, physical measurements, subject 
status, taste assessment and vital signs.3,4,5,6,7,8,9,10,11,12,13,14 These documents are available upon 
request.
8.2.1
Exposure
8.2.1.1
Study Therapy
Derived exposure dates that are used commonly in analyses are defined as follows:

First dose date of study therapy is the earliest start or stop date of ATV identified from 
dosing records with non-missing start or stop dates and non-zero dose. This date is used to 
identify treated subjects and to distinguish study periods.

Last dose date of study therapy is the latest start or stop dates of ATV identified from dosing 
records with non-missing start or stop dates and non-zero dose. This date is derived only for 
subjects with valid dosing records and a subject status CRF page indicating whether the 
subject completed the study. It is used to exclude data in efficacy and safety analyses, and 
also to identify subjects who have discontinued study therapy.
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First and last dose dates of study drug formulations (ie, ATV powder, ATV capsule, RTV oral 
solution) are derived analogously for subjects with valid dosing records. Last dose dates of study 
drugs are derived without regard to the end of treatment subject status.
Time on study therapy is the last dose date of study therapy - first dose date of study therapy + 1.
Time on therapy for an individual drug formulation is the last dose date - first dose date + 1.
The following conventions are applied to dosing calculations for each drug formulation:

Distinct records with non-missing dose start date, total dose, generic drug name and 
formulation are selected.

Missing dose end dates are imputed. The missing end date of a dosing record is set to 1 day 
before the start date of the next available dosing record. If there is no subsequent record, the 
missing end date is set to the start date.

Duration for a dosing record is calculated as imputed end date - start date + 1.

Total amount of drug taken is the sum of total daily dose x duration across dosing records.
8.2.1.2
Interruption or Delay of Study Therapy
Interruptions of ATV powder are identified from complete dosing records (ie, non-missing start 
date, generic drug name and formulation) in which the total dose is 0 and the start date is before 
the last dose date of ATV powder (see Section 8.2.1.1). Duration for an interruption is 
determined using the minimum (last dose date of ATV powder, imputed end date) - start date + 1. 
Interruptions of ATV capsule, RTV oral solution and RTV capsule are identified analogously to 
those of ATV powder. 
Interruptions with missing reasons are categorized as “NOT REPORTED”.
8.2.2
Laboratory Tests
Analyses of laboratory tests use values from the central or local laboratory. 
Laboratory parameters are presented using US standard values and units.
Fasting glucose is identified by the laboratory test ‘GLUCF’, whereas non-fasting glucose is 
identified by ‘GLUC’.
Fasting triglycerides are identified by the laboratory test ‘TRIGF’, whereas non-fasting 
triglycerides are identified by ‘TRIG’. Fasting status for other lipids is determined by the fasting 
indicator.
8.2.3
Physical Measurements
For each baseline parameter (eg, BMI), if there are multiple records on the same measurement 
day, then the last record entered is selected. 
8.2.4
Viral Genotyping and Phenotyping
For baseline HIV subtype, if there are multiple records on the same collection day, then the last
record assayed is selected. Only records from the central laboratory are used.
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8.2.5
Virology
Analyses of HIV RNA use values from the Roche Amplicor Version 1.5 ultrasensitive or 
standard assay, or Abbott RealTime HIV-1 assay after the Roche Amplicor assay is 
discontinued, from the central laboratory. The lower and upper limits of quantification (LOQ) 
are 50 c/mL and 100,000 c/mL for the Roche Amplicor ultrasensitive assay, 400 c/mL and 
750,000 c/mL for the Roche Amplicor standard assay, and 40 c/mL and 10,000,000 c/mL for 
Abbott RealTime HIV-1 assay.
HIV RNA viral loads are reported by the central laboratory as follows: 
Actual numeric values for detectable virus within lower and upper LOQ;  
Upper LOQ with the inequality “>” for detectable virus above upper LOQ; 
Lower LOQ with the inequality “<” for detectable virus below lower LOQ.
The following convention applies to analyses of HIV RNA as a continuous variable. First, HIV 
RNA values are assigned a value of 1 more (or 1 less) if an inequality “>” (“<”) is present. 
Values outside the upper (or lower) LOQ are assigned a value of 1 more (or 1 less) than the limit. 
If there are multiple records on the same collection day, then the last record assayed is selected. 
Modified ITT and observed values analyses use the last value in the analysis week window.
8.2.6
Adverse Events
In order to account for AEs with multiple occurrences in the same subject, AE records are 
collapsed for each subject and preferred term when:

Records have the same onset date.

The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).

The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
The collapsed record contains the earliest onset date (and time, if collected); latest resolution 
date (and time, if collected); highest intensity in the following order (highest to lowest: very 
severe, severe, moderate, or mild); AE type of SAE, if ever reported as a SAE, AE otherwise; 
latest causality, as determined by the last modification time stamp (highest causality in the 
following order [highest to lowest: related, not related], if records contain the same last 
modification time stamp with different causalities); treatment required of yes, if ever required;
highest action taken in the following order (highest to lowest: drug discontinued, drug 
interrupted, dose reduced, dose increased, none); last reported term, as determined by the last 
modification timestamp. Medications and procedures used to treat AEs are merged with 
collapsed AE records for AEs requiring treatment.
Incidence rates per 100 person-years of exposure (IR/100 P-Y) are defined as event count * 100 /
person-years of exposure (see Section 7.6.5). Exposure on ATV powder is defined as time on 
study therapy (see Section 7.4.1), plus 30 days for subjects who discontinued study therapy to 
account for on-treatment safety reporting.
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9
CONTENT OF REPORTS
9.1
Planned Analyses
Two analyses are planned:

The primary analysis is conducted after the last treated subject is treated for 24 weeks (Stage 
1). Safety assessments focus on ATV powder through Week 48. Longitudinal assessments of 
efficacy and safety parameters are presented on ATV powder through Week 48.

The final analysis is conducted after the last subject in Stage 2 completes the study. Safety 
assessments focus on ATV powder through stages combined. Longitudinal assessments of 
efficacy and safety parameters are presented on ATV powder through stages combined.
Additional analyses may be conducted at unscheduled intervals to support regulatory 
questions/interactions, and at the request of the DMC.
9.2
Listings
Reports also contain subject listings described in the DPP. Listings are based on treated subjects, 
unless specified otherwise. Listings may include, but are not limited to, the following:

Batch numbers

Subjects excluded from the efficacy analysis (ie, enrolled subjects not treated)

Relevant protocol deviations

End of Stage 1 subject status

End of Stage 2 subject status

Demographics (enrolled subjects)

Exposure

Non-study medications

HIV RNA (enrolled subjects)

Snapshot algorithm outcomes at Weeks 24 and 48

CD4 cell count and percent (enrolled subjects)

Viral genotyping (enrolled subjects)

Viral phenotyping (enrolled subjects)

Adverse events (enrolled subjects)

AEs requiring treatment with concomitant medications

Deaths (enrolled subjects; see Section 7.6.1)

SAEs (enrolled subjects)

Adverse events leading to discontinuation of study therapy

Renal Toxicity (see Section 7.6.4.1)

Cardiac Disorders (see Section 7.6.4.2)

Rash (see Section 7.6.4.3)
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
CDC Class C AIDS Events (see Section 7.6.4.4)

Lipodystrophy-related AEs (see Section 7.6.4.5)

Potential LAS/SHL (see Section 7.6.4.6)

Hyperbilirubinemia-related AEs (see Section 7.6.4.7)

Cholelithiasis (see Section 7.6.4.8)

Nephrolithiasis (see Section 7.6.4.8)

Laboratory tests (enrolled subjects; excluding CD4 cell count and percent)

Potential DILI (see section 7.6.6.2)

Pregnancy tests

ECGs

Physical measurements

PK parameters of ATV powder and RTV oral solution in Stage 1

Trough concentrations of ATV powder and RTV oral solution in Stage 1

Survey for palatability

Facial Hedonic Scale (only subjects ≥ 3 years of age at time of switch to new 4.2% aspartame 
ATV powder)
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APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS
This appendix lists relevant protocol deviations that can be programmed from the database. The 
list would be updated as appropriate if, in the course of monitoring the study, additional protocol 
deviations are found and considered relevant.
Eligibility Deviations
Eligibility deviations (ie, protocol deviations of entry criteria) are listed below.

Age < 3 months or 11 years at time of first treatment

HIV RNA < 1,000 c/mL at screening 

CDC Class C AIDS events diagnosed between 30 days prior to screening and treatment (ie, 
informed consent date - 30 ≤ onset date ≤ first dose date of study therapy)

Corrected QTcF interval > 440 ms at screening

Weight < 5 kg or 35 kg at date of first dose

> Grade 2 ALT or AST
Relevant Protocol Deviations during Treatment
Relevant protocol deviations during the treatment period through Week 48 on ATV powder 
include: 

 
 
 
.

Remain on treatment > 8 weeks after having met the following definition of virologic failure
(meeting any of the following criteria):
–
Less than 1 log10 decrease from baseline HIV RNA by Week 16, confirmed by a 
second HIV RNA redrawn within 2 and 4 weeks from original sample;
–
Confirmed HIV RNA of ≥ 1000 c/mL (after Week 24); 
–
Confirmed HIV RNA ≥ 400 c/mL and showing Genotypic and/or phenotypic 
resistance to ATV/RTV and/or one or more assigned NRTI study drugs.
Remaining on treatment > 8 weeks is defined as last dosing date > 8 weeks after the 
confirmed HIV RNA drawn date. 
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APPENDIX 2
SNAPSHOT ALGORITHM
This appendix describes the snapshot algorithm for a Week 24 and Week 48 analysis. The 
principal analysis includes all treated subjects. The algorithm uses the last HIV RNA in the 
Week 24 and Week 48 analysis week window (see Section 8.1) to determine response.
See Section 7.4.2 for indentifying subjects who discontinued ATV powder. Discontinuations of 
ATV powder before Week 24 are identified by the (last dose date of ATV powder - first dose 
date of study therapy + 1)/7 < 18, the lower bound of the Week 24 analysis week window. 
Discontinuations of ATV powder before Week 48 are identified by the (last dose date of ATV 
powder - first dose date of study therapy + 1)/7 < 42, the lower bound of the Week 48 analysis 
week window.
Outcomes for HIV RNA < 50 c/mL at Week 24/48
Outcomes, other than virologic success, are based on the primary reason for failure through 
Week 24/48. Each subject’s status is categorized as follows:

Virologic success includes subjects with HIV RNA < 50 c/mL in the Week 24/48 analysis 
week window.

Virologic failure includes subjects in the following subcategories:

HIV RNA ≥ 50 c/mL: subjects with HIV RNA ≥ 50 c/mL in the Week 24/48 analysis 
week window;

Discontinued due to virologic failure: subjects with missing HIV RNA in the Week 
24/48 analysis week window who discontinued ATV powder before Week 24/48 due to 
lack of efficacy (regardless of last on-treatment HIV RNA);

Discontinued due to other reasons and HIV RNA ≥ 50 c/mL at time of 
discontinuation: subjects with missing HIV RNA in the Week 24/48 analysis week 
window who discontinued ATV powder before Week 24/48 for reasons other than AE, 
death or lack of efficacy with last on-treatment HIV RNA ≥ 50 c/mL,  if no on-treatment 
HIV RNA are available, the subject baseline HIV RNA will be used;

OBT changed: subjects who changed optimized background therapy (OBT) to a new 
class or changed OBT not permitted per protocol before the Week 24/48 HIV RNA draw 
date.

No virologic data in Week 24/48 window includes subjects with missing HIV RNA in the 
Week 48 analysis week window in the following subcategories:

Discontinued due to AE or death: subjects who discontinued ATV powder before 
Week 24/48 due to AE or death (regardless of last on-treatment HIV RNA);

Discontinued due to other reasons and HIV RNA < 50 c/mL at time of 
discontinuation: subjects who discontinued ATV powder before Week 24/48 for reasons 
other than AE, death and lack of efficacy with last on-treatment HIV RNA < 50 c/mL;

Missing data in window but on treatment: subjects who did not discontinue ATV 
powder before Week 24/48. 
The snapshot algorithm for HIV RNA < 400 c/mL and for other analysis weeks is assessed 
analogously.
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References: 
1.
FDA Correspondence. Comments on proposed labeling (SDN 316 dated 03/07/2011) for 
sNDA 21567/S-026. 17MAR2011.
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APPENDIX 3
GENOTYPIC AND PHENOTYPIC RESISTANCE
Genotypic Resistance
Genotypic resistance is assessed by searching for (1) all PI substitutions, and (2) select RT 
substitutions in the most current version of the International AIDS Society-USA (IAS-USA) list 
and Stanford HIV Drug Resistance Database (HIVdb).1,2 The HIVdb mutation scoring algorithm 
has been compared and validated with other algorithms. In addition, it has been shown to predict 
clinical response and virologic failure in clinical trials and salvage ARV therapy.3,4,5,6
PI substitutions are categorized as IAS-USA based on amino acid (aa) substitutions at a 
particular position of the HIV enzyme. PI substitutions not listed in IAS-USA are categorized as 
polymorphisms.
PI substitutions listed in IAS-USA are further categorized as major, minor or polymorphism 
using IAS-USA and HIVdb classifications. Note that aa substitutions at a specific position may 
have different classifications (eg, V82A is major, but V82I is a polymorphism). When there is a 
discrepancy between IAS-USA and HIVdb for major vs. minor or minor vs. polymorphism, the 
HIVdb classification takes precedence given its mutation scoring algorithm.
PI polymorphisms, majors and minors are defined as follows:

Polymorphisms

PI substitutions listed as minor in IAS-USA that have mutation scores of 0 for all PIs, 
according to values assigned by HIVdb. 

PI substitutions not listed in IAS-USA (HIV subtype B as reference).

Majors

PI substitutions listed as major in IAS-USA, except Q58E, T74P, N83D (listed as minor 
in HIVdb).

I54ASTV (listed as minor in IAS-USA, but major in HIVdb).

Minors: Q58E, T74P, N83D and PI substitutions listed as minor in IAS-USA, except those 
categorized previously as polymorphisms or majors.
The following table summarizes the PI and RT substitutions searched. All NRTI and NNRTI 
substitutions listed in IAS-USA are included. Also included in bold are RT substitutions not 
listed in IAS-USA that have at least 1 mutation score 5 according to values assigned by 
HIVdb.7
Drug
Substitutions
PI
Any
At least 1 PI substitution. 
IAS-USA
At least 1 of the following listed in IAS-USA: L10CFIRV, V11I, G16E, 
K20IMRTV, L24I, D30N, V32I, L33FIV, E34Q, M36ILV, K43T, M46IL, I47AV, 
G48V, I50LV, F53LY, I54ALMSTV, Q58E, D60E, I62V, L63P, I64LMV, 
H69KR, A71ILTV, G73ACST, T74P, L76V, V77I, V82AFILST, N83D, I84V, 
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Drug
Substitutions
I85V, N88DS, L89IMV, L90M, I93LM. Substitutions are further tabulated at each 
codon. 
Major: D30N, V32I, M46IL, I47AV, G48V, I50LV, I54ALMSTV, L76V, 
V82AFLST, I84V, N88S, L90M. 
Minor: L10FIRV, V11I, K20IT, L24I, L33F, K43T, F53L, Q58E, A71ILTV, 
G73ACST, T74P, N83D, N88D, L89V. 
Polymorphism: L10C, G16E, K20MRV, L33IV, E34Q, M36ILV, F53Y, D60E, 
I62V, L63P, I64LMV, H69KR, V77I, V82I, I85V, L89IM, I93LM. 
Non-IAS-USA 
(polymorphism)
At least 1 PI substitution not listed in IAS-USA. Substitutions are further tabulated 
at each codon.
RT
Any
At least 1 of the following: NNRTI; NRTI. Substitutions are further tabulated at 
each codon.
NRTI
At least 1 of the following: E40F, E44AD, K65N, K66 insertion, K66 deletion,
D67 insertion, D67 deletion, D67EGHST, S68 insertion, S68 deletion, 
T69DGN, T69 deletion, K70 insertion, K70 deletion, K70N, W71 insertion, 
W71 deletion, L74IV, Y115F, V118I, Q151L, N348I; 69 insertion complex; 151 
complex; TAMS; TDF/FTC; ZDV.
69 insertion complex
Substitution at codon 69 with a double amino acid insertion and at least 1 of the 
following: M41L, A62V, K70R, L210W, T215FY, K219EQ.
151 complex
Q151M and at least 1 of the following: A62V, V75AIMST, F77L, F116Y.
TAMS
At least 1 of the following: M41L, D67N, K70R, L210W, T215FY, K219EQ.
TDF/FTC
At least 1 of the following: K65R, K70EGQST, M184IV.
ZDV
At least 1 of the following: M41L, D67N, K70R, L210W, T215ACDEFILNSVY, 
K219 DEHNQRW.
NNRTI
At least 1 of the following: V90I, A98G, L100I, K101EHP, K103HNST, 
V106AIM, V108I, E138AGKQR, V179DEFLT, Y181CISV, Y188CHL, 
G190ACEQSTV, H221Y, P225H, F227CL, M230IL, K238NT, Y318F, N348I.
K103N
TAMS = Thymidine analogue-associated mutations
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Phenotypic Resistance
The phenotypic resistance to a drug is defined as a fold change (ie, ratio of the 50% inhibitory 
concentration [IC50] of the clinical isolate to the IC50 of the reference strain) greater than the 
cut-off for reduced susceptibility. The following table displays cut-offs used by Monogram 
Biosciences, Inc., CA to determine reduced susceptibility to each drug.
Drug
Reduced Susceptibility Cut-offs
PI
atazanavir (ATV) 2.2; atazanavir/ritonavir (ATV/R) 5.2; darunavir/ritonavir (DRV/R) 10; 
fosamprenavir (AMP) 2; fosamprenavir/ritonavir (AMP/R) 4; indinavir/ritonavir (IDV/R) 10; 
lopinavir/ritonavir (LPV/R) 9; nelfinavir (NFV) 3.6; ritonavir (RTV) 2.5; saquinavir (SQV) 
1.7;  saquinavir/ritonavir (SQV/R) 2.3; tipranavir/ritonavir (TPV/R) 2
NNRTI
delavirdine (DLV) 6.2; efavirenz (EFV) 3; etravirine (ETR) 2.9; nevirapine (NVP) 4.5
NRTI
abacavir (ABC) 4.5; didanosine (ddI) 1.3; emtricitabine (FTC) 3.5; lamivudine (3TC) 3.5; 
stavudine (d4T) 1.7; tenofovir (TFV) 1.4; zidovudine (ZDV) 1.9
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DOCUMENT HISTORY
Version 
Number
Author(s)
Description
Original version
See AI424451 SAP Amendment 1
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