Clinical trial NCT00071760
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: pediatrics ritonavir amprenavir AGENERASE HIV Lexiva protease inhibitors HIV Infection fosamprenavir
Sponsor: ViiV Healthcare
Start date: 2003-10-23; Completion date: 2022-03-29
Enrollment: 59 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 48-week study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of an investigational regimen including FDA approved HIV drugs in HIV-infected pediatric subjects, ages 4 weeks to \< 2 years old.

Detailed description:
A 48 week, Phase II, open-label, 2-cohort, multicenter study to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naive and PI-experienced pediatric subjects aged 4 weeks to \<2 years.

Arms: arm 1: Cohort 2A - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID)

Cohort 1A - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID) arm 2: Cohort 2B - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID)

Cohort 1B - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID)
Interventions: intervention 1: GW433908 intervention 2: ritonavir
Intervention descriptions: intervention 1: Fosamprenavir suspension bid intervention 2: Ritonavir solution bid

Protocol documents:
Prot_000.pdf: 
GD2001/00007/12
CONFIDENTIAL
ViiV Healthcare group of companies
APV20002
1
Division: Worldwide Development
Retention Category: GRS019
Information Type: Protocol Amendment
Title:
APV20002: A 48 Week Phase II, Open-label, 2-cohort, 
Multicentre Study to Evaluate the Pharmacokinetics, Safety, 
Tolerability and Antiviral Activity of GW433908 and 
GW433908/RTV When Administered to HIV-1 Infected 
Protease Inhibitor (PI) Naïve and PI-Experienced Pediatric 
Subjects aged 4 weeks to <2 years
Compound Number:
GW433908
Effective Date:
20-NOV-2019
Protocol Amendment Number:  12
Subject: HIV infection, pediatric, protease inhibitor, fosamprenavir, GW433908
Author:
 
Copyright 2019 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD


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APV20002
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Revision Chronology:
GD2001/00007/00
2002-SEP-20
Original
GD2001/00007/01
2003-AUG-05
Amendment No. 1: 
Study Design changes including 
lowering of the age limit from 6 weeks 
to 4 weeks 
Revision of study objectives and 
endpoints Update schedule of 
assessments and interim analyses
Addition of new data from other FPV 
studies
Changes related to initial dose 
selection and dose adjustment criteria
To update the definition of study drug 
overdose
To update the subject management 
options
GD2001/00007/02
2004-MAY-10
Amendment No. 2:
To change the Exclusion Criteria No 8 
to any Grade 3 or greater laboratory 
abnormality
GD2001/00007/03
2005-JUL-01
Amendment No. 3:
To add a new dose recommendation for 
Cohort 1A
To temporarily close Cohort 1B
To revise the study design to allow 
simultaneous enrolment of Cohort 2 
Arm A and B
To update the dose adjustment 
guidance
To provide details pertaining to study 
visit beyond 48 weeks
To clarify that subjects enrolled in 
Cohort 1B or 2B may have their 
treatment switched to a boosted 
regimen only in countries where RTV 
solution is locally available for long-
term use
To provide clarification regarding the 
maximum age allowed for each cohort 
in Inclusion Criteria No 1. 


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GD2001/00007/04
2005-AUG-03
Amendment No. 4:
To add information regarding the 
removal of the unboosted FPV 
Cohort 1 Arm B from the study.
This amendment was sent to the Food 
and Drug Administration (FDA) only 
and was not sent to the sites for 
implementation.
GD2001/00007/05
2007-JUL-05
Amendment No. 5:
Defers enrolment of subjects in the 
unboosted FPV cohorts (Cohort 1 Arm 
B and Cohort 2 Arm B)
Increases the dose of FPV to 60 mg/kg 
at the Week 2 visit for subjects in 
Cohort 1 Arm A
Revises the PK visits and sampling 
times for subjects in Cohort 1 Arm A 
and adds plasma samples for 
determining unbound APV 
concentrations
Increases the single doses for Cohort 2 
Arm A SDV to FPV 45 mg/kg and 
RTV 7 mg/kg
Revisions to the concurrent 
medications; rifabutin and phenytoin 
no longer excluded
Updates information on rash and 
abacavir hypersensitivity reaction
Updates sponsor contact information
Updates the DAIDS toxicity grading 
tables (2004)
Updates background information, 
removes redundancies and corrects 
minor inconsistencies in the protocol.
GD2001/00007/06
2007-NOV-20
Amendment No. 6:  Corrects the 
inaccuracies in the study drug dosing 
tables and an inconsistency in 
exclusion criteria no. 9 (per 
amendment 5)


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GD2001/00007/07
2009-JUN-02
Amendment No. 7:   To add a dose 
recommendation for subjects recruited 
into Cohort 2 Arm A.  Update to the 
number of subjects to be recruited into 
Cohort 2 Arm A.  Remove the Single 
Dose Visit from the assessment flow 
chart for subjects in Cohort 2 Arm A.  
Include the option to use local 
laboratories for haematology and 
clinical chemistry with Sponsor 
approval.
GD2001/00007/08
2009-NOV-23
Amendment No. 8:
To revise the dose recommendation for 
new subjects enrolled into Cohort 1, 
Arm A to FPV/RTV 45/7 mg/kg BID, 
with no increase to 60/7 mg/kg BID at 
Week 2.
To update the number of subjects to be 
recruited into Cohort 1, Arm A.  
To provide additional dosing advice for 
existing subjects in Cohort 1, Arm A 
receiving FPV/RTV 60/7 mg/kg.
To provide guidance on dosing for 
subjects when reaching 2 years and 6 
years of age during the study.
Allows for individual dose adjustment 
on a case by case basis.
Provision for a single repeat test for 
liver enzymes in the event of grade 3 or 
> value to determine eligibility
GD2001/00007/09
2010-OCT-25
Amendment No. 9: 
To specify a change of study sponsor.
To provide information on an external 
review committee. 
To update recruitment status. 
To clarify guidance on dosing for 
subjects reaching 2 years and 6 years 


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of age during the study
GD2001/00007/10
2011-MAR-28
Amendment No. 10: 
To amend information on propylene 
glycol content in FPV oral suspension 
to include contribution from liquid 
flavours.
To close unboosted FPV Cohorts 1B 
and 2B and amend study objectives and 
endpoints accordingly.
To correct study sponsor information.
GD2001/00007/11
2012-OCT-26
Amendment No. 11: 
To include information on 3TC and 
ABC tablets to be provided by GSK as 
background NRTI options.
To update the list of drugs not to be co-
administered with FPV and RTV.
To provide option to discontinue PK 
sampling and monitoring of plasma 
APV, FPV and RTV concentration on 
an individual basis once a subject has 
reached and exceeded 2 years and has 
initiated the 23/3 mg/kg BID dosing 
regimen
To update section on posting of 
information on publicly available
clinical trials registers and publication
GD2001/00007/12
20-NOV-2019
Amendment No.12
To include additional RTV formulation 
options as the oral solution is being 
discontinued in South Africa and 
provide updated FPV and RTV dosing 
tables for children >6 years of age
To update the list of drugs not to be co-
administered with FPV and RTV and 
provide additional information on rash 
management and suspected abacavir 
hypersensitivity 1.
FPV Pediatric 


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APV20002
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Clinical Data references to pediatric 
study results published after 
amendment 11 have been added; sites 
are also now advised to refer to these 
and local labels for summaries of the 
available data
The section regarding reporting of 
SAES was moved to Section 7.9 and 
the previous Section 7.9 (Regulatory 
Reporting Requirements For SAEs) 
was moved to Section 7.8
After 2013, viral load measurements, 
are being performed using the Abbott 
Realtime HIV-1 assay due to 
manufacturer discontinuation of the 
Roche Amplicor assay
Assent forms will be obtained from 
subjects still enrolled in the study as of 
Nov 1, 2019 as the subjects are now of 
an age where they can provide assent 
(consent originally provided by the 
careers) 


PPD
PPD
PPD


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SPONSOR INFORMATION PAGE
Title:
A 48 Week Phase II, Open-label, 2-cohort, Multicentre Study to 
Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral 
Activity of GW433908 and GW433908/RTV When Administered 
to HIV-1 Infected Protease Inhibitor (PI) Naïve and PI-Experienced 
Pediatric Subjects aged 4 weeks to <2 years.
Study Number:
APV20002
This study is sponsored by ViiV Healthcare UK Limited and ViiV Healthcare Company.  
GlaxoSmithKline is responsible for implementing and managing all aspects of this study.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
UK
Telephone: +44 (0)20 8380 6200
ViiV Healthcare Company
Five Moore Drive
Research Triangle Park
North Carolina USA
27709-3398
Telephone: +1 877 844 8872
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: + 001-919-483-2100.
GlaxoSmithKline
Iron Bridge Road
Stockley Park, Uxbridge, Middlesex, UB11 1BT, UK
Telephone: +44(0)208 990 9000
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of GSK and contact person will be 
provided to the relevant regulatory authority as part of the clinical trial submission.
Medical Monitor Contact Information:
, MD PhD
ViiV Healthcare
5 Moore Drive
PPD


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CONFIDENTIAL
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P.O. 13398
Research Triangle Park USA 27709
Mobile: 
Regulatory Agency Identifying Number(s): US IND 58,627
PPD


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INVESTIGATOR AGREEMENT PAGE
For protocol number APV20002
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................15
PROTOCOL SUMMARY...............................................................................................18
1.
INTRODUCTION....................................................................................................28
1.1.
Background ................................................................................................28
1.2.
Rationale ....................................................................................................28
1.3.
Fosamprenavir............................................................................................30
1.3.1.
FPV Neonatal Toxicology ............................................................30
1.3.2.
FPV Pediatric Clinical Data..........................................................31
1.4.
Ritonavir .....................................................................................................31
1.5.
Abacavir .....................................................................................................31
1.6.
Lamivudine .................................................................................................32
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................32
2.1.
Study Objectives.........................................................................................32
2.2.
Study Endpoints..........................................................................................33
3.
INVESTIGATIONAL PLAN.....................................................................................34
3.1.
Study Design ..............................................................................................34
3.2.
Study Population.........................................................................................39
3.2.1.
Inclusion Criteria..........................................................................39
3.2.2.
Exclusion Criteria.........................................................................40
3.2.3.
Other Study Eligibility Criteria Considerations..............................41
3.3.
Treatment During Study..............................................................................41
3.3.1.
Study Drugs.................................................................................41
3.3.2.
Background NRTI Options Provided by GlaxoSmithKline ............42
3.3.3.
Background ART Not Provided by GlaxoSmithKline/ViiV 
Healthcare ...................................................................................43
3.3.4.
Rationale for Study Drug Dose Selection.....................................43
3.3.4.1.
Rationale for Drug Dose Selection for Cohort 1 
(6 months to 2 years)..................................................44
3.3.4.2.
Rationale for Drug Dose Selection for Cohort 2 
(4 weeks to 6 months) ................................................46
3.3.5.
Dosages and dosing ....................................................................50
3.3.5.1.
Dosage Regimen Adjustment Criteria.........................51
3.3.6.
Target Plasma APV Exposure .....................................................52
3.3.6.1.
Pharmacokinetic Targets for a Dose Increase ............52
3.3.6.2.
Pharmacokinetic Targets for a Dose Reduction..........52
3.3.7.
Overdose and Toxicity management............................................52
3.3.7.1.
Overdose....................................................................52
3.3.7.2.
Toxicity Management .................................................54
3.3.7.3.
Specific Events...........................................................55
3.3.7.4.
Abacavir Hypersensitivity Reaction.............................58
3.3.8.
Subject Management Options......................................................62
3.3.9.
Study Treatment Assignment.......................................................63
3.3.10.
Concurrent Medications and Non-Drug Therapies .......................63
3.3.10.1.
GSK Supplied Background NRTI Options...................65


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4.
STUDY DRUG MANAGEMENT .............................................................................69
4.1.
Study Drug Packaging and Labeling...........................................................69
4.2.
Study Drug Handling...................................................................................69
4.3.
Study Drug Accountability Procedures........................................................71
5.
MEASUREMENTS AND EVALUATIONS...............................................................71
5.1.
Time and Events Schedule .........................................................................71
5.2.
Screening and Enrolment ...........................................................................72
5.3.
Demographic and Baseline Characteristics.................................................72
5.4.
Study Drugs and Background NRTIs ..........................................................73
5.5.
Efficacy.......................................................................................................73
5.6.
Health Outcomes........................................................................................74
5.6.1.
Humanistic Outcomes..................................................................74
5.7.
Bioanalysis and Pharmacokinetic Samples.................................................75
5.8.
Safety .........................................................................................................78
5.9.
Premature Discontinuation..........................................................................79
5.9.1.
Premature Discontinuation from the Study...................................79
5.10.
Follow Up....................................................................................................80
6.
DATA ANALYSIS METHODS ................................................................................81
6.1.
Sample Size Determination ........................................................................81
6.2.
General Considerations ..............................................................................81
6.2.1.
Analysis Populations....................................................................81
6.2.2.
Interim Analysis ...........................................................................82
6.2.3.
Other Issues ................................................................................82
6.3.
Efficacy.......................................................................................................83
6.3.1.
Efficacy Measurements................................................................83
6.4.
Viral Resistance Testing .............................................................................83
6.5.
Health Outcomes........................................................................................83
6.5.1.
Humanistic Outcomes..................................................................83
6.6.
Pharmacokinetics .......................................................................................84
6.6.1.
Bioanalysis ..................................................................................84
6.6.2.
Pharmacokinetic Parameters.......................................................84
6.6.3.
Statistical Analysis.......................................................................85
6.6.3.1.
Descriptive Statistics ..................................................85
6.6.3.2.
Assessment of Variables Correlated with 
Plasma APV PK .........................................................85
6.7.
Pharmacokinetics/Pharmacodynamics .......................................................86
6.8.
Safety .........................................................................................................86
6.8.1.
Adverse Events............................................................................86
6.8.2.
Laboratory Test Results...............................................................86
7.
AEs AND SAEs ......................................................................................................87
7.1.
Definition of an AE......................................................................................87
7.2.
Definition of a SAE......................................................................................88
7.2.1.
Events or Outcomes Not Qualifying as SAEs...............................89
7.3.
Lack of Efficacy as an AE or SAE...............................................................89
7.4.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as AEs and SAEs .......................................................................................89
7.5.
Method, Frequency, and Time Period for Detecting AEs and SAEs............90
7.6.
Documenting AEs and SAEs ......................................................................90
7.7.
Follow-up of AEs and SAEs........................................................................91


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7.8.
Regulatory Reporting Requirements For SAEs...........................................91
7.9.
Prompt Reporting of SAEs to GSK..............................................................92
7.9.1.
Timeframes for Submitting SAE Reports to GSK .........................92
7.9.2.
Transmission of the SAE Reports ................................................92
7.10.
Post-study AEs and SAEs ..........................................................................93
7.11.
SAEs Related to Study Participation...........................................................93
7.12.
SAEs Involving a Non-ViiV Healthcare Product...........................................93
8.
STUDY ADMINISTRATION....................................................................................93
8.1.
Data Collection ...........................................................................................93
8.2.
Regulatory and Ethical Considerations .......................................................94
8.2.1.
Notification of Primary Care Physician .........................................94
8.2.2.
Regulatory Authority Approval .....................................................94
8.2.3.
Ethical Conduct of the Study and Ethics Approval .......................95
8.2.4.
Subject Informed Consent ...........................................................95
8.2.5.
Investigator Reporting Requirements...........................................95
8.3.
Posting of Information on Clinicaltrials.gov..................................................95
8.4.
Study Monitoring.........................................................................................95
8.5.
Quality Assurance.......................................................................................96
8.6.
Study and Site Closure ...............................................................................97
8.7.
Records Retention......................................................................................97
8.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................98
8.9.
Information Disclosure and Inventions ........................................................98
8.10.
External Review Committee........................................................................99
9.
REFERENCES.....................................................................................................100
10. TABLES ...............................................................................................................104
11. APPENDICES......................................................................................................106
11.1.
Appendix 1:  1994 CDC Revised Classification System for HIV 
Infection in Children < 13 years of Age .....................................................106
11.2.
Appendix 2:  Declaration of Helsinki (Only Applicable to European 
Sites) ........................................................................................................110
11.3.
Appendix 3:  Grading of Laboratory Test Abnormalities - DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Publish Date: December 2004 .....................................................114
11.4.
Appendix 4:  Grading of Clinical Adverse Experiences - DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Publish Date: December 2004 .....................................................120
11.5.
Appendix 5:  Dosing Table for FPV Oral Suspension................................134
11.6.
Appendix 6:  Dosing Table for RTV Oral Solution, Powder, 
Capsules and Tablets ...............................................................................137
11.7.
Appendix 7:  Country Specific Requirements............................................140
11.8.
Appendix 8:  Protocol Amendment 1.........................................................141
11.9.
Appendix 9:  Protocol Amendment 2.........................................................143
11.10. Appendix 10:  Protocol Amendment 3.......................................................144
11.11. Appendix 11:  Protocol Amendment 4.......................................................146
11.12. Appendix 12:  Protocol Amendment 5.......................................................147
11.13. Appendix 13:  Protocol Amendment 6.......................................................152
11.14. Appendix 14:  Protocol Amendment 7.......................................................157


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11.15. Appendix 15:  Protocol Amendment 8.......................................................185
11.16. Appendix 16:  Protocol Amendment 9.......................................................216
11.17. Appendix 17:  Protocol Amendment 10.....................................................244
11.18. Appendix 18:  Protocol Amendment 11.....................................................259
11.19. Appendix 19:  Protocol Amendment 12.....................................................270


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ABBREVIATIONS
3TC
lamivudine, EPIVIR
ABC
abacavir sulfate, ZIAGEN
AE
adverse event
AGN
Agenerase, amprenavir
ALP
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
APV
amprenavir
ART
antiretroviral therapy
AST
aspartate aminotransferase (SGOT)
AUC
area under the plasma concentration versus time curve 
from time 0 and extrapolated to infinity
AUClast
area under the concentration versus time curve from time 0 
until the last quantifiable concentration during a dosing 
interval
AUClast,ss
area under the concentration versus time curve from time 0 
until the last quantifiable concentration during a dosing 
interval at steady-state
AUCτ,ss
area under the concentration versus time curve during a 
dosing interval, τ, at steady- state
BID
twice daily
Cavg,ss
The average concentration during a dosing interval, , at 
steady-state 
CD4+
helper-inducer T-lymphocyte surface antigen
CD8+
cytotoxic-suppressor T-lymphocyte surface antigen
CDC
Centers for Disease Control and Prevention
CLss
the apparent plasma clearance at steady-state 
Cmax
maximum plasma concentration
Cmax,ss
maximum concentration at steady-state
Cmin,ss
minimum concentration during a dosing interval
CPMP
Committee for Proprietary Medicinal Products
CPK
creatine phosphokinase
CRF
case report form
Cτ,ss
concentration at the end of a dosing interval, τ, at steady-
state
CVb 
coefficient of variability
CYP
cytochrome P450
DQ
data query
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eDQ
electronic data query
EFZ
efavirenz
EISR
Expedited Investigator Safety Report
ERC
External Review Committee
FDA
Food and Drug Administration (US)
FPV
fosamprenavir, GW433908, 908, Telzir, Lexiva
GCP
good clinical practice


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GLP
Good Laboratory Practices
GSK
GlaxoSmithKline
HCV
hepatitis C virus
HDL
high density lipoprotein
HIV-1
human immunodeficiency virus type 1
HSR
hypersensitivity reaction
ICF
informed consent form
IDV
indinavir
IEC
independent ethics committee
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
LDL
low density lipoprotein
LOD
limit of detection
LPV/RTV
lopinavir/ritonavir, Kaletra
LSLV
last subject’s last visit
MCV
mean corpuscular volume
NFV
nelfinavir
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
NVP
nevirapine
PCR
polymerase chain reaction
PI
protease inhibitor
PK
pharmacokinetics
PRO
viral protease
QD
once daily
RNA
ribonucleic acid
RT
reverse transcriptase
RTV
ritonavir, Norvir
SAE
serious adverse event
SCA
standard clarification agreement
SDV
single dose visit
t1/2
the associated apparent terminal elimination half-life
tmax
the first time to reach Cmax
tmax,ss
the first time to reach Cmax,ss
tmin,ss
the time that Cmin occurs 
WBC
white blood cell
z
The apparent terminal plasma elimination rate-constant 
ZDV
zidovudine


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Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Agenerase
LEXIVA
Kaletra 
TELZIR
Norvir
TRIZIVIR
Winnonlin
ZIAGEN


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PROTOCOL SUMMARY
Agenerase (AGN, amprenavir, APV) was a protease inhibitor (PI) developed for the 
treatment of HIV disease.  Although AGN demonstrated antiviral activity and was 
generally safe when given in combination with other antiretroviral agents to subjects at 
all stages of HIV infection, the pill count with the capsule formulation and substantial 
volume of oral solution required (1.5mL/kg BID) was less than optimal and could impact 
long term adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a 
tablet and oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA™/ 
TELZIR™), the phosphate ester prodrug of APV, was developed to facilitate dosing of 
adult and pediatric HIV-1 infected patients. The safety and efficacy of FPV-containing 
regimens was demonstrated in three Phase III clinical trials in adults.
The use of combination therapy with 3 drugs, including either a PI or a non-nucleoside 
reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor, plus a dual nucleoside 
reverse transcriptase inhibitor (NRTI) backbone is the current standard of care for and is 
recommended for initial treatment of most HIV-infected adults and children [DHHS, 
2019; EACS, 2018; Panel on Antiretroviral Therapy and Medical Management of HIV-
Infected Children; 2019]. There remains a need for additional therapies for HIV infected 
children, in particular there are limited choices for a third agent to be given in 
combination with two NRTIs, and the choices are even more limited in children <2 years 
of age. 
Amprenavir, delivered as Agenerase oral solution, required large dosing volumes and 
was approved for restricted use by children of at least 4 years of age who were unable to 
swallow AGN capsules.  This restriction in use was due mainly to concerns about the 
large volume of excipients, including PEG400 and propylene glycol, required for dosing 
[Agenerase Package Insert, 2005]. Further, due to the high propylene glycol content in 
AGN oral solution and the high ethanol content of ritonavir (RTV) oral solution, co-
administration of AGN oral solution and RTV oral solution was contraindicated.  At the 
holder’s request, the Marketing Authorisation for AGN was withdrawn in the EU on 
April 29, 2010 and in the USA on August 18, 2009.
The FPV oral suspension incorporates less propylene glycol than AGN oral solution
thereby facilitating its administration to children of all ages and allows co-administration
with RTV oral solution.  The FPV oral suspension is also easier to formulate than APV 
with an increased concentration (50 mg/mL vs. 15 mg/mL) allowing a significant 
reduction in the total volume of FPV oral suspension required per dose compared to AGN 
solution. 
APV20002 is evaluating the pharmacokinetics (PK), safety, tolerability and antiviral 
activity of FPV when administered to HIV-1 infected PI-naïve and PI-experienced 
pediatric subjects aged 4 weeks to <2 years.  FPV will be administered as either the sole 
PI or in combination with low dose RTV.  Subjects in this study will be enrolled in 2 age 
cohorts (Cohort 1: 6 months to <2 years, and Cohort 2: 4 weeks to <6 months) in order to 
determine FPV and FPV/RTV dosage regimens for pediatric subjects at various stages of 
physiologic development. 


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Dose Rationale
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation. In children, the FPV oral suspension is recommended 
to be administered with food. 
APV20002 was designed to determine FPV/RTV regimens for pediatric subjects 4 weeks 
to <2 years of age that would deliver plasma APV exposures proven to be safe and 
effective in adults. 
In a small subset of five subjects aged 6 months to <2 years (Cohort 1, Arm A) who 
received FPV/RTV 45/7 mg/kg BID, plasma APV AUC(0-) was approximately 48% 
lower, Cmax 26% lower, and C29% lower than the adult target values.  Conversely, 
RTV levels appeared to be similar between these pediatric subjects and adult 
comparators.  Based on these results, Amendment 5 (05-Jul-2007) was undertaken to 
initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks (to allow collection of 
additional data on this regimen) and then increase the dose to FPV/RTV 60/7 mg/kg BID 
(to collect data on a higher dose regimen) for the duration of the study.  
Subsequent to Amendment 5, eleven additional subjects have been enrolled in Cohort 1, 
Arm A.  APV PK was evaluated at Week 2 (sampling predose, 2h, and 4h post dose) for 
the FPV/RTV 45/7 mg/kg BID regimen and at Week 8 (sampling predose, 1, 2, 4, 6, 8h 
post dose) for the FPV/RTV 60/7 mg/kg BID regimen.  Plasma APV Cvalues were 
collected at all subsequent visits.  APV PK parameters for newly enrolled subjects in 
Cohort 1A (6 months to <2 years) are compared to those for the subjects of this age group 
previously report as well as adult counterparts.
APV Cmax and Cfollowing FPV/RTV 45/7 mg/kg BID were higher in the eleven 
newly enrolled subjects than in the original five subjects who received the same dose.  
However, upon re-evaluation of data for the original subjects who received 45/7 mg/kg 
BID, one subject (
) had extremely low PK parameter values at Week 2 that appear to 
have affected the statistical point estimate of each parameter.  Excluding that one subject 
from the originally enrolled group, the geometric mean Cmax for the remaining 4 
subjects is increased from 4.16g/mL to 6.07g/mL, more consistent with adult values 
and more similar to the geometric mean Cmax at 7.5ug.mL of the newly enrolled subjects
receiving 45/7 mg/kg BID at Week 2.  Geometric mean AUC(0-) is increased from 
19.3g*h/mL (n=5) to 31.2g*h/mL (n=4), again much closer to the adult target values; 
AUC(0-) following 45/7 mg/kg BID could not be determined at Week 2 for newly 
enrolled subjects due to limited sampling scheme.  Overall geometric mean (95% CI) C
was increased from 1.54g/mL (1.13, 2.09g/mL, n=5) to 1.81g/mL (1.40, 2.33g/mL 
n=4), also closer to adult targets and newly enrolled subjects.
APV parameters following FPV/RTV 60/7 mg/kg BID in subjects 6 months to <2 years 
were significantly higher than adult target parameters.  Geometric mean APV AUC(0-) 
and Cmax following FPV/RTV 60/7 mg/kg BID were 1.8-fold and 2.6-fold higher than 
the geometric mean values in adults.  
PPD


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Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24 month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and GSK.   
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm A 
(4 week to <6 month age group).  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 weeks to <6 months of age had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose) and lower C(repeat 
dose) values compared with those historically observed for adults.  Repeat dose plasma 
RTV Cmax and AUC values were similar to historical adult data, but plasma RTV C
values were lower in the pediatric subjects.  As plasma APV Cis important for long-
term efficacy and minimization of resistance development, it is important to try to 
achieve plasma APV Cvalues in pediatric subjects similar to those achieved with the 
approved FPV/RTV 700/100 mg BID regimen in adults.  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore 
per Protocol Amendment 7, an increase in the RTV dose from 7 mg/kg BID to 10 mg/kg 
BID for all subsequently enrolled subjects was recommended.  These subjects will 
initiate dosing with FPV/RTV 45/10 mg/kg BID and have serial PK sampling at Week 2 
and trough sampling on subsequent visits. Additionally, a single dose visit (SDV) is no 
longer required for newly enrolled subjects 4 weeks to <6 months of age (Cohort 2 Arm 
A).  
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific FPV/RTV 
cohorts, the dose volumes of unboosted FPV oral suspension necessary to administer the 
calculated therapeutic dose in children aged <2 years would be approximately twice the 
boosted dose volumes.  Enrolment into the unboosted FPV cohorts is therefore not 
advised due to these large volumes of FPV oral suspension that would need to be 
administered as they could result in poor adherence, likely leading to an inadequate 
virologic response and subsequent resistance.
Per Protocol Amendment 12, as sale of RTV oral solution is being discontinued by the 
manufacturer in South Africa, additional RTV formulation options have been added for 
the South African sites.  The RTV dosing is based upon the weight of the child and 
include RTV supplied as 100 mg tablets, capsules or powders/sachets.


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STUDY OBJECTIVES
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5).  This objective has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the safety and tolerability of FPV/RTV when administered as a 
component of combination therapy in HIV-1 infected pediatric subjects aged 
4 weeks to <2 years. The objective to evaluate the safety and tolerability of FPV 
BID dosage regimens has been removed as per Protocol Amendment 10.
Secondary

To evaluate the antiviral activity of FPV/RTV in combination with NRTI therapy in 
HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the immunologic activity of FPV/RTV in combination with NRTI 
therapy in HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events

To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes) 
The secondary objectives to evaluate the antiviral and immunologic activity of FPV 
have been removed as per Protocol Amendment 10.
STUDY ENDPOINTS
Primary

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5). This endpoint has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.


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
Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment 
–limiting toxicities

Proportion of subjects who permanently discontinue FPV/RTV due to adverse 
events.  The endpoint ‘Proportion of subjects who permanently discontinue FPV 
due to adverse events’ has been removed as per Protocol Amendment 10.
Secondary

Proportions of subjects with plasma HIV-1 RNA levels <400copies/mL at each study 
visit

Change from Baseline in plasma HIV-1 RNA at each study visit (absolute values and 
time-averaged)

Proportion of subjects with 1.0 log10 decrease in plasma HIV-1 RNA at each study 
visit

Change from Baseline in the percentage of CD4+ lymphocytes at each study visit 
(absolute values and time-averaged)

Plasma FPV concentrations

Plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Relationship of steady-state plasma APV PK parameters to changes in plasma HIV-1 
RNA concentrations, CD4+ percentages and/or the occurrence of adverse events

Subject adherence and parent/guardian perceptions of study medications

Incidence of viral resistance (where permissible by blood volumes) 


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STUDY DESIGN
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. Per 
protocol amendment 12; only subjects at sites in South Africa remain enrolled as supplies 
of oral FPV suspension are not commercially available in South Africa. Subjects 
successfully completing 48 weeks of therapy and receiving clinical benefit who weigh 
less than 39 kg may continue to receive FPV oral suspension provided by GSK. Once 
subjects reach a weight of 39 kg, South African treatment guidelines permit the use of the 
FPV tablets in children weighing ≥39 kg and these subjects will be withdrawn as FPV 
tablets are commercially available in South Africa.  
Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been 
closed.
Recruitment Status for APV20002 – from Oct 2003 (FSFV) to Jul 2011 (cutoff for 48 
week CSR
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
261 enrolled
11 ongoing2
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
281 enrolled
14 ongoing2
1.
A total of 59 patients were enrolled but 5 discontinued after receiving single dose of FPV; current total enrolled 
patients exceeds the original cohort target because of dose changes in previous amendments
2.
Ongoing as of cutoff for 48 week CSR (July 2011)


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Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 10, enrolment in the 
Arm B cohorts (unboosted FPV) is closed.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.  
Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and Week 8 (over 8-12 
hours; 12 hour sample optional).
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 
subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in 
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 


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Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific FPV/RTV 
cohorts, the dose volumes of unboosted FPV oral suspension necessary to administer the 
calculated therapeutic dose in children aged <2 years would be approximately twice the 
boosted dose volumes.  Enrolment into the unboosted FPV cohorts is therefore not 
advised due to these large volumes of FPV oral suspension that would need to be 
administered as they could result in poor adherence, likely leading to an inadequate 
virologic response and subsequent resistance.
PLANNED SAMPLE SIZE
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, (N=24 for 
PK and safety; enrolment closed per Amendment 10) and FPV/RTV BID, Arm A (N=24 
for PK and safety).  Safety and tolerability assessment of the FPV/RTV BID regimen 
(Arm A) will be for the duration of the study or until a subject permanently discontinues 
study drug.  If less than 8 subjects in a cohort and dosage regimen complete the steady-
state PK analysis on Week 2, additional subjects may be enrolled as replacement 
subjects. Additionally, if dose modification to the cohort dose is warranted, a further 8 
subjects in each arm may be recruited to provide steady-state PK data on the revised 
dose. 
Revisions to the sample size have been made in view of required dose adjustments as 
specified in previous amendments.
STUDY POPULATION
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma 
HIV -RNA 400copies/mL and who meet the eligibility criteria will be recruited into the 
study. 
Following Amendments 5 and 8, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 25 subjects in total to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks 
to <6 months) will enrol approximately 29 subjects in total to receive FPV/RTV BID. 
Enrolment in the unboosted FPV BID cohorts (Arm B) is closed.
Subjects enrolled to receive FPV/RTV (Arm A) may be PI-naïve or PI-experienced.  PI-
experienced subjects will be eligible for Arm A if they have previously been treated with 
3 PIs.  Prior therapy with a RTV-boosted PI regimen will be considered as only 1 prior 
PI as long as the RTV dose was below that recommended for use as an antiretroviral 
agent.


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Prior treatment with NRTIs is permitted and subjects are eligible if an active background 
regimen of two NRTIs can be constructed.  For treatment-experienced subjects, prior 
treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and PIs is 
permitted, however, to be eligible for this study subjects must discontinue their NNRTI 
use at least 14 days prior and, for subjects undergoing SDV, must discontinue their PI at 
least 5 days prior to administration of FPV.  Subjects will NOT be permitted to receive 
concurrent NNRTI therapy while participating in this study.  In addition, concurrent PI 
therapy other than the study treatments described in this protocol will NOT be permitted 
during the course of this study.
STUDY DRUGS AND DOSAGES
Study drugs are defined as FPV and RTV.  FPV will be administered as a 50 mg/mL 
(43.2mg/mL APV molar equivalents) oral suspension.  RTV will be administered as an 
80 mg/mL oral solution, as a 100 mg capsule or tablet, or as a 100 mg powder 
packet/sachet.  Choice of appropriate formulation will depend on participant’s weight, 
availability of formulation and participant/caregiver preference.  Both the FPV and RTV 
oral formulations should be administered with food.  If vomiting or spitting up occurs 
within 30 minutes of administration, parents/guardians should be instructed to re-
administer the study medications.  
Refer to the Dose Rationale section of the Protocol Summary for information on dosing 
in each cohort.
Background Antiretroviral Therapy Options Provided by 
GlaxoSmithKline
ABC and 3TC will be provided as optional background therapy.  Refer to local 
prescribing information for use of ABC and 3TC.
MEASUREMENTS AND EVALUATIONS
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.  Subjects will attend the clinic at Screening (within 
approximately 21 days prior to Baseline/Day 1), Day 1 (Baseline), and Weeks 2, 4, 8, 12, 
16, 24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects who successfully complete 48 weeks on 
therapy may continue to receive FPV oral suspension provided by GSK until they no 
longer derive clinical benefit, weigh 39 kg or more, or according to prior agreements 
between GSK and participating study sites for provision of ART.  A follow-up visit will 
be performed 4 weeks after the permanent discontinuation of study drug.
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 


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every 12 weeks thereafter. Protocol amendment 11 (effective date October 26, 2012) 
provided the option to discontinue PK sampling once a subject had reached and exceeded 
2 years and had initiated the 23/3 mg/kg FPV/RTV BID dosing regimen.  PK sampling 
was discontinued after approval of the amended protocol in South Africa. 
Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. PK sampling was 
subsequently discontinued after approval of APV20002 protocol amendment 11, by 
which time the last enrolled subject had been enrolled in the study for more than 48 
weeks.
To measure the unbound concentration of APV, additional plasma trough PK samples 
will be collected prior to FPV/RTV BID dosing at Weeks 2, 16 and 36 for Cohort 1 Arm 
A subjects and at Weeks 8 and 16 for Cohort 2 Arm A subjects.
Plasma storage samples may be collected from all study participants, where permitted by 
blood volume restrictions, at the Day 1, Weeks 12, 24, 36, 48, every 12 weeks thereafter, 
and premature discontinuation visits.  These samples may be used for retrospective HIV-
1 viral resistance analysis or for repeat laboratory evaluations as needed.  A plasma 
sample for viral resistance analysis may be collected from subjects at the Screening visit 
per the investigator’s discretion if needed to guide selection of an active NRTI 
background regimen.  An additional plasma sample for viral resistance analysis may be 
collected 1 to 4 weeks after a subject meets one of the subject management criteria listed 
in Section 3.3.8.
The scheduled laboratory evaluations will involve collection of a maximum blood 
volume of 7mL/kg in any 56-day period.  A maximum of 3mL/kg of blood will be 
collected at any one study visit from children 4 weeks to <6 months.  Lastly, as defined in 
Section 5.6, subject adherence to study medications will be measured at Day 1, Weeks 2, 
12, 24, 48, and at the time of premature discontinuation visits, and parent/guardian 
perceptions of study medications will be measured at Weeks 2, 24, and 48, and at the 
time of premature discontinuation visits.


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1.
INTRODUCTION
1.1.
Background
Agenerase (AGN, amprenavir, APV) was a protease inhibitor (PI) for the treatment of 
HIV disease.  Although AGN demonstrated antiviral activity and was generally safe 
when given in combination with other antiretroviral agents to subjects at all stages of 
HIV infection, the pill count with the capsule formulation and substantial volume of oral 
solution required (1.5mL/kg BID) were less than optimal and may have impacted long 
term adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a tablet 
and oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA/ 
TELZIR), the phosphate ester prodrug of APV, were developed to facilitate dosing of 
adult and pediatric HIV-1 infected patients. 
The safety and efficacy of three FPV-containing regimens has been demonstrated in three 
Phase III clinical trials, APV30001 (antiretroviral [ART]-naïve subjects), APV30002 
(ART-naïve subjects), and APV30003 (PI-experienced subjects). [GlaxoSmithKline 
Document Number GM2002/00054/00, Study APV30002; GlaxoSmithKline Document 
Number RM2002/00088/00, Study APV30001; GlaxoSmithKline Document Number 
RM2002/00140/00, Study APV30003].  Based on these studies, four dosing regimens in 
adults are approved in the United States (US) for ART-naïve subjects: FPV 1400 mg
BID, FPV 700 mg BID + ritonavir (RTV) 100 mg BID or FPV 1400 mg QD + RTV 200 
mg QD or FPV 1400 mg QD + RTV 100 mg QD and for PI-experienced subjects: FPV 
700 mg BID + RTV 100 mg BID.  In Europe, the FPV 700 mg BID + RTV 100 mg BID 
regimen was approved for PI-naïve or experienced HIV-1 infected adults.  A further 
study in ART-naïve adults (ESS100732, KLEAN) demonstrated non-inferiority of FPV 
700 mg BID + RTV 100 mg BID compared to lopinavir (LPV)/ RTV (Kaletra) BID 
[GlaxoSmithKline Document Number RM2006/00010/00, Study ESS100732].
1.2.
Rationale
The use of combination therapy with 3 drugs, including either a PI or a non-nucleoside 
reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor, plus a dual nucleoside 
reverse transcriptase inhibitor (NRTI) backbone is the current standard of care for and is 
recommended for initial treatment of most HIV-infected adults and children [DHHS, 
2019; EACS, 2018; Panel on Antiretroviral Therapy and Medical Management of HIV-
Infected Children; 2019].  There remains a need for additional therapies for HIV infected 
children, in particular there are limited choices for a third agent to be given in 
combination with two NRTIs, and the choices are even more limited in children <2 years 
of age. 


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At the time the APV20002 study was collecting the primary outcome data (through Week 
48), in the NNRTI class, efavirenz (EFZ) and nevirapine (NVP) were available as liquid 
formulations.  NVP is associated with rare but potentially life threatening adverse 
reactions whilst EFZ is associated with neuropsychiatric adverse reactions 
[Viramune Package Insert, 2010] [Sustiva Package Insert, 2010].
Similarly, at the time the APV20002 study was collecting the primary outcome data 
(through Week 48), in the PI class, six agents - APV, indinavir (IDV), nelfinavir (NFV), 
RTV lopinavir/ritonavir (LPV/RTV), and darunavir were approved for use in HIV-1 
infected children.  APV has subsequently been discontinued. The lower age limits for 
which these PIs were approved for use varies between countries.
LPV/RTV is a PI combination frequently used in children.  Several studies support the 
use of LPV/RTV in children.  An early study in children 6 months to 12 years of age 
demonstrated the antiviral activity of LPV/RTV over a 24 week period, with plasma 
HIV-1 RNA levels of <400 copies/mL being achieved in 82% of ART-naïve children and 
66% of children with a mixture of NRTI-experience and NRTI + PI-experience, and 
accompanying improvements in CD4+ lymphocyte counts, after 24 weeks of therapy 
[Violari, 2000].  In a later study, 100 children ages 6 months to 12 years who were either 
ART naïve or ART-experienced but NNRTI naïve, received LPV/RTV as part of an ART 
regimen.  At Week 48, 79% of subjects had plasma HIV-1 RNA levels of <400 
copies/mL with corresponding mean increases in CD4+ cell counts from baseline [Post, 
2010; Ross, 2015; Saez-Llorens, 2003]. Recently, data on the use of LPV/RTV in infants 
<6 weeks of age has been presented.  In this study, 8 infants ages ≥14 days to ≤6 weeks 
received standard dose LPV/RTV over 24 weeks.  LPV/RTV AUCs were significantly 
lower than seen in an older cohort ages 6 weeks to 6 months, yet the regimen resulted in 
virological suppression (plasma HIV-1 RNA <400 copies/mL) in 7/8 subjects [Pinto, 
2007]. 
Although these PI therapies available for the treatment of HIV-1 infected children 
effectively inhibit HIV replication, most display limitations, such as lack of suitable 
formulations, inflexible dosing schedules and clinical side effects. For instance, no liquid 
formulation is available for indinavir and it is more difficult to assure adequate fluid 
intake to avoid renal complications in children than in adults.  The powder formulation of 
nelfinavir is difficult to administer to children, and consequently the adult tablets are used 
which results in a restrictive dosing schedule [Gibb, 2000b].  The major limitations to the 
pediatric formulation of RTV are the taste, vomiting as an adverse event and high alcohol 
content [Panel on Antiretroviral Therapy and Medical Management of HIV-Infected 
Children. Use of Antiretroviral Agents in Pediatric HIV Infection.  Updated April 16, 
2019. Available at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed August 
20, 2019.
Pelton, 1998]. Although Kaletra is now widely used in treating HIV infected children, the 
pediatric liquid formulation of LPV/RTV does have a similar alcohol content (42%) to 
that in the RTV liquid (43%) [Kaletra Package Insert, 2019; Norvir, Package Insert, 
2019]. 


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These limitations exemplify the need for new and improved potent PI antiretroviral 
therapies with pediatric formulations.
The FPV oral suspension incorporates less propylene glycol than AGN oral solution 
which allows administration to children of all ages and co-administration with RTV oral
solution. FPV is easier to formulate than AGN, with an increased concentration (50 
mg/mL vs. 15 mg/mL) allowing a significant reduction in the total volume of FPV oral 
suspension required per dose compared to AGN solution.  Thus, FPV oral suspension 
offers an improved vehicle for delivering amprenavir compared to AGN oral solution.
The safety, tolerability, pharmacokinetic characteristics, and antiviral activity of FPV in 
combination with RTV in HIV-1 infected pediatric subjects between 2 to 18 years of age 
were studied in protocols APV20003 and APV29005.
APV20002 is evaluating the pharmacokinetics (PK), safety, tolerability and antiviral 
activity of FPV when administered to HIV-1 infected PI-naïve and PI-experienced 
pediatric subjects aged 4 weeks to <2 years.  FPV will be administered as either the sole 
PI or in combination with low dose RTV.  Subjects in this study are enrolled in 2 age 
cohorts (Cohort 1: 6 months to <2 years, and Cohort 2:  4 weeks to <6 months) in order 
to determine FPV and FPV/RTV dosage regimens for pediatric subjects at various stages 
of physiologic development. 
1.3.
Fosamprenavir
FPV is the phosphate ester prodrug of APV which is hydrolyzed to APV and inorganic 
phosphate as it is absorbed through the gut epithelium.  Plasma FPV exposure (AUC) 
was <0.6% of the corresponding plasma APV exposure when FPV was administered for 
2-4 weeks in HIV-1 infected, treatment-naïve adult subjects [GlaxoSmithKline Document 
Number RM2001/00021/00, Study Report for APV20001].  
1.3.1.
FPV Neonatal Toxicology
Toxicity studies of up to 13 weeks duration have been performed with FPV in neonatal 
and juvenile rats [GlaxoSmithKline Document Number RD1999/02344/00, Study 
R40576; GlaxoSmithKline Document Number RD2000/02506/00, Study R40877; 
GlaxoSmithKline Document Number RD2002/00045/01].  In these studies, 
administration of FPV to neonatal and juvenile rats (starting at 4 days of age) at doses up 
to 300 mg/kg/day (213 mg/kg/day APV equivalents) resulted in only slight changes 
indicative of an effect on the liver (increased serum liver enzymes and increased liver 
weights).  Renal hyaline droplet accumulation seen in male rats was due to 2u-globulin 
nephropathy, and hence of limited toxicological relevance to humans [Durham, 2002].  
FPV doses 553 mg/kg/day (389 mg/kg/day APV equivalents) led to high mortality.
The ages of animals during both the initial phases of the FPV general toxicity studies and 
the specific studies investigating effects in juvenile animals, are considered representative 
of administration to pediatric patients in the clinic.  In these studies, there were no effects 
on the development of young animals and no evidence of an increased susceptibility of 
young animals to the effects of FPV.  Therefore, no such effects were predicted, nor have 


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they been observed, during clinical use.  Thus, the results from toxicology studies in both 
juvenile and adult animals indicate that the safety profile of FPV in children is unlikely to 
be different to that seen in adult patients and support the safe clinical use of FPV in HIV-
infected infants and children.
1.3.2.
FPV Pediatric Clinical Data
Pharmacokinetic, safety, and antiviral response data in pediatric subjects 2 to 18 years of 
age receiving FPV with or without RTV are available from Study APV29005 [Fortuny, 
2014], and Study APV20003 [Chadwick, 2007].  Additionally, 48 week data from the
pediatric subjects <2 years of age receiving FPV/RTV in Study APV20002 have also 
been reported [Cotton, 2014;Ross, 2015].  Overall the safety profile of fosamprenavir 
with and without ritonavir in paediatric patients was comparable to that observed in adult 
clinical studies. Refer to the local product information for summaries of the available 
data from these studies.
1.4.
Ritonavir
Ritonavir (Norvir, RTV) is an HIV protease inhibitor discovered and developed by 
Abbott Laboratories.  RTV is most commonly used at reduced dosages in combination 
with other protease inhibitors as a pharmacokinetic enhancer.  In this study, RTV will be 
used to enhance plasma concentrations of APV.  Because the dose of RTV as a 
pharmacokinetic enhancer in this study will be a small fraction of the approved dose for 
antiviral effect, selective pressure and the development of RTV resistant HIV-1 is 
unlikely. 
RTV has been licensed for use as an antiretroviral agent in subjects >1 month of age or 
older and is also licensed for use in combination with lopinavir (Kaletra) in boosted PI 
regimens in subjects of at least 6 months and 2 years of age in the USA and Europe, 
respectively.
Refer to the local Norvir prescribing information for complete information regarding 
RTV.
1.5.
Abacavir
Abacavir (ZIAGENTM, ABC) is a carbocyclic 2’,3’-ene nucleoside analog that inhibits 
replication of HIV-1.  It is triphosphorylated intracellularly to a carbocyclic guanosine 
analog which is a potent inhibitor of the viral reverse transcriptase (RT).  
The most commonly reported adverse events include nausea, fever, lethargy, fatigue, 
headache, vomiting, diarrhea, rash and decreased appetite.  In general, adverse events 
have not been treatment limiting and the majority were mild or moderate in severity.  
Grade 3 or 4 laboratory abnormalities are uncommon and no specific treatment-related 
laboratory trends have been detected to date.  Lactic acidosis and severe hepatomegaly 
with steatosis, including fatal cases, have been reported with the use of antiretroviral 


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nucleoside analogues either alone or in combination, including abacavir.  A majority of 
these cases have been in women. 
In clinical studies, approximately 5% of patients receiving ABC develop a 
hypersensitivity reaction which in rare cases has proved fatal.  See Section 3.3.7.4 for 
specific information regarding Hypersensitivity Reaction identification and management.
ZIAGEN is licensed for treatment of pediatric subjects of at least 3 months of age in the 
USA, the European Union, and South Africa.  Refer to local ZIAGEN prescribing 
information for complete information regarding ABC.
1.6.
Lamivudine
Lamivudine (EPIVIRTM, 3TC), is a dideoxynucleoside analogue (negative enantiomer) 
inhibitor of HIV reverse transcriptase approved as a treatment for HIV-infection in 
combination with other antiretrovirals.  It is phosphorylated intracellularly to its 
triphosphate form and acts as a chain terminator.
Lamivudine is generally safe and well tolerated, with the most commonly reported 
clinical adverse experiences being headache, nausea, vomiting, diarrhea, fatigue, malaise, 
insomnia, fever, abdominal pain, arthralgias, alopecia, and rash.  Laboratory 
abnormalities reported for patients receiving the 3TC/ZDV combination include anemia, 
neutropenia and/or thrombocytopenia.  Pancreatitis has been observed in some patients 
receiving lamivudine although it is unclear whether this was due to the drug treatment or 
the underlying HIV disease.  Lactic acidosis and severe hepatomegaly with steatosis have
been reported with the use of anti-retroviral nucleoside analogues alone or in 
combination, including lamivudine, in the treatment of HIV infection.  In some patients, 
these events have occurred within a few weeks of initiating combination therapy.  
EPIVIR is licensed for treatment of subjects of at least 3 months of age in the USA, 
Europe, and South Africa.  Refer to local EPIVIR prescribing information for complete 
information regarding 3TC.
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objectives
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5).  This objective has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years


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
To evaluate the safety and tolerability of FPV/RTV when administered as a 
component of combination therapy in HIV-1 infected pediatric subjects aged 
4 weeks to <2 years.  The objective to evaluate the safety and tolerability of FPV 
BID dosage regimens has been removed as per Protocol Amendment 10.
Secondary

To evaluate the antiviral activity of FPV/RTV in combination with NRTI therapy in 
HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the immunologic activity of FPV/RTV in combination with NRTI 
therapy in HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events

To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes)
The secondary objectives to evaluate the antiviral and immunologic activity of FPV 
have been removed as per Protocol Amendment 10.
2.2.
Study Endpoints
Primary

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5).  This endpoint has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment-
limiting toxicities

Proportion of subjects who permanently discontinue FPV/RTV due to adverse 
events.  The endpoint ‘Proportion of subjects who permanently discontinue FPV 
due to adverse events’ has been removed as per Protocol Amendment 10.


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Secondary

Proportions of subjects with plasma HIV-1 RNA levels <400copies/mL at each study 
visit

Change from Baseline in plasma HIV-1 RNA at each study visit (absolute values and 
time-averaged)

Proportion of subjects with 1.0 log10 decrease in plasma HIV-1 RNA at each study 
visit

Change from Baseline in the percentage of CD4+ lymphocytes at each study visit 
(absolute values and time-averaged)

Plasma FPV concentrations

Plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Relationship of steady-state plasma APV PK parameters to changes in plasma HIV-1 
RNA concentrations, CD4+ percentages and/or the occurrence of adverse events

Subject adherence and parent/guardian perceptions of study medications

Incidence of viral resistance (where permissible by blood volumes)
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. Per 
protocol amendment 12; only subjects at sites in South Africa remain enrolled as supplies 
of oral FPV suspension are not commercially available in South Africa. Subjects 
successfully completing 48 weeks of therapy and receiving clinical benefit who weigh 
less than 39 kg may continue to receive FPV oral suspension provided by GSK. Once 
subjects reach a weight of 39 kg, South African treatment guidelines permit the use of the 
FPV tablets in children weighing ≥39 kg and these subjects will be withdrawn as FPV 
tablets are commercially available in South Africa.  
Single dose visits (SDVs) for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  Protocol amendment 10 allows for the discontinuation of collection of samples for 


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PK analysis after the age of the subjects exceeds 2 years and the subjects have 
successfully completed 48 weeks of treatment. Therefore, the evaluable PK data for 
approximately 50 to 60 subjects will be analysed when it is available for all subjects 
successfully completing 48 weeks of therapy and will include subjects who have been on 
different dosing regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been closed.
Table 1
Recruitment Status for APV20002 – from Oct 2003 (FSFV) to Jul 2011 
(cutoff for 48 week CSR)
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
261 enrolled
11 ongoing2
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
281 enrolled
14 ongoing2
1.
A total of 59 patients were enrolled but 5 discontinued after receiving single dose of FPV; current total 
enrolled patients exceeds the original cohort target because of dose changes in previous amendments
2.
Ongoing as of cutoff for 48 week CSR (July 2011)
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2 years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 10, enrolment in the 
Arm B cohorts (unboosted FPV) is closed.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.
Refer to Figure 1 and Figure 2 for schematics outlining the study design for Cohort 1 
Arm A and Cohort 2 Arm A, respectively.  


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Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A:  Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years) 
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and  Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  Existing 
subjects in Cohort 1 Arm A whose dose of FPV was increased to 60 mg/kg BID at Week 
2 as per amendment 5 may have their dose adjusted based on ongoing viral load, 
pharmacokinetic and safety assessments. 
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
appropriate multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 
1 without undertaking a SDV.  The dose is be based on the Week 2 plasma PK data from 
the initial 12 subjects in Arm A SDV of Cohort 2 who underwent single dose 
assessments.  Subjects in Cohort 2 Arm A will undergo serial plasma PK sampling over 
8-12 hours (12 hour sample optional) at the Week 2 visit.
Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific FPV/RTV 
cohorts, the dose volumes of unboosted FPV oral suspension necessary to administer the 
calculated therapeutic dose in children aged <2 years would be approximately twice the 
boosted dose volumes.  Enrolment into the unboosted FPV cohorts is therefore not 
advised due to these large volumes of FPV oral suspension that would need to be 
administered as they could result in poor adherence, likely leading to an inadequate 
virologic response and subsequent resistance.


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Figure 1
Study Design for Cohort 1 Arm A: PI-naïve or PI-experienced subjects 6 months to <2 years of age


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Figure 2
Study Design for Cohort 2 Arm A: PI-naïve or PI-experienced subjects 4 weeks to <6 months of age


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3.2.
Study Population
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) was to enrol approximately 
4 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is closed.
Subjects enrolled to receive FPV/RTV (Arm A) may be PI-naïve or PI-experienced.  PI-
experienced subjects will be eligible for Arm A if they have previously been treated with 
3 PIs.  Prior therapy with a RTV-boosted PI regimen will be considered as only 1 prior 
PI as long as the RTV dose was below that recommended for use as an antiretroviral 
agent. 
Prior treatment with NRTIs is permitted and subjects are eligible if an active background 
regimen of two NRTIs can be constructed.  For treatment-experienced subjects, prior 
treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and PIs is 
permitted, however, to be eligible for this study subjects must discontinue their NNRTI 
use at least 14 days prior and, for subjects undergoing SDV, must discontinue their PI at 
least 5 days prior to administration of FPV.  Subjects will NOT be permitted to receive 
concurrent NNRTI therapy while participating in this study.  In addition, concurrent PI 
therapy other than the study treatments described in this protocol will NOT be permitted 
during the course of this study.
3.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1.
Male or female 4 weeks to <2 years of age. 
Cohort 1 (6 months - <2 years): Subjects must be <2 years of age at the Week 2 visit 
therefore the maximum age at screening is 22 months.
Cohort 2 (4 weeks - <6 months): Subjects must be <6 months of age at the Week 2 
visit, therefore the maximum age at screening is 4 months for entry into this cohort.
2.
Parent or legal guardian is willing and able to provide written informed consent for 
the subject to participate in the trial.
3.
Screening plasma HIV-1 RNA level 400 copies/mL.
4.
Subjects, who, in the investigator’s opinion, and following viral resistance testing if 
conducted, are able to construct an active NRTI backbone regimen consisting of 2 
NRTIs.
5.
Subjects must meet one of the following criteria:

Therapy-naïve or PI-naïve subjects (defined as having received less than one 
week of any PI).


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
PI-experienced subjects defined as having prior experience with no more than
three PIs.  Prior RTV-boosted PI therapy will be considered as only one PI as 
long as the RTV dose was lower than that recommended for use of RTV as an 
antiretroviral agent.
3.2.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Prior history of having received AGN.
2.
NNRTI therapy within 14 days prior to study drug administration (single or 
multiple-dose) or anticipated need for concurrent NNRTI therapy during the study 
period.
3.
PI therapy within 5 days prior to study drug administration (applicable only for 
subjects undergoing single dose visits)
4.
Subjects and/or parents/legal guardians who, in the investigator’s opinion, are not 
able to comply with the requirements of the study.
5.
Subject is in the initial acute phase of a CDC Clinical Category C event or infection 
(per 1994 classification) at Baseline.  Subject may be enrolled provided they are 
receiving treatment for the infections, such treatment not being contraindicated with 
FPV, and subjects are clinically improving at the Baseline visit. 
6.
Presence of a malabsorption syndrome or other gastrointestinal dysfunction which 
might interfere with drug absorption or render the subject unable to take oral 
medication.
7.
Presence of any serious medical condition (e.g., hemoglobinopathy, chronic anemia, 
diabetes, cardiac dysfunction, hepatitis, or clinically relevant pancreatitis) which, in 
the opinion of the investigator, might compromise the safety of the subject.
8.
Any acute laboratory abnormality at screen which, in the opinion of the investigator, 
should preclude the subject’s participation in the study of an investigational 
compound.  If subjects are found to have an acute Grade 4 laboratory abnormality at 
screening, this test may be repeated once within the screening window.  Any verified 
Grade 4 laboratory abnormality would exclude a subject from study participation.
9.
Grade 3 or higher (>5x ULN) serum aminotransferase levels (alanine 
aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days prior 
to study drug administration and / or clinically relevant hepatitis within the previous 
6 months. A single repeat test is allowed to determine eligibility.
10. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 
28 days of study drug administration or an anticipated need for such treatment within 
the study period.
11. Treatment with immunomodulating agents (e.g., systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (e.g., 
hydroxyurea or foscarnet) within 28 days of study drug administration.


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12. Treatment with any of the following medications within 28 days prior to receiving 
study medication or the anticipated need during the study:

Amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, 
diazepam, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, 
flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, 
pimozide, piroxicam, propafenone, propoxyphene, quinidine, simvastatin, 
terfenadine, and triazolam (these drugs have been excluded for safety reasons).

Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns 
Wort, (these drugs have been excluded because they have the potential to 
decrease plasma protease inhibitor concentrations).
Note: per Protocol Amendment 11, the list of drugs not to be co-administered with 
FPV and RTV has been updated (see Section 3.3.10, “Concurrent Medications and 
Non-Drug Therapies”).  As recruitment is closed, the exclusion criteria have not 
been amended.
13. Treatment with other investigational drugs/therapies within 28 days prior to 
receiving study medication (note: treatments available through a Treatment IND or 
other expanded-access mechanism will be evaluated on a case-by-case basis in 
consultation with GSK).
14. History of drug or other allergy which, in the opinion of the investigator, 
contraindicates participation in the trial or known hypersensitivity to any study 
medications (e.g. documented hypersensitivity to a nucleoside analogue).
3.2.3.
Other Study Eligibility Criteria Considerations
In order to assess any potential impact on subject eligibility with regard to safety, the 
investigator must refer to the following document(s) for detailed information regarding 
warnings, precautions, contraindications, adverse events, and other significant data 
pertaining to the study drugs: Such documents may include, but are not limited to, the 
local product information or the International Product Information.
3.3.
Treatment During Study
3.3.1.
Study Drugs
Study drugs are defined as only the medications under study (FPV and RTV).  Other 
antiretroviral therapies (including ABC and 3TC provided by GSK) will not be 
considered study drugs but will be considered background antiretroviral therapy (NRTIs) 
and thus a concurrent medication.  Record background NRTIs, including ABC and 3TC, 
on the Background Antiretroviral Therapy page in the case report form (CRF).
In this study FPV, oral suspension will be provided by GSK.  In all countries, RTV oral 
solution, powder, tablets or capsules will be obtained locally and reimbursed if acceptable 
to regulatory authorities.  GSK will provide RTV by other means where reimbursement is 
not acceptable, or GSK may provide RTV if local supplies are not available and RTV is 
able to be obtained from other countries. Both FPV and RTV will be considered study 


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drugs.  Therefore, in the event that a subject permanently discontinues FPV oral 
suspension, the subject will discontinue from this protocol and GSK will no longer 
supply FPV or RTV for that subject.
The FPV 50 mg/mL (43.2mg/mL APV molar equivalents) suspension is a white to off-
white bubblegum and peppermint flavoured suspension for oral administration using a 
dosing syringe.  Each mL of suspension contains 50 mg of FPV, equivalent to 43.2
mg/mL of APV.  The suspension contains the following inactive ingredients: 
hydroxypropylmethyl cellulose, polysorbate 80, methylparaben, propylparaben, 
propylene glycol (overall 20 mg/mL), sucralose, calcium chloride, flavours and purified 
water.  The FPV oral suspension is manufactured by GSK in Mississauga, Ontario, 
Canada.
The RTV oral solution manufactured by Abbvie contains 80 mg/mL of RTV in a 
peppermint and caramel flavoured vehicle and will be administered via a dosing syringe.  
The RTV solution contains the following inactive ingredients: ethanol, water, polyoxyl 
35 castor oil, propylene glycol, anhydrous citric acid, saccharin sodium, peppermint oil, 
creamy caramel flavouring and FD&C Yellow No. 6.
The RTV 100 mg oral powder/sachets manufactured by Abbvie also contains the inactive 
ingredients: copovidone, sorbitan monolaurate, and colloidal silicon dioxide, and are
sugar-free.
The 100 mg RTV tablets manufactured by Abbvie contains the inactive ingredients
copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal 
silicon dioxide, and sodium stearyl fumarate. The film coating contains: hypromellose, 
titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene 
glycol 3350, colloidal silicon dioxide, and polysorbate 80. The 100 mg RTV tablets are 
white, film-coated, ovaloid tablets and are sugar-free.
The 100 mg soft gelatin RTV capsules manufactured by Abbvie contains ritonavir 100 
mg (SSSS enantiomer); other ingredients include ethanol (12 % v/v), butylated 
hydroxytoluene (antioxidant), oleic acid, polyoxyl 35 castor oil, water, gelatin, sugar, 
sorbitol, glycerin, titianium dioxide, medium chain triglycerides, lecithin and black ink.
3.3.2.
Background NRTI Options Provided by GlaxoSmithKline
Abacavir and 3TC will be provided by GSK as optional background NRTIs for subjects 
of at least 3 months of age who are determined to be susceptible to ABC and/or 3TC. 
Susceptibility will be determined by investigator discretion and/or investigator 
interpretation of screening resistance viral genotype data, if available.
ABC and 3TC oral solutions are licensed for the treatment of pediatric subjects of at least 
3 months of age in the USA, the European Union, and South Africa.  Scored 3TC tablets
are licensed in the USA, the European Union, and South Africa for the treatment of 
pediatric subjects weighing greater than or equal to 14 kg for whom a solid dosage form 
is appropriate.  Scored ABC tablets are licensed in the USA and the European Union for 
the treatment of pediatric subjects weighing greater than or equal to 14 kg for whom a 


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solid dosage form is appropriate.  Scored ABC tablets will only be provided by GSK for 
subjects in South Africa when a license has been granted there.
The ABC oral solution contains 20 mg/mL of ABC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 
propylparaben, propylene glycol, saccharin sodium, sodium citrate, and sorbitol solution. 
The ABC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
The ABC tablet contains ABC sulfate equivalent to 300 mg ABC and the inactive 
ingredients colloidal anhydrous silica, magnesium stearate, microcrystalline cellulose, 
and sodium starch glycolate, Type A. The tablet is coated with a film that is made of 
methylhydroxypropylcellulose, polysorbate 80, synthetic yellow iron oxide, titanium 
dioxide, and triacetin. ABC tablets are manufactured by GSK in Ware, Hertfordshire, 
United Kingdom.
The 3TC oral solution contains 10 mg/mL of 3TC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 
propyparaben, propylene glycol, sodium citrate (dihydrous) and sucrose (20% w/v).  The 
3TC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
The 3TC tablet contains 150 mg of 3TC and the inactive ingredients magnesium stearate, 
microcrystalline cellulose, and sodium starch glycolate. The tablet is coated with a film 
that is made of hypromellose, magnesium stearate, microcrystalline cellulose, 
polyethylene glycol, sodium starch glycolate, titanium dioxide, and polysorbate 80. 3TC 
tablets are white, diamond-shaped and scored and manufactured by GSK in Ware, 
Hertfordshire, United Kingdom. 
In the event that a subject permanently discontinues study medication, GSK will no 
longer provide background 3TC and ABC medications.
3.3.3.
Background ART Not Provided by GlaxoSmithKline/ViiV 
Healthcare
GSK/ViiV Healthcare will not provide or reimburse background ART other than ABC or 
3TC.
3.3.4.
Rationale for Study Drug Dose Selection
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation.  In children, the FPV oral suspension is recommended 
to be administered with food due to the following considerations:

Children tend to eat frequently throughout the day

Parents may wish to enhance adherence, medication intake and mask taste by 
offering medication with food


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
FPV will be co-administered with ritonavir, which is recommended to be 
administered with food.
In adults, the FPV oral suspension formulation delivered an equivalent plasma APV 
AUC(0-) and 14.5% higher Cmax compared to the FPV tablet formulation 
[GlaxoSmithKline Document Number RM2006/00240/00, Study APV10024] 
Administration of the FPV suspension with food reduced plasma APV AUC(0-) by 
29% and Cmax by 46% [GlaxoSmithKline Document Number RM2002/00048/00, Study
APV10016].
3.3.4.1.
Rationale for Drug Dose Selection for Cohort 1 (6 months to 2 years)
APV20002 was designed to determine FPV/RTV regimens for pediatric subjects 
1 to 24 months of age that would deliver plasma APV exposures proven to be safe and 
effective in adults.
In a small subset of five subjects aged 6 months to <2 years (Cohort 1, Arm A) who 
received FPV/RTV 45/7 mg/kg BID, plasma APV AUC(0-) was approximately 48% 
lower, Cmax 26% lower, and C29% lower than the adult target values.  Conversely, 
RTV levels appeared to be similar between these pediatric subjects and adult 
comparators.  Based on these results, Amendment 5 (5 July 2007) was undertaken to 
initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks (to allow collection of 
additional data on this regimen) and then increase the dose to FPV/RTV 60/7 mg/kg BID 
(to collect data on a higher dose regimen) for the duration of the study.  
Subsequent to Amendment 5, eleven additional subjects have been enrolled in Cohort 1, 
Arm A.  APV PK was evaluated at Week 2 (sampling predose, 2h, and 4h post dose) for 
the FPV/RTV 45/7 mg/kg BID regimen and at Week 8 (sampling predose, 1, 2, 4, 6, 8h 
post dose) for the FPV/RTV 60/7 mg/kg BID regimen.  Plasma APV Cvalues were 
collected at all subsequent visits.  APV PK parameters for newly enrolled subjects in 
Cohort 1A (6 months to <2 years) are compared to those for the subjects of this age group 
previously report as well as adult counterparts in Table 2.  


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Table 2
Summary of Plasma APV PK in pediatric subjects for Cohort 1 (6 
months to 2 years)
APV 
Parameter
Newly enrolled 
6 months to <2 years
Original 6 months to <2 years
FPV/RTV
45/7 mg/kg
BID
Historical 
Adult
FPV/RTV 
700/100 mg 
BID
(n=159)5
FPV/RTV 45/7
mg/kg BID 
(n=11)
FPV/RTV 60/7
mg/kg BID
(n=7)2
(n=5)3
(n=4) 4
AUC(0-)
g*h/mL1
NA
66.9
(31.5, 142)
[82]
(19.2 – 140)
19.3
(4.64, 79.9)
[165]
(2.77 – 58.1)
31.2
(15.7, 62.1)
[45]
(21.8 – 58.1)
37.0
(35.1, 38.9)
[33]
(15.7 – 95.9)
Cmax
g/mL1
7.50
(5.27, 10.7)
[56]
(4.54 – 28.6)
14.8
(8.09, 27.1)
[73.0]
(4.79 – 29.6)
4.16
(1.35, 12.8)
[113]
(0.92 – 9.29)
6.07
(3.27, 11.3)
[40]
(4.07 – 9.29)
5.62
(5.35, 5.92)
[33]
(2.47 – 13.3)
C
g/mL1
1.92
(1.12, 3.31)
[96]
(0.48 – 5.28)
3.57
(2.42, 5.25)
[99]
(1.09 – 16.4)
1.54
(1.13, 2.09)
[117]
(0.055 – 8.15)
1.81
(1.40, 2.33)
[80]
(0.246 – 8.15)
2.17
(2.05, 2.30)
[38]
(0.75 – 5.83)
1.
Geometric Mean (95% CI) [CVb%] (min – max)
2.
N=6 for AUC(0-) and N=20 for C(across Weeks 8 -24)
3.
N=38 for C(across Weeks 2 -48)
4.
N=32 for C(across Weeks 2 -48)
5.
N=158 for AUC(0-)
APV Cmax and Cfollowing FPV/RTV 45/7 mg/kg BID were higher in the eleven 
newly enrolled subjects than in the original five subjects who received the same dose.  
However, upon re-evaluation of data for the original subjects who received 45/7 mg/kg 
BID, one subject (
) had extremely low PK parameter values at Week 2 that appear to 
have affected the statistical point estimate of each parameter.  Excluding that one subject 
from the originally enrolled group, the geometric mean Cmax for the remaining 4 
subjects is increased from 4.16 g/mL to 6.07 g/mL, more consistent with adult values 
and more similar to the geometric mean Cmax at 7.5 ug/mL of the newly enrolled 
subjects receiving 45/7 mg/kg BID at Week 2.  Geometric mean AUC(0-) is increased 
from 19.3 g*h/mL(n=5) to 31.2 g*h/mL(n=4), again much closer to the adult target 
values; AUC(0-) following 45/7 mg/kg BID could not be determined at Week 2 for 
newly enrolled subjects due to limited sampling scheme.  Overall geometric mean (95% 
CI) Cwas increased from 1.54 g/mL (1.13, 2.09g/mL, n=5) to 1.81 g/mL (1.40, 
2.33 g/mL, n=4), also closer to adult targets and newly enrolled subjects.
APV parameters following FPV/RTV 60/7 mg/kg BID in subjects 6 months – 2 years old 
were significantly higher than adult target parameters.  Geometric mean APV AUC(0-) 
and Cmax following FPV/RTV 60/7 mg/kg BID were 1.8-fold and 2.6-fold higher than 
the geometric mean values in adults.  
PPD


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Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24 month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7
mg/kg may have their dose modified at the discretion of the investigator and GSK.   
3.3.4.2.
Rationale for Drug Dose Selection for Cohort 2 (4 weeks to 6 months)
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm A 
(4 week to <6 month age group).  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 weeks to <6 months of age had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose, Table 3) and lower C
(repeat dose, Table 4) values compared with those historically observed for adults.  
Repeat dose plasma RTV Cmax and AUC values were similar to historical adult data, but 
plasma RTV Cvalues were lower in the pediatric subjects (Table 5).  As plasma APV 
Cis important for long-term efficacy and minimization of resistance development, it is 
important to try to achieve plasma APV Cvalues in pediatric subjects similar to those 
achieved with the approved FPV/RTV 700/100 mg BID regimen in adults. Although 
FPV/RTV 60/10 mg/kg exhibited  APV C,ss, most similar to adults (Figure 3), the APV 
Cmax for this regimen was considered unnecessarily high (Figure 4).  The RTV 10 
mg/kg in the FPV/RTV 60/10 mg/kg regimen provided the most consistently high RTV 
C,ss values as compared to 30/7 and 45/7 mg/kg (Figure 5).  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore 
per Protocol Amendment 7, an increase in the RTV dose from 7 mg/kg BID to 10 mg/kg 
BID for all subsequently enrolled subjects was recommended.  These subjects will 
initiate dosing with FPV/RTV 45/10 mg/kg BID and have serial PK sampling at Week 2 
and trough sampling on subsequent visits. Additionally a SDV is no longer required for 
newly enrolled subjects 4 weeks to <6 months of age (Cohort 2 Arm A).


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Table 3
Summary of Single Dose Plasma APV PK in Pediatric Subjects <6 
months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV 45/7 mg/kg
(N=11)1,3,4
Adult Subjects
FPV/RTV 700/100 mg
(N=17)2
Cmax (g/mL)
9.74
(5.67, 16.2)
3.65
(2.54, 6.76)
AUC(0-) (g.h/mL)
57.5
(20.2, 111)
35.2
(20.8, 114)
C8h (g/mL)
2.64
(0.819, 5.86)
1.10
(0.451, 2.20)
C12h (g/mL)2
1.13
(0.41, 3.76)
1.19
(0.659, 1.92)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Data for pediatric Subject 
 was excluded because exposures were very high: Cmax: 30.9g/mL, AUC(0-): 
335g.h/mL, C8hr: 16.9g/mL.
4.
C12h is extrapolated value for pediatric subjects and observed value for adult subjects
Table 4
Summary of Repeat Dose Plasma APV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV BID
(N=9) 1,3-5
Adult Subjects
FPV/RTV 700/100 mg
(N=14)2
Cmax (g/mL)
8.90
(2.07, 12.1)
4.76
(2.47, 7.68)
AUC(0-) (g.h/mL)
41.0
(16.2, 70.4)
28.3
(17.9, 43.1)
C8h (g/mL)
2.05
(1.10, 3.25)
1.58
(0.816, 2.64)
C(g/mL)3
0.970
(0.438, 1.95)
1.46
(1.06, 2.20)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
 was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
PPD
PPD


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Table 5
Summary of Repeat Dose Plasma RTV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma RTV
PK Parameter
Pediatric Subjects 
1 to <6 months
FPV/RTV BID1
Adult Subjects
FPV/RTV
700/100 mg BID2
(N=9)3-5
(N=8)3-5
(N=24)
Cmax (g/mL)
1.28
(0.228, 7.70)
0.999
(0.228, 2.11)
1.24
(0.520, 3.84)
AUC(0-) (g.h/mL)
6.66
(0.922, 28.8)
4.67
(0.922, 14.30)
5.59
(2.88, 14.4)
C8h (g/mL)
0.270
(0.021, 1.05)
0.239
(0.021, 1.05)
0.260
(0.068, 0.614)
C(g/mL)6
0.075
(NQ, 0.496)
0.069
(NQ, 0.496)
0.165
(0.010, 0.610)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10010
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Data summarized excluding Subject 
who had high RTV Cmax and AUC values.
6.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
Figure 3
Week 2 Plasma APV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
PPD
PPD


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Figure 4
Week 2 Plasma APV Cmax Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)


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Figure 5
Week 2 Plasma RTV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
Per Protocol Amendment 10, enrolment of the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is closed.
Following receipt and review of PK results from subjects in Cohorts 1 or 2, individual 
dose adjustment may be made on a subject by subject basis. 
3.3.5.
Dosages and dosing
FPV and RTV will be administered according to the doses described in Section 3.3.4 and 
in Section 3.3.5.1.
Both the FPV and RTV formulations should be administered with food.  If vomiting or 
spitting up occurs within 30 minutes of administration, parents/guardians should be 
instructed to re-administer the study medications.
The recommended dose of ABC solution is 8 mg/kg BID (up to a maximum of 600
mg/day).
For ABC tablets, the recommended dose is one-half of a scored tablet taken twice daily in 
children weighing between 14 kg and 21 kg and one-half of a scored tablet taken in the 


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morning and one whole tablet taken in the evening in children weighing between 21 kg 
and 30 kg.
The recommended dose of 3TC solution is currently 4 mg/kg BID (up to a maximum of 
300 mg/day). The dosing recommendation in the local label should be followed.
For 3TC tablets, the recommended dose is one-half of a scored tablet taken twice daily in 
children weighing between 14 kg and 21 kg and one-half of a scored tablet taken in the 
morning and one whole tablet taken in the evening in children weighing between 21 kg 
and 30 kg.
3.3.5.1.
Dosage Regimen Adjustment Criteria
Dose Adjustment Due to Subject Weight
Due to subjects’ growth throughout the duration of the study, the dose of all drugs 
administered must be recalculated at each visit and the total daily dose adjusted according 
to the child’s weight and the recommended dosage regimen.  Dose adjustments should 
occur when the dose would change by 10% from the subject’s prior calculated dose.
Dose adjustments due to weight change should be delayed until after completion of the 
PK sampling to ensure that sampling is conducted at steady-state.
Dose Adjustment Due to Subject Physiological Development
Subjects will not automatically change dosage regimens as they increase in age between 
4 weeks and 2 years and grow out of their age assigned cohort.  However, because 
subjects may require dose adjustments as they grow and develop, plasma PK samples 
collected throughout the study will be assayed on an ongoing basis, and if individualized 
dose adjustments are needed to maintain target concentrations, data will be provided to 
the investigators. 
Dose Adjustment Due to Subject Age exceeding 2 and 6 years
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg BID respectively.  The change in 
dosage can be staged gradually over multiple visits and will be based on ongoing viral 
load, pharmacokinetic and safety assessments, at the investigator’s discretion.
Subjects reaching and exceeding 6 years of age may transition to the lower dosage 
regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
In consultation with the investigator, GSK may discontinue PK sampling and monitoring 
of plasma APV, FPV and RTV concentration on an individual basis once a subject has 
reached and exceeded 2 years and has initiated the 23/3 mg/kg BID dosing regimen after 
Week 48. Any further dosing changes would follow the approved dosing 
recommendations without PK sampling, including a transition to FPV/RTV 18/3mg/kg 
BID at 6 years.  Note: after Protocol Amendment 11 became effective, PK sampling and 


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monitoring of plasma APV, FPV and RTV concentration on an individual basis was 
discontinued. 
3.3.6.
Target Plasma APV Exposure
3.3.6.1.
Pharmacokinetic Targets for a Dose Increase
Single Dose
The lower limit of the target plasma APV exposure for subjects receiving a single dose of 
FPV is defined as a plasma APV AUCvalue of 16.8g.h/mL.  This target represents 
the 25th percentile observed in adults receiving FPV 1395 mg in APV20001.
The lower limit of the target plasma APV exposure for subjects receiving single doses of 
FPV + RTV is a 12-hour concentration of 0.800g/mL.  This target represents the 25th
percentile observed in adults receiving single doses of FPV 700 mg + RTV 100 mg in 
APV10013.
Steady-State
The lower limit of the target plasma APV exposure for subjects receiving a FPV (without 
RTV) regimen is defined as a plasma APV C,ss value of 0.25g/mL.  This target 
represents the 25th percentile observed in adult subjects receiving FPV 1395 mg BID for 
2-4 weeks in APV20001.
The lower limit of the target plasma APV exposure for subjects receiving a FPV/RTV 
regimen is defined as a plasma APV C,ss value of 1.48g/mL.  This target represents 
the 25th percentile observed in adult subjects FPV 700 mg BID + RTV 100 mg BID in 
APV10010, APV10011, APV10012, APV10013, and APV10022. 
3.3.6.2.
Pharmacokinetic Targets for a Dose Reduction
No dose-limiting toxicities have been observed in adults receiving FPV or FPV + RTV. 
However, to ensure that children in this study, APV20002, do not maintain 
concentrations higher than those observed in adults, an upper limit to the plasma APV PK 
target has been set.  The upper limit of the target is a plasma APV AUC,ss value of 61.68
h*ug/mL at the Week 2 visit and a plasma APV C,ss value of 3.52ug/mL at subsequent 
visits (where only trough sampling is conducted).  Plasma APV AUC,ss and C,ss values 
are highly correlated, supporting the use of C,ss values at visits subsequent to Week 2.
3.3.7.
Overdose and Toxicity management
3.3.7.1.
Overdose
Experience with either FPV or AGN overdose is very limited, therefore GSK does not 
recommend any specific treatment in the event of an overdose.  It is not known whether 


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APV can be removed by hemodialysis.  The investigator should use clinical judgment in 
treating the overdose.
Experience of acute overdose with RTV is limited.  One patient in a clinical trial took 
RTV 1500 mg/day for 2 days.  The patient reported parasthesias, which resolved after the 
dose was decreased.  A post-marketing case of renal failure with eosinophilia has been 
reported with RTV overdose.  The approximate lethal dose was found to be greater than 
20 times the related human dose in rats and 10 times the related dose in mice.  In case of 
an overdose, general supportive measures should be given.  If indicated, elimination of 
unabsorbed drug may be achieved by emesis or gastric lavage. Administration of 
activated charcoal may also be used to aid in removal of unabsorbed drug.  Since RTV is 
highly protein bound, dialysis is unlikely to significantly remove drug from blood.
Single doses up to 1200 mg and daily doses up to 1800 mg of ABC have been 
administered to patients in clinical studies.  No unexpected adverse reactions were 
reported.  The effects of higher doses are not known.  It is not known whether abacavir 
can be removed by peritoneal dialysis or hemodialysis.
Limited data are available on the consequences of ingestion of acute 3TC overdoses in 
humans.  No fatalities occurred, and patients recovered.  No specific signs or symptoms 
have been identified following such overdose.  Since lamivudine is dialyzable, 
continuous hemodialysis could be used in the treatment of overdose, although this has not 
been studied.  Investigators should refer to local prescribing information for further 
information.
There are currently no known antidotes for FPV, RTV, ABC, or 3TC.  If overdosage 
occurs, the subject should be monitored for evidence of toxicity and standard supportive 
treatment applied as required.
An overdose is any dose greater than those described below for each study drug.  For the 
purposes of this study, an overdose is not considered an adverse event 
(AE, see Section 7.1) unless it is accompanied by a clinical manifestation associated with 
the overdose.
Definition of Overdose
FPV: An overdose of FPV will be defined as 1.5 x individualized dose recommended for 
the first 6-10 subjects or 1.5 x the overall dose recommendation made for the remaining 
subjects in cohort. 
RTV:  a daily dose of >300 mg
ABC:  a daily dose of >600 mg
3TC:   a daily dose of >300 mg


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3.3.7.2.
Toxicity Management
For the purpose of toxicity management, information is provided pertaining to the 
antiretroviral medications supplied for this study by GSK (i.e., FPV, RTV, ABC and 
3TC).  All Adverse Events and Serious Adverse Events must be recorded and reported 
according to Section 7 of this protocol.
The following toxicity management guidelines are intended to ensure the safety of each 
subject.  Should the investigator have compelling evidence that an adverse event does 
NOT appear to be causally related to the study drug(s), dosing with study drug(s) may 
remain unaltered.  Application of these guidelines is discretionary; a stepwise approach to 
the evaluation or management of a subject with severe findings may not be consistent 
with best clinical care. 
Decisions regarding sequential reintroduction of study drugs or temporary interruption of 
one or more but not all drugs within the antiretroviral therapy (ART) regimen should be 
made with the understanding that these changes may result in incomplete viral 
suppression and selection of resistant virus.  Every effort should be made to minimize the 
time that less than the full combination of study drugs is being administered.  Subjects 
undergoing toxicity management should be evaluated at weekly intervals.  Interruption of 
PI therapy may be allowed for evaluation of adverse events.  Subjects intolerant to their 
study PI should be discontinued from the study. 
Subjects who are intolerant to any component of their background NRTI therapy may 
change to another NRTI as directed by the investigator.  All changes to the treatment 
regimen must be accurately recorded on the study drug changes page and the background 
antiretroviral therapy page of the CRF. 
General management guidelines based on the protocol Toxicity Grades follow.  For a 
detailed discussion about specific events, please see Section 3.3.7.3 “Specific Events”. 
Specific events covered include rash management, nausea/vomiting and 
hypertriglyceridemia/ hypercholesterolemia.  Adverse events that occur during the trial 
should be evaluated by the investigator and graded according to the toxicity grades 
provided in Section 11.3, Appendix 3 and in Section 11.4, Appendix 4 (2004 DAIDS 
Tables).
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or 2 AE or toxicity may continue all study drugs and 
background antiretroviral drugs without alteration of the dose at the discretion of the 
investigator (see Section 3.3.7.2).  Subjects who choose to withdraw from study due to a 
Grade 1 or 2 AE should have study withdrawal and follow-up evaluations completed.
Grade 3 Toxicity/Adverse Event
In general, subjects who develop a Grade 3 AE or toxicity should have all study drugs 
and background antiretroviral drugs withheld and be re-evaluated each week until the AE 
returns to Grade 2 or less.  Specific events (rash, nausea and vomiting, hyperlipidemia/ 
hypercholesterolemia) are discussed in Section 3.3.7.3.  If the investigator has compelling 


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evidence that the AE has not been caused by the study drug(s), dosing may continue.  
Once the AE returns to Grade 2 or lower, study treatment may be re-instated at the 
discretion of the investigator or according to standard practice.
For those subjects whose regimen includes ABC, reinitiation of drug should be 
undertaken with caution.  In the event of a discontinuation of ABC for any reason, health 
care providers should obtain a complete history of the events surrounding the 
discontinuation of ABC.  If there are symptoms consistent with a hypersensitivity 
reaction, ABC should not be reinitiated.  If there is no evidence of a prior reaction, the 
subject may restart treatment with ABC.  The subject and health care provider should be 
aware of the possibility of a rapid-onset hypersensitivity reaction upon reinitiation of 
ABC, which may be life-threatening, and the subject should be able to, if necessary, 
receive prompt medical evaluation.
Should the same Grade 3 AE recur after 4 weeks, the management scheme outlined 
above may be repeated.  However, if the same Grade 3 AE recurs within 4 weeks, study 
drug(s) must be permanently discontinued if the investigator considers the AE related to 
study drug.  Subjects experiencing Grade 3 AEs requiring permanent discontinuation of 
study drug therapy should be followed weekly until resolution of the AE and encouraged 
to have withdrawal study evaluations completed.  A follow-up visit should be performed 
4 weeks after the last dose of study drug.
Subjects who develop Grade 3 clinically asymptomatic laboratory abnormalities should 
be investigated for all potential non-drug related causes and study drug(s) may be 
continued if the investigator has compelling evidence that the abnormality is not related 
to the study drug(s).
Grade 4 Toxicity/Adverse Event
Study drug will be permanently discontinued in subjects who develop a Grade 4 AE or 
toxicity.  However, if the investigator has compelling evidence that the AE is not causally 
related to the study drug(s), dosing may continue after discussion with and assent from 
GSK.  Subjects experiencing Grade 4 AEs requiring permanent discontinuation of study 
drug therapy should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal study evaluation.  A follow-up visit should be performed 
4 weeks after the last dose of study drug.
Subjects with Grade 4 clinically asymptomatic laboratory abnormalities should be 
investigated for all potentially non-drug related causes and study drug(s) may be 
continued if the investigator has compelling evidence that the toxicity is NOT related to 
the study drug, following discussion with GSK.
3.3.7.3.
Specific Events
Rash
Erythematous or maculopapular cutaneous eruptions, with or without pruritus, may occur 
during therapy with FPV.  Most rashes are mild or moderate in severity and will 
generally resolve spontaneously.  Appropriate antihistamine (e.g. cetirizine 
dihydrochloride) may reduce pruritus and hasten the resolution of rash. 


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Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, were 
reported in less than 1% of subjects included in the FPV clinical development program.  
FPV should be permanently discontinued in case of severe rash, or in case of rash of 
moderate intensity with systemic or mucosal symptoms. 
A total of 700 adult subjects received FPV either alone or in combination with RTV in 
Phase III clinical trials.  Rash, regardless of causality or grade, occurred in 25% and 9% 
of ART-naïve adult subjects receiving FPV BID (Study APV30001) and FPV/RTV QD 
(Study APV30002), respectively.  In PI-experienced adult subjects in Study APV30003, 
7% of subjects receiving FPV/RTV experienced rash.  Within the FPV treatment arm of 
APV30002, three subjects (<1%) were permanently discontinued due to rash.  No 
permanent discontinuations due to rash were reported in APV30001 or APV30003. 
In an integrated safety analysis of pediatric studies APV29005 and APV20003 in subjects 
2 to 18 years of age receiving FPV or FPV/RTV, rash (all grades, regardless of causality) 
occurred in 19% (27/144) of subjects, when all rash-related preferred terms were 
considered.  There were few cases of drug-related rash events. Most rash events were 
Grade 1 or 2 in severity and no subjects discontinued treatment due to rash.
The appearance of rash in the absence of other symptoms or signs is not indicative of 
hypersensitivity to ABC.  Subjects receiving ABC as part of their NRTI background 
regimen should be evaluated for the possibility of a clinically suspected ABC HSR and 
managed appropriately as outlined in the local prescribing information.  Subjects should 
be instructed to contact the Investigator as soon as possible if they develop a rash while 
on study.
Subjects who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as Stevens-Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN) or Erythema Multiforme. SJS, TEN and Erythema 
Multiforme have been reported very rarely in patients taking ABC-containing products.  
These patients generally do not have the cluster of additional symptoms (e.g., 
gastrointestinal and respiratory) that characterize the ABC HSR, but they do have 
features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s)
suspected in the Investigators causality assessment) should be discontinued, and the 
subject should not be re-challenged with any ABC-containing medicinal product (i.e., 
TRIUMEQ, ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the subject is receiving should also be reviewed and 
discontinued as appropriate.


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Study treatment should be managed as outlined in the following table:
Rash Management
Event
Action to be Taken
FPV BID or FPV/RTV BID
ABC
3TC
Grade 1 rash alone
Therapy can continue
Evaluate for the possibility of 
hypersensitivity.  If there is no 
evidence of any other organ system 
involvement and the subject has no 
constitutional symptoms (fever, 
malaise, fatigue, headache), ABC 
may be continued at the 
investigators discretion with the 
warning to discontinue immediately 
and permanently if other signs 
and/or symptoms consistent with 
HSR appear.  The subject should 
be advised to contact the 
Investigator immediately if there is 
any worsening of the rash, if any 
systemic signs or symptoms 
worsen, or if mucosal involvement 
develops.
Therapy can 
continue
Grade 1 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
Subjects should be treated as 
clinically appropriate and followed 
until resolution of the AE.
Therapy can 
continue
Grade 2 rash alone
Therapy can continue
Follow Grade 1 rash alone 
instructions
Therapy can 
continue
Grade 2 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
The subject should be advised to 
contact the physician immediately if 
rash fails to resolve (after more than 
two weeks), if there is any 
worsening of the rash, if any 
systemic signs or allergic symptoms 
develop, or if mucosal involvement 
develops.
Discontinue 3TC.  
Therapy should 
not be reinitiated 
unless the 
investigator has 
compelling 
evidence that the 
rash is not caused 
by 3TC.
Grade 3/4 rash alone or 
with symptoms indicating 
multi-organ involvement1
Discontinue FPV BID or 
FPV/RTV BID and do not 
reinitiate therapy3
Subjects should be treated 
as clinically appropriate and 
followed until resolution of 
the AE.
Discontinue ABC immediately and 
permanently3
Subjects should be treated as 
clinically appropriate and followed 
until resolution of the AE.
Discontinue 3TC3
Subjects should 
be treated as 
clinically 
appropriate and 
followed until 
resolution of the 
AE.
1.
Symptoms include: systemic symptoms (fever, GI symptoms including nausea, vomiting, diarrhea or 
abdominal pain) or allergic symptoms, or mucosal involvement, or severe tiredness, achiness or generally ill 
feeling.  
2.
ABC therapy should be permanently stopped and another NRTI therapy should be initiated.
3.
Medications should be permanently stopped and the subject withdrawn from the trial. .


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Adjunctive treatment:

For Grade 1 or 2 rash, antihistamines (see Section 3.3.10 for potential interactions) 
or topical corticosteroids may be prescribed.  Systemic corticosteroids are not 
recommended for Grade 1 or 2 rash, as steroid therapy may mask the appearance of 
other symptoms leading to the diagnosis of hypersensitivity to ABC.

Subjects who develop a Grade 3 (vesiculation, moist desquamation, or ulceration) or 
4 rash (exfoliation, mucosal involvement, or target lesions [erythema multiforme]) or 
any evidence of Stevens-Johnson Syndrome should have all study drugs 
discontinued and assessed appropriately.  If Grade 3 or 4 rash is accompanied by 
systemic symptoms, study medications should be permanently discontinued.  
Steroids may be used for treatment of the event. 
Nausea and vomiting
Upper gastrointestinal adverse events may be reduced by taking medications with a meal, 
and by maintaining a steady oral intake, e.g., pretzels or other dry bread.  Subjects who 
experience potentially treatment limiting nausea or vomiting should be treated with 
anti-emetics.  No dose reduction or modification of any study medication (i.e., FPV or 
RTV) will be allowed for the management of adverse events.
Hypertriglyceridemia/ hypercholesterolemia
There is currently no guidance available for the treatment and/or occurrence of 
cardiovascular disease in HIV-1 infected children.  Please see recent recommendations 
[Dube, 2003] for full discussion of management of hyperlipidemia in the context of HIV 
therapy.
During the study, management of these events should be at the investigator’s discretion.
3.3.7.4.
Abacavir Hypersensitivity Reaction
In clinical studies, conducted before the introduction of screening for the HLA-B*5701 
allele, approximately 5% of subjects receiving ABC develop a hypersensitivity reaction 
(HSR) that in rare cases has proved fatal.  However, in the PENTA 5 study [Gibb, 2000a] 
only 1 of the 92 ART-naïve, symptomatic children, aged 3 months to 16 years who were 
treated with a regimen containing ABC developed a classical hypersensitivity reaction.  
In CNAA3006, which utilized an ABC containing backbone, ABC HSR was observed in 
2% of pediatric subjects. The risk for abacavir HSR to occur is significantly increased for 
patients who test positive for the HLA-B*5701 allele. However, abacavir HSRs have 
been reported at a lower frequency in patients who do not carry this allele. In the 
prospective study CNA106030 (PREDICT-1), the use of pre-therapy screening for the 
presence of HLA-B*5701 and subsequently avoiding ABC in HLA-B*5701 positive 
patients, significantly reduced the incidence of clinically suspected ABC HSR from 7.8% 
(66 of 847) to 3.4% (27 of 803) (p<0.0001) [Mallal, 2008]. In clinical studies EPZ108859 
(ARIES) and CNA109586 (ASSERT), 0.8% (4/515) and 3.1% (6/192) of subjects who 
were HLA-B*5701 negative and who received ABC developed a clinically suspected 
ABC HSR, respectively [Post, 2010; Squires, 2010]. 


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It is recommended that any HIV-infected patient without prior exposure to abacavir be
screened for HLA-B*5701 allele. Screening is recommended prior to re-initiation of 
abacavir in patients of unknown HLA-B*5701 status who have previously tolerated 
abacavir. Use of abacavir in patients known to carry the HLA-B*5701 allele is not 
recommended. In any patient treated with abacavir, the clinical diagnosis of suspected 
hypersensitivity reaction must remain the basis of clinical decision making. Even in the 
absence of the HLAB* 5701 allele, it is important to permanently discontinue abacavir 
and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on 
clinical grounds, due to the potential for a severe or even fatal reaction.
The ABC hypersensitivity reaction is characterized by the appearance of symptoms 
indicating multi-organ involvement.  The majority of patients have fever and/or rash as 
part of the syndrome; however reactions have occurred without rash or fever.
Symptoms can occur at any time during treatment with ABC, but the symptoms usually 
appear within the first six weeks of initiation of treatment (median time to onset 11 days).  
The symptoms worsen with continued therapy and can be life-threatening.  These 
symptoms usually resolve shortly after discontinuation of ABC.
Frequently observed signs and symptoms include fever, rash, malaise or fatigue, 
gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain, and 
respiratory symptoms such as dyspnea, sore throat, cough.  Other signs and symptoms 
include myalgia, arthralgia, edema, pharyngitis, headache, paresthesia or myolysis.
Some subjects with hypersensitivity were initially thought to have onset respiratory 
diseases (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis, or 
reactions to other medications.  This delay in diagnosis of hypersensitivity has resulted in 
ABC being continued or re-introduced, leading to more severe hypersensitivity reaction 
or death.  Therefore, the diagnosis of hypersensitivity reaction should be carefully 
considered for patients presenting with symptoms of these diseases.  If hypersensitivity 
reaction cannot be ruled out, no medicinal product containing ABC (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any other ABC-containing product) should be 
restarted.
Physical findings may include rash (usually maculopapular or urticarial), 
lymphadenopathy or mucous membrane lesions (conjunctivitis, mouth ulceration). 
Abnormal chest x-ray findings may also present (predominantly infiltrates, which can be 
localized).  Laboratory abnormalities may include elevated liver function tests (such as 
hepatic transaminases), increased creatine phosphokinase or creatinine levels, and 
lymphopenia.
Anaphylaxis, hypotension, liver failure, renal failure, adult respiratory distress syndrome 
or respiratory failure may occur.
Subjects who develop a hypersensitivity reaction must discontinue ABC and must 
NEVER be rechallenged with any medicinal product that contains ABC (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing product).  Restarting any 
ABC-containing product following a hypersensitivity reaction results in a prompt return 
of symptoms within hours.  This recurrence of the hypersensitivity reaction may be 


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more severe than on initial presentation and may include life-threatening 
hypotension and death.  
There have been infrequent reports of hypersensitivity reactions following reintroduction 
of ABC, where the interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or a respiratory symptom).
On very rare occasions hypersensitivity reactions have been reported in patients who 
have re-started therapy, and who had no preceding symptoms of a hypersensitivity 
reaction (i.e., patients previously considered to be abacavir tolerant).
Management of Hypersensitivity Reactions 
Patients developing signs or symptoms of hypersensitivity MUST contact their 
doctor immediately for advice. 
If a hypersensitivity reaction is diagnosed the ABC-containing product MUST be 
discontinued immediately.  The subject’s parent/legal guardian should be asked to 
return all unused supplies of the ABC-containing product for disposal to prevent an 
accidental re-challenge.
An ABC-containing medicinal product (ZIAGEN, TRIZIVIR or any ABC-
containing fixed dose combination), MUST NEVER be administered following a 
hypersensitivity reaction, as more severe symptoms will recur within hours and may 
include life-threatening hypotension and death. 
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity 
reaction, the ABC-containing product should be permanently discontinued if 
hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory 
diseases, flu-like illness, gastroenteritis or reactions to other medications). 
Symptomatic support for ABC hypersensitivity may be indicated.  This should include, 
for example, administration of intravenous fluids to patients who develop hypotension. 
Antihistamines or corticosteroids have been used in cases of ABC hypersensitivity, 
however there are no clinical data demonstrating the benefit of these in the management 
of the reaction. 
Laboratory and other investigations which may be useful in the evaluation and treatment 
of ABC hypersensitivity include, but may not be limited to, measurement of ALT, AST, 
creatine phosphokinase, serum creatinine and white blood cell differential count and 
chest x-ray, if respiratory symptoms are present.
Special considerations following an interruption of abacavir therapy
If therapy with ABC has been discontinued and restarting therapy is under consideration, 
the reason for discontinuation should be evaluated to ensure that the patient did not have 
symptoms of a hypersensitivity reaction.  If hypersensitivity reaction cannot be ruled 
out, no medicinal product containing ABC (ZIAGEN, TRIZIVIR, KIVEXA, 
TRIUMEQ or any ABC-containing fixed dose combination) should be restarted.


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There have been infrequent reports of hypersensitivity reaction following reintroduction 
of an ABC-containing product where the interruption was preceded by a single key 
symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms or a 
respiratory symptom).  If a decision is made to restart any ABC-containing product in 
these patients, this should be done only under direct medical supervision. 
Rarely, patients who have stopped ABC for reasons other than symptoms of HSR have 
also experienced life-threatening reactions within hours of re- initiating abacavir therapy. 
Subjects must be made aware that HSR can occur with reintroduction of ABC or any 
other medicinal product containing abacavir and that reintroduction of ABC or any other 
medicinal product containing abacavir should be undertaken only if medical care can be 
readily accessed.
Screening for carriage of the HLA-B*5701 allele is recommended prior to re-initiation of
ABC in patients of unknown HLA-B*5701 status who have previously tolerated ABC.
Re-initiation of ABC in such patients who test positive for the HLA B*5701 allele is not
recommended.
Essential Patient Information
Investigators must ensure that subject’s parents/legal guardians are fully informed 
regarding the following information on the hypersensitivity reaction:

Subjects’ parents/legal guardians must be made aware of the possibility of a 
hypersensitivity reaction to ABC that may result in a life threatening reaction or 
death.

Parents/legal guardians of subjects developing signs or symptoms possibly linked 
with a hypersensitivity reaction MUST CONTACT their doctor IMMEDIATELY.

Parents/legal guardians must be reminded that subjects who are hypersensitive to 
ABC must never take any ABC-containing medicinal products (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing fixed-dose combination)
again.

In order to avoid restarting the ABC-containing product, the parents/legal guardians 
of subjects who have experienced a hypersensitivity reaction should be asked to 
return the remaining oral solution to the pharmacy.

Parents/legal guardians of subjects, who have stopped an ABC-containing product 
for any reason, and particularly due to possible adverse reactions or illness, must be 
advised to contact their doctor before restarting.

Each parent/legal guardian should be reminded to read the Package Leaflet included 
in the pack.

Parents/legal guardians should be reminded of the importance of removing the Alert 
Card included in the pack, and keeping it with them at all times.


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Reporting of Hypersensitivity Reactions
All cases of potential ABC hypersensitivity should be reported as Serious Adverse Events 
(SAE) (see Section 7.8).  In addition to reporting the case as an SAE, the HSR CRF 
should be completed and sent to GSK within one week of the onset of the 
hypersensitivity reaction. 
Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme
Serious skin reactions such as Stevens Johnson Syndrome, Toxic Epidermal Necrolysis 
or Erythema Multiforme have been reported very rarely in patients taking ABC-
containing products.  These patients generally do not have the cluster of additional 
symptoms (e.g., gastrointestinal and respiratory) that characterize the ABC 
hypersensitivity reaction, but they do have features typical of these serious skin reactions. 
If a serious skin reaction develops, the ABC-containing product should be discontinued, 
and the patient should not be rechallenged with any ABC-containing medicinal product 
(ZIAGEN, TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing fixed dose 
combination).
As many products other than ABC also cause these serious skin reactions, all other 
medicinal products that the patient is receiving should also be reviewed and discontinued 
as appropriate.
Management of Rash That is Not Accompanied by Systemic Symptoms
Subjects receiving ABC who develop rash of any grade should be evaluated for the 
possibility of a hypersensitivity reaction or a serious skin reaction such as Stevens 
Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme and managed 
appropriately as outlined above.  Rash may be caused by therapies in any of the major 
antiretroviral classes, or by other therapies commonly used as concurrent medications, 
such as cotrimoxazole.  As it is not possible to provide an exhaustive list of products that 
may cause rash in this protocol, please consult the product information leaflets for other 
products for information relating to rash. 
The rash and any associated symptoms should be reported as adverse events (See 
Section 7.1) and appropriate toxicity ratings should be used to grade the events. 
If the etiology of the rash can be definitively diagnosed as being due to a specific medical 
event or a concomitant medicinal product, routine management should be performed and 
documentation of the diagnosis provided. 
3.3.8.
Subject Management Options
If subjects experience the following criteria:

less than 1 log10 copies/mL reduction in plasma HIV-1 RNA by Week 12, or

0.7 log10 copies/mL rise from the nadir of plasma HIV-1 RNA, or


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
a persistent decrease of five percentiles in CD4% in children with a baseline CD4% 
of less than 15%, or criteria as specified in local guidelines, the investigator should 
consider whether a change in therapy and study discontinuation is warranted. 
Investigators are urged to follow country specific guidelines where they exist when 
making decisions about the management of subjects (e.g., when to switch therapy).
Subjects meeting one of the criteria defined above (first occurrence only and providing 
that the subject’s plasma HIV-1 RNA is at least 1000copies/mL) should return, at the 
discretion of the investigator, to the clinic within 1 to 4 weeks to have a blood sample 
drawn for resistance testing.
If a subject develops an AIDS diagnosis (CDC stage C) or other evidence of disease 
progression such that the treating clinician believes that changing therapy is required 
even though the above criteria have not been met, the investigator should contact ViiV 
Healthcare for further discussion on a case by case basis. 
3.3.9.
Study Treatment Assignment
Subject Number
After the parent/guardian has signed the informed consent form (ICF), each subject being 
screened for study enrolment will be assigned a subject number.  This number will be 
given sequentially in chronological order of subject presentation according to a numerical 
roster provided to the site by GSK.  The subject number will be used to identify each 
subject for the duration of the study.  Once a subject number has been assigned to a 
subject, it cannot be re-assigned to any other subject. 
Treatment Number 
The treatment number will be used to identify the specific study drug regimen initiated by 
the subject.  Once a treatment number has been assigned to a subject, it cannot be 
reassigned to any other subject.
Allocation of treatment numbers and consequently treatment assignments will be made 
via a 24-hour central registration telephone system according to the treatment code 
provided by GSK. 
Subjects undergoing SDV will be assigned a treatment number at the SDV.  Subjects not 
undergoing SDV will be assigned a treatment number at Baseline. 
3.3.10.
Concurrent Medications and Non-Drug Therapies
All concurrent medications, including non-prescription medications and herbal 
supplements, should be administered only as medically necessary during the study.  
Chemoprophylaxis for HIV-associated conditions is encouraged, if deemed appropriate 
by the investigator.  All concurrent medications administered during the study must be 
recorded on the CRF for the duration of the trial.


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Hematological supportive therapy with G-CSF, GM-CSF, or erythropoietin will be 
permitted.
Other experimental agents, immunomodulators, cytotoxic chemotherapy or radiation 
therapy may not be administered during the study (see Section 3.2.2. Exclusion Criteria); 
an exception will be made for local therapy or radiation treatment for Kaposi’s sarcoma.
Because vaccines may cause a temporary increase in the level of plasma HIV-1 RNA, it 
is recommended that a vaccine, if necessary, be given during or immediately after a 
scheduled visit.  This approach will minimize the risk of non-specific increases in the 
level of plasma HIV-1 RNA at the next scheduled assessment.  HIV immunotherapeutic 
vaccines are not permitted at any time point during the study.
IMPORTANT: For other potential interactions always refer to the product information 
for any drug used in combination therapy.
Fosamprenavir and Ritonavir
FPV and RTV are metabolized in the liver by cytochrome P450 3A4 (CYP3A4).  APV 
and RTV are predominantly CYP3A4 inhibitors. When FPV and RTV are co-
administered, the ritonavir metabolic drug interaction profile may predominate because 
ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for 
ritonavir must therefore be consulted prior to initiation of therapy with FPV and RTV.
Caution should be used when co-administering medications that are substrates, inhibitors, 
or inducers of CYP3A4.  In addition, RTV has an affinity for other cytochrome P450 
isozymes including CYP2D6, CYP2C9, CYP2C19, CYP2A6, CYP1A2 and CYP2E1, 
and appears to increase the activity of glucuronosyl transferases. 
FPV and RTV should not be co-administered with alfuzosin, amiodarone, astemizole, 
bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine,
encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, halofantrine, 
lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, 
propafenone, propoxyphene, quinidine, ketaconazole, rifampicin, PDE5 inhibitors 
including sildenafil, simvastatin, terfenadine and triazolam. Co-administration may result 
in competitive inhibition of metabolism of these medications and may cause serious or 
life-threatening adverse events. Co-administration of FPV or FPV/RTV with rifabutin 
results in significant increases in plasma rifabutin levels, therefore the dose of rifabutin 
should be reduced by at least 50% when co-administered with FPV and by at least 75% 
when co-administered with FPV/RTV. Caution should be used and subjects should be 
monitored closely for signs of toxicity.
Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, 
have been reported in patients receiving ritonavir and inhaled or intranasally administered 
fluticasone propionate; this interaction is also expected with other corticosteroids 
metabolized via the P450 3A pathway.
Concomitant use of fluticasone propionate and ritonavir should be avoided unless the 
potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.


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FPV and RTV should not be co-administered with carbamazepine, dexamethasone, 
phenobarbital, primidone, rifampin and St. John’s Wort because the PI concentrations 
may be significantly decreased, reducing efficacy. FPV and RTV should also not be co-
administered with hepatitis C virus (HCV) protease inhibitors telaprevir and boceprevir 
because both APV and HCV PI concentrations may be significantly decreased, with the 
possibility of sub-therapeutic concentrations.    
APV and RTV interact with CYP3A4 and are predominantly CYP3A4 inhibitors.  
Medications which interact with CYP3A4, either as substrates, inhibitors, or inducers of 
the isozyme, or medicinal products with narrow therapeutic windows that are substrates 
of cytochrome P450 3A4 (CYP 3A4) should be used with caution include, but are not 
limited to:  alprazolam, amlodipine, atorvastatin, cerivastatin, cimetidine, clarithromycin, 
clindamycin, clonazepam, codeine, dapsone, diltiazem, disopyramide, erythromycin, 
estrogens and progestogens, felodipine, fluvastatin, glucocorticoids, imipramine, 
isradipine, itraconazole, loratadine, miconazole, nicardipine, nifedipine, nimodipine, 
nisoldipine, pravastatin, verapamil and zolpidem. 
The following medications are examples of drugs that require concentration and 
therapeutic effect monitoring when administered in combination with FPV and RTV due 
to the potential for serious and/or life-threatening drug interactions:  cyclosporine, 
systemic lidocaine, rapamycin, tacrolimus, tricyclic antidepressants, theophylline, and 
warfarin.  International Normalized Ratio (INR) monitoring is recommended when 
warfarin is used concomitantly with FPV and RTV.
RTV is not recommended for use with digoxin, voriconazole, blonanserin, salmeterol and 
other drugs not recommended for use with FPV above. RTV is an inhibitor of CYP2D6 
and an inducer of CYP1A2, CYP2C9 and glucuronosyl transferase. Medications which 
interact with CYP2D6, CYP1A2, CYP2C9, and/or glucuronosyl transferase should be 
used with caution and include but are not limited to: bisoprolol, codeine, chlorpromazine, 
cyclobenzaprine, desipramine, doxepin, fluphenazine, fluoxetine, haloperidol, 
hydrocodone, methamphetamine, metoprolol, mexilitine, morphine, propranolol, 
oxycodone, paroxetine, perphenazine, risperidone, thioridazine, timolol, tramadol, 
trazodone, and venlafaxine.  
Because RTV oral solution contains alcohol, drugs such as metronidazole that may 
inhibit alcohol metabolism should be avoided.
IMPORTANT: For further information refer to local product information or the 
International Product Information for more complete information.
3.3.10.1.
GSK Supplied Background NRTI Options
Interactions Relevant to Abacavir
Based on the results of in vitro experiments and the known major metabolic pathways of 
ABC, the potential for drug interactions involving ABC is low. 
ABC shows no potential to inhibit metabolism mediated by the cytochrome P450 3A4 
enzyme. It has also been shown in vitro not to interact with drugs that are metabolised by 


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CYP 3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic metabolism has not been 
observed in clinical studies. Therefore, there is little potential for drug interactions with 
antiretroviral protease inhibitors and other drugs metabolised by major P450 enzymes. 
Clinical studies have shown that there are no clinically significant interactions between 
ABC, zidovudine and 3TC.
Ethanol - The metabolism of ABC is altered by concomitant ethanol resulting in an 
increase in AUC of ABC of about 41%.  Given the safety profile of ABC, these findings 
are not considered clinically significant.  ABC has no effect on the metabolism of 
ethanol.
Methadone - In a PK study, co-administration of 600 mg ABC twice daily with 
methadone showed a 35% reduction in ABC Cmax and a one hour delay in tmax, but 
AUC was unchanged.  The changes in ABC PK are not considered clinically relevant.  In 
this study, ABC increased the mean methadone systemic clearance by 22%.  This change 
is not considered clinically relevant for the majority of patients, however occasionally 
methadone dose re-titration may be required.
Retinoids - Retinoid compounds such as isotretinoin, are eliminated via alcohol 
dehydrogenase. Interaction with ABC is possible but has not been studied.
Refer to the local prescribing information for additional information on concurrent 
therapies.
Interactions Relevant to Lamivudine
The likelihood of interactions is low due to limited metabolism and plasma protein 
binding and almost complete renal elimination of unchanged lamivudine.
Lamivudine is predominantly eliminated by active organic cationic secretion. The 
possibility of interactions with other medicinal products administered concurrently 
should be considered, particularly when their main route of elimination is active renal 
secretion via the organic cationic transport system, e.g. trimethoprim. Other medicinal 
products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and 
were shown not to interact with lamivudine.
Active substances shown to be predominately excreted either via the active organic 
anionic pathway, or by glomerular filtration are unlikely to yield clinically significant 
interactions with lamivudine.
Zidovudine - A modest increase in Cmax (28%) was observed for zidovudine when 
administered with lamivudine, however overall exposure (AUC) was not significantly 
altered. Zidovudine had no effect on the pharmacokinetics of lamivudine. 
Trimethoprim/sulphamethoxazole - Administration of trimethoprim/sulphamethoxazole 
160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because 
of the trimethoprim component. However, unless the patient has renal impairment, no 
dosage adjustment of lamivudine is necessary (see Dosage and Administration).  
Lamivudine has no effect on the pharmacokinetics of trimethoprim or 
sulphamethoxazole. The effect of co-administration of lamivudine with higher doses of 


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co-trimoxazole for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis 
has not been studied. 
Zalcitabine - Lamivudine may inhibit the intracellular phosphorylation of zalcitabine 
when the two medicinal products are used concurrently.  Lamivudine is therefore not 
recommended to be used in combination with zalcitabine.
Emtricitabine: Lamivudine may inhibit the intracellular phosphorylation of emtricitabine 
when the two medicines are used concurrently. Additionally, the mechanism of viral 
resistance for both lamivudine and emtricitabine is mediated via mutation of the same 
viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these 
medicines in combination therapy may be limited. 3TC is not recommended for use in 
combination with emtricitabine.
Refer to the local prescribing information for additional information on concurrent 
therapies.
Packaging and Labeling of GSK Supplied Background NRTI Options
GSK will provide ABC and/or 3TC as optional background NRTIs for subjects whose 
screening HIV-1 genotype, if available, shows susceptibility to ABC and/or 3TC, or per 
investigator discretion.
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
ABC and 3TC will be supplied in their own bottle and labeled with the following 
information: protocol number, container contents, batch/inventory number, quantity, 
dosing instructions and storage conditions/instructions.  Qualified study site personnel 
should calculate the drug dose at the site. 
GSK supplied background NRTIs will be packaged such that the site investigator or 
pharmacist can dispense sufficient drug for each subject until the next scheduled study 
visit.  
Handling of GSK Supplied Background NRTI Options
GSK supplied background NRTIs will be dispatched to a site only after receipt of 
required documents in accordance with all applicable regulatory requirements and GSK 
procedures.  These documents include, but are not limited to the signed FDA Form 1572 
or equivalent, signed Financial Disclosure Agreement, signed protocol agreement and 
IEC/IRB approval letter.
ABC and 3TC will be shipped to the investigational sites by GSK.  At each visit the 
investigator or designated site staff should dispense sufficient amount of background 
NRTIs to provide adequate supply for each subject until the next scheduled visit.  All 
GSK supplied background NRTIs that are not utilized during the study will be destroyed 
at the completion of the trial.  Drug disposition records will be regularly reviewed by the 
study monitor.


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GSK supplied background NRTIs must be dispensed or administered according to 
procedures described below.  Only subjects whose HIV-1 genotype shows susceptibility 
to ABC and/or 3TC and who meet the minimum age requirements may receive GSK 
supplied background NRTIs, in accordance with all applicable regulatory requirements. 
Only authorized site personnel may supply or administer GSK supplied background 
NRTIs.  All GSK supplied background NRTIs must be stored in a secure area with access 
limited to the investigator and authorized study site personnel and under physical 
conditions that are consistent with study drug-specific requirements.
All GSK supplied background NRTIs should be stored until the time of dispensing as 
follows:
Abacavir oral solution
US/Canada/Latin America – Store between 20C - 25C 
(68F - 77F) DO NOT FREEZE. May be refrigerated.
Europe/ South Africa – Store below 30C DO NOT 
FREEZE
Abacavir tablet*
South Africa – Store at or below 30C.
Lamivudine oral solution
US/Canada/Latin America – Store in tightly closed bottles 
at 25C (77F)
Europe/ South Africa – Store at or below 25C
Lamivudine tablet
South Africa – Store at or below 30C.
*Only supplied when licensed in South Africa.
Accountability Procedures for GSK Supplied Background NRTI Options
The investigator is responsible for GSK supplied background NRTIs accountability, 
reconciliation, and record maintenance.  In accordance with all applicable regulatory 
requirements, the investigator or designated study site personnel must maintain drug 
accountability records throughout the course of the study.  This person(s) will document 
the amount of background NRTIs received from GSK, the amount supplied and/or 
administered to and returned by subjects, if applicable.
All GSK supplied background NRTIs will be handled and stored in accordance with the 
product label or information provided by GSK.
Within each subject’s CRF, start and stop dates of each background ART (both GSK 
supplied and those supplied by the subject via prescription) must be recorded on the 
background antiretroviral therapy page.  In addition, dose changes and interruptions of 
greater than 24 hours duration must be recorded.
Separate from the CRF, the site will maintain GSK Supplied Background NRTI 
Accountability Logs to include the following:

subject number

treatment number 


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
quantity of drug dispensed/returned (the unit of accountability will be 
full/partial/empty bottles)

dispensing/return date

signature or initials of individual dispensing the drug

comment area for noting discrepancies
Subjects must be instructed to return all GSK supplied background NRTIs to the site at 
each study visit for volume assessments.  This includes bottles that are empty, partially 
full and completely full.  
At the end of the study and at appropriate intervals during the study, all unused 
background NRTIs must be returned to GSK according to procedures dictated by the 
study monitor or destroyed at site and adequately documented.  
The investigator is responsible for assuring that GSK supplied background NRTIs are 
stored, dispensed and returned appropriately.  GSK monitors will regularly access 
pharmacy/dispensing records.  Cases of suspected negligence will be investigated.
4.
STUDY DRUG MANAGEMENT
4.1.
Study Drug Packaging and Labeling
The contents of the label on all study drugs will be in accordance with all applicable 
regulatory requirements.
FPV 50 mg/mL oral suspension will be supplied in its own bottle and labeled with the 
following information: protocol number, container contents, batch/inventory number and 
quantity, storage conditions/instructions, dosing instructions and shaking instructions to 
ensure adequate redispersal of the oral suspension prior to dosing.  Qualified study site 
personnel should calculate the drug dose at the site.
RTV oral solution, powder, tablets or capsules will be provided locally by the 
investigator as required and should be stored according to the local product information.
GSK will provide RTV by other means where reimbursement is not acceptable, or GSK 
may provide RTV if local supplies are not available and RTV is able to be obtained from 
other countries.
In this trial, ‘study drugs’ are defined as FPV and RTV for the purposes of recording 
adverse events and serious adverse events.  The FPV oral suspension will be packaged 
such that the site investigator or pharmacist can dispense sufficient drug for each subject 
until the next scheduled study visit.
4.2.
Study Drug Handling
Study drug will be dispatched to a site only after receipt of required documents in 
accordance with all applicable regulatory requirements and GSK procedures.  These 
documents include but are not limited to the signed FDA Form 1572 or equivalent, 
signed Financial Disclosure Agreement, signed protocol agreement and IEC/IRB 
approval letter.


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FPV will be shipped to the investigational sites by GSK.  In all countries, RTV oral 
solution, powder, tablets or capsules will be obtained locally and reimbursed if acceptable 
to regulatory authorities.  GSK will provide RTV by other means where reimbursement is 
not acceptable, or GSK may provide RTV if local supplies are not available and RTV is 
able to be obtained from other countries. At each visit, the investigator or designated site 
staff should dispense sufficient amount of study drug to provide adequate supply for each 
subject until the next scheduled visit.  All study drug that is not utilized during the study 
will be destroyed at the completion of the trial.  Drug disposition records will be regularly 
reviewed by the study monitor.
Study drug must be dispensed or administered according to procedures described below.  
Only subjects enrolled in the study may receive study drug, in accordance with all 
applicable regulatory requirements.  Only authorized site personnel may supply or 
administer study drug.  All study drugs must be stored in a secure area with access 
limited to the investigator and authorized study site personnel and under physical 
conditions that are consistent with study drug-specific requirements.
The FPV suspension should be shaken as per the label instructions prior to measuring.  
Site staff designated to dispense FPV oral suspension will also be instructed to rigorously 
shake all bottles at the point of dispensing for a minimum of 20 seconds.  The time the 
bottles were shaken for should be recorded in the Study Drug Accountability Log and this 
information will be transcribed into the corresponding page of the subject’s CRF.
Both FPV oral suspension and RTV oral solution should be measured and administered 
using separate appropriately sized oral dosing syringes.  Administration via dosing cups 
is not allowed as residual FPV oral suspension and RTV oral solution could remain in the 
cups. 
Note per Amendment 12; for subjects weighing less than 33 kg, if RTV oral solution is 
not available, the RTV powder can be substituted.  For doses less than 100 mg or partial 
doses between 100 mg increments the following instructions should be followed. Mix 1 
packet/sachet of oral powder (100 mg) with 9.4 mL of liquid (such as water, chocolate 
milk, or infant formula) in a mixing cup. Once mixed, use an oral dosing syringe to 
measure and administer the prescribed volume.  Once the powder is mixed, the dosage 
must be consumed within 2 hours. Discard any mixture remaining in the mixing cup.
Additional guidance is provided in Section 11.6.
IMPORTANT:  Do NOT mix FPV with RTV or other background NRTI medications in 
the same syringe.
Study medications should be stored until the time of dispensing as follows:
FPV 50 mg/mL oral suspension
Store below 30C (86F) DO NOT FREEZE
RTV 80 mg/mL oral solution
Store according to local product information
RTV oral powder
Store according to local product information
RTV 100 mg tablet
Store according to local product information
RTV 100 mg soft gelatin capsules
Store according to local product information


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4.3.
Study Drug Accountability Procedures
The investigator is responsible for study drug accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the investigator 
or designated study site personnel must maintain study drug accountability records 
throughout the course of the study.  This person(s) will document the amount of study 
drug received from GSK, the amount supplied and/or administered to and returned by 
subjects, if applicable.
All study drugs will be handled and stored in accordance with the product label or 
information provided by GSK.
Within each subject’s CRF, the Study Drug Record page will list the name and dose 
regimen of each study drug.  Start and stop dates of each study drug must be recorded on 
this page.  In addition, dose changes and interruptions of greater than 24 hours duration 
must be recorded.
Separate from the CRF, the site will maintain a Study Drug Accountability Log to 
include the following:

subject number

treatment number 

batch/inventory number

quantity of drug dispensed/returned (the unit of accountability will be 
full/partial/empty bottles)

dispensing/return date

signature or initials of individual dispensing the drug

comment area for noting discrepancies
Subjects must be instructed to return all study drug to the site at each study visit for 
volume assessments.  This includes bottles that are empty, partially full and completely 
full.
At the end of the study and at appropriate intervals during the study, all unused drug must 
be returned to GSK according to procedures dictated by the study monitor or destroyed at 
site and adequately documented.
The investigator is responsible for assuring that study medications are stored, dispensed 
and returned appropriately.  GSK monitors will regularly access pharmacy/dispensing 
records.  Cases of suspected negligence will be investigated.
5.
MEASUREMENTS AND EVALUATIONS
5.1.
Time and Events Schedule
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.


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After determining that a subject is potentially eligible for enrolment, written informed 
consent from each subject’s parent/guardian must be obtained before any investigations 
are performed which are for the sole purposes of this study.
Subjects will attend the clinic at Screening, Day 1 (Baseline), and Weeks 2, 4, 8, 12, 16, 
24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects may continue to receive FPV until they no 
longer derive clinical benefit or according to prior agreements between GSK and 
participating study sites for provision of ART.  A follow-up visit will be performed 
4 weeks after the permanent discontinuation of study drug.
The scheduled laboratory evaluations will involve collection of a maximum blood 
volume of 7mL/kg in any 56-day period in all subjects.  Additionally, a maximum of 
3mL/kg of blood will be collected at any one study visit from children 4 weeks to 
<6 months old.
5.2.
Screening and Enrolment
Subjects will undertake the procedures listed in the schedules in Section 10.  Screening 
will be within approximately 21 days of Baseline/Day 1 for all subjects.  As per 
amendments 5 and 7, SDV assessments are no longer required for Cohort 1 Arm A and 
Cohort 2 Arm A.
Reports of screening assessments of lymphocyte subsets, HIV-1 RNA PCR and HIV-1 
resistance testing (if performed) should be reviewed prior to Baseline/Day 1 to confirm 
that the subject meets the full eligibility criteria.  
5.3.
Demographic and Baseline Characteristics

Demography:  Subject date of birth, gender and race will be collected at the 
Screening visit.

Baseline characteristics: 
Information to be collected will include:

HIV risk factors and mode of transmission (collected at Screening visit)

CDC classification (collected at the Screening visit and summarised at Baseline)

Current medical conditions (collected at Day 1)

HIV-associated conditions (collected from Day 1)

Prior antiretroviral therapy (collected at Day 1 or the initial Single Dose Visit if 
applicable)

Background antiretroviral therapy (collected from Day 1 or the initial Single 
Dose Visit if applicable) 


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
Height, weight, head circumference and vital signs (blood pressure and pulse, 
collected at all visits)
5.4.
Study Drugs and Background NRTIs
The start and stop date for all study drugs and background NRTIs, any temporary 
interruptions or dose changes >24 hours, and information on premature discontinuation 
of study drug and background NRTIs will be collected on Day 1 and throughout the study 
period. In this trial, study drugs are defined as FPV and RTV, whereas ABC and 3TC are 
GSK supplied background NRTIs.
5.5.
Efficacy
All evaluations listed below will be performed at Screening, Day 1 and at Weeks 4, 12, 
24, 36, 48, every 12 weeks thereafter, and Withdrawal.  Refer to the study manual 
provided by the central laboratory for specific instructions on sample collection, 
preparation and shipment.

Quantitative plasma HIV-1 RNA (Roche Amplicor HIV-1 Monitor Test; version 1.5, 
ultrasensitive limit of detection (LOD) = 50 copies/mL).  Samples with >75,000
copies/mL will be retested using the Roche Amplicor HIV-1 Monitor Test, version 
1.5, standard assay LOD = 400 copies/mL.  (NOTE:  At the Screening and Baseline 
(Day 1) visits, the Roche Amplicor HIV-1 Monitor Test, version 1.5, standard assay 
will be used). Per Protocol Amendment 12: the Roche Amplicor HIV-1 Monitor Test 
Version 1.5 was subsequently discontinued after the July 2011 cut-off date for the 
week 48 CSR.  By January 2013, only two APV20002 study sites, both in South 
Africa had actively enrolled subjects; and efficacy for these subjects was evaluated 
using the Abbott Realtime HIV-1 Test, which has a LOD of 40 copies/mL.  

Lymphocyte subsets to include total lymphocytes, absolute and percent CD4+ and 
CD8+ cell counts.  

HIV associated conditions: The subject will be assessed for any new or recurring 
HIV-associated conditions at all study visits from Baseline.

Genotypic HIV-1 resistance testing: Plasma samples may be collected at the 
Screening visit at the investigator’s discretion if needed to guide selection of 
background ART.  Resistance analysis will also include an assessment of the HIV-1 
protease (PRO) coding region.  Where blood volumes permit, a sample will also be 
collected if the subject meets one of the criteria described in Section 3.3.8 with 
results provided to the investigator.

Additional storage samples may be collected at Day 1, Weeks 12, 24, 36, 48, every 
12 weeks thereafter, and Withdrawal and stored for possible HIV 
genotype/phenotype testing in the future or for repeat laboratory assessments as 
needed. 


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5.6.
Health Outcomes
5.6.1.
Humanistic Outcomes
Adherence Questionnaire
Medication adherence will be measured by the subject’s parent or guardian via 
completion of an adherence questionnaire.  The adherence questionnaire will be 
completed in order to quantify the number of doses of FPV BID and/or FPV/RTV BID 
that were missed during the course of the study.  The adherence questionnaire will be 
administered on Day 1 (Baseline practice questionnaire), Weeks 2, 12, 24, 48 and at the 
time of premature study discontinuation.
Parent/Guardian Perception of Study Medication
Parent/guardian’s attitude or perceptions of medications can impact on the acceptability 
of a medication to a child, affecting adherence and the subsequent drug efficacy in the 
pediatric population.  Parent/guardian perceptions of FPV BID and FPV/RTV BID will 
be assessed using a Parent/Guardian Perception of Study Medication assessment 
administered during Weeks 2, 24 and 48/premature study discontinuation.  
Administration of the Humanistic Questionnaires
Completeness and Accuracy of Subject Questionnaire Responses
The parent/guardian should be asked to complete the questionnaires as completely and as 
accurately as possible.  If a parent/guardian is unable to complete a questionnaire by him 
or herself, study site personnel may administer the questionnaire via an interview at the 
discretion of the investigator.  With the exception of helping parents/guardians identify 
which antiretroviral drugs the subjects are supposed to be taking, the investigator will not 
provide an answer to any question nor interpret any portion of the question.  If the 
parent/guardian requests help or clarification of any question, he or she should be asked 
to read the instructions again, or to listen again as the instructions and question are 
repeated if administration is undertaken via interview, and to give the best answer 
possible to each question.  Parents/guardians should be encouraged that it is their 
experiences and opinions that are requested, and that the subject’s treatment during the 
study will not be affected by their answers.
Recording of Data
Black ink should be used to complete the questionnaires.  Parents/guardians must be 
instructed to make any changes by drawing a line through the undesired response, dating 
the change, and then recording the desired response.
Collection and Storage of Subject Questionnaires
Upon completion of the questionnaires, the investigator will retrieve the questionnaires 
from the parent/guardian, check that the header sections (Subject Number, Visit Date, 
etc.) are complete, ensure the parent/guardian did not unintentionally skip questions or a 


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page of questions, and return them to the subject’s CRF notebook.  At this point, the 
subject questionnaires are considered complete, and they should not be given back to the 
parent/guardian.  No changes should be registered once they have been completed and 
returned to the investigator. Investigators are to record the method of administration of 
the questionnaires on the "Method of Administration for Questionnaires and Subject 
Dosing Card" CRF page.  If respondents experience difficulties or are unable to answer 
any question, then the investigator should document the reason in the investigator 
comments log.  Possible reasons for not completing the questionnaires are the 
parent/guardian refused, parent/guardian unable to understand a question or other.
Source Documents and Monitoring Procedures for Subject Questionnaires
Each questionnaire completed by the subject’s parent/guardian serves as a source 
document; therefore there are no other source documents for data validation by the 
clinical research team member.
No attempt should be made by the investigator to reconcile data recorded on the subject’s 
parent/guardian questionnaire booklets with data recorded on the clinical CRF, except for 
subject identification data (e.g., Subject Number, Treatment Number, Visit Date, Gender, 
etc.).  Neither the investigator nor any member of the clinical research team is under any 
obligation to validate the accuracy of the parent/guardian completed sections of the 
questionnaires.
5.7.
Bioanalysis and Pharmacokinetic Samples
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter.
Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. 
To measure the unbound concentration of APV, additional plasma trough PK samples 
will be collected prior to FPV/RTV BID dosing at Weeks 2, 16 and 36 for Cohort 1 Arm 
A subjects and at Weeks 8 and 16 for Cohort 2 Arm A subjects.
A maximum of 7mL/kg of blood for PK, safety, and virological assessments will be 
collected during any 56-day period for all subjects.  A maximum of 3mL/kg of blood will 
be collected at any one study visit for subjects 4 weeks to <6 months old.
Single Dose Visit (SDV)
Cohort 1 (6 months - <2 years)
Per protocol amendment 5, no additional subjects in this age group are required to 
undertake SDV assessments.


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Cohort 2 (4 weeks - <6 months)
Per protocol amendment 7, no additional subjects in this age group are required to 
undertake SDV assessments.
Week 2 PK Sampling
Subjects enrolled in both cohorts (Arm A, FPV/RTV BID) will undergo plasma PK 
sampling on Week 2.  Plasma concentrations of APV, FPV and RTV will be determined: 

Cohort 1 Arm A: A plasma trough PK sample of 1.0mL whole blood will be 
collected prior to FPV/RTV dosing.  A 2.0mL whole blood sample will be collected 
prior to dosing to determine plasma concentrations of unbound APV.  Three 1.0mL 
whole blood samples will be collected at 0, 2, and 4 hours post-dosing.

Cohort 2 Arm A: Seven whole blood samples of 0.5mL each will be collected at 0, 1, 
2, 4, 6, 8, and 12 hours post-dosing (optional 12-hour sample).
Week 4 PK Sampling
No PK sampling will be collected at Week 4 for either Cohort.
Week 8 PK Sampling
Subjects in Cohort 1 Arm A will undergo serial plasma PK sampling on Week 8.  Plasma 
concentrations of APV, FPV and RTV will be determined.  Seven whole blood samples 
will be collected at 0, 1, 2, 4, 6, 8, and 12 hours post-dosing (optional 12 hour sample).  
One mL whole blood samples will be drawn at each time point specified.
Subjects in Cohort 2 Arm A will have a plasma trough PK sample of 1.0mL whole blood 
collected prior to FPV/RTV BID dosing.  A 2.0mL whole blood sample will be collected 
prior to dosing to measure the unbound APV concentration.
Weeks 12, 16, 24, 36, 48 and every 12 weeks thereafter
All subjects will undergo additional plasma trough PK sampling of 1.0mL of whole blood 
(just prior to receiving a scheduled dose of FPV/RTV BID) at Weeks 12, 16, 24, 36, 48
and every 12 weeks thereafter.  
In addition, at Week 16 (both Cohorts) and Week 36 (Cohort 1 only), subjects will have a 
plasma trough PK sample of 2.0mL whole blood collected (prior to receiving the 
scheduled dose of FPV/RTV BID) to determine the unbound concentration of APV.
In consultation with the investigator, GSK may discontinue PK sampling and monitoring 
of plasma APV, FPV and RTV concentration on an individual basis once a subject has 
reached and exceeded 2 years and has initiated the 23/3 mg/kg BID dosing regimen after 
Week 48.  Any further dosing changes would follow the approved dosing 
recommendations without PK sampling, including a transition to FPV/RTV 18/3 mg/kg 
BID at 6 years.


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Directly Observed Therapy
Because plasma PK sampling needs to occur at steady-state, it is imperative that subjects 
consistently receive their medications prior to PK sampling.  To improve the quality of 
the serial PK samples, it is strongly recommended that the administration of study drugs 
on the evening prior to the serial PK visits and on the morning of the serial PK visits 
(after the pre-dose PK sample is collected) be directly observed by study personnel.  The 
actual method of observation will be at the discretion of the investigator and may require 
the subject to attend the clinic for dosing or may require study personnel or a home 
healthcare provider to visit the subject at their home to observe the dosing.
Logistical Considerations
Site personnel will contact each subject’s parent/guardian 3-4 days prior to each of the 
Week 2, 8, 12, 16, 24, 36, and 48 visits, and at the visits every 12 weeks thereafter, to 
remind them to record the doses, dates, and times of the three FPV/RTV doses 
administered prior to attending the study site.  Site personnel will need to schedule each 
subject’s visits so that the plasma PK trough sample is collected within 10-14 hours 
following a dose of FPV/RTV.  All subject’s parents/guardians will be provided with a 
“dosing card” as a tool to help them record doses for the 3 doses prior to plasma PK 
steady-state sampling.  The dates and times of the 3 doses administered prior to collection 
of each plasma PK sample and the doses of FPV and RTV that were administered at each 
of these times will be recorded in the CRF.  Information will also be collected on whether 
or not the subject spit up or vomited these three doses.  If the “dosing card” is missing, 
blank or incomplete, then the corresponding PK CRF pages “Prior Dosing GW433908 
and “Prior Dosing Ritonavir” may be completed by oral interview at the site at the 
discretion of the investigator.  The investigator should document the reason in the 
investigator comments log.
Information regarding partial dosing and subsequent re-dosing, if required, due to 
subjects either spitting up or vomiting their FPV oral suspension and/or RTV oral 
solution doses will be collected for the 3 doses prior to any PK sampling and for the dose 
administered immediately following the pre-dose (0 hour) PK sample on the SDV and 
Week 2 PK. 


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It is strongly advised that subject compliance should be carefully reviewed prior to all PK 
sampling.  If a significant deviation affecting kinetic sampling is noted, the investigator is 
advised to counsel the parent/caregiver as to the importance of compliance and 
reschedule the sampling until the specific issue is resolved. 
For details on collection, processing and shipping of samples consult the Study Reference 
Manual.
5.8.
Safety
The following safety evaluations will be performed during the study (see Section 10 for 
schedule of events). 

Hematology:  including hemoglobin, white blood cell (WBC) count with differential, 
mean corpuscular volume (MCV) and platelet count to be performed at the Screen 
visit, Day 1 and Weeks 4, 12, 24, 36, 48, every 12 weeks thereafter, and Withdrawal.

Clinical chemistry: including sodium, potassium, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), total bilirubin, creatinine, albumin, glucose, 
alkaline phosphatase and creatine phosphokinase (CPK) to be performed at the 
Screen visit, Day 1 and Weeks 4, 12, 24, 36, 48, every 12 weeks thereafter, and 
Withdrawal.

Lipid measures to include triglycerides, total cholesterol, high density lipoprotein 
(HDL), low density lipoprotein (LDL) to be collected at Day 1 and Weeks 24 and 48, 
every 12 weeks thereafter, and Withdrawal.

Clinical adverse events to be collected at the Screen visit, the Single Dose Visit, Day 
1 and Weeks 2, 4, 8, 12, 16, 24, 36, 48, every 12 weeks thereafter, and Withdrawal: 
Refer to Section 7 for details.

Concurrent medications/blood products and background antiretroviral medication to 
be collected at the Single Dose Visit, Day 1 and Weeks 2, 4, 8, 12, 16, 24, 36, 48, 
every 12 weeks thereafter, and Withdrawal.
Scheduled laboratory evaluations within the study will be undertaken by a central 
laboratory nominated by GSK.  However, evaluation of hematology and clinical 
chemistry may be undertaken at a local accredited laboratory with the approval of GSK.
Refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipping for each laboratory test.  Hematology and clinical 
chemistry undertaken at a local laboratory should be handled according the standard local 
procedures.


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5.9.
Premature Discontinuation
5.9.1.
Premature Discontinuation from the Study
A subject will be said to have completed the study if the subject does not permanently 
stop study drug dosing prior to end of the study and completes all scheduled study visits.
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

Subject, subject’s parent/guardian or investigator non-compliance.

At the request of the subject’s parent/guardian, investigator or GSK.

Progression of any medical condition which, in the opinion of the principal 
investigator, should preclude further participation.

If the subject requires treatment with any of the medications listed in the Exclusion 
Criteria (Section 3.2.2).

If the subject requires cytotoxic chemotherapy or radiation therapy (with the 
exception of local treatment for Kaposi’s sarcoma).

If the subject requires another investigational drug which when combined with the 
study drug would, in the opinion of the investigator or GSK, jeopardize the validity 
of the subject’s continued participation.
Subjects who prematurely discontinue from the study will not be replaced unless 
<8 subjects from each treatment regimen in each cohort have completed PK analysis after 
2 weeks on their selected regimen.  In this case, additional subjects will be added to the 
cohorts as replacement subjects.
Withdrawal
Subjects who prematurely discontinue from the study, whether voluntarily or not, should 
have the Withdrawal visit assessments performed (refer to Section 10).  Once a subject’s 
weight has increased to 39 kg or more, they should be withdrawn from the study (refer to 
Section 3.1).  A Follow-up visit will be performed 4 weeks after the Withdrawal visit.
A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time.  If a subject is prematurely discontinued from participation in 
the study for any reason, the investigator must make every effort to perform the following 
evaluations listed below.  These data should be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any subject from the study.


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Clinical Evaluations

Body weight and height

Head circumference

Vital Signs

Concurrent medications/blood products

Background ART

HIV-associated conditions

Adverse events

Questionnaires for humanistic outcomes
Laboratory Evaluations

Hematology (hemoglobin, WBC with differential, MCV and platelet count).

Lymphocyte subsets by flow cytometry (total lymphocytes and absolute and 
percentage CD4+ and CD8+ lymphocyte counts).

Clinical chemistry panel and transaminase levels (sodium, potassium, AST, ALT, 
total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and CPK).

Lipid measures including triglycerides, and total cholesterol, HDL, and LDL 
cholesterol.

Quantitative plasma HIV-1 RNA PCR.

Plasma for storage where permitted by blood volume restrictions.  This sample may 
be used for HIV-1 genotype and phenotype testing.
In the event that a subject is prematurely discontinued from the study at any time due to 
an AE (as defined in Section 7.1, “Definition of an AE”) or SAE (as defined in 
Section 7.2, “Definition of a SAE”), the procedures stated in Section 7, (“AEs and 
SAEs”) must be followed.
5.10.
Follow Up
All study subjects should have a follow up study visit 4 weeks following permanent 
discontinuation of study drug.  The follow up assessments required are detailed below 
and in Section 10.
Clinical Evaluations

Concurrent medications/blood products

Current ART

HIV-associated conditions

Adverse events

Serious adverse events


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Laboratory Evaluations

Hematology (hemoglobin, WBC with differential, MCV and platelet count).

Clinical chemistry panel and transaminase levels (sodium, potassium, AST, ALT, 
total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and CPK).
6.
DATA ANALYSIS METHODS
6.1.
Sample Size Determination
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, Arm B 
(N=24 for PK and safety; enrolment closed per Amendment 10) and FPV/RTV BID, Arm 
A (N=24 for PK and safety).  Safety and tolerability assessment of the FPV/RTV BID 
regimen (Arm A) will be for the duration of the study or until a subject permanently 
discontinues study drug.  If less than 8 subjects in a cohort and dosage regimen complete 
the steady-state PK analysis on Week 2, additional subjects may be enrolled as 
replacement subjects.  Additionally, if dose modification to the cohort dose is warranted, 
a further 8 subjects in each arm may be recruited to provide steady-state PK data on the 
revised dose. 
Based on plasma APV PK data from previous studies, the highest variability was 
observed for the FPV oral suspension formulation in APV10008.  The inter-subject 
standard deviation of loge (AUC) was 0.42.  Assuming 12 subjects provide plasma APV 
PK data for the each regimen, the width of the 95% CI for plasma APV AUCτ,ss will be 
54% of the geometric mean; therefore, the 95% CI for a FPV/RTV BID regimen 
geometric mean of 33.8g*h/mL (the value estimated in adults) will be 25.9-
44.2g*h/mL, and the 95% CI for a FPV BID geometric mean of 16.5g*h/mL (the 
value estimated in adults) will be 12.6-21.5g*h/mL.
6.2.
General Considerations
Only descriptive methods will be used in the analysis of the data obtained from this 
study.  No statistical hypothesis testing will be performed.
Data will be summarized by treatment (FPV and FPV/RTV) and may be further 
summarized by cohort and ART-experience.
6.2.1.
Analysis Populations
All subjects receiving FPV or FPV/RTV at any dose will be included in the safety 
population.  This will be the primary population for any efficacy and safety analyses.
Other populations, such as “per-protocol” population may also be considered as 
secondary populations for efficacy analysis.  Per-protocol analyses will only include 
subject data collected during treatment with FPV or FPV/RTV and will exclude data 
following major protocol deviations (these will be defined in the data analysis plan).


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Pharmacokinetic Population
All subjects for whom a plasma PK sample has been analyzed will be included in the 
listing of plasma APV, FPV and RTV concentration-time data.
Pharmacokinetic Summary Population
All subjects for whom a plasma APV, RTV and/or FPV PK parameter value is estimated 
will be included in the listings and summaries of derived plasma APV, FPV and RTV PK 
parameters and the summaries of plasma APV and FPV concentration-time data.
Pharmacokinetic/Pharmacodynamic Population
The pharmacokinetic/pharmacodynamic population will consist of all subjects with 
Baseline factors including age, body weight, height, sex, race, CD4+ cell percentage, 
plasma HIV-1 RNA concentration, and viral susceptibility data and who have at least one 
evaluable plasma APV trough concentration.
6.2.2.
Interim Analysis
For the first 6-10 subjects enrolled in each cohort, rapid turn-around plasma APV, RTV 
and FPV PK analysis will occur in order to provide individual dosage regimen 
recommendations to investigators.  In addition, expedited analysis of plasma APV, RTV 
and FPV may be undertaken on a case-by-case basis on PK trough samples collected to 
allow for dose regimen adjustment due to the physiological development with age.
Interim analyses of safety, antiviral activity, and plasma APV, FPV and RTV PK data 
will be performed as required for regulatory submissions.  No stopping rules will be 
applied.
6.2.3.
Other Issues
For any analyses which use HIV-1 RNA levels as a continuous measure (e.g., change 
from Baseline) the values will be logged to the base 10.  HIV-1 RNA values recorded as 
<400copies/mL (using the Roche HIV-1 Monitor test, version 1.5, standard assay LOD = 
400copies/mL) will be given a value of 399copies/mL.  Similarly, HIV-1 RNA values 
recorded as <50copies/mL will be given a value of 49copies/mL.  For plasma HIV-1 
RNA, lymphocyte subsets and other clinical laboratory parameters, the Baseline value 
will be defined as the value observed on Day 1 (or, if this value is missing, the last value 
observed before the start of multiple dosing with FPV or FPV/RTV). 
Response to treatment within various subgroups (e.g. age, gender, background 
antiretroviral therapy) may be investigated descriptively by the presentation of summary 
statistics by subgroup.


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6.3.
Efficacy
No formal inferential analyses are planned. Data will be presented in summary or 
graphical form.
6.3.1.
Efficacy Measurements

Proportions of subjects with plasma HIV-1 RNA levels <400 copies/mL at each 
study visit

Change from Baseline in plasma HIV-1 RNA at each study visit (absolute values and 
time-averaged)

Proportion of subjects with ≥1.0 log10 decrease in HIV-1 RNA at each study visit

Change from Baseline in CD4+ % at each study visit (absolute values and time-
averaged)
These efficacy measures will be summarized by treatment (FPV and FPV/RTV) and visit, 
and may be further summarized by cohort and ART-experience.
6.4.
Viral Resistance Testing
Viral resistance testing may be performed for subjects at Screening at the investigator’s 
discretion if needed to guide selection of background ART.
Where permitted by blood volume restrictions, viral resistance testing may also be 
performed on samples collected at Baseline/Day 1, Weeks 12, 24, 36, 48, every 12 weeks 
thereafter, and Withdrawal (time of premature discontinuation).  In addition, where blood 
volumes permit, viral resistance testing may be performed if the subject meets one of the 
criterion described in Section 3.3.8.
Analysis of viral resistance data, including an investigation of any potential correlations 
between clinical response and genotype/phenotype data, will be performed in at least a 
subset of subjects.  Viral resistance testing will evaluate pre-existing or emerging viral 
resistance in both the PI and RT coding regions of the pol gene and in the cleavage site 
coding region of the gag gene.  Viral mutations at codons associated with drug resistance 
will be evaluated with the HIV RNA response.  In addition, any difference in emerging 
resistance patterns between FPV alone or FPV enhanced with RTV will be assessed.
6.5.
Health Outcomes
6.5.1.
Humanistic Outcomes
Adherence Questionnaire
Items 1-4 of the Adherence Questionnaire measure adherence behavior during the last 
3 days for each medication prescribed to the subject.  The subject’s parent/guardian will 
respond “yes/no” to questions 1-4, assessing whether the subjects were adherent with 


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FPV or FPV/RTV.  The frequency of yes/no responses will be summarized per treatment 
group for questions 1-4, by visit.  Item 5 asks about the number of doses of FPV or 
FPV/RTV missed since the subject’s last study visit.  Number of doses missed will be 
summarized per treatment group, by visit. 
Perfect adherence: Answering “no” to items 1-4 (must respond “no” to all four items) and 
answering “0” to item 5 will result in a perfect adherence score.  The number of subjects 
per treatment group with perfect adherence scores will be calculated by visit and across 
all visits.  Depending on the data, perfect adherence may be further analyzed, looking at 
the number of subjects per treatment group who were perfectly adherent across all visits 
and relationship to viral load and Cmin.
Parent/Guardian Perception of Study Medication
Parent/guardian’s attitude or perceptions of medications can impact on the acceptability 
of a medication to a child, affecting adherence and the subsequent drug efficacy in the 
pediatric population.  Parent/guardian perceptions of FPV BID and FPV/RTV BID will 
be assessed using a Parent/Guardian Perception of Study Medication assessment 
administered during Weeks 2, 24 and 48/premature study discontinuation. Data from the 
Parent/Guardian Perception of Study Medication questionnaire will be summarized by 
visit for each question.  Between treatment group comparisons will be made, adjusting 
for country if the data permit.
6.6.
Pharmacokinetics
6.6.1.
Bioanalysis
Plasma PK samples will be analyzed for APV, RTV and where plasma volumes allow 
FPV concentrations using a validated analytical method.
6.6.2.
Pharmacokinetic Parameters
The GSK division of Clinical Pharmacology will conduct noncompartmental PK analysis 
of plasma APV and RTV concentration-time data using Winnonlin Professional, Version 
3.0 (or higher), computer software (Pharsight Corporation, Mountain View, CA.)
Values for the following single-dose plasma APV PK parameters will be estimated:

The maximum plasma concentration (Cmax) and the first time to reach Cmax (tmax) 
will be the actual observed values.

The apparent terminal plasma elimination rate-constant (z) will be estimated from 
log-linear regression analysis of the terminal phase of the plasma concentration-time 
profile.  The associated apparent terminal elimination half-life (t1/2) will be 
calculated as t1/2=ln2/z.


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
The area under the plasma concentration-time curve to the last sample time 
(AUClast) and to infinity (AUC0-) will be calculated by the log-linear trapezoidal 
method.

The apparent plasma clearance (CL/F) will be calculated as Dose/AUC.
Values for the following steady-state plasma APV and RTV PK parameters will be 
estimated:

The maximum concentration at steady-state (Cmax,ss), the first time to reach 
Cmax,ss (tmax,ss), the minimum concentration during a dosing interval (Cmin,ss), 
and the time that Cmin,ss occurs (tmin,ss) will be the actual observed values.

The concentration at the end of a dosing interval, , at steady-state (C,ss) will be 
calculated as the mean of the pre-dose and 12-hour plasma APV concentrations.

The area under the concentration-time curve during a dosing interval, , at steady-
state (AUC,ss) will be calculated by the log-linear trapezoidal method.

The average concentration during a dosing interval, , at steady-state (Cavg,ss) will 
be calculated as AUC,ss/.

The apparent plasma clearance at steady-state (CLss/F) will be calculated as Dose/ 
AUC,ss.
PK analysis of plasma FPV concentrations will not be conducted because were few 
quantifiable FPV concentrations are expected based on data in adults and older children.
Plasma APV and RTV concentration data may be also analyzed using population PK 
methods.
6.6.3.
Statistical Analysis
6.6.3.1.
Descriptive Statistics
Plasma APV, FPV and RTV concentrations will be listed by subject and planned 
sampling time and summarized by treatment regimen, dose (mg/kg), cohort, and planned 
sampling time.  Plasma APV, FPV and RTV concentrations may also be summarized by 
treatment regimen, dose (mg/kg) and planned sampling time (combined cohorts).  Plasma 
APV and RTV PK parameter values will be listed by subject and summarized by 
treatment regimen, dose (mg/kg) and cohort and may be plotted.  Plasma APV and RTV 
PK values may also be summarized by treatment (combined cohorts).  Plasma APV PK 
parameters collected for this study will be plotted with plasma APV PK data collected in 
adult subjects in FPV studies.
6.6.3.2.
Assessment of Variables Correlated with Plasma APV PK
The relationship between age, body weight, sex, height, race, Baseline CD4+ percentage, 
Baseline plasma HIV-1 RNA concentration, treatment and steady- state plasma APV PK 
parameters will be examined.


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6.7.
Pharmacokinetics/Pharmacodynamics
The pharmacokinetic/pharmacodynamic population will consist of all subjects with 
baseline factors including age, body weight, height, sex, race, CD4+ cell percentage, 
plasma HIV-1 RNA concentration, and viral resistance data and who have at least one 
evaluable plasma APV trough concentration.
The association of the above mentioned baseline factors, treatment, plasma APV trough 
concentration, and the ratio of plasma APV trough concentration to baseline viral 
resistance with changes in HIV-1 RNA concentrations, CD4+ cell counts and adverse 
events may be explored to determine which factors are important for predicting 
virological response, immunologic response and the occurrence of adverse events.  
Categorical analysis and stepwise logistic regression analysis may be used to estimate 
these relationships.
6.8.
Safety
No formal inferential analyses are planned.  Data will be presented in summary or 
graphical form.
6.8.1.
Adverse Events
Adverse events (AEs) will be coded and assigned system organ classifications, which 
will be used when summarizing the data.  The verbatim text will be used in listings 
together with the preferred and group terms.
Summaries of treatment-emergent AEs by treatment group will be produced for all AEs, 
drug-related AEs, serious AEs, AEs leading to permanent discontinuation of study drug, 
and Grade 3/4 AEs.  An adverse event is considered treatment emergent if it has onset 
date on or after the date of the first dose of study drug, and on or before the date of the 
final dose of study drug.
6.8.2.
Laboratory Test Results
Summary statistics of measured results and changes from Baseline for each hematology 
and clinical chemistry parameter will be presented.  Quartile plots for selected parameters 
will also be presented. 
Treatment-emergent toxicity grades will be presented for each graded laboratory 
parameter by treatment group.  A toxicity is considered treatment emergent if it is greater 
than the Baseline grade and if it is observed on or after the date of the first dose of study 
drug, and on or before the date of the final dose of study drug.


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7.
AEs AND SAEs
The investigator is responsible for the detection and documentation of events meeting the 
definition of an AE or SAE as provided in this protocol.  During each treatment period, 
when there is a safety evaluation, the investigator or study site personnel will be 
responsible for detecting AEs and SAEs, as detailed in this section of the protocol.  In 
order to fulfill international safety reporting obligations, the investigator will include in 
his or her assessment any SAEs resulting from study participation (e.g., complications 
resulting from the taking of a blood sample).
7.1.
Definition of an AE
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (that could include a 
clinically significant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE does include a/an:

exacerbation of a pre-existing illness.

increase in frequency or intensity of a pre-existing episodic event or condition.

condition detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study.

continuous persistent disease or symptoms present at Baseline that worsen following 
the start of the study.
An AE does not include a/an:

medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an AE.

pre-existing disease or conditions present or detected at the start of the study that do 
not worsen.

situations where an untoward medical occurrence has not occurred 
(e.g., hospitalizations for cosmetic elective surgery, social and/or convenience 
admissions).

the disease or disorder being studied or sign or symptom associated with the disease 
or disorder unless more severe than expected for the subject’s condition.

overdose of either study drug or concurrent medication without any signs or 
symptoms.


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For ViiV Healthcare clinical trials, AEs may include pre- or post-treatment events that 
occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification 
of subject’s previous therapeutic regimen).
Information on managing an overdose, including drug and non-drug therapies, is 
described in Section 3.3.7, “Overdose and Toxicity Management”.
7.2.
Definition of a SAE
An SAE is any adverse event occurring at any dose that results in any of the following 
outcomes:
a.
Death
b.
A life-threatening adverse event
c.
Inpatient hospitalization or prolongation of existing hospitalization
d.
A disability/incapacity
e.
A congenital anomaly in the offspring of a subject who received drug
f.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
g.
All presumed hypersensitivity reactions to abacavir should be reported as SAEs.
Clarifications:

“Occurring at any dose” does not imply that the subject is receiving study drug.

Life-threatening means that the subject was, in the view of the investigator, at 
immediate risk of death from the event as it occurred.  This definition does not 
include an event that, had it occurred in a more severe form, might have caused 
death.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
during the study is not considered an AE.

Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE.

“Inpatient” hospitalization means the subject has been formally admitted to a 
hospital for medical reasons.  This may or may not be overnight. It does not include 
presentation at a casualty or emergency room.

With regard to criteria “f” above, medical and scientific judgment should be used in 
deciding whether prompt reporting is appropriate in this situation.


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7.2.1.
Events or Outcomes Not Qualifying as SAEs
The events or outcomes listed in Section 11.1, Appendix 1 will be recorded in the 
“Disease-Related Events” CRF page if they occur.  However, these individual events or 
outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory 
abnormality that can be linked to any of these events or outcomes, are not reported to 
GSK as SAEs even though such event or outcome may meet the definition of SAE, 
unless the following conditions apply:

the investigator determines that the event or outcome qualifies as an SAE under part 
“f” of the SAE definition (see Section 7.2, “Definition of a SAE”), or 

the event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, or

death occurring for any reason during a study, including death due to a 
disease-related event, will always be reported promptly.

lymphomas and invasive cervical carcinomas are excluded from this exemption; they 
must be reported as SAEs even if they are considered to be HIV related.
7.3.
Lack of Efficacy as an AE or SAE
“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms or 
clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or 
SAE definition (including clarifications).
7.4.
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as AEs and SAEs
Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other 
abnormal assessments (e.g., electrocardiogram [ECGs], X-rays, vital signs) that are 
judged by the investigator as clinically significant must be recorded as AEs or SAEs if 
they meet the definition of an AE, as defined in Section 7.1, (“Definition of an AE”), or 
SAE, as defined in Section 7.2, (“Definition of a SAE”).  Clinically significant abnormal 
laboratory findings or other abnormal assessments that are detected after study drug 
administration or that are present at Baseline and worsen following the start of the study 
are included as AEs or SAEs.  However, clinically significant abnormal laboratory 
findings or other abnormal assessments that are associated with the disease being studied, 
unless judged by the investigator as more severe than expected for the subject’s 
condition, or that are present or detected at the start of the study that do not worsen, are 
not included as AEs or SAEs.
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.


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7.5.
Method, Frequency, and Time Period for Detecting AEs and 
SAEs
One of the aims of this study is to assess the safety and tolerability of FPV and the 
combination of FPV/RTV.  The investigator (or his/her designee) should record all 
adverse events and serious adverse events as defined above.  At each visit, after the 
subject’s parent/guardian has had an opportunity to spontaneously mention any problems, 
the investigator should inquire about the occurrence of adverse events through 
open-ended verbal questioning of the parent/guardian.  Appropriate open-ended verbal 
questions include:

“How is the subject feeling?”

“Has the subject had any (other) medical problems since his/her last 
visit/assessment?”

“Has the subject taken any new medicines, other than those provided for him/her in 
this study, since his/her last visit/assessment?”
Care must be taken in any instance not to introduce bias when detecting AEs and/or 
SAEs.  For this reason, the use of checklists for soliciting AEs and SAEs should be 
avoided.
All adverse event and serious adverse event information will be collected at each visit 
starting from SDV/Day 1 through to the Follow-up visit. Only serious adverse events 
relating to study participation will be collected by the investigator, starting from the 
Screening visit (Screening will be within approximately 21 days prior to Baseline/Day 1 
for all subjects.) through to the initial dosing visit (SDV/Day 1 visit).
7.6.
Documenting AEs and SAEs
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostic reports) relative 
to the event.  The investigator must then record all relevant information regarding an 
AE/SAE on the CRF.
Any AE occurring during the study must be documented in the subject’s medical records, 
in accordance with the investigator’s normal clinical practice, and on the AE page of the 
CRF.  SAEs that occur during the study must be documented in the subject’s medical 
record and on the “SAE” page of the CRF.
A separate set of “SAE” pages should be used for each SAE.  However, if at the time of 
initial reporting, multiple SAEs are present that are temporally and/or clinically related, 
they may be reported on the same “SAE” page.
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.


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If a clinically significant abnormal laboratory finding or other abnormal assessment 
meets the definition of an AE or SAE, then the AE CRF page or “SAE” CRF page must 
be completed, as appropriate.  A diagnosis, if known, or clinical signs and symptoms if 
diagnosis is unknown, rather than the clinically significant abnormal laboratory finding, 
should be completed on AE or “SAE” CRF page.  If no diagnosis is known and clinical 
signs and symptoms are not present, then the abnormal finding should be recorded.  The 
laboratory data should either be recorded in Section 1 of the “SAE” form with the 
reference range and Baseline value(s) or copies of the laboratory reports and reference 
ranges should be sent with the “SAE” CRF pages.
The “SAE” pages of the CRF should be completed as thoroughly as possible and signed 
by the investigator or his/her designee before transmittal to GSK.  It is very important
that the investigator provide his/her assessment of causality to study drug at the time of 
the initial SAE report.
AEs and subject-completed questionnaires are independent components of the study.  
Responses to each question in the questionnaires will be treated in accordance with 
standard scoring and statistical procedures detailed by the scale’s developer.  The use of a 
single question from a multidimensional health survey to designate a cause-effect 
relationship to an AE is inappropriate.
7.7.
Follow-up of AEs and SAEs
All AEs and SAEs must be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or the subject is lost to follow-up.  The investigator is 
responsible to ensure that follow-up includes any supplemental investigations as may be 
indicated to elucidate as completely as practical the nature and/or causality of the AE or 
SAE.  This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
GSK may request that the investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations.  If a subject dies during participation in 
the study or during a recognized follow-up period, GSK will be provided with a copy of 
any post-mortem findings, including histopathology.
New or updated information will be recorded on the originally completed “SAE” CRF 
with all changes signed and dated by the investigator.
7.8.
Regulatory Reporting Requirements For SAEs
The investigator must promptly report all SAEs to GSK in accordance with the 
procedures detailed in Section 7.9, “Prompt Reporting of SAEs to GSK”.  GSK has a 
legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a drug under clinical investigation.  Prompt notification of 
SAEs by the investigator to the appropriate project contact for SAE receipt is essential so 
that legal obligations and ethical responsibilities towards the safety of other subjects are 
met.


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The investigator, or responsible person according to local requirements, must comply 
with the applicable local regulatory requirements related to the reporting of SAEs to 
regulatory authorities and the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC).
This protocol has been filed under an Investigational New Drug (IND) application with 
the US Food and Drug Administration (FDA).  A given SAE may qualify as an IND 
Safety Report if the SAE is both attributable to the investigational product and 
unexpected.  In this case, all investigators filed to the IND (and associated INDs for the 
same compound) will receive an Expedited Investigator Safety Report (EISR), identical 
in content to the IND Safety Report submitted to the FDA.
EISRs are prepared according to GSK policy and are forwarded to investigators as 
necessary.  An EISR is prepared for a SAE that is both attributable to the investigational 
product and unexpected.  The purpose of the EISR is to fulfill specific regulatory and 
Good Clinical Practice (GCP) requirements, regarding the product under investigation.
When a site receives from GSK an Initial or Follow-up EISR or other safety information 
(e.g., Investigator’s Brochure Supplement and local product information or the 
International Product Information), the responsible person according to local 
requirements is required to promptly notify his or her IRB or IEC.
7.9.
Prompt Reporting of SAEs to GSK
SAEs must be reported promptly to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition of an SAE.
7.9.1.
Timeframes for Submitting SAE Reports to GSK
Initial SAE Reports
Additional Information on a 
Previously Reported SAE
Type of SAE
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hrs
“SAE” CRF pages
24 hrs
Updated “SAE” 
CRF pages
7.9.2.
Transmission of the SAE Reports
Facsimile transmission of the “SAE” CRF is the preferred method to transmit this 
information to the project contact for SAE receipt.  In the absence of facsimile 
equipment, notification by telephone is acceptable for deaths and life-threatening events, 
with a copy of the “SAE” CRF sent by overnight mail.  For SAEs that are not deaths or 
life-threatening events, telephone notification, in the absence of facsimile equipment, is 
not acceptable. Instead, a copy of the “SAE” CRF will be sent by overnight mail.  GSK 
will provide separately a list of project contacts for SAE receipt, fax numbers, and 
mailing addresses.


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7.10.
Post-study AEs and SAEs
Investigators are not obligated to actively seek AEs or SAEs in former study participants.  
However, if the investigator learns of any SAE at any time after a subject has been 
discharged from the study, and such event(s) is (are) reasonably related to the study drug, 
the investigator will promptly notify GSK.
7.11.
SAEs Related to Study Participation
An SAE considered related to study participation (e.g., procedures, invasive tests), even 
if it occurs during the pre- or post-treatment period, will be reported promptly to GSK 
(see Section 7.9, “Prompt Reporting of SAEs to GSK”).
7.12.
SAEs Involving a Non-ViiV Healthcare Product
In those instances where an SAE has occurred in a subject receiving a non-ViiV 
Healthcare product as a comparator or concurrent medication, the report must be sent to 
the appropriate project contact for SAE receipt in the same time frames as if it were a 
ViiV Healthcare product (see Section 7.9, “Prompt Reporting of SAEs to GSK”).
8.
STUDY ADMINISTRATION
8.1.
Data Collection
All subjects who are screened for the trial must be documented. The screening pages of 
the CRF will be used for this purpose.  Additionally, each site will keep a log of subjects 
who are screened and not registered.  Further information on the use of this log can be 
found in the Study Reference Manual.
GSK will provide full CRFs for each subject.  At site - all data on the CRFs must be 
entered legibly in black ink or typed, in English.  Amendments and errors on the CRFs 
should NOT be erased, covered with correction fluid or white-out, or completely crossed 
out.  Instead, a single line should be drawn through the error and the correction initialed 
and dated by the investigator or his/her authorized designee.  In those countries where the 
Committee for Proprietary Medicinal Products (CPMP) guidelines are accepted by law, 
an explanatory note for the change should also be written on the CRF.  The CRF must be 
currently maintained and should never bear the study participant’s name.  Subjects will 
be identified by subject number and treatment number only.
The investigator or designee must record all required subject data using the previously 
specified data collection method defined by GSK.  An explanation must be documented 
for any missing data.  Entering ‘ND’, ‘UNK’ or ‘NA’ should identify any requested 
information, which is not obtained or unanswerable.  The investigator must sign and date 
a declaration on the CRF attesting to his/her responsibility for the quality of all data 
recorded and that the data represents a complete and accurate record of each subject’s 
participation in the study.  Details and procedures for the completion of the CRFs are 
specified in the Study Procedures Manual.


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Pages will be reviewed by the monitor and clarified in accordance with the GSK protocol 
specific Review and Data handling guidelines.  Original CRFs will be returned to 
Data Management for processing and copies will be retained by the investigator.
CRF data will be converted to electronic form via a data entry application and loaded into 
a quality controlled database.
Validation checks will be performed on the database.  Data failing any check will be 
flagged for output on an approved hard copy form: Data query (DQ) form or via the 
electronic data query system (eDQ).  If the query cannot be resolved in house (ie: is not 
subject to a standard clarification agreement (SCA) or a data processing error), the 
original query form is sent to the GSK monitor and/or study site investigator for query 
resolution.  In such cases the investigator is requested to sign and date any explanation or 
correction.  This signed copy is the original DQ.  On return, the database will be updated 
appropriately and the original DQ stored (and eventually archived) with the original CRF.  
The database will be subject to agreed Quality Control checks before authorization and 
database lock.
Data management should ensure the completion of the protocol data specifications, which 
are supplied to an approved central laboratory.  A data manager will receive laboratory 
study files upon an agreed method of transfer (ie: electronically or via diskette) as noted 
in the specification package from the central laboratory.  The central laboratory is 
responsible for resolving and documenting validation discrepancies with study site 
personnel and/or project team members.  Discrepancies identified during data 
management validation will be communicated to the central lab.
All data requiring analysis retrieved from the site and confirmed will be entered into a 
quality controlled database.  The data will subsequently be analyzed according to the 
methods outlined in Section 6, “Data Analysis Methods.”
8.2.
Regulatory and Ethical Considerations
8.2.1.
Notification of Primary Care Physician
If agreed by the subject’s parent/guardian, the investigator should notify the subject’s 
primary care physician (if applicable) of the subject’s participation in the study.  The 
primary care physician may contact the investigator for any further information regarding 
the subject’s participation in the study.
8.2.2.
Regulatory Authority Approval
GSK will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulations prior to a site initiating the 
study in that country.


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8.2.3.
Ethical Conduct of the Study and Ethics Approval
The study will be conducted in accordance with “good clinical practice” (GCP) and all 
applicable regulations, including, where applicable, the Declaration of Helsinki.
It is the investigator’s responsibility to ensure that this protocol, the site’s informed 
consent form, and any other information (e.g., advertisements or information that 
supports or supplements the informed consent) is reviewed and approved by the 
appropriate IEC or IRB.  GSK must receive copies of the IEC or IRB approval and the 
approved informed consent materials before shipment of study drug.
If, during the study, it is necessary to amend either the protocol or the informed consent 
form, the investigator is responsible for ensuring the IEC or IRB reviews and approves 
these amended documents.  IEC or IRB approval of the amended informed consent form 
must be obtained before new subjects consent to take part in the study using this version 
of the form.  Copies of the IEC or IRB approval of the amended informed consent form 
and the approved amended informed consent form must be forwarded to GSK as soon as 
available.
8.2.4.
Subject Informed Consent
Informed consent will be obtained before the subject can participate in the study.  The 
contents and process of obtaining informed consent will be in accordance with all 
applicable regulatory requirements.
If the informed consent form is amended during the study, the investigator must follow 
all applicable regulatory requirements pertaining to approval of the amended informed 
consent form by the IEC or IRB and use of the amended form.
Per protocol amendment 12: Assent forms will also be obtained from subjects still 
enrolled in the study as of Nov 1, 2019. 
8.2.5.
Investigator Reporting Requirements
In accordance with applicable local regulatory requirements, the investigator may be 
obligated to provide periodic safety updates on the conduct of the study at his or her site 
and notification of study closure to the IRB or IEC.  Such periodic safety updates and 
notifications are the responsibility of the investigator and not of GSK.
8.3.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov.
8.4.
Study Monitoring
In accordance with applicable regulations, GCP, and GSK procedures, monitors will 
periodically contact the site, including conducting on-site visits.  The extent, nature and 


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frequency of on-site visits will be based on such considerations as the study objective 
and/or endpoints, the purpose of the study, study design complexity, and enrolment rate.
During these contacts, the monitor will:

check and assess the progress of the study

review study data collected

conduct Source Document Verification

identify any issues and address their resolution
This will be done in order to verify that the:

data are authentic, accurate, and complete

safety and rights of subjects are being protected

study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements.
The investigator agrees to allow the monitor direct access to all relevant documents and 
to allocate his/her time and the time of his/her staff to the monitor to discuss findings and 
any relevant issues.
In addition to contacts during the study, the monitor will also contact the site prior to the 
start of the study to discuss the protocol and data collection procedures with site 
personnel.
At study closure, monitors will also conduct all activities as indicated in Section 8.6, 
“Study and Site Closure”. 
The monitor is also responsible for reviewing parent/guardian-completed health outcome 
questionnaires.  The monitor will review the parent/guardian-completed health outcome 
questionnaires for extraneous written comments that could indicate possible AEs.  
Information collected in the CRF and in the parent/guardian-completed health outcome 
questionnaires are independent components of this study.  Except for header section 
information (e.g., subject number, treatment number, visit date), and other information as 
defined in the standard clarification agreement (SCA), neither the monitor nor the 
investigator will reconcile data recorded on the parent/guardian-completed health 
outcome questionnaire with data recorded in the CRFs. Parent/guardian-completed health 
outcome questionnaires generally serve as the source document; therefore, unless 
otherwise specified in the source document verification agreement, no other source 
document is available for data validation.
8.5.
Quality Assurance
At its discretion, GSK may conduct a quality assurance audit of this study.  If such an 
audit occurs, the investigator agrees to allow the auditor direct access to all relevant 
documents and to allocate his/her time and the time of his/her staff to the auditor to 
discuss findings and any relevant issues.


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In addition, regulatory agencies may conduct a regulatory inspection of this study.  If 
such an inspection occurs, the investigator agrees to allow the inspector direct access to 
all relevant documents and to allocate his/her time and the time of his/her staff to the 
inspector to discuss findings and any relevant issues.
8.6.
Study and Site Closure
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the investigator, as appropriate: 

Return of all study data to GSK.

Data clarifications and/or resolutions.

Accountability, reconciliation, and arrangements for unused study drugs.

Review of site study records for completeness.

Return of treatment codes to GSK.

Shipment of pharmacokinetic and/or pharmacodynamic samples to assay laboratory
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single site or at all sites at any time and for reasons including, but are 
not limited to, safety or ethical issues or severe non-compliance.  If such action is taken, 
GSK will discuss this with the investigator (including the reasons for taking such action) 
at that time.  GSK will promptly inform all other investigators and/or institutions 
conducting the study if the study is suspended or terminated for safety reasons, and will 
also inform the regulatory authorities of the suspension or termination of the study and 
the reason(s) for the action.  If required by applicable regulations, the investigator must 
inform the IRB or IEC promptly and provide the reason for the suspension or 
termination.
If the study is prematurely discontinued, all study data must be returned to GSK.  In 
addition, arrangements will be made for all unused study drugs in accordance with GSK 
procedures for the study.
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and GSK.
8.7.
Records Retention
In accordance with applicable regulatory requirements, following closure of the study, 
the investigator will maintain a copy of all site study records in a safe and secure 
location.  GSK will inform the investigator of the time period for retaining these records 
in order to comply with applicable regulatory requirements.


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8.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
GSK will provide the investigator with a copy of the CRF data collected from the site.  
When a clinical study report is completed, GSK will provide the major findings of the 
study to the investigator.
In addition, details of the study treatment assignment will be provided to the investigator 
to enable him/her to review the data to determine the outcome of the study for his/her 
subject.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary.
8.9.
Information Disclosure and Inventions
Ownership:
All data and records provided by GSK or generated during the study (other than a 
subject’s medical records) and all inventions discovered in the course of conducting the 
study are the property of ViiV Healthcare. If a written contract for the conduct of the 
study which includes ownership provisions inconsistent with this statement is executed, 
that contract’s ownership provisions shall apply rather than this statement.
Confidentiality:
The investigator and other study site personnel will keep confidential any information 
provided by GSK (including this protocol) related to this study and all data and records 
generated in the course of conducting the study, and will not use the information, data, or 
records for any purpose other than conducting the study.  These restrictions do not apply 
to:  (1) information which becomes publicly available through no fault of the investigator 
or study site personnel; (2) information which it is necessary to disclose in confidence to 
an IEC or IRB solely for the evaluation of the study; (3) information which it is necessary 
to disclose in order to provide appropriate medical care to a study subject, or (4) study 
results which may be published as described in the next paragraph.  If a written contract 
for the conduct of the study which includes confidentiality provisions inconsistent with 


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this statement is executed, that contract’s confidentiality provisions shall apply rather 
than this statement.
Publication:
For multi-center studies, the first publication or disclosure shall be a complete, joint 
multi-center publication or disclosure that GSK will coordinate. Thereafter, any 
secondary publications will reference the original publication(s).
The investigator shall inform GSK of any publication plans.  Prior to submitting for 
publication, presenting, using for instructional purposes or otherwise disclosing the 
results of the study, the investigator shall allow GSK a period of at least thirty (30) days 
or, for abstracts, at least five (5) working days, to review the proposed publication or 
disclosure prior to its submission for publication or other disclosure.  Publications or 
disclosures of study results shall not include other, confidential information of GSK’s.  If 
the proposed publication/disclosure risks GSK’s ability to patent any invention related to 
the study, the publication or disclosure will be modified or delayed, at the investigator’s 
option, a sufficient time to allow GSK to seek patent protection of the invention.  This 
statement does not give GSK any editorial rights over the content of a publication or 
disclosure, other than to restrict the disclosure of GSK’s confidential information.  If a 
written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement.
8.10.
External Review Committee
As per Amendment 9, an External Review Committee (ERC) will be established and 
utilized in this study. The ERC will provide external oversight of study conduct and 
medical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study. The schedule of any 
planned interim analysis and the analysis plan for ERC review is described in the charter, 
which is available upon request.


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9.
REFERENCES
Agenerase (amprenavir) Product Information. May, 2005. 
Chadwick EG, Borkowsky W, Fortuny Guasch C, et al. Antiviral activity of 
fosamprenavir/ritonavir (FpV/RtV) QD regimens in HIV-infected pediatric subjects ages 
2 to 18 years (48 week interim data, study ApV20003). In: 14th Conference on 
Retroviruses and Opportunistic Infections (CROI), Los Angeles, CA, February 25–28, 
2007. Abstract 719.
Cotton M, Cassim H, Pavía-Ruz N, et al. Pharmacokinetics, safety and antiviral activity 
of fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 
2 years-48-week study data. Pediatr Infect Dis J. 2014; 33:57-62. doi: 
10.1097/INF.0b013e3182a1123a.
Department of Health and Human Services (DHHS). Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Updated July 10, 2019. 
Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 
Accessed August 19, 2019.
Dube M, Stein J, Aberg J. Guidelines for the evaluation and management of dyslipidemia 
in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: 
Recommendations of the HIV Medicine Association of the Infectious Disease Society of 
America and the Adult AIDS Clinical Trial Group. Clin Infect Dis. 2003;37:613-627.
Durham and Swenberg. Risk Assessment:  The Changing Paradigm. In: Handbook of 
Toxicologic Pathology, Vol 1 (Eds.: Haschek WM, Rousseaux CG and Wallig MA), 
Academic Press, San Diego, 2002: 437-445.
European AIDS Clinical Society (EACS) guidelines,V9.1 updated Oct 2018. Available 
at: http://www.eacsociety.org/files/guidelines_9.1-english.pdf. Accessed on Sept 16, 
2019.
Fortuny C, Duiculescu D, Cheng K, et al. Pharmacokinetics and 48-week safety and 
antiviral activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old 
children. Pediatr Infect Dis J. 2014; 33:50-6. doi: 10.1097/INF.0b013e3182a1126a.
Gibb D, for the PENTA 5 Executive and the PENTA Steering Committee. A randomised 
trial evaluating 3 NRTI regimens (3TC/ZDV or ABC/ZDV or ABC/3TC) with and 
without nelfinavir in previously untreated HIV-infected children: 48-week follow-up 
data. (abstract) 5th International Congress on Drug Therapy in HIV Infection, Glasgow, 
UK, 2000a. also published in AIDS 2000, Vol 14, supp4 p.58 (abstractPL6.8) 
Gibb D, Giaquinto C et.al., A randomized trial evaluating nucleoside reverse transcriptor 
inhibitor (NRTI) regimens with and without nelfinavir (NFV) in HIV- infected children –
preliminary results from the PENTA 5 Trial. (abstract) 13th World AIDS Conference, 
Durban, South Africa, 2000b. Accessable at 
http://gateway.nlm.nih.gov/MeetingAbstracts/102239155.html .


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GlaxoSmithKline Document Number GM2002/00054/00 Study APV30002. A 
Randomized, Open-Label, Two Arm Trial to Compare the Safety and Antiviral Efficacy 
of GW433908/Ritonavir QD to Nelfinavir BID When Used in Combination with 
Abacavir and Lamivudine BID for 48 Weeks in Antiretroviral Therapy Naïve HIV-1 
Infected Subjects. Effective date: 6 November 2002.
GlaxoSmithKline Document Number RD1999/02344/00 Study R40576.  GW433908: 
Oral Gavage Pilot Toxicity Study in Neonatal Rats. Effective date: 18 October 2001.
GlaxoSmithKline Document Number RD2000/02506/00 Study R40877 GW433908: Two 
Week Oral Gavage Pilot Toxicity Study in Neonatal and Juvenile Wistar Han Rats. 
Effective date: 5 October 2001.
GlaxoSmithKline Document Number RD2002/00045/01 Thirteen Week Oral Gavage 
Toxicity Study in Neonatal and Juvenile Wistar Hannover Rats. Effective date: 12 July 
2004.
GlaxoSmithKline Document Number RM2001/00021/00 Study APV20001. Report on 
the first six weeks-Open-Label Phase Report of: A Randomized, Multicenter, Partially 
Double-Blinded, Repeat Dose, Cross-Over Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Antiviral Effect of Two Doses of GW433908 Compared With 
Agenerase (1200 mg BID) when Given for 28 Days to Subjects Infected With HIV-1. 
Effective date: 20 August 2001.
GlaxoSmithKline Document Number RM2002/00048/00 Study APV10016 A Pivotal, 
Phase I, Single-dose, Open-label, Randomized, Four Period, Balanced Crossover Study 
to Assess the Relative Bioavailability of the GW433908 Oral Suspension and Oral Film-
coated 700 mg Tablet Formulations and the Effect of Food on the Bioavailability of 
These Formulations in Healthy Adult Subjects Effective date: 04 November 2002.
GlaxoSmithKline Document Number RM2002/00088/00 Study APV30001. A Phase III 
Randomized, Multicenter, Parallel, Open-Label to Compare the Efficacy, Safety and 
Tolerability of GW433908 (1400 mg BID) and Nelfinavir (1250 mg BID) Over 48 
Weeks in Antiretroviral Therapy-Naïve HIV-1 Infected Adults. Effective date: 28 
October 2002.
GlaxoSmithKline Document Number RM2002/00140/00 Study APV30003. A Phase III, 
Randomized, Multicenter, Parallel Group, Open-Label, Three Arm Study to Compare the 
Efficacy and Safety of Two Dosing Regimens of GW433908/ritonavir (700 mg/100 mg
twice daily or 1400 mg/200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg
twice daily) for 48 Weeks in Protease Inhibitor Experienced HIV-Infected Adults 
Experiencing Virological Failure. Effective date: 11 November 2002.
GlaxoSmithKline Document Number RM2006/00010/00 Study ESS100732.  A Phase 
IIIB, Randomized, Open-Label, Multicenter Study of the Safety and Efficacy of 
GW433908 (700 mg BID) plus ritonavir (100 mg BID) Versus Lopinavir/ritonavir (400 
mg/100 mg BID) when Administered in Combination with the Abacavir/Lamivudine 
(600 mg/300 mg) Fixed-Dose Combination Tablet QD in Antiretroviral-Naive HIV-1 
Infected Adults Over 48 Weeks. Effective date: August 2006.


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GlaxoSmithKline Document Number RM2006/00240/00 Study APV10024.  A Pivotal, 
Phase I, Open-label, Randomized, Four-Period, Two-Part, Crossover Study to Assess the 
Relative Bioavailability of the Fosamprenavir 50 mg/mL Oral Suspension and 700 mg
Oral Film-coated Tablet Formulations Following Administration of Single 1400 mg
Doses and Following Administration of 1400 mg BID for 10 days in Healthy Adult 
Subjects Effective date: 26 July 2006.
Kaletra (lopinavir/ritonavir) Product Information August, 2019.
Mallal S, Phillips E, Carosi G, et al.  HLA-B*5701 screening for hypersensitivity to 
abacavir.  N Engl J Med. 2008; 358:568-79. doi: 10.1056/NEJMoa0706135. 
Norvir (ritonavir) Product Information June, 2019.
Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. 
Use of Antiretroviral Agents in Pediatric HIV Infection.  Updated April 16, 2019. 
Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf.
Accessed August 20, 2019.
Pelton S., Stanley K., et al. First large US study of efficacy and tolerability of ritonavir in 
HIV- infected children. (abstract) 12th World AIDS Conference, Geneva, 1998. 
Accessable at http://gateway.nlm.nih.gov/MeetingAbstracts/102227274.html  
Pinto J, Robbins B, Chen, J et al.  Pharmacokinetics and 24-Week Efficacy and Safety of 
Lopinavir/Ritonavir in HIV-1-infected Infants <6 Weeks of Age.  Poster Abstract 716, 
CROI, Los Angeles, 2007. Accessable at 
http://www.retroconference.org/2007/PDFs/716.pdf
Post FA, Moyle GJ, Stellbrink HJ et al. Randomized comparison of renal effects, 
efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, 
administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week 
results from the ASSERT study.  J Acquir Immune Defic Syndr. 2010; 55:49-57. doi: 
10.1097/QAI.0b013e3181dd911e.
Ross LL, Cotton MF, Cassim H, et al. Treatment-Emergent Mutations and Resistance in 
HIV-Infected Children Treated with Fosamprenavir-Containing Antiretroviral Regimens.
Open AIDS J. 2015; 9:38-44. doi: 10.2174/1874613601509010038
Saez-Llorens X, Violari A, Deetz C, et al.  Forty-eight-week evaluation of 
lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected 
children. Pediatr Infect Dis J, 2003;22:216–23.
South Africa Guidelines for the management of HIV-infected children-2010.  Accessible 
at https://sahivsoc.org/Files/Guidelines_for_Management_of_HIV_in_Children_2010.pdf
.Accessed Oct 24, 2019.
Squires KE, Young B, Dejesus E, et al.  Similar efficacy and tolerability of atazanavir 
compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial 


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suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected 
patients.  AIDS. 2010; 24:2019-27. doi: 10.1097/QAD.0b013e32833bee1b.
Sustiva (efavirenz) Product Information January, 2010.
Violari A, Saez – Llorens X, et al.  ABT-378 / ritonavir in HIV-1 infected children. 
(abstract) 13th World AIDS Conference, Durban, 2000. Accessable at 
http://gateway.nlm.nih.gov/MeetingAbstracts/102237697.html
Viramune (nevirapine) Product Information June, 2010.
Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected 
Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 
October 26, 2006. Accessable at 
http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf


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10.
TABLES
Revised Flow Chart of Clinical Scheduled Assessments (Per Amendments 5 and 7)
CLINCAL EVALUATION
Screening 
Visit 1
Single 
Dose 
Visit 2
Day 1 
(Baseline) 3
Week 
2
4
8
12
16
24
36
48
Every 12 
weeks 
thereafter
With-
drawal
Follow-up 
4
Written Informed Consent
Inclusion/Exclusion Criteria
Demography (date of birth, sex, and race)
HIV Risk Factors
CDC HIV-1 Classification
Current Medical Conditions
Body Weight , Height and Vital Signs














Head Circumference














Prior Antiretroviral Therapy History
Background Antiretroviral Therapy













Concurrent Medications/Blood Products













HIV-associated Conditions












Adverse Experience Surveillance
5






Adherence Questionnaire






Parent/Guardian Perception of Study Medication




1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects.  At screening only, the evaluation of the hematology, clinical chemistry and liver function 
tests may be undertaken at a local accredited laboratory at the discretion of the investigator and with approval of GlaxoSmithKline.
2.
SDVs are no longer needed for Cohort 1 Arm A and Cohort 2 Arm A..  
3.
Subjects will initiate multiple dosing on Day 1 (Baseline)
4.
4 weeks after permanent study drug discontinuation
5.
Record serious adverse events related to study participation only during screening.


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Revised Flow Chart of Laboratory Scheduled Assessments (Per Amendments 5 and 7)
LABORATORY EVALUATION2
Screening 
Visit1
Single 
Dose 
Visit
Day1 
(Baseline)
Week
2
4
8
12
16
24
36
48
Every 12 
weeks 
thereafter12
Withdrawal
Follow-
up
Lipids 3


Hematology 4



Clinical Chemistry and Liver Function 
Tests 5

Lymphocyte subsets

Quanatitative plasma HIV-1 RNA PCR

Plasma for storage 6


Pharmacokinetic Sampling10, 11
7
8
9






HIV-1 resistance testing13
1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects. 
2.
Laboratory assessments for all cohorts are prioritized as follows: hematology, chemistry, PK, plasma HIV-1 RNA PCR, lymphocyte subsets, HIV-1 RNA resistance testing, lipids, 
and plasma for storage. 
3.
Lipid measures include: triglycerides and total, high density lipoprotein (HDL), and LDL cholesterol. 
4.
Hematology includes: hemoglobin, WBC with differential, MCV and platelet count.
5.
Clinical chemistry panel and transaminase levels (sodium, potassium, AST, ALT, total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and CPK). 
6.
Plasma collected for storage where permitted by blood volume restrictions at Day 1 and Week 12, 24, 36, 48, every 12 weeks thereafter and Withdrawal.  This sample may be 
used for HIV-1 resistance testing in subjects experiencing virologic failure.
7.
SDV plasma PK sampling no longer required for Cohort 1 Arm A and Cohort 2 Arm A.
8.
Week 2: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for Cohort 2 Arm A subjects and over 4 hours (at 
0 [pre-dose], 2 and 4 hours) post-dosing for subjects in Cohort 1 Arm A 
9.
Week 8: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for subjects in Cohort 1 Arm A.
10. Samples for APV/RTV trough concentration determination collected 12 hours after the last dose at Week 8 (Cohort 2 Arm A only) and Weeks 12, 16, 24, 36, 48, and every 12 
weeks thereafter (both cohorts).  In consultation with the investigator, GSK may discontinue PK sampling and monitoring of plasma APV, FPV and RTV concentration on an 
individual basis once a subject has reached and exceeded 2 years and has initiated the 23/3 mg/kg BID dosing regimen after Week 48.  Any further dosing changes would follow 
the approved dosing recommendations without PK sampling, including a transition to FPV/RTV 18/3 mg/kg BID at 6 years.
11. Samples for unbound APV concentration evaluation should be collected 12 hours after the last dose at Week 2 (Cohort 1 Arm A), Week 8 (Cohort 2 Arm A), Week 16 (both 
cohorts), and Week 36 (Cohort 1 Arm A).
12. After Protocol Amendment 11 became effective and after the last enrolled subject had completed their 48 week visit, PK sample collection was discontinued.
13. A sample for HIV-1 RNA resistance testing may be collected at Screening at the investigator’s discretion if needed to guide selection of background ART.


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11.
APPENDICES
11.1.
Appendix 1:  1994 CDC Revised Classification System for 
HIV Infection in Children < 13 years of Age
Reference – 1994 revised classification system for human immunodeficiency virus 
infection in children less than 13 years of age. MMWR 1994: 43 (No. RR-12): 1-10.
Pediatric Human Immunodeficiency Virus (HIV) Classification1
Immunologic 
Categories
Clinical Categories
N:  No 
signs/symptoms
A:  Mild
signs/symptoms
B:2 Moderate 
signs/symptoms
C:2 Severe 
signs/symptoms
1.  No evidence of 
suppression
N1
A1
B1
C1
2.  Evidence of 
moderate 
suppression
N2
A2
B2
C2
3.  Severe 
suppression
N3
A3
B3
C3
1.
Children whose HIV infection status is not confirmed are classified by using the above grid with a letter E (for 
perinatally exposed) placed before the appropriate classification code (e.g., EN2).
2.
Both Category C and lymphoid interstitial pneumonitis in Category B are reportable to state and local health 
departments as acquired immunodeficiency syndrome.
Immunologic Categories Based on Age-Specific CD4+ T-Lymphocyte Counts and 
Percent of Total Lymphocytes
Age of Child
< 12 Months
1-5 Years
6-12 Years
Immunologic Categories
µl
 (%)
µl
  (%)
µl
   (%)
1.  No evidence of 
suppression
1,500     (25)
1,000       (25)
500         (25)
2.  Evidence of moderate 
suppression
750-1,499   (15-24)
500-999     (15-24)
200-499     (15-24)
3.  Severe suppression
< 750
(< 15)
< 500 
 (< 15)
< 200          (< 15)


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Box 2.  Clinical Categories for Children with Human Immunodeficiency Virus (HIV) Infection
CATEGORY N:  NOT SYMPTOMATIC
Children who have no signs or symptoms considered to be the result of HIV infection or who have 
only one of the conditions listed in Category A.
CATEGORY A:  MILDLY SYMPTOMATIC
Children with two or more of the conditions listed below but none of the conditions listed in 
Categories B and C.

Lymphadenopathy ( 0.5 cm at more than two sites:  bilateral - one site)

Hepatomegaly

Splenomegaly

Dermatitis

Parotitis

Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
CATEGORY B:  MODERATELY SYMPTOMATIC
Children who have symptomatic conditions other than those listed for Category A or C that are 
attributed to HIV infection.  Examples of conditions in clinical Category B include but are not limited 
to: 

Anemia (< 8gm/dl), neutropenia (< 1,000/mm3) or thrombocytopenia (< 100,000/mm3) 
persisting 30 days

Bacterial meningitis, pneumonia, or sepsis (single episode)

Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children >6 months of age

Cardiomyopathy

Cytomegalovirus infection with onset before  one month of age

Diarrhea, recurrent or chronic

Hepatitis

Herpes simplex virus (HSV) stomatitis, recurrent (more than two episodes within one year)

HSV bronchitis, pneumonitis, or esophagitis with onset before one month of age

Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome

Leiomyosarcoma

Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex

Nephropathy

Nocardiosis

Persistent fever (lasting >1 month)

Toxoplasmosis, onset before 1 month of age

Varicella, disseminated (complicated chickenpox)
CATEGORY C:  SEVERELY SYMPTOMATIC
Children who have any condition listed in the 1987 surveillance case definition for acquired 
immunodeficiency syndrome (10), with the exception of LIP (Box 3).


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Box 3.  Conditions Included in Clinical Category C for Children Infected with Human 
Immunodeficiency Virus (HIV)
CATEGORY C:  SEVERELY SYMPTOMATIC

Serious bacterial infections, multiple or recurrent (i.e., any combination of at least two culture-
confirmed infections within a two-year period) of the following types:  septicemia, pneumonia, 
meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding 
otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections)

Candidiasis, esophageal or pulmonary (bronch, trachea, lungs)

Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar 
lymph nodes)

Cryptococcosis, extrapulmonary

Cryptosporidiosis or isosporiasis  with diarrhea persisting greater than one month

Cytomegalovirus disease with onset of symptoms at age greater than one month (at a site 
other than liver, spleen, or lymph nodes)

Encephalopathy (at least one of the following progressive findings present for at least two 
months in the absence of a concurrent illness other than HIV infection that could explain the  
findings):
A. Failure to attain or loss of developmental milestones or loss of intellectual ability, verified 
by standard developmental scale or neuropsychological tests;  
B. Impaired brain growth or acquired microcephaly demonstrated by head circumference 
measurements or brain atrophy demonstrated by computerized tomography or magnetic 
resonance imaging (serial imaging is required for children < two years of age);
C. Acquired symmetric motor deficit manifested by two or more of the following:
1.
Paresis
2.
Pathologic reflexes
3.
Ataxia
4.
Gait disturbance

Herpes simplex virus infection causing a mucocutaneous ulcer that persists for greater than 
one month, or bronchitis, pneumonitis, or esophagitis for any duration affecting a child greater 
than one  month of age  

Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar 
lymph nodes)

Kaposi’s sarcoma

Lymphoma, primary, in brain

Lymphoma, small, noncleaved cell (Burkitt’s), or immunoblastic or large cell lymphoma of b-
cell or unknown immunologic phenotype

Mycobacterium tuberculosis, disseminated or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated (at a site other than or in 
addition to lungs, skin, or cervical or hilar lymph nodes)

Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or 
in addition to lungs, skin, or cervical or hilar lymph nodes)

Pneumocystis carinii pneumonia

Progressive multifocal leukoencephalopathy


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
Salmonella (nontyphoid) septicemia, recurrent

Toxoplasmosis of the brain with onset at greater than one month of age

Wasting syndrome in the absence of a concurrent illness other than HIV infection that could 
explain the following findings:
A. Persistent weight loss greater than 10% of baseline , or  
B. Downward crossing of at least two of the following percentile lines on the weight-for-age 
chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child greater than or equal to one year of age ; 
or
C. Less than 5th percentile on weight-for-height chart on two consecutive measurements.  
Greater than or equal to 30 days apart PLUS (1) chronic diarrhea (i.e., at least two loose 
stools per day for greater than or equal to 30 days; OR (2) documented fever (for greater 
than or equal to 30 days, intermittent or constant)


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11.2.
Appendix 2:  Declaration of Helsinki (Only Applicable to 
European Sites)
Initiated:  1964 17.C
Original:  English
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles
for
Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly
Helsinki, Finland, June 1964
and amended by the
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996


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A Introduction / I.Basic Principles / II.Medical Research Combined with Medical Care /
III. Non-Therapeutic Biomedical Research / Other Options
INTRODUCTION
It is the mission of the physician to safeguard the health of the people.  His or her 
knowledge and conscience are dedicated to the fulfilment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician with 
the words:  “The health of my patient will be my first consideration”, and the 
International Code of Medical Ethics declares that “A physician shall act only in the 
patient’s interest when providing medical care which might have the effect of weakening 
the physical and mental condition of the patient.”
The purpose of biomedical research involving human subjects must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the 
aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic procedures 
involve hazards.  This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, 
and medical research, the essential object of which is purely scientific and without direct 
diagnostic or therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to human 
beings to further scientific knowledge and to help suffering humanity, the World Medical 
Association has prepared the following recommendations as a guide to every physician in 
biomedical research involving human subjects.  They should be kept under review in the 
future.  It must be stressed that the standards as drafted are only a guide to physicians all 
over the world.  Physicians are not relieved from criminal, civil and ethical 
responsibilities under the laws of their own countries.
I.
BASIC PRINCIPLES
1.
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and 
animal experimentation and on a thorough knowledge of the scientific literature.
2.
The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol which should be 
transmitted for consideration. Comment and guidance to a specially appointed 
committee independent of the investigator and the sponsor provided that this 
independent committee is in conformity with the laws and regulations of the country 
in which the research experiment is performed.


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3.
Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person. The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even though 
the subject has given his or her consent.
4.
Biomedical research involving human subjects cannot legitimately be carried out 
unless the importance of the objective is in proportion to the inherent risk to the 
subject.
5.
Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over 
the interest of science and society.
6.
The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and 
to minimize the impact of the study on the subject’s physical and mental integrity 
and on the personality of the subject.
7.
Physicians should abstain from engaging in research projects involving human 
subjects unless they are satisfied that the hazards involved are believed to be 
predictable. Physicians should cease any investigation if the hazards are found to 
outweigh the potential benefits.
8.
In publication of the results of his or her research, the physician is obliged to 
preserve the accuracy of the results. Reports of experimentation not in accordance 
with the principles laid down in this Declaration should not be accepted for 
publication.
9.
In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, anticipated benefits and potential hazards of the 
study and the discomfort it may entail.  He or she should be informed that he or she 
is at liberty to abstain from participation in the study and that he or she is free to 
withdraw his or her consent to participation at any time.  The physician should then 
obtain the subject’s freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent 
of this official relationship.
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation.  Where physical or mental 
incapacity makes it impossible to obtain informed consent, or when the subject is a 
minor, permission from the responsible relative replaces that of the subject in 
accordance with national legislation.  Whenever the minor child is in fact able to 
give a consent, the minor’s consent must be obtained in addition to the consent of the 
minor’s legal guardian.


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12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration 
are complied with.
II.
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(Clinical Research)
1.
In the treatment of the sick person the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgement it offers hope of saving life, re-
establishing health or alleviating suffering.
2.
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods.
3.
In any medical study, every patient – including those of a control group, if any –
should be assured of the best proven diagnostic and therapeutic method. This does 
not exclude the use of inert placebo in studies where no proven diagnostic or 
therapeutic method exists.
4.
The refusal of the Patient to participate in the study must never interfere with the 
physician-patient relationship.
5.
If the physician considers it essential not to obtain informed consent the specific 
reasons for this proposal should be stated in the experimental protocol for 
transmission to the independent committee (I. 2).
6.
The physician can combine medical research with professional care, the objective 
being the acquisition of new medical knowledge, only to the extent that medical 
research is justified by its potential diagnostic or therapeutic value for the patient.
III.
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (Non-clinical biomedical research)
1.
In the purely scientific application of medical research carried out on a human being, 
it is the duty of the physician to remain the protector of the life and health of that 
person on whom biomedical research is being carried out.
2.
The subjects should be volunteers – either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness.
3.
The investigator or the investigating team should discontinue the research if in 
his/her or their judgement it may, if continued, be harmful to the individual.
4.
In research on man, the interest of science and society should never take precedence 
over considerations related to the wellbeing of the subject.


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11.3.
Appendix 3:  Grading of Laboratory Test Abnormalities - DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Publish Date: December 2004
LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Standard International Units are listed in italics
Absolute CD4+ count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
300 – 400/mm3
300 – 400/µL
200 – 299/mm3
200 – 299/µL
100 – 199/mm3
100 – 199/µL
< 100/mm3
< 100/µL
Absolute lymphocyte
count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
600 – 650/mm3
0.600 x 109 –
0.650 x 109/L
500 – 599/mm3
0.500 x 109 –
0.599 x 109/L
350 – 499/mm3
0.350 x 109 –
0.499 x 109/L
< 350/mm3
< 0.350 x 109/L
Absolute neutrophil count (ANC)
Adult and Pediatric,
> 7 days
1,000 – 1,300/mm3
1.000 x 109 –
1.300 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
500 – 749/mm3
0.500 x 109 –
0.749 x 109/L
< 500/mm3
< 0.500 x 109/L
Infant1,2, 2 – 7 days1,250 – 1,500/mm3
1.250 x 109 –
1.500 x 109/L
1,000 – 1,249/mm3
1.000 x 109 –
1.249 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
< 750/mm3
< 0.750 x 109/L
Infant1,2, 1 day
4,000 – 5,000/mm3
4.000 x 109 –
5.000 x 109/L
3,000 – 3,999/mm3
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm3
1.500 x 109 –
2.999 x 109/L
< 1,500/mm3
< 1.500 x 109/L
Fibrinogen, decreased
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
0.75 – 0.99 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
0.50 – 0.74 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
0.25 – 0.49 x LLN
< 50 mg/dL
< 0.50 g/L
OR
< 0.25 x LLN
OR
Associated with gross bleeding
Continued


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hemoglobin (Hgb)
Adult and Pediatric
57 days
(HIV POSITIVE ONLY)
8.5 – 10.0 g/dL
1.32 – 1.55 mmol/L
7.5 – 8.4 g/dL
1.16 – 1.31 mmol/L
6.50 – 7.4 g/dL
1.01 – 1.15 mmol/L
< 6.5 g/dL
< 1.01 mmol/L
Adult and Pediatric
57 days
(HIV NEGATIVE ONLY)
10.0 – 10.9 g/dL
1.55 – 1.69 mmol/L
OR
Any decrease
2.5 – 3.4 g/dL
0.39 – 0.53 mmol/L
9.0 – 9.9 g/dL
1.40 – 1.54 mmol/L
OR
Any decrease
3.5 – 4.4 g/dL
0.54 – 0.68 mmol/L
7.0 – 8.9 g/dL
1.09 – 1.39 mmol/L
OR
Any decrease
4.5 g/dL
0.69 mmol/L
< 7.0 g/dL
< 1.09 mmol/L
Infant1,2, 36 – 56 
days
(HIV POSITIVE OR 
NEGATIVE)
8.5 – 9.4 g/dL
1.32 – 1.46 mmol/L
7.0 – 8.4 g/dL
1.09 – 1.31 mmol/L
6.0 – 6.9 g/dL
0.93 – 1.08 mmol/L
< 6.00 g/dL
< 0.93 mmol/L
Infant1,2, 22 – 35 
days
(HIV POSITIVE OR 
NEGATIVE)
9.5 – 10.5 g/dL
1.47 – 1.63 mmol/L
8.0 – 9.4 g/dL
1.24 – 1.46 mmol/L
7.0 – 7.9 g/dL
1.09 – 1.23 mmol/L
< 7.00 g/dL
< 1.09 mmol/L
Infant1,2, 1 – 21 days
(HIV POSITIVE OR 
NEGATIVE)
12.0 – 13.0 g/dL
1.86 – 2.02 mmol/L
10.0 – 11.9 g/dL
1.55 – 1.85 mmol/L
9.0 – 9.9 g/dL
1.40 – 1.54 mmol/L
< 9.0 g/dL
< 1.40 mmol/L
International Normalized
Ratio of prothrombin time
(INR)
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0 – 10.0%
10.1 – 15.0%
15.1 – 20.0%
> 20.0%
Prothrombin Time (PT)
1.1 – 1.25 x ULN
1.26 – 1.50 x ULN
1.51 – 3.00 x ULN
> 3.00 x ULN
Partial Thromboplastin
Time (PTT)
1.1 – 1.66 x ULN
1.67 – 2.33 x ULN
2.34 – 3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm3
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm3
50.000 x 109 –
99.999 x 109/L
25,000 –
49,999/mm3
25.000 x 109 –
49.999 x 109/L
< 25,000/mm3
< 25.000 x 109/L


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Continued
WBC, decreased
2,000 – 2,500/mm3
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm3
1.500 x 109 –
1.999 x 109/L
1,000 – 1,499/mm3
1.000 x 109 –
1.499 x 109/L
< 1,000/mm3
< 1.000 x 109/L
CHEMISTRIES
Standard International Units are listed in italics
Acidosis
NA
pH < normal, but 7.3
pH < 7.3 without life-
threatening consequences
pH < 7.3 with life-threatening 
consequences
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/Dl
< 20 g/L
NA
Alkaline Phosphatase
1.25 – 2.5 x ULN2
2.6 – 5.0 x ULN2
5.1 – 10.0 x ULN2
> 10.0 x ULN2
Alkalosis
NA
pH > normal, but 7.5
pH > 7.5 without life-
threatening consequences
pH > 7.5 with life-threatening 
consequences
ALT (SGPT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
AST (SGOT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
Bilirubin (Total)
Adult and Pediatric 
>14 days
1.1 – 1.5 x ULN
1.6 – 2.5 x ULN
2.6 – 5.0 x ULN
> 5.0 x ULN
Infant1,2, 14 days
(non-hemolytic)
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
25.1 – 30.0 mg/dL
429 – 513 µmol/L
> 30.0 mg/dL
> 513.0 µmol/L
Infant1,2, 14 days
(hemolytic)
NA
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
> 25.0 mg/dL
> 428 µmol/L
Calcium, serum, high (corrected for albumin)
Adult and Pediatric 7 
days
10.6 – 11.5 mg/dL
2.65 – 2.88 mmol/L
11.6 – 12.5 mg/dL
2.89 – 3.13 mmol/L
12.6 – 13.5 mg/dL
3.14 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Infant1,2, < 7 days
11.5 – 12.4 mg/dL
2.88 – 3.10 mmol/L
12.5 – 12.9 mg/dL
3.11 – 3.23 mmol/L
13.0 – 13.5 mg/dL
3.245 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Calcium, serum, low (corrected for albumin)
Adult and Pediatric 7 
days
7.8 – 8.4 mg/dL
1.95 – 2.10 mmol/L
7.0 – 7.7 mg/dL
1.75 – 1.94 mmol/L
6.1 – 6.9 mg/dL
1.53 – 1.74 mmol/L
< 6.1 mg/dL
< 1.53 mmol/L
Continued


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Infant1,2, < 7 days
6.5 – 7.5 mg/dL
1.63 – 1.88 mmol/L
6.0 – 6.4 mg/dL
1.50 – 1.62 mmol/L
5.50 – 5.90 mg/dL
1.38 – 1.51 mmol/L
< 5.50 mg/dL
< 1.38 mmol/L
Cardiac troponin I (cTnI)
NA
NA
NA
Levels consistent with 
myocardial infarction or unstable 
angina as defined by the 
manufacturer
Cardiac troponin T (cTnT)
NA
NA
NA
0.20 ng/mL
OR
Levels consistent with 
myocardial infarction or unstable 
angina as defined by the 
manufacturer
Cholesterol (fasting)
Adult 18 years
200 – 239 mg/dL
5.18 – 6.19 mmol/L
240 – 300 mg/dL
6.20 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Pediatric < 18 years
170 – 199 mg/dL
4.40 – 5.15 mmol/L
200 – 300 mg/dL
5.16 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Creatine Kinase
3.0 – 5.9 x ULN2
6.0 – 9.9 x ULN2
10.0 – 19.9 x ULN2
20.0 x ULN2
Creatinine
1.1 – 1.3 x ULN2
1.4 – 1.8 x ULN2
1.9 – 3.4 x ULN2
3.5 x ULN2
Glucose, serum, high
Nonfasting
116 – 160 mg/dL
6.44 – 8.88 mmol/L
161 – 250 mg/dL
8.89 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Fasting
110 – 125 mg/dL
6.11 – 6.94 mmol/L
126 – 250 mg/dL
6.95 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Glucose, serum, low
Adult and Pediatric 1 
month
55 – 64 mg/dL
3.05 – 3.55 mmol/L
40 – 54 mg/dL
2.22 – 3.06 mmol/L
30 – 39 mg/dL
1.67 – 2.23 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Infant1,2, < 1 month
50 – 54 mg/dL
2.78 – 3.00 mmol/L
40 – 49 mg/dL
2.22 – 2.77 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Continued


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Lactate
< 2.0 x ULN without
acidosis
2.0 x ULN without
acidosis
Increased lactate with pH < 
7.3 without life-threatening 
consequences
Increased lactate with pH <7.3 
with life-threatening 
consequences
LDL cholesterol (fasting)
Adult 18 years
130 – 159 mg/dL
3.37 – 4.12 mmol/L
160 – 190 mg/dL
4.13 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Pediatric > 2 - < 18 
years
110 – 129 mg/dL
2.85 – 3.34 mmol/L
130 – 189 mg/dL
3.35 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Lipase
1.1 – 1.5 x ULN
1.6 – 3.0 x ULN
3.1 – 5.0 x ULN
> 5.0 x ULN
Magnesium, serum, low
1.2 – 1.4 mEq/L
0.60 – 0.70 mmol/L
0.9 – 1.1 mEq/L
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L
0.30 – 0.44 mmol/L
< 0.60 mEq/L
< 0.30 mmol/L
Pancreatic amylase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Phosphate, serum, low
Adult and Pediatric > 
14 years
2.5 mg/dL – < LLN
0.81 mmol/L – < LLN
2.0 – 2.4 mg/dL
0.65 – 0.80 mmol/L
1.0 – 1.9 mg/dL
0.32 – 0.64 mmol/L
< 1.00 mg/dL
< 0.32 mmol/L
Pediatric 1 year – 14 
years
3.0 – 3.5 mg/dL
0.97 – 1.13 mmol/L
2.5 – 2.9 mg/dL
0.81 – 0.96 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Pediatric < 1 year
3.5 – 4.5 mg/dL
1.13 – 1.45 mmol/L
2.5 – 3.4 mg/dL
0.81 – 1.12 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Potassium, serum, high
5.6 – 6.0 mEq/L
5.6 – 6.0 mmol/L
6.1 – 6.5 mEq/L
6.1 – 6.5 mmol/L
6.6 – 7.0 mEq/L
6.6 – 7.0 mmol/L
> 7.0 mEq/L
> 7.0 mmol/L
Potassium, serum, low
3.0 – 3.4 mEq/L
3.0 – 3.4 mmol/L
2.5 – 2.9 mEq/L
2.5 – 2.9 mmol/L
2.0 – 2.4 mEq/L
2.0 – 2.4 mmol/L
< 2.0 mEq/L
< 2.0 mmol/L
Sodium, serum, high
146 – 150 mEq/L
146 – 150 mmol/L
151 – 154 mEq/L
151 – 154 mmol/L
155 – 159 mEq/L
155 – 159 mmol/L
160 mEq/L
160 mmol/L
Sodium, serum, low
130 – 135 mEq/L
130 – 135 mmol/L
125 – 129 mEq/L
125 – 129 mmol/L
121 – 124 mEq/L
121 – 124 mmol/L
120 mEq/L
120 mmol/L
Triglycerides (fasting)
NA
500 – 750 mg/dL
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL
8.49 – 13.56 mmol/L
> 1,200 mg/dL
> 13.56 mmol/L
Uric acid
7.5 – 10.0 mg/dL
0.45 – 0.59 mmol/L
10.1 – 12.0 mg/dL
0.60 – 0.71 mmol/L
12.1 – 15.0 mg/dL
0.72 – 0.89 mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
Continued


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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
URINALYSIS
Standard International Units are listed in italics
Hematuria (microscopic)
6 – 10 RBC/HPF
> 10 RBC/HPF
Gross, with or without clots 
OR with RBC casts
Transfusion indicated
Proteinuria, random
Collection
1 +
2 – 3 +
4 +
NA
Proteinuria, 24 hour collection
Adult and Pediatric  
10 years
200 – 999 mg/24 h
0.200 – 0.999 g/d
1,000 – 1,999 mg/24 h
1.000 – 1.999 g/d
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d
> 3,500 mg/24 h
> 3.500 g/d
Pediatric > 3 mo -< 10 
years
201 – 499 mg/m2/24 h
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 g/d
1.
Values are for term infants.
2.
Use age and sex appropriate values (e.g., bilirubin), including preterm infants


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11.4.
Appendix 4:  Grading of Clinical Adverse Experiences - DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Publish Date: December 2004
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event NOT 
identified elsewhere in this DAIDS 
AE grading table
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions OR Medical or 
operative intervention indicated to 
prevent permanent impairment, 
persistent disability, or death
SYSTEMIC
Acute systemic allergic reaction
Localized urticaria (wheals) with 
no medical intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild bronchospasm
Acute anaphylaxis OR Life-threatening 
bronchospasm OR laryngeal edema
Chills
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
NA
Fatigue
Malaise
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Incapacitating fatigue/malaise 
symptoms
causing inability to perform basic self-
care functions
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C
Pain (indicate body site)
DO NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain)
See also Headache, Arthralgia, 
and Myalgia
Pain causing no or minimal 
interference with usual social & 
functional activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to perform 
usual social & functional activities
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization (other than emergency 
room visit) indicated
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Unintentional weight loss
NA
5 – 9% loss in body weight from 
baseline
10 – 19% loss in body weight from 
baseline
20% loss in body weight from 
baseline OR Aggressive intervention 
indicated [e.g., tube feeding or total 
parenteral nutrition (TPN)]
INFECTION
Infection (any other than HIV 
infection)
Localized, no systemic 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial treatment 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual
social & functional activities OR 
Operative intervention (other than 
simple incision and drainage) 
indicated
Life-threatening consequences (e.g.,
septic shock)
INJECTION SITE REACTIONS
Injection site pain (pain without 
touching)
Or
Tenderness (pain when area is 
touched)
Pain/tenderness causing no or 
minimal limitation of use of limb
Pain/tenderness limiting use of limb 
OR Pain/tenderness causing greater 
than minimal interference with usual 
social & functional activities
Pain/tenderness causing inability to 
perform usual social & functional 
activities
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than emergency 
room visit) indicated for management of 
pain/tenderness
Injection site reaction (localized)
Adult > 15 years
Erythema OR Induration of 5x5 cm 
– 9x9 cm (or 25 cm2 – 81cm2)
Erythema OR Induration OR Edema 
> 9 cm any diameter (or > 81 cm2)
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess OR 
Drainage
Necrosis (involving dermis and deeper
tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR Edema 
> 2.5 cm diameter but < 50% 
surface area of the extremity 
segment (e.g., upper arm/thigh)
Erythema OR Induration OR Edema 
involving 50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR Phlebitis 
OR Sterile abscess OR Drainage
Necrosis (involving dermis and deeper 
tissue)
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Pruritis associated with injection
See also Skin: Pruritis (itching - no 
skin lesions)
Itching localized to injection site 
AND Relieved spontaneously or 
with < 48 hours treatment
Itching beyond the injection site but 
not generalized OR Itching localized 
to injection site requiring 48 hours 
treatment
Generalized itching causing inability 
to perform usual social & functional 
activities
NA
SKIN – DERMATOLOGICAL
Alopecia
Thinning detectable by study 
participant (or by caregiver for 
young children and disabled 
adults)
Thinning or patchy hair loss 
detectable by health care provider
Complete hair loss
NA
Cutaneous reaction – rash
Localized macular rash
Diffuse macular, maculopapular, or 
morbilliform rash OR Target lesions
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site
Extensive or generalized bullous 
lesions OR Stevens-Johnson syndrome 
OR Ulceration of mucous membrane 
involving two or more distinct mucosal 
sites OR Toxic epidermal necrolysis 
(TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis (itching – no skin lesions)
(See also Injection Site Reactions: 
Pruritis associated with injection)
Itching causing no or minimal 
interference with usual social & 
functional activities
Itching causing greater than minimal 
interference with usual social & 
functional activities
Itching causing inability to perform 
usual social & functional activities
NA
CARDIOVASCULAR
Cardiac arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-urgent 
medical intervention indicated
Symptomatic, non-life-threatening 
AND Non-urgent medical 
intervention indicated
Life-threatening arrhythmia OR Urgent 
intervention indicated
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Cardiac-ischemia/infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia
Unstable angina OR Acute myocardial 
infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No transfusion 
indicated
Symptomatic AND Transfusion of 
2 units packed RBCs (for children 
10 cc/kg) indicated
Life-threatening hypotension OR 
Transfusion of > 2 units packed RBCs 
(for children >10 cc/kg) indicated
Hypertension
Adult > 17 years
(with repeat testing at same 
visit)
> 140 – 159 mmHg systolic
OR
> 90 – 99 mmHg diastolic
> 160 – 179 mmHg systolic
OR
> 100 – 109 mmHg diastolic
> 180 mmHg systolic
OR
> 110 mmHg diastolic
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
Pediatric 17 Years
(with repeat testing at same 
visit)
NA
91st – 94th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic)
95th percentile adjusted for age, 
height, and gender (systolic and/or 
diastolic)
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
Hypotension
NA
Symptomatic, corrected with oral 
fluid replacement
Symptomatic, IV fluids indicated
Shock requiring use of vasopressors or 
mechanical assistance to maintain 
blood pressure
Pericardial effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or larger 
effusion requiring no intervention
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent 
intervention indicated
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval
0.21 – 0.25 sec
PR interval
> 0.25 sec
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec
Complete AV block
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Pediatric 16 Years
1st degree AV block (PR > normal 
for age and rate)
Type I 2nd degree AV block
Type II 2nd degree AV block
Complete AV block
Prolonged QTc
Adult > 16 years
Asymptomatic, QTc interval 0.45 –
0.47 sec OR Increase interval < 
0.03 sec above baseline
Asymptomatic, QTc interval 0.48 –
0.49 sec OR Increase in interval 
0.03 – 0.05 sec above baseline
Asymptomatic, QTc interval 0.50 
sec OR Increase in interval 0.06 
sec above baseline
Life-threatening consequences, e.g. 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Pediatric 16 years
Asymptomatic, QTc
interval 0.450 –
0.464 sec
Asymptomatic, QTc
interval 0.465 –
0.479 sec
Asymptomatic, QTc
interval 0.480 sec
Life-threatening consequences, e.g. 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Thrombosis/embolism
NA
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus)
Vasovagal episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular dysfunction 
(congestive heart failure)
NA
Asymptomatic diagnostic finding 
AND intervention indicated
New onset with symptoms OR 
Worsening symptomatic congestive 
heart failure
Life-threatening congestive heart failure
GASTROINTESTINAL
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss
Loss of appetite associated with 
significant weight loss
Life-threatening consequences OR 
Aggressive intervention indicated [e.g., 
tube feeding or   total parenteral 
nutrition (TPN)]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite intervention
Life-threatening consequences
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences (e.g., 
sepsis or perforation)
Constipation
NA
Persistent constipation requiring 
regular use of dietary modifications, 
laxatives, or enemas
Obstipation with manual evacuation 
indicated
Life-threatening consequences (e.g., 
obstruction)
Diarrhea
Adult and
Pediatric 1 year
Transient or intermittent episodes 
of unformed stools OR Increase of 
3 stools over baseline per 24-hour 
period
Persistent episodes of unformed to 
watery stools OR Increase of 4 – 6 
stools over baseline per 24-hour 
period
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV 
fluid replacement indicated
Life-threatening consequences (e.g., 
hypotensive shock)
Pediatric < 1 year
Liquid stools (more unformed than 
usual) but usual number of stools
Liquid stools with increased number 
of stools OR Mild dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in severe 
dehydration with aggressive rehydration 
indicated OR Hypotensive shock
Dysphagia-
Odynophagia
Symptomatic but able to eat usual 
diet
Symptoms causing altered dietary 
intake without medical intervention 
indicated
Symptoms causing severely altered 
dietary intake with medical 
intervention indicated
Life-threatening reduction in oral intake
Mucositis/stomatitis (clinical exam)
Indicate site (e.g., larynx, oral)
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-Odynophagia 
and Proctitis
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations
Confluent pseudomembranes or 
ulcerations OR Mucosal bleeding 
with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking)
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Nausea
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake
Persistent nausea resulting in 
decreased oral intake for 24 – 48 
hours
Persistent nausea resulting in 
minimal oral intake for > 48 hours 
OR Aggressive rehydration 
indicated (e.g., IV fluids)
Life-threatening consequences (e.g., 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND Hospitalization 
not indicated (other than emergency 
room visit)
Symptomatic AND Hospitalization 
indicated (other than emergency 
room visit)
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, sepsis)
Proctitis (functional-symptomatic)
Also see Mucositis/stomatitis for 
clinical exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual
social & functional activities OR 
Medical intervention indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Operative intervention 
indicated
Life-threatening consequences (e.g., 
perforation)
Vomiting
Transient or intermittent vomiting 
with no or minimal interference 
with oral intake
Frequent episodes of vomiting with 
no or mild dehydration
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(e.g., IV fluids)
Life-threatening consequences (e.g., 
hypotensive shock)
NEUROLOGIC
Alteration in personality-behavior 
or in mood (e.g., agitation, anxiety, 
depression, mania, psychosis)
Alteration causing no or minimal 
interference with usual social & 
functional activities
Alteration causing greater than 
minimal interference with usual 
social & functional activities
Alteration causing inability to 
perform usual social & functional 
activities
Behavior potentially harmful to self or 
others (e.g., suicidal and homicidal 
ideation or attempt, acute psychosis) 
OR Causing inability to perform basic 
self-care functions
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Altered Mental Status
For Dementia, see Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
Changes causing no or minimal 
interference with usual social & 
functional activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social & 
functional activities
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social & 
functional activities
Delirium OR obtundation, OR coma
Ataxia
Asymptomatic ataxia detectable 
on exam OR Minimal ataxia 
causing no or minimal interference 
with usual  social & functional 
activities
Symptomatic ataxia causing greater 
than minimal interference with usual 
social & functional activities
Symptomatic ataxia causing inability 
to perform usual social & functional 
activities
Disabling ataxia causing inability to 
perform basic self-care functions
Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
Disability causing no or minimal 
interference with usual social & 
functional activities OR 
Specialized resources not 
indicated
Disability causing greater than 
minimal interference with usual 
social & functional activities OR 
Specialized resources on part-time 
basis indicated
Disability causing inability to perform 
usual social & functional activities 
OR Specialized resources on a full-
time basis indicated
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated
CNS ischemia (acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident (CVA, 
stroke) with neurological deficit
Developmental delay
– Pediatric 16 Years
Mild developmental delay, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting
Moderate developmental delay, 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, either 
motor or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting
Developmental regression, either motor 
or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Headache
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions OR 
Hospitalization indicated (other than 
emergency room visit) OR Headache 
with significant impairment of alertness 
or other neurologic function
Insomnia
NA
Difficulty sleeping causing greater 
than minimal interference with usual 
social & functional activities
Difficulty sleeping causing inability 
to perform usual social & functional 
activities
Disabling insomnia causing inability to 
perform basic self-care functions
Neuromuscular weakness 
(including myopathy & 
neuropathy)
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no or 
minimal interference with usual 
social & functional activities
Muscle weakness causing greater 
than minimal interference with usual 
social & functional activities
Muscle weakness causing inability 
to perform usual social & functional 
activities
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation
Neurosensory Alteration (including 
paresthesia and painful 
neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or minimal 
interference with usual social & 
functional activities
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social & 
functional activities
Sensory alteration or paresthesia 
causing inability to perform usual 
social & functional activities
Disabling sensory alteration or 
paresthesia causing inability to perform 
basic self-care functions
Seizure: (new onset)
– Adult 18 years
See also Seizure: (known pre-
existing seizure disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Seizure: (known pre-existing 
seizure disorder)
– Adult 18 years
For worsening of existing epilepsy 
the grades should be based on an 
increase from previous level of 
control to any of these levels.
NA
Increased frequency of pre-existing 
seizures (non-repetitive) without 
change in seizure character OR 
Infrequent break-through seizures 
while on stable medication in a 
previously controlled seizure 
disorder
Change in seizure character from 
baseline either in duration or quality 
(e.g., severity or focality)
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
Seizure
– Pediatric < 18 years
Seizure, generalized onset with or 
without secondary generalization, 
lasting < 5 minutes with < 24 
hours post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting 5 – 20 minutes with <24 
hours post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting >20 minutes
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation
Syncope (not associated with a 
procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or minimal 
interference with usual social & 
functional activities
Vertigo causing greater than 
minimal interference with usual 
social & functional activities
Vertigo causing inability to perform 
usual social & functional activities
Disabling vertigo causing inability to 
perform basic self-care Functions
RESPIRATORY
Bronchospasm (acute)
FEV1 or peak flow reduced to 70 –
80%
FEV1 or peak flow 50 – 69%
FEV1 or peak flow 25 – 49%
Cyanosis OR FEV1 or peak flow < 25% 
OR Intubation
Dyspnea or respiratory distress
Adult 14 years
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities
Dyspnea at rest causing inability to 
perform usual social & functional 
activities
Respiratory failure with ventilatory 
support Indicated
Pediatric < 14 years
Wheezing OR minimal increase in 
respiratory rate for age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 –
95%
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 90%
Respiratory failure with ventilatory 
support indicated
continued


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


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
GENITOURINARY
Cervicitis (symptoms)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions
Cervicitis (clinical exam)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
Minimal cervical abnormalities on 
examination (erythema,
Mucopurulent discharge, or 
friability) OR Epithelial disruption < 
25% of total surface
Moderate cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or friability) 
OR Epithelial disruption of 25 – 49% 
total surface
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or friability) 
OR Epithelial disruption 50 – 75% 
total surface
Epithelial disruption > 75% total surface
Inter-menstrual bleeding (IMB)
Spotting observed by participant 
OR Minimal blood observed during 
clinical or colposcopic examination
Inter-menstrual bleeding not greater 
in duration or amount than usual 
menstrual cycle
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle
Hemorrhage with life-threatening 
hypotension OR Operative intervention 
indicated
Urinary tract obstruction (e.g., 
stone)
NA
Signs or symptoms of urinary tract 
obstruction without hydronephrosis 
or renal dysfunction
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction
Obstruction causing life-threatening 
consequences
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Vulvovaginitis (symptoms)
(Use in studies evaluating topical 
study agents) 
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
Symptoms causing no or minimal 
interference with usual social & 
functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & functional 
activities
Symptoms causing inability to perform 
basic self-care functions
Vulvovaginitis (clinical exam)
(Use in studies evaluating topical 
study agents)
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
Minimal vaginal abnormalities on 
examination OR Epithelial 
disruption <25% of total surface
Moderate vaginal abnormalities on 
examination OR Epithelial disruption 
of 25 - 49% total surface
Severe vaginal abnormalities on 
examination OR Epithelial disruption 
50 - 75% total surface
Vaginal perforation OR Epithelial 
disruption > 75% total surface
OCULAR/VISUAL
Uveitis
Asymptomatic but detectable on 
exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention indicated
Disabling visual loss in affected eye(s)
Visual changes (from baseline)
Visual changes causing no or 
minimal interference with usual 
social & functional activities
Visual changes causing greater than 
minimal interference with usual 
social & functional activities
Visual changes causing inability to 
perform usual social & functional 
activities
Disabling visual loss in affected eye(s)
ENDOCRINE/METABOLIC
Abnormal fat accumulation (e.g., 
back of neck, breasts, abdomen)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious changes on 
casual visual inspection
NA
Continued


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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Diabetes mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current medications to regain 
glucose control
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-ketotic 
coma)
Gynecomastia
Detectable by study participant or 
caregiver (for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
Hyperthyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification
Life-threatening consequences (e.g., 
thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification
Life-threatening consequences (e.g., 
myxedema coma)
Lipoatrophy (e.g., fat loss from the 
face, extremities, buttocks)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
1.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
2.
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).
3.
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.
4.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).


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11.5.
Appendix 5:  Dosing Table for FPV Oral Suspension
FPV 45 mg/kg BID (<2 years old)
Weight (kg)
Dose (mg): 45 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
3
135
2.7
1
3.5
158
3.2
1
4
180
3.6
1
4.5
203
4.1
2
5
225
4.5
2
5.5
248
5.0
2
6.0
270
5.4
2
6.5
293
5.9
2
7.0
315
6.3
2
7.5
338
6.8
2
8
360
7.2
2
8.5
383
7.7
3
9
405
8.1
3
9.5
428
8.6
3
10
450
9.0
3
10.5
473
9.5
3
11
495
9.9
3
11.5
518
10.4
3
12
540
10.8
3
12.5
563
11.3
4
13
585
11.7
4


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FPV 60 mg/kg BID (<2 years old)
Weight (kg)
Dose (mg): 60 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
3
180
3.6
1
3.5
210
4.2
2
4
240
4.8
2
4.5
270
5.4
2
5
300
6
2
5.5
330
6.6
2
6.0
360
7.2
2
6.5
390
7.8
3
7.0
420
8.4
3
7.5
450
9
3
8
480
9.6
3
8.5
510
10.2
3
9
540
10.8
3
9.5
570
11.4
4
10
600
12
4
10.5
630
12.6
4
11
660
13.2
4
11.5
690
13.8
4
12
720
14.4
4
12.5
750
15
5
13
780
15.6
5
As per Section 3.3.5.1, for subjects exceeding 6 years of age, the following weight-based 
dosing for FPV should be used:
FPV 18 mg/kg BID (>6 years old)
Weight (kg)
Dose (mg): 18 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
25
450
9
3
26
468
9.4
3
27
486
9.7
3
28
504
10.1
3
29
522
10.4
3
30
540
10.8
3
31
558
11.2
3
32
576
11.5
4
33
594
11.9
4
34
612
12.2
4
35
630
12.6
4
36
648
13
4


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Weight (kg)
Dose (mg): 18 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
37
666
13.3
4
38
684
13.7
4


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11.6.
Appendix 6:  Dosing Table for RTV Oral Solution, Powder, 
Capsules and Tablets
RTV Oral Solution 7 mg/kg BID (<2 years old)
Weight (kg)
Dose (mg): 7 
mg/kg
Amount of 80 mg/mL solution 
(mL) per Dose
3
21
0.26
3.5
24.5
0.31
4
28
0.35
4.5
31.5
0.39
5
35
0.44
5.5
38.5
0.48
6.0
42
0.53
6.5
45.5
0.57
7.0
49
0.61
7.5
52.5
0.66
8
56
0.70
8.5
59.5
0.74
9
63
0.79
9.5
66.5
0.83
10
70
0.88
10.5
73.5
0.92
11
77
0.96
11.5
80.5
1.01
12
84
1.05
12.5
87.5
1.09
13
91
1.14


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As per Section 3.3.5.1, for subjects exceeding 6 years of age, the following weight-based 
dosing for RTV oral solution should be used:
RTV Oral Solution 3 mg/kg BID (>6 years old)
Weight (kg)
Dose (mg): 3 mg/kg
Amount of 80 mg/mL 
suspension (mL) per Dose
25
75
0.9
26
78
1.0
27
81
1.0
28
84
1.1
29
87
1.1
30
90
1.1
31
93
1.2
32
96
1.2
≥33a
99
1.2
Subjects who are ≥33kg and are receiving RTV oral solution at a dose of 3mg/kg should 
remain at the recommended optimal dose for ≥33kg (99mg BID for 3mg/kg dosing) even 
as their weight increases above 33kg. The maximum allowed total daily dose for RTV 
oral solution is 200mg.
The following weight-based dosing for RTV oral powder can be used if RTV oral 
solution is not available.  For doses less than 100 mg or partial doses between 100 mg 
increments: Mix 1 packet/sachet of oral powder (100 mg) with 9.4 mL of liquid (such as 
water, chocolate milk, or infant formula) in a mixing cup. Once mixed, use an oral dosing 
syringe to measure and administer the prescribed volume.  Once the powder is mixed, the 
dosage must be consumed within 2 hours. Discard any mixture remaining in the mixing 
cup.
RTV Oral Powder (100 mg sachets) 3 mg/kg BID (>6 year old)
Weight (kg)
Dose (mg): 3 mg/kg
Amount of liquid per dose 
once the sachet with 100 mg
powder is dissolved in 9.4 
mL of liquid (10 mg/mL)
25
75
7.5 mL
26
78
7.8 mL
27
81
8.1 mL
28
84
8.4 mL
29
87
8.7 mL
30
90
9.0 mL
31
93
9.3 mL
32
96
9.6 mL
≥33a
99
10.0 mL


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As per Section 3.3.5.1, for subjects exceeding 6 years of age who weigh ≥33kg and can 
swallow capsules or tablets whole, the following weight-based dosing for RTV oral 100 
mg tablets or 100 mg capsules should be used: 1 capsule or tablet (dose of 100 mg) BID.  
The maximum allowed total daily dose of RTV capsules or tablets is 200 mg. 


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11.7.
Appendix 7:  Country Specific Requirements
Country-Specific Requirements
No country-specific requirements exist.


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11.8.
Appendix 8:  Protocol Amendment 1
A summary of protocol changes for Amendment 1 are listed below.  These changes were 
incorporated into the protocol at the time Amendment was issued and are incorporated 
into Amendment 7. 
STUDY DESIGN CHANGES

To change the lower age limit for subject participation from 6 weeks to 4 weeks.

To revise the study design.

To revise the stratification within the two age cohorts.

To revise the details of the study population in line with the revised study design.

To describe study measurements and evaluations.

To revise the study objectives.

To revise the study endpoints.

To revise details of subject allocation to treatment groups.

To add details of screening and enrolment procedures.

To reschedule the administration of the adherence questionnaire from week 4 to 
week 2.

To revise details of scheduled safety assessments and selected safety laboratories.

To revise details of planned interim analysis.

To revise details of dose volumes required.

To revise the flow chart of scheduled assessments.

To revise the timelines for cohort recruitment and Dosing of Subjects with 
GW433908 and / or GW433908/RTV.

To revise the rash management table.
ADDITION OF NEW DATA FROM OTHER FPV STUDIES

To update information pertaining the phase III pivotal adult studies.

To update study background and rationale.

To update the FPV neonatal toxicology section.
CHANGES RELATING TO DOSE SELECTION AND PHARMACOKINETIC 
ASSESSMENTS

To revise the dose selection for FPV and RTV.

To describe the revised starting and maximum doses of FPV and RTV.

To describe study drug dose adjustment criteria.


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
To revise the definition of a study drug overdose.

To revise the details of PK sampling and bioanalysis.

To change details of analytes for PK samples to allow for analysis and RTV 
concentrations and to clarify the concentrations of FPV will only be measured where 
plasma volumes allow.

To update the analysis plan for PK samples collected.

To revise the target plasma APV exposures.
OTHER CHANGES

To revise subject management options.

To include details of additional references.

To add additional items the List of Abbreviations.

To update the list of concurrent medications and non drug therapies.


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11.9.
Appendix 9:  Protocol Amendment 2
There was one change to the protocol as a result of Protocol Amendment 2.  Exclusion 
criteria number 8 was modified as follows:
Original Wording:
Any acute laboratory abnormality at screen which, in the opinion of the investigator, 
should preclude the subject’s participation in the study of an investigational compound.  
Any Grade 4 laboratory abnormality at screen will exclude a subject from study 
participation.
Revised Wording:
Any acute laboratory abnormality at screen which, in the opinion of the investigator, 
should preclude the subject’s participation in the study of an investigational compound.  
Any Grade 3 or higher laboratory abnormality at screen will exclude a subject from study 
participation.
This change is incorporated into Amendment 7.


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11.10.
Appendix 10:  Protocol Amendment 3
A summary of protocol changes for Amendment 3 are listed below.  These changes were 
incorporated into the protocol at the time Amendment 3 was issued and are thus 
incorporated into Amendment 7. 
1.
To add the revised dose recommendation for Cohort 1A (PI-naïve or PI-experienced 
subjects 6 months to < 2 years of age receiving boosted GW433908 (908) + RTV).  
The revised dose recommendation is 908 45 mg/kg BID + RTV 7 mg/kg BID, which 
represents a 25% increase from the original dose of 908 30 mg/kg BID and 16% 
increase from the original RTV 6 mg/kg BID dose.  Consequently, screening was re-
opened to PI- naïve and PI-experienced subjects to enrol within Arm A2 of Cohort 
1A.  Any further subjects randomized into Cohorts 1A Arm A2 and receiving 908 
oral suspension + RTV should be placed on the revised dosing recommendation 
listed above.  It is recommended that subjects already randomized should remain on 
their current 908+RTV BID dosing regimen.
2.
Reason for change:  Following PK analysis of the first 9 subjects from Cohort 1A1, a 
revised dose recommendation was determined and communicated to the sites. It is 
now being added to the protocol for completeness.
3.
To update information regarding closing of the unboosted GW433908 Arm B for 
Cohort 1 pending discussions with regulatory authorities around dosing volumes.  
4.
Reason for change:  In the original study design, Cohort 1 Arm B would open to 
enrolment following determination of the revised dose for Cohort 1 Arm A.  Due to 
concerns regarding dosing volumes, Cohort 1 Arm B remains closed until 
discussions with regulators have been completed.
5.
To amend the current study design to allow the simultaneous enrolment of Cohort 2 
Arms A and B. 
6.
Reason for change: Due to the increasing non-availability of RTV OS in several 
participating countries, we are allowing the parallel enrolment of Arm A and Arm B 
of Cohort 2 to facilitate enrolment in countries where the RTV solution is no longer 
available. Consequently, two SDVs will occur for subjects now enrolling into Arm B 
to ensure an appropriate starting unboosted FPV dose at Day 1, and to determine a 
boosted dose should the subject elect to switch to the boosted regimen after Week 2. 
Additionally, the SDV visits for Cohort 2 Arm A have been amended to only collect 
boosted FPV serial PK samples.
7.
To clarify the statement that subjects enrolled in Cohort 1B or Cohort 2B may have 
their treatment switched from the 908 BID regimen to the 908/RTV BID regimen at 
any time after the Week 2 visit by adding the caveat “only in countries where RTV 
solution is locally available for long-term use”.
8.
Reason for change:  After the study started RTV oral solution became unavailable in 
some participating countries. 
9.
To update the Study Drugs and Dosages and Dosage Regimen Adjustment Criteria
10. Reason for change:  To provide updated information per protocol amendment No 3.


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11. To add information regarding continuation of subjects in APV20002 past Week 48.
12. Reason for change:  To provide details surrounding the continuation of study visits 
and laboratory assessments past Week 48.  Subjects may remain in the study until 
908 oral suspension is locally available, or until the subject is no longer deriving any 
clinical benefit from 908.
13. To provide clarification regarding the maximum age allowed for each cohort. 
14. Reason for change: The existing inclusion criteria number 1 was unclear as to which 
study visit the age criteria applied.  Inclusion criteria 1 has been revised to state that 
Cohort 1 (6 months - <2 years) subjects must be <2 years of age at the Week 2 visit 
therefore the maximum age at screening is 22 months, and Cohort 2 (4 weeks - <6 
months) subjects must be <6 months of age at the Week 2 visit, therefore the 
maximum age at screening is 4 months.
15. To update the protocol with current information and to correct minor inconsistencies.


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11.11.
Appendix 11:  Protocol Amendment 4
Protocol Amendment 4 was sent to the FDA for review and comment but because of 
the outcome of discussions with FDA, this amendment was not sent to the sites for 
implementation.  The change suggested in Amendment 4 is also incorporated into 
Amendment 5.
This amendment consisted of the following changes:
1.
To add information regarding removal of the unboosted GW433908 Arm B for 
Cohort 1.  
Reason for change:  Due to the required increase in 908 dose in Cohort 1A (6 months 
to 2 years of age) to 45 mg/kg BID, the unboosted dose would have also increased 
from 15 mg/kg BID to 22.5 mg/kg BID and resulted in unacceptable dosing volumes 
for these children.  Based on the weight range of the currently enrolled subjects in 
Cohort 1A (6 kg to 12.6 kg, range 9 months to 2 years of age) and using the CDC 
weight for age percentile growth charts (6 kg to 13.4 kg), the required dosing 
volumes for the unboosted 908 dose(s) is estimated to be in the range of 10.8 mls to 
24.1 mls per dose for Cohort 1B.  Physician feedback has indicated that these dosing 
volumes would lead to unacceptably low levels of adherence in this age group.  


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11.12.
Appendix 12:  Protocol Amendment 5
Title: A 48 Week Phase II, Open-label, 2-cohort, Multicentre Study to Evaluate the 
Pharmacokinetics, Safety, Tolerability and Antiviral Activity of GW433908 and 
GW433908/RTV When Administered to HIV-1 Infected Protease Inhibitor (PI) Naïve 
and PI-Experienced Pediatric Subjects aged 4 weeks to <2 years.
This format 2 protocol amendment will apply to all study sites.  
This amendment is considered substantial since the changes may impact the safety of the 
subjects and the conduct/management of the study.  
This amendment is being implemented to defer the enrolment of subjects in the 
unboosted FPV cohorts (Cohort 1 Arm B and Cohort 2 Arm B), to increase the dose of 
FPV at the Week 2 visit and revise the PK visits and sampling times for subjects in 
Cohort 1 Arm A (FPV/RTV BID), to include trough PK samples to determine the 
concentration of unbound APV, to revise the doses given to Cohort 2 Arm A at the single 
dose visit, to revise the list of excluded concurrent medications to remove rifabutin and 
phenytoin, and to update the DAIDS toxicity grading tables (2004), information on rash, 
abacavir hypersensitivity reaction, background information, and to correct minor 
inconsistencies in the protocol.  As all new sites will be receiving this protocol and 
amendments for the first time, the content and organization of the protocol were also 
updated and revised to simplify and improve clarity.
This amendment consists of the following changes:
1.
Defer the enrolment of subjects in the unboosted FPV cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B)
2.
Reason for change:  Enrolment into Cohort 1 Arm B and Cohort 2 Arm B is deferred 
until serial PK data from the age-specific FPV/RTV cohorts are available to assist in 
the dose selection for the corresponding unboosted FPV cohort and any concerns 
regarding the high FPV dosing volumes have been addressed.
3.
Increasing the FPV dose to 60 mg/kg at the Week 2 visit for subjects in Cohort 1 
Arm A only.
4.
Reason for change:  Data from five 6 months to <2 year old subjects who received 
the revised dose of FPV 45 mg/kg BID + RTV 7 mg/kg BID were compared with the 
historical adult population (based on a FPV 700 mg BID + RTV 100 mg BID 
regimen and an average weight of 77kg).  Despite an approximate 5-fold increase in 
FPV and RTV doses, plasma APV AUC(0-) was approximately 48% lower, Cmax 
26% lower, and C29% lower in the pediatric subjects.  In addition, high APV and 
RTV CL/F values were observed in these 5 pediatric subjects suggesting that 
children 6 months to <2 years old may require higher doses of FPV and RTV.  
Therefore new subjects will increase the FPV dose from 45 mg/kg BID to 60 mg/kg 
BID with RTV 7 mg/kg BID after the PK evaluations at the Week 2 visit.


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5.
Revision to the PK visits and sampling times for subjects in Cohort 1 Arm A and the 
addition of trough PK samples to determine the concentration of unbound APV for 
all subjects. 
6.
Reason for change:  Subjects in Cohort 1 will start at baseline receiving FPV 45 
mg/kg BID + RTV 7 mg/kg BID, and a “mini” PK profile will be conducted over 4 
hours at Week 2 to confirm adequate exposure after attaining steady-state.  The dose 
of FPV will be then be increased to 60 mg/kg BID + RTV 7 mg/kg BID after the 
Week 2 PK, and serial PK sampling will be conducted over 8-12 hours at Week 8 to 
confirm the target exposure after attaining steady-state.
7.
Current PK data from children <2 years old in APV20002 is highly variable.  Since 
subjects who are <2 years old may have reduced protein binding, it is possible that 
these pediatric subjects may achieve therapeutic plasma unbound APV 
concentrations even if plasma total APV concentrations are below target when 
compared to adult exposure.  Therefore, measuring plasma unbound APV 
concentrations may help to determine dosing recommendations at acceptable dosing 
volumes.
8.
The single doses administered in Cohort 2 Arm A SDV changed from FPV 30 mg/kg 
and RTV 6mg/kg to FPV 45 mg/kg and RTV 7 mg/kg to be aligned with dosing in 
Cohort 1 Arm A.
9.
Revisions to the concurrent medications, specifically removing rifabutin and 
phenytoin from the list of excluded medications.
10. Updated information on rash and abacavir hypersensitivity reaction
11. Updated DAIDS table for the grading of adult and pediatric adverse events to the 
2004 version.
12. Updated background information, removal of redundant wording, and correction of 
minor inconsistencies throughout the protocol.


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Summary of Primary Changes for Amendment 5
Section 1 Introduction

Section 1.1 Backgrond and Section 1.2 Rationale were updated with current 
information, reorganized, and condensed.

Section 1.3 Fosamprenavir was condensed, Section 1.3.1 FPV Neonatal Toxicology 
was revised with current information and condensed, and Section 1.3.2 FPV 
Pediatric Clinical Data was added.

Section 1.4 Ritonavir, Section 1.5 Abacavir, and Section 1.6 Lamivudine were 
updated and condensed.
Section 2 Study Objectives and Endpoints

Section 2.1 Study Objectives and Section 2.2 Study Endpoints were revised to 
indicate which of the objectives and endpoints are deferred as a result of the deferral 
of the unboosted FPV Arm B cohorts.  One new primary study endpoint was added: 
Plasma unbound APV C,ss and percent protein binding
Section 3 Investigational Plan

Section 3.1 Study Design

Study center regions revised to include Africa. 

Statement about subjects continuing on study until commercial supplies of FPV 
are available locally was updated to include a statement about continued FPV 
according to agreements between GSK and participating study sites.  

Updated with text and a revised table to state approximately how many 
additional subjects are required. 

Schematics were revised according to the changes in this amendment, moved to 
follow the Overview section and renamed Figure 1 and Figure 2.

Overview: Updated to explain the terminology of Arm A SDV and Arm A.

Cohort 1 Arm A SDV- original wording deleted as it is no longer 
applicable; wording added to clarify that no additional subjects in this 
Cohort are required to undergo SDV assessments.

Cohort 2 Arm A SDV- Single doses changed from FPV 30 mg/kg and RTV 
6mg/kg to FPV 45 mg/kg and RTV 7 mg/kg. Wording added to explain that 
the 12 hour sample may be omitted with prior agreement of the sponsor.

Cohort 1 Arm A- dosing updated as follows: All new subjects who enrol in 
Cohort 1 Arm A should commence multiple dosing with FPV 45 mg/kg 
BID + RTV 7 mg/kg BID at the Baseline visit.  After the Week 2 PK 
samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo plasma 
PK serial sampling at Week 8 (over 8-12 hours).  


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
Cohort 1 Arm B and Cohort 2 Arm B- wording added to explain these 
cohorts are deferred and the rationale for deferment.

Figure 1 and Figure 2 were revised

Section 3.2 Study Population clarifies the approximate number of additional subjects 
to be enrolled.

Section 3.2.2 Exclusion Criteria 

#3 revised to state that the exclusion of subjects receiving PI therapy within 5 
days prior to study drug administration is applicable only for subjects 
undergoing single dose visits

#5 CDC Class C event criteria revised

#7 revised to include clinically relevant pancreatitis

#8 lab abnormality criteria revised

former #9 criteria about serum lipase removed

Section 3.3.2 Background NRTI options, the manufacturing sites of abacavir oral 
solution and lamivudine oral solution were changed from Speke, UK to Mississauga, 
Ontario, Canada. Section 3.3.3 was revised to Background ART Not Provided by 
GSK, and new wording added to state that GSK will not provide or reimburse 
background ART other than ABC or 3TC.

Section 3.3.4 was updated with current information and condensed.  Previous 
sections Original Dose Selection and Revised Dose Selection were removed as the 
data was no longer applicable. 

Section 3.3.5 Study Drugs and Dosages- condensed and redundant text removed; 
instructions added for sites in case of vomiting after administration of study drug. 
Section 3.3.5.1 Dosage Regimen Adjustment Criteria- text updated and condensed.

Section 3.3.7.3 Rash and Section 3.3.7.4 Abacavir Hypersensitivity Reaction 
sections updated to provide the most current information and guidance to 
investigators. 

Section 3.3.8 Subject Management Options were revised to allow for greater 
flexibility according to local guidelines and local standard of care.

Section 3.3.10 Concurrent Medications- rifabutin and phenytoin were removed as 
excluded medications.  Additional guidance added for co-administration of rifabutin.
Section 4 Study Drug Management- No changes
Section 5 Measurements and Evaluations

Section 5.5 Efficacy- Collection of plasma samples at screening for reistance testing, 
formerly required, was revised per this amendment to state collection of this sample 
is left to the investigator’s discretion if needed to guide selection of background 
ART.  


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
Section 5.7 Bioanalysis and Pharmacokinetic Samples- section extensively revised to 
reflect the new dosing and new PK sample schedule implemented with this 
amendment; paragraph added regarding directly observed therapy

Section 5.8 Safety- collection of samples for serum lipase testing and serum 1-Acid 
Glycoprotein (AAG) concentrations removed as these parameters will no longer be 
tested.  Lipid measures will no longer be collected at the Screening visit. 
Section 6 Data Analysis Methods- No changes
Section 7 AEs and SAEs- No changes
Section 8 Study Administration- No changes
Section 9 References - updated
Section 10 Tables- The time and events tables were updated to reflect the changes per 
the current amendment
Section 11 Appendices

Appendix 3 -The previous DAIDS table for the grading of adult and pediatric 
adverse events was replaced with the more current DAIDS 2004 version.

Appendix 5 and Appendix 6- The dosing tables were revised according to the 
updated dosing schedule.


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11.13.
Appendix 13:  Protocol Amendment 6
Title: APV20002: A 48 Week Phase II, Open-label, 2-cohort, Multicentre Study to 
Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral Activity of GW433908 
and GW433908/RTV When Administered to HIV-1 Infected Protease Inhibitor (PI) 
Naïve and PI-Experienced Pediatric Subjects aged 4 weeks to <2 years
This format 2 protocol amendment will apply to all study sites.  
This amendment is considered non-substantial since the changes to the FPV and RTV 
dosing tables and exclusion criteria No. 9 did not impact the safety of the subjects or the 
conduct/management of the study.  The inaccurate RTV dosing table was provided in 
amendment 5 of the protocol but since this amendment had not been implemented at the 
sites, no subjects were at risk of any RTV dosing issues.
This amendment is being implemented to correct inaccuracies in the FPV and RTV 
dosing tables and in exclusion criteria No 9 (per amendment 5).
1.
In the FPV 45 mg/kg BID dosing table, revisions were made to the number of bottles 
of FPV OS required by the subject per month based on their weight.  In the RTV 7 
mg/kg BID dosing table, corrections were made to the amount of RTV oral solution 
administered per dose to each subject based on their weight.
2.
In exclusion criteria No. 9 (per amendment 5), the ULN (>10x ULN) stated for a 
Grade 3 ALT and/or AST was changed to (>5x ULN) to correctly represent a Grade 
3.
Change 1:  To update the FPV 45 mg/kg BID dosing table to reflect the correct supply of 
FPV OS required per month and to correct the dose of RTV oral solution to be 
administered per dose to each subject based on their weight.


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Amend:
11.15, Appendix 5:  Dosing Table for FPV Oral Suspension, FPV 45 mg/kg BID
Original Table:
Dosing Table for FPV Oral Suspension
FPV 45 mg/kg BID
Weight (kg)
Dose (mg): 45 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
3
135
2.7
1
3.5
158
3.2
1
4
180
3.6
1
4.5
203
4.1
2
5
225
4.5
2
5.5
248
5.0
2
6.0
270
5.4
2
6.5
293
5.9
2
7.0
315
6.3
2
7.5
338
6.8
2
8
360
7.2
2
8.5
383
7.7
2
9
405
8.1
2
9.5
428
8.6
2
10
450
9.0
2
10.5
473
9.5
3
11
495
9.9
3
11.5
518
10.4
3
12
540
10.8
3
12.5
563
11.3
3
13
585
11.7
3


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Revised Table:
FPV 45 mg/kg BID
Weight (kg)
Dose (mg): 45 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
3
135
2.7
1
3.5
158
3.2
1
4
180
3.6
1
4.5
203
4.1
2
5
225
4.5
2
5.5
248
5.0
2
6.0
270
5.4
2
6.5
293
5.9
2
7.0
315
6.3
2
7.5
338
6.8
2
8
360
7.2
2
8.5
383
7.7
3
9
405
8.1
3
9.5
428
8.6
3
10
450
9.0
3
10.5
473
9.5
3
11
495
9.9
3
11.5
518
10.4
3
12
540
10.8
3
12.5
563
11.3
4
13
585
11.7
4


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Amend:
11.16, Appendix 6:  Dosing Table for RTV Oral Solution, RTV 7 mg/kg BID
Original Table:
Dosing Table for RTV Oral Solution
RTV 7 mg/kg BID
Weight (kg)
Dose (mg): 7 
mg/kg
Amount of 80 mg/mL solution 
(mL) per Dose
3
21
0.42
3.5
24.5
0.49
4
28
0.56
4.5
31.5
0.63
5
35
0.70
5.5
38.5
0.77
6.0
42
0.84
6.5
45.5
0.91
7.0
49
0.98
7.5
52.5
1.05
8
56
1.12
8.5
59.5
1.19
9
63
1.26
9.5
66.5
1.33
10
70
1.40
10.5
73.5
1.47
11
77
1.54
11.5
80.5
1.61
12
84
1.68
12.5
87.5
1.75
13
91
1.82


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Revised Table:
RTV 7 mg/kg BID
Weight (kg)
Dose (mg): 7 
mg/kg
Amount of 80 mg/mL solution 
(mL) per Dose
3
21
0.26
3.5
24.5
0.31
4
28
0.35
4.5
31.5
0.39
5
35
0.44
5.5
38.5
0.48
6.0
42
0.53
6.5
45.5
0.57
7.0
49
0.61
7.5
52.5
0.66
8
56
0.70
8.5
59.5
0.74
9
63
0.79
9.5
66.5
0.83
10
70
0.88
10.5
73.5
0.92
11
77
0.96
11.5
80.5
1.01
12
84
1.05
12.5
87.5
1.09
13
91
1.14
Change 2:  To correct the ULN for Grade 3 ALT and /or AST to (>5x ULN)
Amend:
Section 3.1.2, Exclusion Criteria, bullet # 9 (per amendment 5)
Original Text:
9.
Grade 3 or higher (>10x ULN) serum aminotransferase levels (alanine 
aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days prior 
to study drug administration and / or clinically relevant hepatitis within the previous 
6 months.
Revised Text:
9.
Grade 3 or higher (>5x ULN) serum aminotransferase levels (alanine 
aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days prior 
to study drug administration and / or clinically relevant hepatitis within the previous 
6 months.


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11.14.
Appendix 14:  Protocol Amendment 7
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment will apply to all study sites.
This amendment is being implemented to provide the dose recommendation for new 
subjects enrolled in Cohort 2 Arm A, to remove the Single Dose Visit (SDV) for subjects 
enrolled into this cohort and to increase the overall number of subjects to be enrolled into 
Cohort 2 Arm A.  This amendment also allows for the option to use local accredited 
laboratories for hematology and clinical chemistry on approval from GSK.
This amendment is considered substantial since the changes impact the conduct of the 
study.
This amendment consists of the following changes:
1. Add a dose recommendation for subjects recruited into Cohort 2 Arm A.
Reason for change:  Following the analysis of available PK data from the first 12 
subjects enrolled in Cohort 2 Arm A (4 weeks to <6 months), a FPV/RTV dose 
regiment of 45/10 mg/kg BID is being recommended for all new subjects enrolled 
into this cohort.
Dose rationale:  Plasma APV PK data are available from the first 12 subjects enrolled 
in Cohort 2 Arm 1 (4 week to <6 month age group).  On both single dose and repeat 
dose administration of FPV/RTV, pediatric subjects 4 weeks to <6 month old had 
higher plasma APV Cmax and AUC values, but similar C12 (single dose) and lower 
C(repeat dose) values than historically observed for adults.  Repeat dose plasma 
RTV Cmax and AUC values were similar to historical adult data, but plasma RTV C
values were lower in the pediatric subjects.  Because plasma APV Cis important for 
long-term efficacy and minimization of resistance development, it is important to try 
to achieve plasma APV Cvalues in pediatric subjects similar to those achieved with 
the FPV/RTV 700/100 mg BID regimen that has demonstrated efficacy in adults.  It 
is possible that the lower plasma RTV Cvalues are responsible for the lower plasma 
APV Cvalues; therefore, an increase in the RTV dose for all subsequently enrolled 
subjects is being recommended.  Therefore, the recommended dosage regimen for 4 
weeks to <6 month old subjects enrolled into Study APV20002 is FPV/RTV 45/10 
mg/kg BID.  Newly enrolled subjects will not undergo the SDV, but will have serial 
PK sampling on Week 2 and trough sampling on subsequent visits.
2. Single Dose Visit is deleted from the assessments, and Flow Chart of Clinical 
Scheduled Assessments for subjects recruited into Cohort 2 Arm A.


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Reason for change:  As per Section 3.3.4 of the protocol, sufficient PK data is now 
available to inform on the dose recommendation for subjects enrolled into Cohort 2 
Arm A and therefore this visit is no longer required.
3. Update to the number of subjects to be recruited into Cohort 2 Arm A.
Reason for change:  Additional subjects need to be enrolled into Cohort 2 Arm A to 
provide sufficient data on the FPV/RTV 45/10 mg/kg BID dose.
4. Include the option to use a local accredited laboratory for hematology and clinical 
chemistry at the discretion of the investigator and with approval of GSK.
Reason for change:  To add the option to use local accredited laboratories for 
hematology and clinical chemistry to aid subject management.
5. Correction of some typographical errors.
Individual Changes:
Change 1:  
Amend:
Sponsor Information Page
Original Text:
Sponsor Medical Representatives:
, MD
GlaxoSmithKline
891-995 Greenford Road
Greenford, Middlesex, UB6 0HE, UK
Telephone: 
, MD
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Revised Text:
, MD
GlaxoSmithKline
891-995 Greenford Road
Greenford, Middlesex, UB6 0HE, UK
Telephone: 
PPD
PPD
PPD
PPD
PPD
PPD


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Change 2:
Amend:
Protocol Summary, Dose Rationale, 5th paragraph
Original Text:
Plasma APV PK data are not available for the 4 week to <6 month age group (Cohort 2).  
Based on the higher doses required in the 6 month to <2 year age group (Cohort 1), a 
single dose of FPV/RTV 45/7 mg/kg will be administered at the SDV for Cohort 2 Arm 
A SDV.  Further dose modification is described in Section 3.1 and Section 3.3.5.1.  When 
sufficient data are available to provide a dose recommendation for Cohort 2 Arm A, the 
information will be communicated to the sites through a letter, followed by a formal 
protocol amendment.
Revised Text:
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm 1 
(4 week to <6 month age group).  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 week to <6 month old had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose) and lower C(repeat 
dose) values compared with that historically observed for adults.  Repeat dose plasma 
RTV Cmax and AUC values were similar to historical adult data, but plasma RTV C
values were lower in the pediatric subjects.  As plasma APV Cis important for long-
term efficacy and minimization of resistance development, it is important to try to 
achieve plasma APV Cvalues in pediatric subjects similar to those achieved with the 
approved FPV/RTV 700/100 mg BID regimen in adults.  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore, 
an increase in the RTV dose for all subsequently enrolled subjects is  recommended.
Per Protocol Amendment 7, a SDV is no longer required for newly enrolled 4 week to <6 
month age subjects (Cohort 2 Arm A).  These subjects will initiate dosing with FPV/RTV 
45/10 mg/kg BID and have serial PK sampling at Week 2 and trough sampling on 
subsequent visits.
Change 3: 
Amend:
Protocol Summary, Study Design
Original Text:
As per Amendment 5, the approximate number of subjects required in APV20002 in 
addition to the 13 previously enrolled is illustrated in the following table.


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Approximate Number of Additional Subjects Required in APV20002 (as of Protocol 
Amendment 05)
Approximate Number of Additional 
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
1
6 months – <2 years
12
NA1
2
4 weeks – <6 months
12
NA1
1.
Not Applicable as Arm B enrolment is deferred
Revised Text:
As per Amendments 5 and 7, the approximate number of additional subjects required in 
APV20002 in addition to the 13 previously enrolled is illustrated in the following table.
Number of Additional Subjects Required in APV20002 (as of Protocol 
Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred
Change 4:
Amend:
Protocol Summary, Study Design, Overview, 2nd paragraph onwards
Original Text:
The initial group of subjects enrolled who undergo single dose visit (SDV) assessments 
before commencing multiple dosing with for example FPV/RTV at Baseline are referred 
to as Arm A SDV.  The subsequent group of subjects enrolled that do not undertake 
single dose visit assessments and begin multiple dosing with FPV/RTV at Baseline are 
simply referred to as Arm A. 


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Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
The first 6-10 subjects in Cohort 2 Arm A will undergo one Single Dose Visit (SDV). 
The SDV will be undertaken a minimum of 15 days prior to the Baseline visit/Day 1. At 
the SDV, the subject will receive a single dose of FPV 45 mg/kg and a single dose of 
RTV 7 mg/kg administered simultaneously and undergo serial plasma PK sampling over 
8-12 hours.  With prior agreement of the sponsor, the 12-hour sample may be omitted if 
logistical reasons do not allow collection of this sample. The SDV plasma PK samples 
will be analyzed for APV, RTV and where plasma volumes allow, FPV concentrations in 
order to construct an individualized dosing regimen prior to initiation of multiple dosing 
at Baseline/Day 1 (See Section 3.3.4). Every effort will be made to ensure that the 
investigator is advised, within 14 days after completion of the SDV evaluations of the 
individualized dose regimen selected.  Multiple dosing with FPV/RTV may not be 
initiated until the subject’s single dose PK data are available. 
The first 6-10 subjects in Cohort 2 Arm A will also undertake further plasma PK 
sampling over 8-12 hours (12 hour sample optional) after attaining steady-state at the 
Week 2 visit.  Following the Week 2 evaluations, the plasma PK samples will be 
analyzed for APV, RTV and where plasma volumes allow FPV concentrations and every 
effort will be made to ensure that the investigator is advised, within 14 days, whether the 
subject should remain on the current regimen or undergo a dosage regimen adjustment at 
the Week 4 visit.  The Week 4 visit should not be undertaken until Week 2 PK data are 
available.
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit. After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo plasma PK serial 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional). Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.


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Cohort 2 (4 weeks to <6 months)
Additional PI-experienced or PI-naïve subjects will subsequently be recruited into Cohort 
2 Arm A and will commence multiple dosing with FPV/RTV BID on study Day 1 
without undertaking a SDV.  The dose will be based on the Week 2 plasma PK data from 
the initial 6-10 subjects in Arm A SDV of Cohort 2 who underwent single dose 
assessments.  Subjects in Cohort 2 Arm A will undergo plasma PK serial sampling over 
8-12 hours (12 hour sample optional) at the Week 2 visit. 
Revised Text:
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments. Refer to Section 3.1 (Figure 1 and Figure 2) 
for schematics outlining the study design for Cohort 1 Arm A and Cohort 2 Arm A, 
respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments.
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit. After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo plasma PK serial 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional). Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 


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subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in 
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen.
Change 5:
Amend:
Protocol Summary, Study Population, 2nd paragraph
Original Text:
As of Amendment 5, Cohort 1 Arm A (6 months to <2 years) will enrol approximately 12 
additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 12 subjects to receive FPV/RTV BID. Enrolment in the 
unboosted FPV BID cohorts (Arm B) is deferred.
Revised Text:
As per Amendments 5 and 7, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 12 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A 
(4 weeks to <6 months) will enrol approximately 20-24 subjects to receive FPV/RTV 
BID. Enrolment in the unboosted FPV BID cohorts (Arm B) is deferred.
Change 6:
Amend:
Protocol Summary, Measurements and Evaluations
Original Text:
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.  Subjects will attend the clinic at Screening (within 
approximately 21 days prior to Baseline/Day 1), the Single Dose Visit (first 6-10 
subjects, Cohort 2 Arm A SDV only), Day 1 (Baseline), and Weeks 2, 4, 8, 12, 16, 24, 
36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral suspension 
are available locally and pediatric dosing is approved in the relevant age groups. In 
countries where local availability is delayed or the drug is not yet available through 
national treatment programs, subjects may continue to receive FPV until they no longer 
derive clinical benefit or according to prior agreements between GSK and participating 
study sites for provision of ART.  A follow-up visit will be performed 4 weeks after the 
permanent discontinuation of study drug.
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter. 


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Cohort 2 (4 weeks to <6 months) Arm A SDV/ Arm A: Plasma samples for evaluation of 
PK parameters will be collected at the Single Dose Visit for the first 6-10 subjects (Arm 
A SDV).  For all subjects in Cohort 2 Arm A, plasma PK samples will be collected over 
8-12 hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be 
collected at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter.
Revised Text:
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.  Subjects will attend the clinic at Screening (within 
approximately 21 days prior to Baseline/Day 1),  Day 1 (Baseline), and Weeks 2, 4, 8, 12, 
16, 24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects may continue to receive FPV until they no 
longer derive clinical benefit or according to prior agreements between GSK and 
participating study sites for provision of ART.  A follow-up visit will be performed 
4 weeks after the permanent discontinuation of study drug.
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter. 
Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter.
Change 7:
Amend:
Section 3.1 Study Design, 2nd paragraph onwards
Original Text:
As per Amendment 5, the approximate number of subjects required in APV20002 in 
addition to the 13 previously enrolled is illustrated in Table 1.


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Table 1.
Approximate Number of Additional Subjects Required in APV20002 
(as of Protocol Amendment 05)
Approximate Number of Additional 
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
1
6 months – <2 years
12
NA1
2
4 weeks – <6 months
12
NA1
1.
Not Applicable as Arm B enrolment is deferred
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects enrolled who undergo single dose visit (SDV) assessments 
before commencing multiple dosing with for example FPV/RTV at Baseline are referred 
to as Arm A SDV.  The subsequent group of subjects enrolled that do not undertake 
single dose visit assessments and begin multiple dosing with FPV/RTV at Baseline are 
simply referred to as Arm A. 
Refer to Figure 1 and Figure 2 for schematics outlining the study design for Cohort 1 
Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
The first 6-10 subjects in Cohort 2 Arm A will undergo one Single Dose Visit (SDV). 
The SDV will be undertaken a minimum of 15 days prior to the Baseline visit/Day 1. At 
the SDV, the subject will receive a single dose of FPV 45 mg/kg and a single dose of 
RTV 7 mg/kg administered simultaneously and undergo serial plasma PK sampling post-
dosing over 8-12 hours.  With prior agreement of the sponsor, the 12-hour sample may be 
omitted if logistical reasons do not allow collection of this sample. The SDV plasma PK 
samples will be analyzed for APV, RTV and where plasma volumes allow, FPV 
concentrations in order to construct an individualized dosing regimen prior to initiation of 
multiple dosing at Baseline/Day 1. (See Section 3.3.4) Every effort will be made to 
ensure that the investigator is advised, within 14 days after completion of the SDV 
assessments, of the individualized dose regimen selected.  Multiple dosing with 
FPV/RTV may not be initiated until the subject’s single dose PK data are available. 


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The first 6-10 subjects in Cohort 2 Arm A will also undertake further plasma PK 
sampling over 8-12 hours (12-hour sample optional) after attaining steady-state at the 
Week 2 visit.  Following the Week 2 evaluations, the plasma PK samples will be 
analyzed for APV, RTV and where plasma volumes allow FPV concentrations and every 
effort will be made to ensure that the investigator is advised, within 14 days, whether the 
subject should remain on the current regimen or undergo a dosage regimen adjustment at 
the Week 4 visit.  The Week 4 visit should not be undertaken until Week 2 PK data are 
available.
Arm A:  Subjects Not Undertaking Single Dose Visit Assessments 
Cohort 1 (6 months to <2 years) 
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit.  After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo serial plasma PK 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional).  Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.
Cohort 2 (4 weeks to <6 months) 
Additional PI-experienced or PI-naïve subjects will subsequently be recruited into Cohort 
2 Arm A and will commence appropriate multiple dosing with FPV/RTV BID on study 
Day 1 without undertaking a SDV.  The dose will be based on the Week 2 plasma PK 
data from the initial 6-10 subjects in Arm A SDV of Cohort 2 who underwent single dose 
assessments.  Subjects in Cohort 2 Arm A will undergo serial plasma PK sampling over 
8-12 hours (12 hour sample optional) at the Week 2 visit. 
Revised Text:
As per Amendments 5 and 7, the approximate number of additional subjects required in 
APV20002 in addition to the 13 previously enrolled is illustrated in Table 1. 


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Table 1
Number of Additional Subjects Required in APV20002 (as of 
Protocol Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.
Refer to Figure 1 and Figure 2 for schematics outlining the study design for Cohort 1 
Arm A and Cohort 2 Arm A, respectively.
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments.


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Arm A:  Subjects Not Undertaking Single Dose Visit Assessments 
Cohort 1 (6 months to <2 years) 
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit.  After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo serial plasma PK 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional).  Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.
Cohort 2 (4 weeks to <6 months) 
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence  
multiple dosing with FPV 45 mg/kg BID + RTV10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is be based on the Week 2 plasma PK data from the initial 
12 subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  
Subjects in Cohort 2 Arm A will undergo serial plasma PK sampling over 8-12 hours (12 
hour sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-
experienced subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 
Change 8:
Amend:
Section 3.3.4, 6th paragraph
Original Text:
Plasma APV PK data are not yet available for the 4 week to <6 month age group (Cohort 
2).  Based on the higher doses required in the 6 month to <2 year age group, a single dose 
of FPV/RTV 45/7 mg/kg will be administered at the SDV for Cohort 2 Arm A SDV (4 
weeks to <6 months).  Further dose modification is described in Section 3.1 and 
Section 3.3.5.1.  When sufficient data are available to provide a dose recommendation for 
Cohort 2 Arm A, the information will be communicated to the sites through a letter, 
followed by a formal protocol amendment.
Revised Text:
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm 1 
(4 week to <6 month age group).  Overall, pediatric subjects 4 week to <6 month old had 
higher plasma APV Cmax and AUC values, but similar C12 (single dose, Table 2) and 
lower C(repeat dose, Table 3) values than historically observed for adults.  Repeat dose 
plasma RTV Cmax and AUC values were similar to historical adult data, but plasma 
RTV Cvalues were lower in the pediatric subjects overall (Table 4).  Because plasma 
APV Cis important for long-term efficacy and minimization of resistance development, 
it is important to try to achieve plasma APV Cvalues in pediatric subjects similar to 
those achieved with the FPV/RTV 700/100 mg BID regimen that has demonstrated 


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efficacy in adults.  Although FPV/RTV 60/10 mg/kg exhibited APV C,ss most similar to 
adults (Figure 3), the APV Cmax for this regimen was considered unnecessarily high 
(Figure 4).   The RTV 10 mg/kg in the FPV/RTV 60/10 mg/kg regimen provided the 
most consistently high RTV C,ss values as compared to 30/7 and 45/7 mg/kg (Figure 5).  
It is possible that the lower plasma RTV Cvalues resulted in the lower plasma APV C
values for the lower two regimens.  Therefore, all subjects <6 months in age subsequently 
enrolled in the study will receive FPV/RTV 45/10 mg/kg to maximize RTV Cwhile 
maintaining APV Cmax values that are not excessively high. 
Per Protocol Amendment 7, newly enrolled 4 week to <6 month age subjects (Cohort 2 
Arm A) will initiate dosing with FPV/RTV 45/10 mg/kg BID.  Newly enrolled subjects 
will not undergo the SDV, but will have serial PK sampling on Week 2 and trough 
sampling on subsequent visits.
Table 2
Summary of Single Dose Plasma APV PK in Pediatric Subjects <6 
months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV 45/7 mg/kg
(N=11)1
Adult Subjects
FPV/RTV 700/100 mg
(N=17)
Cmax (g/mL)
9.74
(5.67, 16.2)
3.65
(2.54, 6.76)
AUC(0-) (g.h/mL)
57.5
(20.2, 111)
35.2
(20.8, 114)
C8h (g/mL)
2.64
(0.819, 5.86)
1.10
(0.451, 2.20)
C12h (g/mL)2
1.13
(0.41, 3.76)
1.19
(0.659, 1.92)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Data for pediatric Subject 
 was excluded because exposures were very high: Cmax: 30.9g/mL, AUC(0-): 
335g.h/mL, C8hr: 16.9g/mL.
4.
C12h is extrapolated value for pediatric subjects and observed value for adult subjects
PPD


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Table 3
Summary of Repeat Dose Plasma APV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV BID1
(N=9)2
Adult Subjects
FPV/RTV 700/100 mg
(N=14)
Cmax (g/mL)
8.90
(2.07, 12.1)
4.76
(2.47, 7.68)
AUC(0-) (g.h/mL)
41.0
(16.2, 70.4)
28.3
(17.9, 43.1)
C8h (g/mL)
2.05
(1.10, 3.25)
1.58
(0.816, 2.64)
C(g/mL)3
0.970
(0.438, 1.95)
1.46
(1.06, 2.20)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
 was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
Table 4
Summary of Repeat Dose Plasma RTV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma RTV
PK Parameter
Pediatric Subjects 
1 to <6 months
FPV/RTV BID1
Adult Subjects
FPV/RTV
700/100 mg BID
(N=9)2
(N=8)2,3
(N=24)
Cmax (g/mL)
1.28
(0.228, 7.70)
0.999
(0.228, 2.11)
1.24
(0.520, 3.84)
AUC(0-) 
(g.h/mL)
6.66
(0.922, 28.8)
4.67
(0.922, 14.30)
5.59
(2.88, 14.4)
C8h (g/mL)
0.270
(0.021, 1.05)
0.239
(0.021, 1.05)
0.260
(0.068, 0.614)
C(g/mL)3
0.075
(NQ, 0.496)
0.069
(NQ, 0.496)
0.165
(0.010, 0.610)
1.
2.
Pediatric data from Study APV20002
3.
Adult data from Study APV10010
4.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 
45/7 mg/kg BID (N=4), 45/10 mg/kg BID (N=1), and 60/10 mg/kg BID 
(N=4).
5.
Data for pediatric Subject 
was excluded because pre-dose APV 
concentration was non-quantifiable (NQ).
6.
Data summarized excluding Subject 
who had high RTV Cmax and 
AUC values.
7.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) 
values.
PPD
PPD
PPD


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Figure 3
Week 2 Plasma APV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Ctau,ss (ug/mL)
0.5
1.0
1.5
2.0
2.5


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Figure 4
Week 2 Plasma APV Cmax Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Cmax (ug/mL)
0.0
2.5
5.0
7.5
10.0
12.5


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Figure 5
Week 2 Plasma RTV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=24)
RTV Ctau,ss (ug/mL)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Change 9:
Amend:
Section 5.1 Time and Events Schedule, 1st to 3rd paragraphs
Original Text:
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.
After determining that a subject is potentially eligible for enrolment, written informed 
consent from each subject’s parent/guardian must be obtained before any investigations 
are performed which are for the sole purposes of this study.
Subjects will attend the clinic at Screening, the Single Dose Visit (first 6-10 subjects, 
Cohort 2 Arm A only), Day 1 (Baseline), and Weeks 2, 4, 8, 12, 16, 24, 36, 48, and every 
12 weeks thereafter until commercial supplies of FPV oral suspension are available 
locally and pediatric dosing is approved in the relevant age groups.  In countries where 
local availability is delayed or the drug is not yet available through national treatment 
programs, subjects may continue to receive FPV until they no longer derive clinical 


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benefit or according to prior agreements between GSK and participating study sites for 
provision of ART.  A follow-up visit will be performed 4 weeks after the permanent 
discontinuation of study drug.  
Revised Text:
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.
After determining that a subject is potentially eligible for enrolment, written informed 
consent from each subject’s parent/guardian must be obtained before any investigations 
are performed which are for the sole purposes of this study.
Subjects will attend the clinic at Screening, Day 1 (Baseline), and Weeks 2, 4, 8, 12, 16, 
24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects may continue to receive FPV until they no 
longer derive clinical benefit or according to prior agreements between GSK and 
participating study sites for provision of ART.  A follow-up visit will be performed 
4 weeks after the permanent discontinuation of study drug.  
Change 10:
Amend:
Section 5.2 Screening and Enrolment
Original Text:
Subjects will undertake the procedures listed in the schedules in Section 1  Screening will 
be within approximately 21 days of Baseline/Day 1 for all subjects.  The Single Dose 
Visits to be undertaken by the first 6-10 subjects in Cohort 2 Arm A SDV may be 
scheduled as soon as screening hematology, clinical chemistry and liver function tests 
confirming subject eligibility are available.
Reports of screening assessments of lymphocyte subsets, HIV-1 RNA PCR and HIV-1 
resistance testing (if performed) should be reviewed prior to Baseline/Day 1 to confirm 
that the subject meets the full eligibility criteria.  Subjects who undertake the Single Dose 
Visit but whose subsequently reported screening assessments of lymphocyte subsets, 
HIV-1 RNA PCR and HIV-1 resistance testing (if performed) do not meet with the 
eligibility criteria may not initiate multiple dosing with FPV.
Revised Text:
Subjects will undertake the procedures listed in the schedules in Section 10.  Screening 
will be within approximately 21 days of Baseline/Day 1 for all subjects.   As per 
amendments 5 and 7, SDV assessments are no longer required for Cohort 1 Arm A and 
Cohort 2 Arm A.  


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Reports of screening assessments of lymphocyte subsets, HIV-1 RNA PCR and HIV-1 
resistance testing (if performed) should be reviewed prior to Baseline/Day 1 to confirm 
that the subject meets the full eligibility criteria.  
Change 11:
Amend:
Section 5.7  Bioanalysis and Pharmacokinetic Samples, 2nd paragraph
Original Text:
Cohort 2 (4 weeks to <6 months) Arm A: Plasma samples for evaluation of PK 
parameters will be collected at the Single Dose Visits for the first 6-10 subjects (Arm A 
SDV).  For all subjects in Cohort 2 Arm A, plasma PK samples will be collected over 8-
12 hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be 
collected at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. 
To measure the unbound concentration of APV, additional plasma trough PK samples 
will be collected prior to FPV/RTV BID dosing at Weeks 2, 16 and 36 for Cohort 1 Arm 
A subjects and at Weeks 8 and 16 for Cohort 2 Arm A subjects.
A maximum of 7mL/kg of blood for PK, safety, and virological assessments will be 
collected during any 56-day period for all subjects.  A maximum of 3mL/kg of blood will 
be collected at any one study visit for subjects 4 weeks to <6 months old.
Single Dose Visit (SDV)
Cohort 1 (6 months - <2 years)
Per protocol amendment 5, no additional subjects in this age group are required to 
undertake SDV assessments.
Cohort 2 (4 weeks - <6 months)
The first 6-10 subjects in Arm A, who may be either PI-experienced or PI-naïve, will 
undergo one Single Dose Visit (SDV).  The SDV will be undertaken a minimum of 15 
days prior to the Baseline visit/Day 1.  At the SDV, the subject will receive a single 45 
mg/kg dose of FPV and a single 7 mg/kg dose of RTV and undergo plasma PK sampling 
over 8-12 hours (seven whole blood samples of 0.5mL each will be collected at 0, 1, 2, 4, 
6, 8, and 12 hours post-dosing).  With prior agreement of the sponsor, the 12-hour sample 
may be omitted if logistical reasons do not allow collection of this sample.
Revised Text:
Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. 


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To measure the unbound concentration of APV, additional plasma trough PK samples 
will be collected prior to FPV/RTV BID dosing at Weeks 2, 16 and 36 for Cohort 1 Arm 
A subjects and at Weeks 8 and 16 for Cohort 2 Arm A subjects.
A maximum of 7mL/kg of blood for PK, safety, and virological assessments will be 
collected during any 56-day period for all subjects.  A maximum of 3mL/kg of blood will 
be collected at any one study visit for subjects 4 weeks to <6 months old.
Single Dose Visit (SDV)
Cohort 1 (6 months - <2 years)
Per protocol amendment 5, no additional subjects in this age group are required to 
undertake SDV assessments.
Cohort 2 (4 weeks - <6 months)
Per protocol amendment 7, no additional subjects in this age group are required to 
undertake SDV assessments.
Change 12:
Amend:
Section 5.7  Bioanalysis and Pharmacokinetic Samples, Logistical Considerations, 
4th paragraph
Original Text:
Where expedited analysis of PK samples is required to construct individualized dose 
regimens or undertake individualized dose adjustments (see Section 3.3.4), every effort 
will be made to ensure that the investigator is advised, within 14 days after completion of 
the Single Dose Visit evaluations of the individualized dose regimen selected. (On receipt 
of samples at the nominated bioanalytical laboratory, GSK has contracted that 
preliminary APV, RTV and where plasma volumes allow FPV concentrations will be 
made available within 5 working days.  It is anticipated that GSK evaluation of the 
preliminary PK data will be complete and released to the investigator following a further 
2 working days.)
Revised Text:
Paragraph deleted


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Change 13:
Amend:
Section 5.8 Safety, 2nd and 3rd paragraphs
Original Text:
All routine scheduled laboratory evaluations within the study will be undertaken by a 
central laboratory nominated by the sponsor.  However, evaluation of hematology, 
clinical chemistry and liver function tests at screening only may be undertaken at a local 
accredited laboratory at the discretion of the investigator and with the approval of GSK.
Refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipping for each laboratory test.   Screening hematology, clinical 
chemistry and liver function tests undertaken at a local laboratory should be handled 
according the standard local procedures.
Revised Text:
Scheduled laboratory evaluations within the study will be undertaken by a central 
laboratory nominated by the sponsor.  However, evaluation of hematology and clinical 
chemistry may be undertaken at a local accredited laboratory with the approval of GSK.
Refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipping for each laboratory test.  Hematology and clinical 
chemistry undertaken at a local laboratory should be handled according the standard local 
procedures.


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Change 14:
Amend
Figure 2:  Study Design for Cohort 2 Arm A: PI-naïve or PI-experienced subjects 4 weeks to <6 months of age
Original Figure:
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A SDV will 
undertake a single dose visit.  Subsequently enrolled subjects In 
Cohort 2 Arm A will have their dose determined on the basis of the 
initial subjects’ Week 2 PK and will initiate multiple dosing with 
FPV/RTV BID from baseline.
≤21 DAYS
≥15 DAYS
14 DAYS
SUBSEQUENTLY
≤21 DAYS
SCREENING
Quest or local
Lab
SDV
FPV/ RTV
8-12 Hr PK
BASELINE/ 
DAY 1
Initiate 
FPV/RTV BID 
multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
ARM A: Subjects will initiate multiple dosing 
with FPV/RTV BID from baseline.
Approximately 12 additional subjects will be 
enrolled.
SCREENING
WEEK 2
8-12 Hr PK
14 DAYS
14 DAYS
BASELINE/ 
DAY 1
Initiate 
FPV/RTV BID 
multiple dosing


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Revised Figure:
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
Note:   Cohort 2 Arm A SDV is complete.  
Further subjects will enroll in Cohort 2 Arm A and initiate multiple dosing with FPV/RTV BID from Baseline
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
Note:   Cohort 2 Arm A SDV is complete.  
Further subjects will enroll in Cohort 2 Arm A and initiate multiple dosing with FPV/RTV BID from Baseline


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Change 15:
Amend:
Section 10, Original Chart
Revised Flow Chart of Clinical Scheduled Assessments (Per Amendment 5)
CLINCAL EVALUATION
Screening 
Visit 1
Single 
Dose 
Visit 2
Day 1 
(Baseline) 3
Week 
2
4
8
12
16
24
36
48
Every 12 
weeks 
thereafter
With-
drawal
Follow-up 
4
Written Informed Consent
Inclusion/Exclusion Criteria
Demography (date of birth, sex, and race)
HIV Risk Factors
CDC HIV-1 Classification
Current Medical Conditions
Body Weight , Height and Vital Signs














Head Circumference














Prior Antiretroviral Therapy History
Background Antiretroviral Therapy













Concurrent Medications/Blood Products













HIV-associated Conditions












Adverse Experience Surveillance
5






Adherence Questionnaire






Parent/Guardian Perception of Study Medication




1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects.  At screening only, the evaluation of the hematology, clinical chemistry and liver function 
tests may be undertaken at a local accredited laboratory at the discretion of the investigator and with approval of GlaxoSmithKline.
2.
The first 6-10 subjects in Cohort 2 Arm A will undergo a Single Dose Visit (SDV).  The SDV will be undertaken a minimum of 15 days prior to Baseline/Day 1.  Note: 
SDVs are no longer needed for Cohort 1 Arm A.  
3.
Subjects will initiate multiple dosing on Day 1 (Baseline)
4.
4 weeks after permanent study drug discontinuation
5.
Record serious adverse events related to study participation only during screening.


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Revised Flow Chart of Laboratory Scheduled Assessments (Per Amendment 5)
LABORATORY EVALUATION2
Screening 
Visit1
Single 
Dose 
Visit 
Day1 
(Baseline) 
Week
2
4
8
12
16
24
36
48
Every 12 weeks 
thereafter
Withdrawal
Follow-
up 
Lipids 3


Hematology 4



Clinical Chemistry and Liver Function 
Tests 5

Lymphocyte subsets

Quanatitative plasma HIV-1 RNA PCR

Plasma for storage 6


Pharmacokinetic Sampling10, 11
7
8
9






HIV-1 resistance testing12
1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects. 
2.
Laboratory assessments for all cohorts are prioritized as follows: hematology, chemistry, PK, plasma HIV-1 RNA PCR, lymphocyte subsets, HIV-1 RNA resistance testing, lipids, 
and plasma for storage. 
3.
Lipid measures include: triglycerides and total, high density lipoprotein (HDL), and LDL cholesterol. 
4.
Hematology includes: hemoglobin, WBC with differential, MCV and platelet count.
5.
Clinical chemistry panel and transaminase levels (sodium, potassium, AST, ALT, total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and CPK). 
6.
Plasma collected for storage where permitted by blood volume restrictions at Day 1 and Week 12, 24, 36, 48, every 12 weeks thereafter and Withdrawal.  This sample may be 
used for HIV-1 resistance testing in subjects experiencing virologic failure.
7.
SDV: Plasma PK sampling over 8-12 hours (at 0 [pre dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing following a single dose of FPV and RTV 
administered simultaneously for the first 6-10 subjects in Cohort 2 Arm A SDV.
8.
Week 2: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for Cohort 2 Arm A subjects and over 4 
hours (at 0 [pre-dose], 2 and 4 hours) post-dosing for subjects in Cohort 1 Arm A 
9.
Week 8: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for subjects in Cohort 1 Arm A.
10. Samples for APV/RTV trough concentration determination collected 12 hours after the last dose at Week 8 (Cohort 2 Arm A only) and Weeks 12, 16, 24, 36, 48, and 
every 12 weeks thereafter (both cohorts).
11. Samples for unbound APV concentration evaluation should be collected 12 hours after the last dose at Week 2 (Cohort 1 Arm A), Week 8 (Cohort 2 Arm A), Week 16 
(both cohorts), and Week 36 (Cohort 1 Arm A).
12. A sample for HIV-1 RNA resistance testing may be collected at Screening at the investigator’s discretion if needed to guide selection of background ART.


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Revised Chart:
Revised Flow Chart of Clinical Scheduled Assessments (Per Amendments 5 and 7)
CLINCAL EVALUATION
Screening 
Visit 1
Single 
Dose 
Visit 2
Day 1 
(Baseline) 3
Week 
2
4
8
12
16
24
36
48
Every 12 
weeks 
thereafter
With-
drawal
Follow-up 
4
Written Informed Consent
Inclusion/Exclusion Criteria
Demography (date of birth, sex, and race)
HIV Risk Factors
CDC HIV-1 Classification
Current Medical Conditions
Body Weight , Height and Vital Signs














Head Circumference














Prior Antiretroviral Therapy History
Background Antiretroviral Therapy













Concurrent Medications/Blood Products













HIV-associated Conditions












Adverse Experience Surveillance
5






Adherence Questionnaire






Parent/Guardian Perception of Study Medication




1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects.  At screening only, the evaluation of the hematology, clinical chemistry and liver function 
tests may be undertaken at a local accredited laboratory at the discretion of the investigator and with approval of GlaxoSmithKline.
2.
SDVs are no longer needed for Cohort 1 Arm A and Cohort 2 Arm A .  
3.
Subjects will initiate multiple dosing on Day 1 (Baseline)
4.
4 weeks after permanent study drug discontinuation
5.
Record serious adverse events related to study participation only during screening.


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Revised Flow Chart of Laboratory Scheduled Assessments (Per Amendments 5 and 7)
LABORATORY EVALUATION2
Screening 
Visit1
Single 
Dose 
Visit 
Day1 
(Baseline) 
Week
2
4
8
12
16
24
36
48
Every 12 weeks 
thereafter
Withdrawal
Follow-
up 
Lipids 3


Hematology 4



Clinical Chemistry and Liver Function 
Tests 5

Lymphocyte subsets

Quanatitative plasma HIV-1 RNA PCR

Plasma for storage 6


Pharmacokinetic Sampling10, 11
7
8
9






HIV-1 resistance testing12
1.
Screening will be within approximately 21 days prior to Baseline/Day 1 for all subjects. 
2.
Laboratory assessments for all cohorts are prioritized as follows: hematology, chemistry, PK, plasma HIV-1 RNA PCR, lymphocyte subsets, HIV-1 RNA resistance testing, lipids, 
and plasma for storage. 
3.
Lipid measures include: triglycerides and total, high density lipoprotein (HDL), and LDL cholesterol. 
4.
Hematology includes: hemoglobin, WBC with differential, MCV and platelet count.
5.
Clinical chemistry panel and transaminase levels (sodium, potassium, AST, ALT, total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and CPK). 
6.
Plasma collected for storage where permitted by blood volume restrictions at Day 1 and Week 12, 24, 36, 48, every 12 weeks thereafter and Withdrawal.  This sample may be 
used for HIV-1 resistance testing in subjects experiencing virologic failure.
7.
SDV plasma PK sampling no longer required for Cohort 1 Arm A and Cohort 2 Arm A..
8.
Week 2: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for Cohort 2 Arm A subjects and over 4 
hours (at 0 [pre-dose], 2 and 4 hours) post-dosing for subjects in Cohort 1 Arm A 
9.
Week 8: Plasma PK sampling over 8-12 hours (at 0 [pre-dose], 1, 2, 4, 6, 8, and 12 hours (12 hour sample optional) post-dosing for subjects in Cohort 1 Arm A.
10. Samples for APV/RTV trough concentration determination collected 12 hours after the last dose at Week 8 (Cohort 2 Arm A only) and Weeks 12, 16, 24, 36, 48, and 
every 12 weeks thereafter (both cohorts).
11. Samples for unbound APV concentration evaluation should be collected 12 hours after the last dose at Week 2 (Cohort 1 Arm A), Week 8 (Cohort 2 Arm A), Week 16 
(both cohorts), and Week 36 (Cohort 1 Arm A).
12. A sample for HIV-1 RNA resistance testing may be collected at Screening at the investigator’s discretion if needed to guide selection of background ART.


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Change 16:
Amend:
Appendix 6:  Dosing Table for RTV Oral Solution
Change:
Add a dosing 
table for RTV 10 mg/kg BID
RTV 10 mg/kg BID
Weight (kg)
Dose (mg): 10 
mg/kg
Amount of 80 mg/mL solution 
(mL) per Dose
3
30
0.38
3.5
35
0.44
4
40
0.50
4.5
45
0.56
5
50
0.63
5.5
55
0.69
6.0
60
0.75
6.5
65
0.81
7.0
70
0.88
7.5
75
0.94
8
80
1.00
8.5
85
1.06
9
90
1.13
9.5
95
1.19
10
100
1.25


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11.15.
Appendix 15:  Protocol Amendment 8
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment will apply to all study sites.
This amendment is considered substantial since the changes impact the dosing regime in 
Cohort 1A.
This amendment is being implemented to provide the dose recommendation for new 
subjects enrolled in Cohort 1 Arm A, to provide guidance for the dosing of subjects 
already in Cohort 1 Arm A, and how dosing should be managed for subjects who reach 2 
years of age during the conduct of the study. 
This amendment consists of the following changes:
a.
Revision of the dose recommendation for new subjects enrolled into Cohort 1, Arm A 
to FPV/RTV 45/7 mg/kg with no increase to 60/7 mg/kg at week 2 and up date the 
number of subjects to be recruited into Cohort 1, Arm A.
Reason for change:  An analysis of available PK data in 2009 from the first five
subjects enrolled in Cohort 1 Arm A (6 months to 2 years) and from 11 newly 
enrolled  subjects indicated that  exposure in this age group was closer to adult target 
exposure with  a dose of 45/7 mg/kg BID than 60/7 mg/kg BID. Therefore, it is 
recommended that for all new subjects enrolled into this cohort, the dose of FPV 
remains 45 mg/kg BID at week 2. 
b. Additional dosing advice for existing subjects in Cohort 1 Arm A, receiving 
FPV/RTV 60/7 mg/kg .
Reason for change:  Following the analysis of available PK data from the first five  
subjects enrolled in Cohort 1 Arm A (6 months to <2 years) and 11 newly enrolled 
subjects,  guidance is provided to allow individual dose adjustments , based on viral 
load, pharmacokinetic and safety assessments
c.
Guidance on  dosing for subjects when reaching 2 and 6 years of age during the study  
Reason for change:  Dosing recommendations for patients reaching 2 years of age 
and 6 years of age to allow staged dose reductions to the recommended doses for 
these ages.
d. Guidance to allow individual dose adjustments
Reason for change:  To allow flexibility to make individual dose adjustments based 
on results and review of available PK data from Cohort 1 and 2.


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e.
Provision for a single repeat testing for liver enzymes  in the event of grade 3 or 
higher within 28 days prior to study drug administration  to determine eligibility
Reason for change:  To allow retesting of eligible patients with an unexpected acute 
sporadic raised liver enzyme result at screening.
Individual Changes:
Change 1:  
Amend:
SPONSOR INFORMATION PAGE
Original Text:
Sponsor Medical Representatives:
, MD
GlaxoSmithKline
891-995 Greenford Road
Greenford, Middlesex, UB6 0HE, UK
Telephone: 
Revised Text:
Sponsor Medical Representatives:
, MD
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
Mobile: 
Change 2:  
Amend:
INVESTIGATOR AGREEMENT PAGE
Original Text:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
PPD
PPD
PPD
PPD
PPD


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Investigator Name:  _____________________________
Investigator Signature
Date
Revised Text:
For protocol number APV20002
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:  _____________________________
Investigator Signature
Date
Change 3:  
Amend:
ABBREVIATIONS
Original Text:
FPV
fosamprenavir, GW433908, 908
Revised Text:
FPV
fosamprenavir, GW433908, 908, Telzir, Lexiva


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Change 4:  
Amend:
PROTOCOL SUMMARY, Dose Rationale
Original Text:
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation. In children, the FPV oral suspension is recommended 
to be administered with food. 
Per protocol amendment 5, the FPV/RTV doses being studied are based on data from 
previously enrolled subjects in APV20002.  All 13 previously enrolled subjects 
underwent PK sampling during the study and 12 subjects provided evaluable PK data.  
Only two subjects below the age of 6 months provided PK data. Ten subjects between the 
ages of 6 months to <2 years provided PK data. 
Plasma APV PK parameter values were highly variable (CVb ranging from 113 to 165% 
across the PK parameters) for the subjects 6 months to <2 years of age (Cohort 1).  Nine 
of these subjects 6 months to <2 years of age receiving FPV/RTV BID regimens ranging 
from 29.4/5.6 to 51.1/8.2mg/kg BID had steady-state plasma APV CL/F values 
approximately 7-fold and RTV CL/F values approximately 4.2-fold higher than those 
observed in the historical adult population.  Compared to the historical adult population, a 
subset of five pediatric subjects ages 6 months to <2 years receiving FPV/RTV 45/7 
mg/kg BID demonstrated that despite an approximate 5-fold increase in FPV and RTV 
doses on a mg/kg basis, plasma APV AUC(0-) was approximately 48% lower, Cmax 
26% lower, and C29% lower in the pediatric subjects.  This data suggest that children 6 
months to <2 years of age old require higher doses of FPV and RTV than were 
previously explored in this study.
Per Protocol Amendment 5, newly enrolled 6 month to <2 year old subjects (Cohort 1 
Arm A) will initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks and then 
increase to FPV/RTV 60/7 mg/kg BID.  This will allow additional PK data for the 
FPV/RTV 45/7 mg/kg BID regimen and also for an increased dosage regimen.  However, 
further dose increases could be problematic because they would require high volumes of 
the FPV oral suspension.  Thus, plasma unbound APV concentrations (free drug) are 
being measured in order to determine if these concentrations are similar to historical adult 
values even if plasma total concentrations are lower.
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm 1 
(4 week to <6 month age group).  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 week to <6 month old had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose) and lower C(repeat 
dose) values compared with that historically observed for adults.  Repeat dose plasma 
RTV Cmax and AUC values were similar to historical adult data, but plasma RTV C


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values were lower in the pediatric subjects.  As plasma APV Cis important for long-
term efficacy and minimization of resistance development, it is important to try to 
achieve plasma APV Cvalues in pediatric subjects similar to those achieved with the 
approved FPV/RTV 700/100 mg BID regimen in adults.  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore, 
an increase in the RTV dose for all subsequently enrolled subjects is  recommended.
Per Protocol Amendment 7, a SDV is no longer required for newly enrolled 4 week to <6 
month age subjects (Cohort 2 Arm A).  These subjects will initiate dosing with FPV/RTV 
45/10 mg/kg BID and have serial PK sampling at Week 2 and trough sampling on 
subsequent visits.
Per Protocol Amendment 5, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.
Revised Text:
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation. In children, the FPV oral suspension is recommended 
to be administered with food. 
APV20002 was designed to determine FPV/RTV regimens for pediatric subjects 4 weeks 
to <2 years of age that would deliver plasma APV exposures proven to be safe and 
effective in adults. 
In a small subset of five subjects aged 6 months to <2 years (Cohort 1, Arm A) who 
received FPV/RTV 45/7 mg/kg BID, plasma APV AUC(0-) was approximately 48% 
lower, Cmax 26% lower, and C29% lower than the adult target values.  Conversely, 
RTV levels appeared to be similar between these pediatric subjects and adult 
comparators.  Based on these results, Amendment 5 (05-Jul-2007) was undertaken to 
initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks (to allow collection of 
additional data on this regimen) and then increase the dose to FPV/RTV 60/7 mg/kg BID 
(to collect data on a higher dose regimen) for the duration of the study.  
Subsequent to Amendment 5, eleven additional subjects have been enrolled in Cohort 1, 
Arm A.  APV PK was evaluated at Week 2 (sampling predose, 2h, and 4h post dose) for 
the FPV/RTV 45/7 mg/kg BID regimen and at Week 8 (sampling predose, 1, 2, 4, 6, 8h 
post dose) for the FPV/RTV 60/7 mg/kg BID regimen.  Plasma APV Cvalues were 
collected at all subsequent visits.  APV PK parameters for newly enrolled subjects in 
Cohort 1A (6 months to <2 years) are compared to those for the subjects of this age group 
previously report as well as adult counterparts.
APV Cmax and Cfollowing FPV/RTV 45/7 mg/kg BID were higher in the eleven 
newly enrolled subjects than in the original five subjects who received the same dose.  
However, upon re-evaluation of data for the original subjects who received 45/7 mg/kg 
BID, one subject (
) had extremely low PK parameter values at Week 2 that appear to 
PPD


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have affected the statistical point estimate of each parameter.  Excluding that one subject 
from the originally enrolled group,the  geometric mean Cmax for the remaining 4 
subjects is increased from 4.16g/mL to 6.07g/mL, more consistent with adult values 
and more similar to the geometric mean Cmax at 7.5ug.mL of the newly enrolled subjects 
receiving 45/7 mg/kg BID at Week 2.  Geometric mean AUC(0-) is increased from 
19.3g*h/mL (n=5) to 31.2g*h/mL (n=4), again much closer to the adult target values;  
AUC(0-) following 45/7 mg/kg BID could not be determined at Week 2 for newly 
enrolled subjects due to limited sampling scheme.  Overall geometric mean (95% CI) C
was increased from 1.54g/mL (1.13, 2.09g/mL, n=5) to 1.81g/mL (1.40, 2.33g/mL 
n=4), also closer to adult targets and newly enrolled subjects.
APV parameters following FPV/RTV 60/7 mg/kg BID in subjects 6 months to <2 years 
were significantly higher than adult target parameters.  Geometric mean APV AUC(0-) 
and Cmax following FPV/RTV 60/7 mg/kg BID were 1.8-fold and 2.6-fold higher than 
the geometric mean values in adults.  
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24 month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and Sponsor.   
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm A 
(4 week to <6 month age group)  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 weeks to <6 months of age had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose) and lower C(repeat 
dose) values compared with those historically observed for adults.  Repeat dose plasma 
RTV Cmax and AUC values were similar to historical adult data, but plasma RTV C
values were lower in the pediatric subjects.  As plasma APV Cis important for long-
term efficacy and minimization of resistance development, it is important to try to 
achieve plasma APV Cvalues in pediatric subjects similar to those achieved with the 
approved FPV/RTV 700/100 mg BID regimen in adults.  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore 
per Protocol Amendment 7, an increase in the RTV dose from 7 mg/kg BID to 10 mg/kg 
BID for all subsequently enrolled subjects was  recommended.  These subjects will 
initiate dosing with FPV/RTV 45/10 mg/kg BID and have serial PK sampling at Week 2 
and trough sampling on subsequent visits. Additionally a SDV is no longer required for 
newly enrolled 4 week to <6 month age subjects (Cohort 2 Arm A).  


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Per Protocol Amendment 5, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.
Change 5:  
Amend:
PROTOCOL SUMMARY, STUDY DESIGN
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 5 and 7, the approximate number of additional subjects required in 
APV20002 in addition to the 13 previously enrolled is illustrated in the following table.  
Number of Additional Subjects Required in APV20002 (as of Protocol 
Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred


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Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.  
Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit. After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo plasma PK serial 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional). Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 
subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in 
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 


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Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.
Revised Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 7 and 8, the approximate number of additional subjects required in 
APV20002 is illustrated in the following table.  
Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in this and previous protocol amendments (3, 
5, 7 and 8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed 
at the end of the study and will include subjects who have been on different dosing 
regimens.
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been 
deferred.


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Recruitment Status for APV20002 – from (FSFV) Oct 03 to 21 Sep. 09
Age
(yrs)
Cohorts
No. of Subjects 
originally planned
Cumulative enrolment 
and current status
No. still to be 
recruited to receive 
latest dose as per 
current protocol
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV
(boosted)
12
211 enrolled
12 ongoing 
Approx 4 more 
subjects
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV
(boosted)
        
12
251 enrolled
22 Ongoing
Approx 4 more 
subjects
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments


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Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.  
Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  Per 
Amendment 8, approximately 4  new subjects will be enrolled at this dose regimen (45/7 
mg/kg BID) .
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 
subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in 
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 


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Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.
Change 6:  
Amend:
PROTOCOL SUMMARY, PLANNED SAMPLE SIZE, Additional 2nd Paragraph
Revised Text:
Revisions to the planned sample size have been made following dose adjustments as 
specified in previous amendments.
Change 7:  
Amend:
PROTOCOL SUMMARY, STUDY POPULATION, 2nd Paragraph
Original Text:
As per Amendments 5 and 7, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 12 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A 
(4 weeks to <6 months) will enrol approximately 20-24 subjects to receive FPV/RTV 
BID. Enrolment in the unboosted FPV BID cohorts (Arm B) is deferred.
Revised Text:
Following Amendments 5 and 8, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 25 subjects in total to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks 
to <6 months) will enrol approximately 29 subjects in total to receive FPV/RTV BID. 
Enrolment in the unboosted FPV BID cohorts (Arm B) is deferred.


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Change 8:  
Amend:
3.1
Study Design
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 5 and 7, the approximate number of additional subjects required in 
APV20002 in addition to the 13 previously enrolled is illustrated in Table 1. 
Table 1
Number of Additional Subjects Required in APV20002 (as of Protocol 
Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred
Revised Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 


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dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 7 and 8, the approximate number of additional subjects required in 
APV20002 is illustrated in Table 1.
SDV for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in this and previous protocol amendments (3, 
5, 7 and 8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed 
at the end of the study and will include subjects who have been on different dosing 
regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been deferred.
Table 1
Recruitment Status for APV20002 – from (FSFV) Oct 03 to 21 Sep. 09
Age
(yrs)
Cohorts
No. of Subjects 
originally planned
Cumulative enrolment 
and current status
No. still to be 
recruited to receive 
latest dose as per 
current protocol
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV
(boosted)
12
211 enrolled
12 ongoing 
Approx 4 more 
subjects
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV
(boosted)
        
12
251 enrolled
22 Ongoing
Approx 4 more 
subjects
Notes
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
2.
Approximately 8 more subjects required to complete the study


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Table 2
Number of Additional Subjects Required in APV20002 (as of Protocol 
Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred
Change 9:  
Amend:
3.1
Study Design, Arm A:  Subjects Not Undertaking Single Dose Visit 
Assessments
Original Text:
Cohort 1 (6 months to <2 years) 
Per Amendment 5, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit.  After 
the Week 2 PK samples have been collected (sampling over 4 hours), these subjects will 
receive FPV 60 mg/kg BID + RTV 7 mg/kg BID and will undergo serial plasma PK 
sampling at Week 8 (over 8-12 hours; 12 hour sample optional).  Refer to Section 3.3.4 
for further information.  Approximately 12 PI-naïve or PI-experienced subjects are to be 
enrolled in Cohort 1 Arm A to receive this dosing regimen.
Revised Text:
Cohort 1 (6 months to <2 years) 
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and  Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  
Approximately 4 PI-naïve or PI-experienced subjects are to be enrolled in Cohort 1 Arm 
A to receive this dosing regimen following amendment 8.  Existing subjects in Cohort 1 
Arm A whose dose of FPV was increased to 60 mg/kg BID at Week 2 as per amendment 
5 may have their dose adjusted based on ongoing viral load, pharmacokinetic and safety 
assessments. 


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Change 10:  
Amend:
3.2 
Study Population, 1st Paragraph
Original Text: 
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 5, Cohort 1 Arm A (6 months to <2 years) will enrol approximately 12 
additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 12 subjects to receive FPV/RTV BID.  Enrolment in the 
unboosted FPV BID cohorts (Arm B) is deferred.
Revised Text:
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) will enrol approximately 4 
additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is deferred.
Change 11:  
Amend:
3.2.2
Exclusion Criteria, 9th Criterium
Original Text:
9.
Grade 3 or higher (>5x ULN) serum aminotransferase levels (alanine 
aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days 
prior to study drug administration and / or clinically relevant hepatitis within the 
previous 6 months.
Revised Text:
9.
Grade 3 or higher (>5x ULN) serum aminotransferase levels (alanine 
aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days 
prior to study drug administration and / or clinically relevant hepatitis within the 
previous 6 months. A single repeat test is allowed to determine eligibility.


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Change 12:  
Amend:
3.3.4
Rationale for Study Drug Dose Selection
Original Text:
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation.  In children, the FPV oral suspension is recommended 
to be administered with food due to the following considerations:

Children tend to eat frequently throughout the day

Parents may wish to enhance adherence, medication intake and mask taste by 
offering medication with food

FPV will be co-administered with ritonavir, which is recommended to be 
administered with food.
In adults, the FPV oral suspension formulation delivered an equivalent plasma APV 
AUC(0-) and 14.5% higher Cmax compared to the FPV tablet formulation 
[GlaxoSmithKline Document Number RM2006/00240/00, Study APV10024] 
Administration of the FPV suspension with food reduced plasma APV AUC(0-) by 
29% and Cmax by 46% [GlaxoSmithKline Document Number RM2002/00048/00, Study
APV10016].
Per protocol amendment 5, the FPV/RTV doses being studied are based on data from 
previously enrolled subjects in APV20002 [GlaxoSmithKline Document Number 
RM2006/00360/00, Study APV20002]. All 13 previously enrolled subjects underwent 
PK sampling during the study and 12 subjects provided evaluable PK data.  Only two 
subjects below the age of 6 months provided PK data; one subject was 3 months and the 
other was 4 months of age at study entry.  Ten subjects between the ages of 6 months to 
<2 years of age provided PK data.  Of these 10 subjects, study entry ages ranged from 8 
to 23 months, weights from 6 to 12kg, and heights from 65 to 87cm.  All 10 subjects 
were Hispanic and 5 (50%) were female and 5 (50%) were male.
Plasma APV PK parameter values were highly variable (CVb ranging from 113 to 165% 
across the PK parameters) for the pediatric subjects 6 months to <2 years of age.  Nine of 
these subjects ages 6 month to <2 years receiving FPV/RTV BID regimens ranging from 
29.4/5.6 to 51.1/8.2mg/kg BID had steady-state plasma APV CL/F values approximately 
7-fold and RTV CL/F values approximately 4.2-fold higher than those observed in the 
historical adult population.  Compared to the historical adult population, a subset of five 
pediatric subjects ages 6 months to <2 years of age receiving FPV/RTV 45/7 mg/kg BID 
demonstrated that despite an approximate 5-fold increase in FPV and RTV doses on a 
mg/kg basis, plasma APV AUC(0-) was approximately 48% lower, Cmax 26% lower, 
and C29% lower in the pediatric subjects.  This data suggest that children 6 months to 
<2 years of age require higher doses of FPV and RTV than were previously explored in 
this study. Refer to the local product information and subsequent APV20002 study 


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publications for safety and antiviral response data in this initial group of subjects from 
APV20002 [Cotton, 2014].
Per Protocol Amendment 5, newly enrolled subjects in Cohort 1 Arm A (6 months to <2 
years) will initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks and then 
increase to FPV/RTV 60/7 mg/kg BID.  This will allow additional PK data for the 
FPV/RTV 45/7 mg/kg BID regimen and also for an increased dosage regimen.  However, 
further dose increases could be problematic because they would require high volumes of 
the FPV oral suspension.  Thus, plasma unbound APV concentrations (free drug) are
being measured in order to determine if these concentrations are similar to historical adult 
values even if plasma total concentrations are lower.
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm 1 
(4 week to <6 month age group).  Overall, pediatric subjects 4 week to <6 month old had 
higher plasma APV Cmax and AUC values, but similar C12 (single dose, Table 2 and 
lower C(repeat dose, Table 5) values than historically observed for adults.  Repeat dose 
plasma RTV Cmax and AUC values were similar to historical adult data, but plasma 
RTV Cvalues were lower in the pediatric subjects overall (Table 4).  Because plasma 
APV Cis important for long-term efficacy and minimization of resistance development, 
it is important to try to achieve plasma APV Cvalues in pediatric subjects similar to 
those achieved with the FPV/RTV 700/100 mg BID regimen that has demonstrated 
efficacy in adults.  Although FPV/RTV 60/10 mg/kg exhibited APV C,ss most similar to 
adults (Figure 3), the APV Cmax for this regimen was considered unnecessarily high 
(Figure 4).   The RTV 10 mg/kg in the FPV/RTV 60/10 mg/kg regimen provided the 
most consistently high RTV C,ss values as compared to 30/7 and 45/7 mg/kg (Figure 5).  
It is possible that the lower plasma RTV Cvalues resulted in the lower plasma APV C
values for the lower two regimens.  Therefore, all subjects <6 months in age subsequently 
enrolled in the study will receive FPV/RTV 45/10 mg/kg to maximize RTV Cwhile 
maintaining APV Cmax values that are not excessively high. 
Per Protocol Amendment 7, newly enrolled 4 week to <6 month age subjects (Cohort 2 
Arm A) will initiate dosing with FPV/RTV 45/10 mg/kg BID.  Newly enrolled subjects 
will not undergo the SDV, but will have serial PK sampling on Week 2 and trough 
sampling on subsequent visits.


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Table 2
Summary of Single Dose Plasma APV PK in Pediatric Subjects <6 
months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV 45/7 mg/kg
(N=11)1
Adult Subjects
FPV/RTV 700/100 mg
(N=17)
Cmax (g/mL)
9.74
(5.67, 16.2)
3.65
(2.54, 6.76)
AUC(0-) (g.h/mL)
57.5
(20.2, 111)
35.2
(20.8, 114)
C8h (g/mL)
2.64
(0.819, 5.86)
1.10
(0.451, 2.20)
C12h (g/mL)2
1.13
(0.41, 3.76)
1.19
(0.659, 1.92)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Data for pediatric Subject 
was excluded because exposures were very high: Cmax: 30.9g/mL, AUC(0-): 
335g.h/mL, C8hr: 16.9g/mL.
4.
C12h is extrapolated value for pediatric subjects and observed value for adult subjects
Table 3
Summary of Repeat Dose Plasma APV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV BID1
(N=9)2
Adult Subjects
FPV/RTV 700/100 mg
(N=14)
Cmax (g/mL)
8.90
(2.07, 12.1)
4.76
(2.47, 7.68)
AUC(0-) (g.h/mL)
41.0
(16.2, 70.4)
28.3
(17.9, 43.1)
C8h (g/mL)
2.05
(1.10, 3.25)
1.58
(0.816, 2.64)
C(g/mL)3
0.970
(0.438, 1.95)
1.46
(1.06, 2.20)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
 was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
PPD
PPD


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Table 4
Summary of Repeat Dose Plasma RTV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma RTV
PK Parameter
Pediatric Subjects 
1 to <6 months
FPV/RTV BID1
Adult Subjects
FPV/RTV
700/100 mg BID
(N=9)2
(N=8)2,3
(N=24)
Cmax (g/mL)
1.28
(0.228, 7.70)
0.999
(0.228, 2.11)
1.24
(0.520, 3.84)
AUC(0-) (g.h/mL)
6.66
(0.922, 28.8)
4.67
(0.922, 14.30)
5.59
(2.88, 14.4)
C8h (g/mL)
0.270
(0.021, 1.05)
0.239
(0.021, 1.05)
0.260
(0.068, 0.614)
C(g/mL)3
0.075
(NQ, 0.496)
0.069
(NQ, 0.496)
0.165
(0.010, 0.610)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10010
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
 was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Data summarized excluding Subject 
who had high RTV Cmax and AUC values.
6.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
Figure 3
Week 2 Plasma APV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Ctau,ss (ug/mL)
0.5
1.0
1.5
2.0
2.5
PPD
PPD


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Figure 4
Week 2 Plasma APV Cmax Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Cmax (ug/mL)
0.0
2.5
5.0
7.5
10.0
12.5


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Figure 5
Week 2 Plasma RTV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=24)
RTV Ctau,ss (ug/mL)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Per Protocol Amendment 5, enrolment of the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.
Revised Text:
Given the young age of the children enrolled into this study, subjects will receive the 
FPV oral suspension formulation.  In children, the FPV oral suspension is recommended 
to be administered with food due to the following considerations:

Children tend to eat frequently throughout the day

Parents may wish to enhance adherence, medication intake and mask taste by 
offering medication with food

FPV will be co-administered with ritonavir, which is recommended to be 
administered with food.


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In adults, the FPV oral suspension formulation delivered an equivalent plasma APV 
AUC(0-) and 14.5% higher Cmax compared to the FPV tablet formulation 
[GlaxoSmithKline Document Number RM2006/00240/00, Study APV10024] 
Administration of the FPV suspension with food reduced plasma APV AUC(0-) by 
29% and Cmax by 46% [GlaxoSmithKline Document Number RM2002/00048/00, Study
APV10016].
Rationale for Drug Dose Selection for Cohort 1 (6 months to 2 years)
APV20002 was designed to determine FPV/RTV regimens for pediatric subjects 
1 to 24 months of age that would deliver plasma APV exposures proven to be safe and 
effective in adults.
In a small subset of five subjects aged 6 months to <2 years (Cohort 1, Arm A) who 
received FPV/RTV 45/7 mg/kg BID, plasma APV AUC(0-) was approximately 48% 
lower, Cmax 26% lower, and C29% lower than the adult target values.  Conversely, 
RTV levels appeared to be similar between these pediatric subjects and adult 
comparators.  Based on these results, Amendment 5 (05-Jul-2007) was undertaken to 
initiate dosing with FPV/RTV 45/7 mg/kg BID for two weeks (to allow collection of 
additional data on this regimen) and then increase the dose to FPV/RTV 60/7 mg/kg BID 
(to collect data on a higher dose regimen) for the duration of the study.  
Subsequent to Amendment 5, eleven additional subjects have been enrolled in Cohort 1, 
Arm A.  APV PK was evaluated at Week 2 (sampling predose, 2h, and 4h post dose) for 
the FPV/RTV 45/7 mg/kg BID regimen and at Week 8 (sampling predose, 1, 2, 4, 6, 8h 
post dose) for the FPV/RTV 60/7 mg/kg BID regimen.  Plasma APV Cvalues were 
collected at all subsequent visits.  APV PK parameters for newly enrolled subjects in 
Cohort 1A (6 months to <2 years) are compared to those for the subjects of this age group 
previously report as well as adult counterparts in Table 3.  


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Table 3
Summary of Plasma APV PK in pediatric subjects for Cohort 1 (6 
months to 2 years)
APV 
Parameter
Newly enrolled 
6 months to <2 years
Original 6 months to <2 
years
FPV/RTV
45/7 mg/kg
BID
Historical 
Adult
FPV/RTV 
700/100 mg 
BID
(n=159)5
FPV/RTV 
45/7 mg/kg 
BID 
(n=11)
FPV/RTV 
60/7 mg/kg 
BID
(n=7)2
(n=5)3
(n=4) 4
AUC(0-)
g*h/mL
NA
66.9
(31.5, 142)
[82]
(19.2 – 140)
19.3
(4.64, 79.9)
[165]
(2.77 – 58.1)
31.2
(15.7, 62.1)
[45]
(21.8 – 58.1)
37.0
(35.1, 38.9)
[33]
(15.7 – 95.9)
Cmax
g/mL
7.50
(5.27, 10.7)
[56]
(4.54 – 28.6)
14.8
(8.09, 27.1)
[73.0]
(4.79 – 29.6)
4.16
(1.35, 12.8)
[113]
(0.92 – 9.29)
6.07
(3.27, 11.3)
[40]
(4.07 – 9.29)
5.62
(5.35, 5.92)
[33]
(2.47 – 13.3)
C
g/mL
1.92
(1.12, 3.31)
[96]
(0.48 – 5.28)
3.57
(2.42, 5.25)
[99]
(1.09 – 16.4)
1.54
(1.13, 2.09)
[117]
(0.055 –
8.15)
1.81
(1.40, 2.33)
[80]
(0.246 –
8.15)
2.17
(2.05, 2.30)
[38]
(0.75 – 5.83)
1.
Geometric Mean (95% CI) [CVb%] (min – max)
2.
N=6 for AUC(0-) and N=20 for C(across Weeks 8 -24)
3.
N=38 for C(across Weeks 2 -48)
4.
N=32 for C(across Weeks 2 -48)
5.
N=158 for AUC(0-)
APV Cmax and Cfollowing FPV/RTV 45/7 mg/kg BID were higher in the eleven 
newly enrolled subjects than in the original five subjects who received the same dose.  
However, upon re-evaluation of data for the original subjects who received 45/7 mg/kg 
BID, one subject (
) had extremely low PK parameter values at Week 2 that appear to 
have affected the statistical point estimate of each parameter.  Excluding that one subject 
from the originally enrolled group,the  geometric mean Cmax for the remaining 4 
subjects is increased from 4.16g/mL to 6.07g/mL, more consistent with adult values 
and more similar to the geometric mean Cmax at 7.5ug.mL of the newly enrolled subjects 
receiving 45/7 mg/kg BID at Week 2.  Geometric mean AUC(0-) is increased from 
19.3g*h/mL(n=5) to 31.2g*h/mL(n=4), again much closer to the adult target values;  
AUC(0-) following 45/7 mg/kg BID could not be determined at Week 2 for newly 
enrolled subjects due to limited sampling scheme.  Overall geometric mean (95% CI) C
was increased from 1.54g/mL (1.13, 2.09g/mL, n=5) to 1.81g/mL (1.40, 2.33g/mL, 
n=4), also closer to adult targets and newly enrolled subjects.
PPD


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APV parameters following FPV/RTV 60/7 mg/kg BID in subjects 6 months – 2 years old 
were significantly higher than adult target parameters.  Geometric mean APV AUC(0-) 
and Cmax following FPV/RTV 60/7 mg/kg BID were 1.8-fold and 2.6-fold higher than 
the geometric mean values in adults.  
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and Sponsor.   
3.3.4.2 Rationale for Drug Dose Selection for Cohort 2 (4 weeks to 6 months)
Plasma APV PK data are available from the first 12 subjects enrolled in Cohort 2 Arm A 
(4 week to <6 month age group).  All 12 subjects received FPV/RTV 45/7 mg/kg as a 
single dose, and 11 subjects underwent repeat administration of FPV/RTV BID at 
individualized dosage regimens ranging from FPV 30-60 mg/kg and RTV 7-10 mg/kg 
based on each subject’s single dose PK data.  On both single dose and repeat dose 
administration of FPV/RTV, pediatric subjects 4 weeks to <6 months of age had higher 
plasma APV Cmax and AUC values, but similar C12 (single dose, Table 4) and lower C
(repeat dose, Table 5) values compared with those historically observed for adults.  
Repeat dose plasma RTV Cmax and AUC values were similar to historical adult data, but 
plasma RTV Cvalues were lower in the pediatric subjects (Table 6).  As plasma APV 
Cis important for long-term efficacy and minimization of resistance development, it is 
important to try to achieve plasma APV Cvalues in pediatric subjects similar to those 
achieved with the approved FPV/RTV 700/100 mg BID regimen in adults. Although 
FPV/RTV 60/10 mg/kg exhibited  APV C,ss, most similar to adults (Figure 3), the APV 
Cmax for this regimen was considered unnecessarily high (Figure 4).  The RTV 10 
mg/kg in the FPV/RTV 60/10 mg/kg  regimen provided the most consistently high RTV 
C,ss values as compared to 30/7 and 45/7 mg/kg (Figure 5).  It is possible that the lower 
plasma RTV Cvalues are responsible for the lower plasma APV Cvalues; therefore 
per Protocol Amendment 7, an increase in the RTV dose from 7 mg/kg BID to 10 mg/kg 
BID for all subsequently enrolled subjects was  recommended.  These subjects will 
initiate dosing with FPV/RTV 45/10 mg/kg BID and have serial PK sampling at Week 2 
and trough sampling on subsequent visits. Additionally a SDV is no longer required for 
newly enrolled 4 week to <6 month age subjects (Cohort 2 Arm A).


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Table 4
Summary of Single Dose Plasma APV PK in Pediatric Subjects <6 
months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV 45/7 mg/kg
(N=11)1
Adult Subjects
FPV/RTV 700/100 mg
(N=17)
Cmax (g/mL)
9.74
(5.67, 16.2)
3.65
(2.54, 6.76)
AUC(0-) (g.h/mL)
57.5
(20.2, 111)
35.2
(20.8, 114)
C8h (g/mL)
2.64
(0.819, 5.86)
1.10
(0.451, 2.20)
C12h (g/mL)2
1.13
(0.41, 3.76)
1.19
(0.659, 1.92)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Data for pediatric Subject 
 was excluded because exposures were very high: Cmax: 30.9g/mL, AUC(0-): 
335g.h/mL, C8hr: 16.9g/mL.
4.
C12h is extrapolated value for pediatric subjects and observed value for adult subjects
Table 5
Summary of Repeat Dose Plasma APV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma APV
PK Parameter
Pediatric Subjects 1 to <6 months
FPV/RTV BID1
(N=9)2
Adult Subjects
FPV/RTV 700/100 mg
(N=14)
Cmax (g/mL)
8.90
(2.07, 12.1)
4.76
(2.47, 7.68)
AUC(0-) (g.h/mL)
41.0
(16.2, 70.4)
28.3
(17.9, 43.1)
C8h (g/mL)
2.05
(1.10, 3.25)
1.58
(0.816, 2.64)
C(g/mL)3
0.970
(0.438, 1.95)
1.46
(1.06, 2.20)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10013
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
 was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
PPD
PPD


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Table 6
Summary of Repeat Dose Plasma RTV PK in Pediatric Subjects 
<6 months old and Adults (median [min, max])
Plasma RTV
PK Parameter
Pediatric Subjects 
1 to <6 months
FPV/RTV BID1
Adult Subjects
FPV/RTV
700/100 mg BID
(N=9)2
(N=8)2,3
(N=24)
Cmax (g/mL)
1.28
(0.228, 7.70)
0.999
(0.228, 2.11)
1.24
(0.520, 3.84)
AUC(0-) (g.h/mL)
6.66
(0.922, 28.8)
4.67
(0.922, 14.30)
5.59
(2.88, 14.4)
C8h (g/mL)
0.270
(0.021, 1.05)
0.239
(0.021, 1.05)
0.260
(0.068, 0.614)
C(g/mL)3
0.075
(NQ, 0.496)
0.069
(NQ, 0.496)
0.165
(0.010, 0.610)
1.
Pediatric data from Study APV20002
2.
Adult data from Study APV10010
3.
Pediatric FPV/RTV dosage regimens included: 30/7 mg/kg BID (N=2), 45/7 mg/kg BID (N=4), 45/10 mg/kg BID 
(N=1), and 60/10 mg/kg BID (N=4).
4.
Data for pediatric Subject 
was excluded because pre-dose APV concentration was non-quantifiable (NQ).
5.
Data summarized excluding Subject 
who had high RTV Cmax and AUC values.
6.
Ccalculated as the mean of the pre-dose and C12h (extrapolated) values.
Figure 3
Week 2 Plasma APV Ctau,ss Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Ctau,ss (ug/mL)
0.5
1.0
1.5
2.0
2.5
PPD
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Figure 4
Week 2 Plasma APV Cmax Following Repeat Administration in 
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=14)
APV Cmax (ug/mL)
0.0
2.5
5.0
7.5
10.0
12.5


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Figure 5
Week 2 Plasma RTV Ctau,ss Following Repeat Administration in
Pediatric Subjects <6 months (30/7, 45/7 and 60/10 mg/kg) Compared 
to Adults (700/100 mg)
FPV/RTV Dose
30/7 (n=2)
45/7 (n=4)
60/10 (n=3)
700/100 (n=24)
RTV Ctau,ss (ug/mL)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Per Protocol Amendment 5, enrolment of the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.
Following receipt and review of PK results from subjects in Cohorts 1 or 2, individual 
dose adjustment may be made on a subject by subject basis. 
Change 13:  
Amend:
3.3.5.1
Dosage Regimen Adjustment Criteria, additional paragraphs
Original Text:


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Dose Adjustment Due to Subject Weight
Due to subjects’ growth throughout the duration of the study, the dose of all drugs 
administered must be recalculated at each visit and the total daily dose adjusted according 
to the child’s weight and the recommended dosage regimen.  Dose adjustments should 
occur when the dose would change by 10% from the subject’s prior calculated dose.
Dose adjustments due to weight change should be delayed until after completion of the 
PK sampling to ensure that sampling is conducted at steady-state.
Dose Adjustment Due to Subject Physiological Development
Subjects will not automatically change dosage regimens as they increase in age and grow 
out of their age assigned cohort.  However, because subjects may require dose 
adjustments as they grow and develop, plasma PK samples collected throughout the study 
will be assayed on an ongoing basis, and if individualized dose adjustments are needed to 
maintain target concentrations, data will be provided to the investigators. 
Revised Text:
Dose Adjustment Due to Subject Weight
Due to subjects’ growth throughout the duration of the study, the dose of all drugs 
administered must be recalculated at each visit and the total daily dose adjusted according 
to the child’s weight and the recommended dosage regimen.  Dose adjustments should 
occur when the dose would change by 10% from the subject’s prior calculated dose.
Dose adjustments due to weight change should be delayed until after completion of the 
PK sampling to ensure that sampling is conducted at steady-state.
Dose Adjustment Due to Subject Physiological Development
Subjects will not automatically change dosage regimens as they increase in age and grow 
out of their age assigned cohort.  However, because subjects may require dose 
adjustments as they grow and develop, plasma PK samples collected throughout the study 
will be assayed on an ongoing basis, and if individualized dose adjustments are needed to 
maintain target concentrations, data will be provided to the investigators. 
Dose Adjustment Due to Subject Age
Subjects reaching and exceeding 2 years of age during the study in Cohort 1 should 
transition to the lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg  BID respectively, 
in accordance with the  dosage regimen recommended  for this age group in protocol 
APV29005.  The change in dosage can  be staged gradually over multiple visits and will 
be based on ongoing viral load, pharmacokinetic and safety assessments, at the 
investigator’s discretion.


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Subjects reaching and exceeding 6 years of age in Cohort 2 may transition to the lower 
dosage regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
Change 14:  
Additional text added:
8.3   Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov. 
Change 15:
Amend:
8.7
Investigator Access to Data and Provision of Study Results
Original Text:
GSK will provide the investigator with a copy of the CRF data collected from the site.  
When a clinical study report is completed, GSK will provide the major findings of the 
study to the investigator.
In addition, details of the study treatment assignment will be provided to the investigator 
to enable him/her to review the data to determine the outcome of the study for his/her 
subject.
Revised Text:
8.8
Investigator Access to Data and Provision of Study Results
GSK will provide the investigator with a copy of the CRF data collected from the site.  
When a clinical study report is completed, GSK will provide the major findings of the 
study to the investigator.
In addition, details of the study treatment assignment will be provided to the investigator 
to enable him/her to review the data to determine the outcome of the study for his/her 
subject.
The results summary will be posted to the Clinical Study Register no later than 12 
months after the last subject’s last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV. When manuscript publication in a 
peer-reviewed journal is not feasible, further study information will be posted to the GSK 
Clinical Study Register to supplement the results summary.


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11.16.
Appendix 16:  Protocol Amendment 9
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment will apply to all study sites.
This amendment is being implemented to specify a change of study sponsor, to provide 
information on an external review committee, to update recruitment status and to clarify 
guidance on dosing for subjects reaching 2 years and 6 years of age during the study.
The amendment consists of the following changes:
1.
Change of study sponsor
Reason for change: ViiV Healthcare was established as a new specialist HIV 
company by GSK and Pfizer.  Sponsorship of this study transfers from GSK to ViiV 
Healthcare.
2.
Establishment of an External Review Committee
Reason for change: An External Review Committee (ERC) will be established and 
utilized in this study to provide external oversight of study conduct and medical 
review of safety and/or efficacy issues.
3.
Update on recruitment status
Reason for change: Further subjects have been recruited since Protocol Amendment 
8 became effective.
4.
Clarification of guidance on dosing for subjects reaching 2 years and 6 years of age 
during the study
Reason for change: Dosing recommendations for patients reaching 2 and 6 years of 
age during the study to allow staged dose reductions to the recommended doses of 
these ages apply to all subjects regardless of the cohort they were originally enrolled 
into.
Individual Changes:
Change 1:
Amend:
TITLE PAGE
Original Text:
Author:
 
PPD


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Copyright 2009 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
Revised Text:
Author:
 
Copyright 2010 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
Change 2:
Amend:
SPONSOR SIGNATORY PAGE:
Original Text:
Sponsor Signatory:
Judith Ng-Cashin, MD
Vice President, Infectious Diseases Medicine Development Centre
Revised Text:
Sponsor Signatory:
James M. Goodrich, Ph.D., M.D.
Vice President Global Medical Strategy, ViiV Healthcare
Change 3:
Amend:
SPONSOR INFORMATION PAGE
Original Text:
Title:
A 48 Week Phase II, Open-label, 2-cohort, Multicentre Study to 
Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral 
Activity of GW433908 and GW433908/RTV When Administered 
to HIV-1 Infected Protease Inhibitor (PI) Naïve and PI-Experienced 
Pediatric Subjects aged 4 weeks to <2 years.
Study Number:
APV20002
PPD


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GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: + 001-919-483-2100.
GlaxoSmithKline
891-995 Greenford Road
Greenford, Middlesex, UB6 0HE, UK
Telephone: + 44-(0)20-8422-3434.
Sponsor Medical Representatives:
, MD
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
Mobile: 
Revised Text:
Title:
A 48 Week Phase II, Open-label, 2-cohort, Multicentre Study to 
Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral 
Activity of GW433908 and GW433908/RTV When Administered 
to HIV-1 Infected Protease Inhibitor (PI) Naïve and PI-Experienced 
Pediatric Subjects aged 4 weeks to <2 years.
Study Number:
APV20002
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is responsible for 
implementing and managing all aspects of this study.
ViiV Healthcare
980 Great West Road
Brentford
Middlesex
TW8 9GS
UK
Telephone: +44 (0)20 8380 6200
ViiV Healthcare
Five Moore Drive
Research Triangle Park
North Carolina USA
27709-3398
Telephone: +1 877 844 8872
PPD
PPD
PPD


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GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: + 001-919-483-2100.
GlaxoSmithKline
Iron Bridge Road
Stockley Park, Uxbridge, Middlesex, UB11 1BT, UK
Telephone: +44(0)208 990 9000
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline 
affiliate company (or designee).  Where applicable, the details of GSK and contact 
person will be provided to the relevant regulatory authority as part of the clinical 
trial submission.
Medical Monitor Contact Information:
, MD
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
Mobile: 
Regulatory Agency Identifying Number(s): US IND 58,627.
Change 4:
Amend:
TRADEMARK INFORMATION
Original Text:
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
AGENERASE
Norvir
EPIVIR
Kaletra
LEXIVA
Winnonlin
TELZIR
TRIZIVIR
ZIAGEN
PPD
PPD
PPD


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Revised Text:
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Agenerase
LEXIVA
Norvir
TELZIR
Kaletra
TRIZIVIR
Winnonlin
ZIAGEN
Change 5:
Amend:
PROTOCOL SUMMARY PAGE, 3rd paragraph
Original Text:
Amprenavir, delivered as AGENERASE oral solution, requires large dosing volumes and 
is approved for restricted use by children of at least 4 years of age who are unable to 
swallow AGN capsules.  This restriction in use is due mainly to concerns about the large 
volume of excipients, including PEG400 and propylene glycol, required for dosing 
[Agenerase Package Insert, 2005]. Further, due to the high propylene glycol content in 
AGN oral solution and the high ethanol content of ritonavir (RTV) oral solution, co-
administration of AGN oral solution and RTV oral solution is contraindicated.
Revised Text:
Amprenavir, delivered as Agenerase oral solution, requires large dosing volumes and is 
approved for restricted use by children of at least 4 years of age who are unable to 
swallow AGN capsules.  This restriction in use is due mainly to concerns about the large 
volume of excipients, including PEG400 and propylene glycol, required for dosing 
[Agenerase Package Insert, 2005]. Further, due to the high propylene glycol content in 
AGN oral solution and the high ethanol content of ritonavir (RTV) oral solution, co-
administration of AGN oral solution and RTV oral solution is contraindicated. At the 
holder’s request, the Marketing Authorisation for AGN was withdrawn in the EU 
on April 29, 2010 and in the USA on August 18, 2009.
Change 6:
Amend:
PROTOCOL SUMMARY, Dose Rationale, 7th paragraph
Original Text:
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24 month olds upon exclusion of the one low outlier and since APV parameters following 


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FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and sponsor.
Revised Text:
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24 month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and GSK.
Change 7:
Amend:
PROTOCOL SUMMARY, STUDY DESIGN
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 7 and 8, the approximate number of additional subjects required in
APV20002 is illustrated in the following table.
Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in this and previous protocol amendments (3, 
5, 7 and 8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed 
at the end of the study and will include subjects who have been on different dosing 
regimens.


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Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been 
deferred.
Recruitment Status for APV20002 – from (FSFV) Oct 03 to 21 Sep. 09
Age
(yrs)
Cohorts
No. of Subjects 
originally planned
Cumulative 
enrolment and 
current status
No. still to be 
recruited to 
receive latest 
dose as per 
current protocol
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV
(boosted)
12
211 enrolled
12 ongoing
Approx 4 more 
subjects
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV
(boosted)
12
251 enrolled
22 Ongoing
Approx 4 more 
subjects
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.  
Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.


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Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  Per 
Amendment 8, approximately 4 new subjects will be enrolled at this dose regimen (45/7 
mg/kg BID) .
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 
subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 
Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.
Revised Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 


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Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been 
deferred.
Recruitment Status for APV20002 – from (FSFV) Oct 03 to Oct. 10
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
12 ongoing
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
15 ongoing
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.  As per Amendments 5 and 7, no additional subjects 
are required to undergo SDV assessments.  
Refer to Section 3.1 (Figure 1 and Figure 2) for schematics outlining the study design for 
Cohort 1 Arm A and Cohort 2 Arm A, respectively.  


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Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A: Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 1 without 
undertaking a SDV.  The dose is based on the Week 2 plasma PK data from the initial 12 
subjects in Arm A SDV of Cohort 2 who underwent single dose assessments.  Subjects in 
Cohort 2 Arm A will undergo plasma PK serial sampling over 8-12 hours (12 hour 
sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve or PI-experienced 
subjects are to be enrolled in Cohort 2 Arm A to receive this dosing regimen. 
Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.
Change 8:
Amend:
1.2
Rationale, 2nd and 3rd paragraph


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Original Text:
In the NNRTI class, no liquid formulation of efavirenz is currently available 
[Sustiva Package Insert, 2007], and the other NNRTI approved for use in children, 
nevirapine (NVP), is available as an oral solution but is associated with rare but 
potentially life threatening adverse reactions [Viramune Package Insert, 2007]. 
In the PI class, only five agents- APV, indinavir (IDV), nelfinavir (NFV), RTV, and 
lopinavir/ritonavir (LPV/RTV) - are currently approved for use in HIV-1 infected 
children.  The lower age limits for which these PIs are approved for use differ between 
countries but range from >1 month (RTV) or 6 months (LPV/RTV) in some countries, 
to 2 years of age or older for the other currently approved PIs.
Revised Text:
In the NNRTI class, efavirenz (EFZ) and nevirapine (NVP) are available as liquid 
formulations.  NVP is associated with rare but potentially life threatening adverse 
reactions whilst EFZ is associated with neuropsychiatric adverse reactions
[Viramune Package Insert, 2010] [Sustiva Package Insert, 2010]. 
In the PI class, six agents - APV, indinavir (IDV), nelfinavir (NFV), RTV 
lopinavir/ritonavir (LPV/RTV), and darunavir - are currently approved for use in HIV-1 
infected children.  The lower age limits for which these PIs are approved for use differ 
between countries but range from >1 month (RTV) or 6 months (LPV/RTV) in some 
countries, to 2 years of age or older for the other currently approved PIs (6 years or older 
for darunavir).
Change 9:
Amend:
3.1
Study Design
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
As per Amendments 7 and 8, the approximate number of additional subjects required in 
APV20002 is illustrated in Table 1.


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SDV for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in this and previous protocol amendments (3, 
5, 7 and 8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed 
at the end of the study and will include subjects who have been on different dosing 
regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been deferred.
Table 1
Recruitment Status for APV20002 – from (FSFV) Oct 03 to 21 Sep. 09
Age
(yrs)
Cohorts
No. of Subjects 
originally planned
Cumulative 
enrolment and 
current status
No. still to be 
recruited to 
receive latest 
dose as per 
current protocol
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV
(boosted)
12
211 enrolled
12 ongoing
Approx 4 more 
subjects
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV
(boosted)
12
251 enrolled
22 Ongoing
Approx 4 more 
subjects
1.
Notes
2.
1.  Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
3.
2.   Approximately 8 more subjects required to complete the study 
Table 2
Number of Additional Subjects Required in APV20002 (as of 
Protocol 
Amendments 5 and 7)
Approximate Number of  
Subjects Required
Cohort
Age
Arm A 
FPV/ RTV BID
PI Naïve or Experienced
Arm B
FPV BID
PI Naive
SDV1
Initiate multiple-
dosing at baseline
1
6 months – <2 years
6-10
122
NA4
2
4 weeks – <6 months
6-10
8-123
NA4
1.
Recruitment complete for Cohort  1 Arm A SDV and Cohort 2 Arm A SDV
2.
Subjects initiate multiple dosing with FPV/RTV 45/7 mg/kg BID from baseline, after Week 2 PK, subjects will 
receive FPV/RTV 60/7 mg/kg BID (Amendment 5)
3.
Subjects initiate multiple dosing with FPV/RTV 45/10 mg/kg BID from baseline (Amendment 7)
4.
Not Applicable as Arm B enrolment is deferred


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Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.   As per Amendments 5 and 7, no additional 
subjects are required to undergo SDV assessments.
Refer to Figure 1 and Figure 2 for schematics outlining the study design for Cohort 1 
Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A:  Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years) 
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and  Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  
Approximately 4 additional PI-naïve or PI-experienced subjects are to be enrolled in 
Cohort 1 Arm A to receive this dosing regimen following amendment 8.  Existing 
subjects in Cohort 1 Arm A whose dose of FPV was increased to 60 mg/kg BID at Week 
2 as per amendment 5 may have their dose adjusted based on ongoing viral load, 
pharmacokinetic and safety assessments. 
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
appropriate multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 
1 without undertaking a SDV.  The dose is be based on the Week 2 plasma PK data from 
the initial 12 subjects in Arm A SDV of Cohort 2 who underwent single dose 


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assessments.  Subjects in Cohort 2 Arm A will undergo serial plasma PK sampling over 
8-12 hours (12 hour sample optional) at the Week 2 visit.  Approximately 8-12 PI-naïve 
or PI-experienced subjects are to be enrolled in Cohort 2 Arm A to receive this dosing 
regimen.
Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.


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Figure 1
Study Design for Cohort 1 Arm A: PI-naïve or PI-experienced subjects 6 months to <2 years of age
Note:  Cohort 1 Arm A SDV is complete.  Further subjects will enroll in Cohort 1 Arm A and initiate multiple 
dosing with FPV/RTV BID from Baseline.
ARM A SDV: The initial subjects in Cohort 1 Arm A SDV 
underwent single dose visits. Subsequently enrolled subjects in 
Cohort 1 Arm A initiate multiple dosing with FPV/RTV BID from 
baseline (with no SDV) and their dose is determined on the basis
of the initial subjects’ Week 2 PK.
≤21 DAYS
≥15 DAYS
≥14 DAYS
14 DAYS
SUBSEQUENTLY
≤21 DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
Peak/trough
PK
SDV
FPV
12 Hr PK
BASELINE/ 
DAY 1
Initiate 
FPV/RTV BID 
multiple 
dosing
WEEK 2
12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
SCREENING
WEEK 2
4 Hr PK
WEEK 8
8-12 Hr PK
ARM A: Subjects initiate multiple dosing 
with FPV/RTV BID from baseline
Approximately 12 additional subjects will 
be enrolled.
28 DAYS
14 DAYS
BASELINE/ 
DAY 1
Initiate 
FPV/RTV BID 
multiple 
dosing
14 DAYS


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Figure 2
Study Design for Cohort 2 Arm A: PI-naïve or PI-experienced subjects 4 weeks to <6 months of age
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
Note:   Cohort 2 Arm A SDV is complete.  
Further subjects will enroll in Cohort 2 Arm A and initiate multiple dosing with FPV/RTV BID from Baseline
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
ARM A SDV: The initial 6-10 subjects in Cohort 2 Arm A 
SDV will undertake a single dose visit.  Subsequently enrolled 
subjects in Cohort 2 Arm A will have their dose determined 
on the basis of the initial subjects’ Week 2 PK and will initiate 
multiple dosing with FPV/RTV BID from baseline.
ARM A: Subjects will initiate multiple dosing
With FPV/RTV BID from baseline.
Approximately 8-12 subjects will be enolled.
21DAYS
SCREENING
Quest or local
Lab
SDV
FPV/RTV
8-12 Hr PK
BASELINE/
DAY 1
Initiate
FPV/RTV BID
Multiple dosing
WEEK 2
8-12 Hr PK
WEEK 4
Potential
Dose
Adjustment
Based on
Week 2 PK
15 DAYS
14DAYS
14DAYS
BASELINE/
DAY 1
Initiate
FPV/RTV BID
multiple dosing
WEEK 2
8-12 Hr PK
21 DAYS
14DAYS
SCREENING
SUBSEQUENTLY
Note:   Cohort 2 Arm A SDV is complete.  
Further subjects will enroll in Cohort 2 Arm A and initiate multiple dosing with FPV/RTV BID from Baseline


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Revised Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
SDV for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been deferred.
Table 1
Recruitment Status for APV20002 – from (FSFV) Oct 03 to Oct 10
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
12 ongoing
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
15 ongoing
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
Overview
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV.   As per Amendments 5 and 7, no additional 
subjects are required to undergo SDV assessments.


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Refer to Figure 1 and Figure 2 for schematics outlining the study design for Cohort 1 
Arm A and Cohort 2 Arm A, respectively.  
Enrolment of Arm A (FPV/RTV BID)
Arm A SDV: Subjects Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years)
Per Amendment 5, no additional subjects in this age group are required to undertake SDV 
assessments.
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, no additional subjects in this age group are required to undertake SDV 
assessments. 
Arm A:  Subjects Not Undertaking Single Dose Visit Assessments
Cohort 1 (6 months to <2 years) 
Per Amendment 8, all new subjects who enrol in Cohort 1 Arm A should commence 
multiple dosing with FPV 45 mg/kg BID + RTV 7 mg/kg BID at the Baseline visit and 
will undergo plasma PK serial sampling at Week 2 (over 4 hours) and  Week 8 (over 8-12 
hours; 12 hour sample optional). Refer to Section 3.3.4 for further information.  Existing 
subjects in Cohort 1 Arm A whose dose of FPV was increased to 60 mg/kg BID at Week 
2 as per amendment 5 may have their dose adjusted based on ongoing viral load, 
pharmacokinetic and safety assessments. 
Cohort 2 (4 weeks to <6 months)
Per Amendment 7, all new subjects who enrol in Cohort 2 Arm A will commence 
appropriate multiple dosing with FPV 45 mg/kg BID + RTV 10 mg/kg BID on study Day 
1 without undertaking a SDV.  The dose is be based on the Week 2 plasma PK data from 
the initial 12 subjects in Arm A SDV of Cohort 2 who underwent single dose 
assessments.  Subjects in Cohort 2 Arm A will undergo serial plasma PK sampling over 
8-12 hours (12 hour sample optional) at the Week 2 visit.
Enrolment of Arm B (FPV BID)
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.


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Figure 1
Study Design for Cohort 1 Arm A: PI-naïve or PI-experienced subjects 6 months to <2 years of age


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Figure 2
Study Design for Cohort 2 Arm A: PI-naïve or PI-experienced subjects 4 weeks to <6 months of age


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Change 10:
Amend:
3.2.
Study Population, 1st Paragraph
Original Text:
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) will enrol approximately 4 
additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is deferred.
Revised Text:
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) was to enrol approximately 
4 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is deferred.
Change 11:
Amend:
3.2.2. Exclusion Criteria
Original Text:
13.
Treatment with other investigational drugs/therapies within 28 days prior to 
receiving study medication (note: treatments available through a Treatment IND 
or other expanded-access mechanism will be evaluated on a case-by-case basis in 
consultation with the sponsor).
Revised Text:
13.
Treatment with other investigational drugs/therapies within 28 days prior to 
receiving study medication (note: treatments available through a Treatment IND 
or other expanded-access mechanism will be evaluated on a case-by-case basis in 
consultation with GSK).


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Change 12:
Amend:
3.3.4.1 Rationale for Drug Dose Selection for Cohort 1 (6 months to 2 years), last 
paragraph
Original Text:
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high C values 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and Sponsor.
Revised
Per protocol amendment 8, since APV parameters following FPV/RTV 45/7 mg/kg BID 
were closer to adult targets in the newly enrolled subjects and in the original 6 month to 
24month olds upon exclusion of the one low outlier and since APV parameters following 
FPV/RTV 60/7 mg/kg BID were significantly higher than adult targets, subjects enrolled 
in the future will receive FPV/RTV 45/7 mg/kg BID continuously without an increase to 
FPV/RTV 60/7 mg/kg BID at Week 2.  Some subjects with consistently high Cvalues 
following FPV/RTV 60/7 mg/kg BID have had their dose reduced to FPV/RTV 45/7 
mg/kg BID.  Other subjects previously enrolled and currently receiving FPV/RTV 60/7 
mg/kg may have their dose modified at the discretion of the investigator and GSK.
Change 13:
Amend:
3.3.5.1.
Dosage Regimen Adjustment Criteria, 
Original Text:
Dose Adjustment Due to Subject Age exceeding 2 and 6 years
Subjects reaching and exceeding 2 years of age during the study in Cohort 1 should 
transition to the lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg  BID respectively, 
in accordance with the  dosage regimen recommended  for this age group in protocol 
APV29005.  The change in dosage can be staged gradually over multiple visits and will 
be based on ongoing viral load, pharmacokinetic and safety assessments, at the 
investigator’s discretion.


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Subjects reaching and exceeding 6 years of age in Cohort 2 may transition to the lower 
dosage regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
Revised Text:
Dose Adjustment Due to Subject Age exceeding 2 and 6 years
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg  BID respectively, in accordance 
with the  dosage regimen recommended  for this age group in protocol APV29005.  The 
change in dosage can be staged gradually over multiple visits and will be based on 
ongoing viral load, pharmacokinetic and safety assessments, at the investigator’s 
discretion.
Subjects reaching and exceeding 6 years of age may transition to the lower dosage 
regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
Change 14:
Amend:
3.3.7.2.
Toxicity Management
Original Text:
Grade 4 Toxicity/Adverse Event
Study drug will be permanently discontinued in subjects who develop a Grade 4 AE or 
toxicity.  However, if the investigator has compelling evidence that the AE is not causally 
related to the study drug(s), dosing may continue after discussion with and assent from 
the sponsor.  Subjects experiencing Grade 4 AEs requiring permanent discontinuation of 
study drug therapy should be followed weekly until resolution of the AE and encouraged 
to complete the withdrawal study evaluation.  A follow-up visit should be performed 4 
weeks after the last dose of study drug.
Subjects with Grade 4 clinically asymptomatic laboratory abnormalities should be 
investigated for all potentially non-drug related causes and study drug(s) may be 
continued if the investigator has compelling evidence that the toxicity is NOT related to 
the study drug, following discussion with the sponsor.


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Revised Text:
Grade 4 Toxicity/Adverse Event
Study drug will be permanently discontinued in subjects who develop a Grade 4 AE or 
toxicity.  However, if the investigator has compelling evidence that the AE is not causally 
related to the study drug(s), dosing may continue after discussion with and assent from 
GSK.  Subjects experiencing Grade 4 AEs requiring permanent discontinuation of study 
drug therapy should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal study evaluation.  A follow-up visit should be performed 4 
weeks after the last dose of study drug.
Subjects with Grade 4 clinically asymptomatic laboratory abnormalities should be 
investigated for all potentially non-drug related causes and study drug(s) may be 
continued if the investigator has compelling evidence that the toxicity is NOT related to 
the study drug, following discussion with GSK.
Change 15:
Amend:
3.3.8. Subject Management Options, last Paragraph
Original Text:
If a subject develops an AIDS diagnosis (CDC stage C) or other evidence of disease 
progression such that the treating clinician believes that changing therapy is required 
even though the above criteria have not been met, the investigator should contact the 
sponsor for further discussion on a case by case basis.
Revised Text:
If a subject develops an AIDS diagnosis (CDC stage C) or other evidence of disease 
progression such that the treating clinician believes that changing therapy is required 
even though the above criteria have not been met, the investigator should contact GSK
for further discussion on a case by case basis.
Change 16:
Amend:
3.3.10.1.
GSK Supplied Background NRTI Options, 10th Paragraph
Original Text:
All GSK supplied background NRTIs will be handled and stored in accordance with the 
product label or information provided by the sponsor.


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Revised Text:
All GSK supplied background NRTIs will be handled and stored in accordance with the 
product label or information provided by GSK.
Change 17:
Amend:
4.3.
Study Drug Accountability Procedures, 2nd Paragraph
Original Text:
All study drugs will be handled and stored in accordance with the product label or 
information provided by the sponsor.
Revised Text:
All study drugs will be handled and stored in accordance with the product label or 
information provided by GSK.
Change 18:
Amend:
5.8.
Safety, 2nd Paragraph
Original Text:
Scheduled laboratory evaluations within the study will be undertaken by a central 
laboratory nominated by the sponsor.  However, evaluation of hematology and clinical 
chemistry may be undertaken at a local accredited laboratory with the approval of GSK.
Revised Text:
Scheduled laboratory evaluations within the study will be undertaken by a central 
laboratory nominated by GSK.  However, evaluation of hematology and clinical 
chemistry may be undertaken at a local accredited laboratory with the approval of GSK.
Change 19:
Amend:
5.9.1. Premature Discontinuation from the Study, 2nd Paragraph
Original Text:
Subjects may be prematurely discontinued from the study for any of the following 
reasons:
•
Subject, subject’s parent/guardian or investigator non-compliance.


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•
At the request of the subject’s parent/guardian, investigator or sponsor.
•
Progression of any medical condition which, in the opinion of the principal 
investigator, should preclude further participation.
•
If the subject requires treatment with any of the medications listed in the Exclusion 
Criteria (Section 3.2.2).
•
If the subject requires cytotoxic chemotherapy or radiation therapy (with the exception 
of local treatment for Kaposi’s sarcoma).
•
If the subject requires another investigational drug which when combined with the 
study drug would, in the opinion of the investigator or sponsor, jeopardize the validity 
of the subject’s continued participation.
Revised Text:
Subjects may be prematurely discontinued from the study for any of the following 
reasons:
•
Subject, subject’s parent/guardian or investigator non-compliance.
•
At the request of the subject’s parent/guardian, investigator or GSK.
•
Progression of any medical condition which, in the opinion of the principal 
investigator, should preclude further participation.
•
If the subject requires treatment with any of the medications listed in the Exclusion 
Criteria (Section 3.2.2).
•
If the subject requires cytotoxic chemotherapy or radiation therapy (with the exception 
of local treatment for Kaposi’s sarcoma).
•
If the subject requires another investigational drug which when combined with the 
study drug would, in the opinion of the investigator or GSK, jeopardize the validity of 
the subject’s continued participation.
Change 20:
Amend:
7.1.
Definition of an AE, 5th Paragraph
Original Text:
For GSK clinical trials, AEs may include pre- or post-treatment events that occur as a 
result of protocol-mandated procedures (i.e., invasive procedures, modification of 
subject’s previous therapeutic regimen).


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Revised Text:
For ViiV Healthcare clinical trials, AEs may include pre- or post-treatment events that 
occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification 
of subject’s previous therapeutic regimen).
Change 21:
Amend:
7.12.
SAEs Involving a Non-GSK Product
Original Text:
7.12.
SAEs Involving a Non-GSK Product
In those instances where an SAE has occurred in a subject receiving a non-GSK product 
as a comparator or concurrent medication, the report must be sent to the appropriate 
project contact for SAE receipt in the same time frames as if it were a GSK product (see 
Section 7.8, “Prompt Reporting of SAEs to GSK”).
Revised Text:
7.12.
SAEs Involving a Non-ViiV Healthcare Product
In those instances where an SAE has occurred in a subject receiving a non-ViiV 
Healthcare product as a comparator or concurrent medication, the report must be sent to 
the appropriate project contact for SAE receipt in the same time frames as if it were a 
ViiV Healthcare product (see Section 7.8, “Prompt Reporting of SAEs to GSK”).
Change 22:
Amend:
8.8.
Investigator Access to Data and Provision of Study Results, 3rd Paragraph
Original Text:
The results summary will be posted to the Clinical Study Register no later than 12 
months after the last subject’s last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV. When manuscript publication in a 
peer-reviewed journal is not feasible, further study information will be posted to the GSK 
Clinical Study Register to supplement the results summary.


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Revised Text:
A results summary will be posted to a publicly available study register no later than 
12 months after the last subject’s last visit (LSLV) or sooner if required by legal 
agreement, local law or regulation. In addition, a manuscript will be submitted to a peer-
reviewed journal for publication within 18 months of LSLV.
Change 23:
Amend:
8.9.
Information Disclosure and Inventions
Original Text:
Ownership:
All data and records provided by GSK or generated during the study (other than a 
subject’s medical records) and all inventions discovered in the course of conducting the 
study are the property of GSK. If a written contract for the conduct of the study which 
includes ownership provisions inconsistent with this statement is executed, that contract’s 
ownership provisions shall apply rather than this statement.
Revised Text:
Ownership:
All data and records provided by GSK or generated during the study (other than a 
subject’s medical records) and all inventions discovered in the course of conducting the 
study are the property of ViiV Healthcare. If a written contract for the conduct of the 
study which includes ownership provisions inconsistent with this statement is executed, 
that contract’s ownership provisions shall apply rather than this statement.
Change 24:
Additional text added:
8.10.
External Review Committee
As per Amendment 9, an External Review Committee (ERC) will be established and 
utilized in this study. The ERC will provide external oversight of study conduct and 
medical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study. The schedule of any 
planned interim analysis and the analysis plan for ERC review is described in the charter, 
which is available upon request.


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11.17.
Appendix 17:  Protocol Amendment 10
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment will apply to all study sites.
This amendment is being implemented to amend information on the content of propylene 
glycol in FPV oral suspension, to close unboosted FPV Cohorts 1B and 2B and remove 
objectives and endpoints pertaining to unboosted FPV and to correct study sponsor 
information.
This amendment is considered substantial since a Dear Investigator Letter was sent to 
active study sites informing them of new information on the overall propylene glycol 
content of FPV oral suspension.
The amendment consists of the following changes:
1.
Amend information on overall propylene glycol content in FPV oral suspension
Reason for change: FPV oral suspension contains 10 mg/ml of propylene glycol as a 
solubilising agent for the preservatives.  The contribution of propylene glycol arising 
from the two flavouring agents has recently been identified.  Propylene glycol is 
present in these flavouring agents at 10 mg/ml, resulting in a total propylene glycol 
concentration of 20 mg/ml in the oral suspension.
2.
Close unboosted FPV Cohorts 1B and 2B and remove objectives and endpoints 
pertaining to unboosted FPV.
Reason for change: Based on the PK data from the age-specific FPV/RTV cohorts, 
the dose volumes of unboosted FPV oral suspension necessary to administer the 
calculated therapeutic dose in children aged <2 years would be approximately twice 
the boosted dose volumes.  Enrolment into the unboosted FPV cohorts is therefore 
not advised due to these large volumes of FPV oral suspension that would need to be 
administered as they could result in poor adherence, likely leading to an inadequate 
virologic response and subsequent resistance.
3.
Change of study sponsor information
Reason for change: Study APV20002 is sponsored by ViiV Healthcare UK Limited 
and ViiV Healthcare Company.


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Individual Changes:
Change 1:
Amend:
TITLE PAGE
Original Text:
Author:
 
Revised Text:
Author:
 
Change 2:
Amend:
SPONSOR INFORMATION PAGE
Original Text:
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is responsible for 
implementing and managing all aspects of this study.
ViiV Healthcare
980 Great West Road
Brentford
Middlesex
TW8 9GS
UK
Telephone: +44 (0)20 8380 6200
ViiV Healthcare
Five Moore Drive
Research Triangle Park
North Carolina USA
27709-3398
Telephone: +1 877 844 8872
PPD
PPD


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Revised Text:
This study is sponsored by ViiV Healthcare UK Limited and ViiV Healthcare
Company.  GlaxoSmithKline is responsible for implementing and managing all aspects 
of this study.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
UK
Telephone: +44 (0)20 8380 6200
ViiV Healthcare Company
Five Moore Drive
Research Triangle Park
North Carolina USA
27709-3398
Telephone: +1 877 844 8872
Change 3:
Amend:
PROTOCOL SUMMARY, 4th Paragraph
Original Text:
The FPV oral suspension incorporates minimal propylene glycol thereby facilitating its 
administration to children of all ages and allows co-administration with RTV oral 
solution.  
Revised Text:
The FPV oral suspension incorporates less propylene glycol than AGN oral solution
thereby facilitating its administration to children of all ages and allows co-administration 
with RTV oral solution.
Change 4:
Amend:
PROTOCOL SUMMARY, Dose Rationale, 9th Paragraph
Original Text:
Per Protocol Amendment 5, enrolment in the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.


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Revised Text:
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific 
FPV/RTV cohorts, the dose volumes of unboosted FPV oral suspension necessary to 
administer the calculated therapeutic dose in children aged <2 years would be 
approximately twice the boosted dose volumes.  Enrolment into the unboosted FPV 
cohorts is therefore not advised due to these large volumes of FPV oral suspension 
that would need to be administered as they could result in poor adherence, likely 
leading to an inadequate virologic response and subsequent resistance.
Change 5:
Amend:
STUDY OBJECTIVES 
Original Text:
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5)

To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the safety and tolerability of FPV (deferred per amendment 5) and
FPV/RTV when administered as a component of combination therapy in HIV-1 
infected pediatric subjects aged 4 weeks to <2 years
Secondary

To evaluate the antiviral activity of FPV (deferred per amendment 5) and FPV/RTV 
in combination with NRTI therapy in HIV-1 infected pediatric subjects aged 4 weeks 
to <2 years

To evaluate the immunologic activity of FPV (deferred per amendment 5) and 
FPV/RTV in combination with NRTI therapy in HIV-1 infected pediatric subjects 
aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events


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
To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes) 
Revised Text:
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5).  This objective has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the safety and tolerability of FPV/RTV when administered as a 
component of combination therapy in HIV-1 infected pediatric subjects aged 
4 weeks to <2 years. The objective to evaluate the safety and tolerability of FPV 
BID dosage regimens has been removed as per Protocol Amendment 10.
Secondary

To evaluate the antiviral activity of FPV/RTV in combination with NRTI therapy in 
HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the immunologic activity of FPV/RTV in combination with NRTI 
therapy in HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events

To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes) 
The secondary objectives to evaluate the antiviral and immunologic activity of FPV 
have been removed as per Protocol Amendment 10.


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Change 6:
Amend:
STUDY ENDPOINTS, Primary
Original Text:

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5).

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment 
–limiting toxicities

Proportion of subjects who permanently discontinue FPV (deferred per 
amendment 5) or FPV/RTV due to adverse events.
Revised Text:

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5). This endpoint has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment 
–limiting toxicities

Proportion of subjects who permanently discontinue FPV/RTV due to adverse 
events.  The endpoint ‘Proportion of subjects who permanently discontinue FPV 
due to adverse events’ has been removed as per Protocol Amendment 10.
Change 7:
Amend:
STUDY DESIGN, 4th Paragraph
Original Text:
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been 
deferred.


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Revised Text:
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been 
closed.
Change 8:
Amend:
STUDY DESIGN, Overview, 1st Paragraph
Original Text:
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
Revised Text:
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 10, enrolment in the 
Arm B cohorts (unboosted FPV) is closed.
Change 9:
Amend:
STUDY DESIGN, Overview, Enrolment of Arm B (FPV BID)
Original Text:
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.
Revised Text:
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific 
FPV/RTV cohorts, the dose volumes of unboosted FPV oral suspension necessary to 
administer the calculated therapeutic dose in children aged <2 years would be 
approximately twice the boosted dose volumes.  Enrolment into the unboosted FPV 


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cohorts is therefore not advised due to these large volumes of FPV oral suspension 
that would need to be administered as they could result in poor adherence, likely 
leading to an inadequate virologic response and subsequent resistance.
Change 10:
Amend:
PLANNED SAMPLE SIZE, 1st Paragraph
Original Text:
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, (N=24 for 
PK and safety; enrolment deferred per Amendment 5) and FPV/RTV BID, Arm A (N=24 
for PK and safety).  Safety and tolerability assessment of the FPV/RTV BID regimen 
(Arm A) will be for the duration of the study or until a subject permanently discontinues 
study drug.  If less than 8 subjects in a cohort and dosage regimen complete the steady-
state PK analysis on Week 2, additional subjects may be enrolled as replacement 
subjects. Additionally, if dose modification to the cohort dose is warranted, a further 8 
subjects in each arm may be recruited to provide steady-state PK data on the revised
dose.
Revised Text:
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, (N=24 for 
PK and safety; enrolment closed per Amendment 10) and FPV/RTV BID, Arm A 
(N=24 for PK and safety).  Safety and tolerability assessment of the FPV/RTV BID 
regimen (Arm A) will be for the duration of the study or until a subject permanently 
discontinues study drug.  If less than 8 subjects in a cohort and dosage regimen complete 
the steady-state PK analysis on Week 2, additional subjects may be enrolled as 
replacement subjects. Additionally, if dose modification to the cohort dose is warranted, a 
further 8 subjects in each arm may be recruited to provide steady-state PK data on the 
revised dose.
Change 11:
Amend:
STUDY POPULATION, 2nd Paragraph
Original Text:
Following Amendments 5 and 8, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 25 subjects in total to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks 
to <6 months) will enrol approximately 29 subjects in total to receive FPV/RTV BID. 
Enrolment in the unboosted FPV BID cohorts (Arm B) is deferred.


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Revised Text:
Following Amendments 5 and 8, Cohort 1 Arm A (6 months to <2 years) will enrol 
approximately 25 subjects in total to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks 
to <6 months) will enrol approximately 29 subjects in total to receive FPV/RTV BID. 
Enrolment in the unboosted FPV BID cohorts (Arm B) is closed.
Change 12:
Amend:
1.2 Rationale, 7th Paragraph
Original Text:
The FPV oral suspension incorporates minimal propylene glycol which allows 
administration to children of all ages and co-administration with RTV oral solution.
Revised Text:
The FPV oral suspension incorporates less propylene glycol than AGN oral solution
which allows administration to children of all ages and co-administration with RTV oral 
solution.
Change 13:
Amend:
2. STUDY OBJECTIVES AND ENDPOINTS
Original Text:
2.1
Study Objectives
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5)

To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the safety and tolerability of FPV (deferred per amendment 5) and
FPV/RTV when administered as a component of combination therapy in HIV-1 
infected pediatric subjects aged 4 weeks to <2 years


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Secondary

To evaluate the antiviral activity of FPV (deferred per amendment 5) and FPV/RTV 
in combination with NRTI therapy in HIV-1 infected pediatric subjects aged 4 weeks 
to <2 years

To evaluate the immunologic activity of FPV (deferred per amendment 5) and 
FPV/RTV in combination with NRTI therapy in HIV-1 infected pediatric subjects 
aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events

To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes)
2.2
Study Endpoints
Primary

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5).  

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment-
limiting toxicities

Proportion of subjects who permanently discontinue FPV (deferred per 
amendment 5) or FPV/RTV due to adverse events.  
Revised Text:
2.1
Study Objectives
Primary

To define the FPV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected PI-naïve pediatric subjects aged 4 weeks to 
<2 years (deferred per amendment 5).  This objective has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.


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
To define the FPV/RTV BID dosage regimens which will provide target steady-state 
plasma APV exposure to HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the safety and tolerability of FPV/RTV when administered as a 
component of combination therapy in HIV-1 infected pediatric subjects aged 
4 weeks to <2 years.  The objective to evaluate the safety and tolerability of FPV 
BID dosage regimens has been removed as per Protocol Amendment 10.
Secondary

To evaluate the antiviral activity of FPV/RTV in combination with NRTI therapy in 
HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To evaluate the immunologic activity of FPV/RTV in combination with NRTI 
therapy in HIV-1 infected pediatric subjects aged 4 weeks to <2 years

To assess systemic exposure to FPV when administered to HIV-1 infected pediatric 
subjects aged 4 weeks to <2 years

To assess plasma RTV AUC,ss, Cmax,ss and C,ss following multiple dose 
administration of FPV/RTV BID

To investigate the relationship of steady-state plasma APV PK parameters to changes 
in plasma HIV-1 RNA concentrations, CD4+ percentages and/or the occurrence of 
adverse events

To assess subject adherence and parent/guardian perceptions of study medications

To assess viral resistance patterns and to compare these patterns with treatment 
outcome (where permissible by blood volumes)
The secondary objectives to evaluate the antiviral and immunologic activity of FPV 
have been removed as per Protocol Amendment 10.
2.2
Study Endpoints
Primary

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV BID (deferred per amendment 5).  This endpoint has been removed with 
enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 Arm B) 
closed as per Protocol Amendment 10.

Plasma APV AUC,ss, Cmax,ss and C,ss following multiple dose administration of 
FPV/RTV BID

Plasma unbound APV C,ss and percent protein binding

The incidence and nature of adverse events, laboratory abnormalities, and treatment-
limiting toxicities

Proportion of subjects who permanently discontinue FPV/RTV due to adverse 
events.  The endpoint ‘Proportion of subjects who permanently discontinue FPV 
due to adverse events’ has been removed as per Protocol Amendment 10.


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Change 14:
Amend:
3.1. Study Design, 4th Paragraph
Original Text:
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 5 has been deferred.
Revised Text:
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been closed.
Change 15:
Amend:
3.1. Study Design, Overview, 1st Paragraph
Original Text:
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 5, enrolment in the 
Arm B cohorts (unboosted FPV) is deferred.
Revised Text:
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) are open in parallel.  Cohort 1 Arm A and Cohort 2 Arm A will 
recruit either PI-naïve or experienced subjects.  As per Amendment 10, enrolment in the 
Arm B cohorts (unboosted FPV) is closed.
Change 16:
Amend:
3.1. Study Design, Overview, Enrolment of Arm B (FPV BID)
Original Text:
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 5, the decision to open the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) will be deferred until the Week 2 PK data from the age-specific 
FPV/RTV cohorts are available to assist in the dose selection for the corresponding 
unboosted FPV cohort and any concerns regarding the high FPV dosing volumes have 
been addressed.


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Revised Text:
Cohort 1 (6 months to <2 years) and Cohort 2 (4 weeks to <6 months)
Per Protocol Amendment 10, enrolment in the unboosted cohorts (Cohort 1 Arm B 
and Cohort 2 Arm B) is closed.  Based on the PK data from the age-specific 
FPV/RTV cohorts, the dose volumes of unboosted FPV oral suspension necessary to 
administer the calculated therapeutic dose in children aged <2 years would be 
approximately twice the boosted dose volumes.  Enrolment into the unboosted FPV 
cohorts is therefore not advised due to these large volumes of FPV oral suspension 
that would need to be administered as they could result in poor adherence, likely 
leading to an inadequate virologic response and subsequent resistance.
Change 17:
Amend:
3.2 Study Population, 1st Paragraph
Original Text:
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) was to enrol approximately 
4 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is deferred.
Revised Text:
HIV-1 infected pediatric subjects 4 weeks to <2 years of age with screening plasma HIV-
RNA 400copies/mL and who meet the eligibility criteria will be recruited into the study. 
As of Amendment 8, Cohort 1 Arm A (6 months to <2 years) was to enrol approximately 
4 additional subjects to receive FPV/RTV BID.  Cohort 2 Arm A (4 weeks to <6 months) 
will enrol approximately 20-25 subjects in total to receive FPV/RTV BID.  Enrolment in 
the unboosted FPV BID cohorts (Arm B) is closed.
Change 18:
Amend:
3.3.1 Study Drugs, 3rd Paragraph
Original Text:
The FPV 50 mg/mL (43.2mg/mL APV molar equivalents) suspension is a white to off-
white bubblegum and peppermint flavoured suspension for oral administration using a 
dosing syringe.  Each mL of suspension contains 50 mg of FPV, equivalent to 
43.2mg/mL of APV.  The suspension contains the following inactive ingredients: 


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hydroxypropylmethyl cellulose, polysorbate 80, methylparaben, propylparaben, 
propylene glycol (overall 10 mg/mL), sucralose, calcium chloride, flavours and purified 
water.  The FPV oral suspension is manufactured by GSK in Mississauga, Ontario, 
Canada.
Revised Text:
The FPV 50 mg/mL (43.2mg/mL APV molar equivalents) suspension is a white to off-
white bubblegum and peppermint flavoured suspension for oral administration using a 
dosing syringe.  Each mL of suspension contains 50 mg of FPV, equivalent to 
43.2mg/mL of APV.  The suspension contains the following inactive ingredients: 
hydroxypropylmethyl cellulose, polysorbate 80, methylparaben, propylparaben, 
propylene glycol (overall 20 mg/mL), sucralose, calcium chloride, flavours and purified 
water.  The FPV oral suspension is manufactured by GSK in Mississauga, Ontario, 
Canada.
Change 19:
Amend:
3.3.4.2. Rationale for Drug Dose Selection for Cohort 2 (4 weeks to 6 months), 2nd
Paragraph
Original Text:
Per Protocol Amendment 5, enrolment of the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is deferred until serial PK data from the age-specific FPV/RTV cohorts 
are available to assist in the dose selection for the corresponding unboosted FPV cohort 
and any concerns regarding the high FPV dosing volumes have been addressed.
Revised Text:
Per Protocol Amendment 10, enrolment of the unboosted cohorts (Cohort 1 Arm B and 
Cohort 2 Arm B) is closed.
Change 20:
Amend:
6.1. Sample Size Determination, 1st Paragraph
Original Text:
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, Arm B 
(N=24 for PK and safety; enrolment deferred per Amendment 5) and FPV/RTV BID, 
Arm A (N=24 for PK and safety).  Safety and tolerability assessment of the FPV/RTV 
BID regimen (Arm A) will be for the duration of the study or until a subject permanently 
discontinues study drug.  If less than 8 subjects in a cohort and dosage regimen complete 
the steady-state PK analysis on Week 2, additional subjects may be enrolled as 


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replacement subjects.  Additionally, if dose modification to the cohort dose is warranted, 
a further 8 subjects in each arm may be recruited to provide steady-state PK data on the 
revised dose.
Revised Text:
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, Arm B 
(N=24 for PK and safety; enrolment closed per Amendment 10) and FPV/RTV BID, 
Arm A (N=24 for PK and safety).  Safety and tolerability assessment of the FPV/RTV 
BID regimen (Arm A) will be for the duration of the study or until a subject permanently 
discontinues study drug.  If less than 8 subjects in a cohort and dosage regimen complete 
the steady-state PK analysis on Week 2, additional subjects may be enrolled as 
replacement subjects.  Additionally, if dose modification to the cohort dose is warranted, 
a further 8 subjects in each arm may be recruited to provide steady-state PK data on the 
revised dose.


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11.18.
Appendix 18:  Protocol Amendment 11
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment will apply to all study sites.
This amendment is being implemented to include information on 3TC and ABC tablets to 
be provided by GSK as background NRTI options, to update the list of drugs not to be 
co-administered with FPV and RTV, to provide the option to discontinue PK sampling 
and monitoring of plasma APV, FPV and RTV concentration on an individual basis, and 
to update information on posting study results on publicly available clinical trials 
registers and publication.
The amendment consists of the following changes:
1.
3TC and ABC tablets provided by GSK as background NRTI options
Reason for change: Some subjects have reached an age and weight that would allow 
them to switch from 3TC and ABC solutions to scored tablets.
2.
Updated list of drugs not to be co-administered with FPV and RTV
Reason for change: based on recent drug interaction data studies, the list of drugs not 
to be co-administered with FPV and RTV has been amended. Information on drug 
interactions relevant to abacavir and lamivudine has also been added.
3.
Discontinuation of PK sampling and monitoring of plasma APV, FPV and RTV 
concentration on an individual basis
Reason for change:
FPV/RTV regimens for pediatric subjects 4 weeks to <2 years of age have been 
determined based on 24-week PK, safety and efficacy results from this study.  
Further collection of plasma APV, FPV and RTV trough concentrations should also 
not inform any further individualised dose adjustments as ongoing subjects are 
receiving recommended FPV/RTV regimens and any further dosing changes would 
follow the approved dosing recommendations without PK sampling, including a 
transition to FPV/RTV 18/3 mg/kg BID at 6 years.
4.
Information on posting study results on publicly available clinical trials registers and 
publication updated.
Reason for change: GSK aims to post a results summary to the GSK Clinical Study 
Register and other publicly available registers no later than 8 months after the last 
subject’s last visit, to publish the full study protocol on the GSK Clinical Study 
Register at the time the results of the study are published as a manuscript in the 


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scientific literature, and to post further study information to the GSK Clinical Study 
Register to supplement the results summary when manuscript publication in a peer-
reviewed journal is not feasible.
Individual Changes:
Change 1:
Amend: 3.2.2 Exclusion Criteria, Exclusion criterion 12
Original Text:
12. Treatment with any of the following medications within 28 days prior to receiving 
study medication or the anticipated need during the study:

Amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, 
diazepam, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, 
flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, 
pimozide, piroxicam, propafenone, propoxyphene, quinidine, simvastatin, 
terfenadine, and triazolam (these drugs have been excluded for safety reasons).

Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns 
Wort, (these drugs have been excluded because they have the potential to 
decrease plasma protease inhibitor concentrations).
Revised Text:
12. Treatment with any of the following medications within 28 days prior to receiving 
study medication or the anticipated need during the study:

Amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, 
diazepam, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, 
flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, 
pimozide, piroxicam, propafenone, propoxyphene, quinidine, simvastatin, 
terfenadine, and triazolam (these drugs have been excluded for safety reasons).

Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns 
Wort, (these drugs have been excluded because they have the potential to 
decrease plasma protease inhibitor concentrations).
Note: per Protocol Amendment 11, the list of drugs not to be co-administered 
with FPV and RTV has been updated (see Section 3.3.10, “Concurrent 
Medications and Non-Drug Therapies”).  As recruitment is closed, the exclusion 
criteria have not been amended.
Change 2:
Amend: 3.3.2 Background NRTI Options Provided by GlaxoSmithKline
Original Text:
Abacavir and 3TC will be provided by GSK as optional background NRTIs for subjects 
of at least 3 months of age who are determined to be susceptible to ABC and/or 3TC. 


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Susceptibility will be determined by investigator discretion and/or investigator 
interpretation of screening resistance viral genotype data, if available.  ABC and 3TC are 
licensed for the treatment of pediatric subjects of at least 3 months of age in the USA, the 
European Union, and South Africa.
The ABC oral solution contains 20 mg/mL of ABC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 
propylparaben, propylene glycol, saccharin sodium, sodium citrate, and sorbitol solution. 
The ABC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
The 3TC oral solution contains 10 mg/mL of 3TC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 
propyparaben, propylene glycol, sodium citrate (dihydrous) and sucrose (20% w/v).  The 
3TC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
In the event that a subject permanently discontinues study medication, GSK will no 
longer provide background 3TC and ABC medications.
Revised Text:
Abacavir and 3TC will be provided by GSK as optional background NRTIs for subjects 
of at least 3 months of age who are determined to be susceptible to ABC and/or 3TC. 
Susceptibility will be determined by investigator discretion and/or investigator 
interpretation of screening resistance viral genotype data, if available.    
ABC and 3TC oral solutions are licensed for the treatment of pediatric subjects of at least 
3 months of age in the USA, the European Union, and South Africa.  Scored 3TC tablets 
are licensed in the USA, the European Union, and South Africa for the treatment of 
pediatric subjects weighing greater than or equal to 14kg for whom a solid dosage 
form is appropriate.  Scored ABC tablets are licensed in the USA and the European 
Union for the treatment of pediatric subjects weighing greater than or equal to 14kg 
for whom a solid dosage form is appropriate.  Scored ABC tablets will only be 
provided by GSK for subjects in South Africa when a licence has been granted 
there.
The ABC oral solution contains 20 mg/mL of ABC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 
propylparaben, propylene glycol, saccharin sodium, sodium citrate, and sorbitol solution. 
The ABC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
The ABC tablet contains ABC sulfate equivalent to 300 mg ABC and the inactive 
ingredients colloidal anhydrous silica, magnesium stearate, microcrystalline 
cellulose, and sodium starch glycolate, Type A. The tablet is coated with a film that 
is made of methylhydroxypropylcellulose, polysorbate 80, synthetic yellow iron 
oxide, titanium dioxide, and triacetin. ABC tablets are manufactured by GSK in 
Ware, Hertfordshire, United Kingdom.
The 3TC oral solution contains 10 mg/mL of 3TC in aqueous solution and the inactive 
ingredients strawberry and banana flavours, citric acid (anhydrous), methylparaben, 


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propyparaben, propylene glycol, sodium citrate (dihydrous) and sucrose (20% w/v).  The 
3TC oral solution is manufactured by GSK in Mississauga, Ontario, Canada.
The 3TC tablet contains 150 mg of 3TC and the inactive ingredients magnesium 
stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet is coated 
with a film that is made of hypromellose, titanium dioxide, macrogol, and 
polysorbate 80. 3TC tablets are manufactured by GSK in Ware, Hertfordshire, 
United Kingdom.
In the event that a subject permanently discontinues study medication, GSK will no 
longer provide background 3TC and ABC medications.
Change 3:
Amend: 3.3.5 Dosages and dosing
Original Text:
FPV and RTV will be administered according to the doses described in Section 3.3.4.
Both the FPV and RTV oral formulations should be administered with food.  If vomiting 
or spitting up occurs within 30 minutes of administration, parents/guardians should be 
instructed to re-administer the study medications.
The recommended dose of ABC is 8 mg/kg BID (up to a maximum of 600 mg/day).
The recommended dose of 3TC is 4 mg/kg BID (up to a maximum of 300 mg/day).
Revised Text:
FPV and RTV will be administered according to the doses described in Section 3.3.4.
Both the FPV and RTV oral formulations should be administered with food.  If vomiting 
or spitting up occurs within 30 minutes of administration, parents/guardians should be 
instructed to re-administer the study medications.
The recommended dose of ABC solution is 8 mg/kg BID (up to a maximum of 600 
mg/day).
For ABC tablets, the recommended dose is one-half of a scored tablet taken twice 
daily in children weighing between 14kg and 21kg and one-half of a scored tablet 
taken in the morning and one whole tablet taken in the evening in children weighing 
between 21kg and 30kg.
The recommended dose of 3TC solution is 4 mg/kg BID (up to a maximum of 300 
mg/day).
For 3TC tablets, the recommended dose is one-half of a scored tablet taken twice 
daily in children weighing between 14kg and 21kg and one-half of a scored tablet 


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taken in the morning and one whole tablet taken in the evening in children weighing 
between 21 kg and 30 kg.
Change 4:
Amend: 3.3.5.1 Dosage Regimen Adjustment Criteria, Dose Adjustment Due to 
Subject Age exceeding 2 and 6 years
Original Text:
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg  BID respectively, in accordance 
with the  dosage regimen recommended  for this age group in protocol APV29005.  The 
change in dosage can be staged gradually over multiple visits and will be based on 
ongoing viral load, pharmacokinetic and safety assessments, at the investigator’s 
discretion.
Subjects reaching and exceeding 6 years of age may transition to the lower dosage 
regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
Revised Text:
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg  BID respectively, in accordance 
with the  dosage regimen recommended  for this age group in protocol APV29005.  The 
change in dosage can be staged gradually over multiple visits and will be based on 
ongoing viral load, pharmacokinetic and safety assessments, at the investigator’s 
discretion.
Subjects reaching and exceeding 6 years of age may transition to the lower dosage 
regimen (FPV 18 mg/kg and RTV 3 mg/kg BID) in accordance with the regimen 
approved for this age group. This dose change can be implemented gradually as the 
subject ‘grows into’ the new dose or at the time of their 6th birthday at the investigator’s 
discretion.
In consultation with the investigator, GSK may discontinue PK sampling and 
monitoring of plasma APV, FPV and RTV concentration on an individual basis 
once a subject has reached and exceeded 2 years and has initiated the 23/3 mg/kg 
BID dosing regimen after Week 48.  Any further dosing changes would follow the 
approved dosing recommendations without PK sampling, including a transition to 
FPV/RTV 18/3 mg/kg BID at 6 years.


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Change 5:
Amend: 3.3.10. Concurrent Medications and Non-Drug Therapies, 7th and 8th
paragraph
Original Text:
FPV and RTV should not be co-administered with amiodarone, astemizole, bepridil, 
bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, encainide, 
ergonovine, ergotamine, estazolam, flecainide, flurazepam, lovastatin, meperidine, 
methylergonovine, midazolam, pimozide, piroxicam, propafenone, propoxyphene, 
quinidine, simvastatin, terfenadine and triazolam.  Co-administration may result in 
competitive inhibition of metabolism of these medications and may cause serious or life-
threatening adverse events.  Co-administration of FPV or FPV/RTV with rifabutin results 
in significant increases in plasma rifabutin levels, therefore the dose of rifabutin should 
be reduced by at least 50% when co-administered with FPV and by at least 75% when co-
administered with FPV/RTV.  Caution should be used and subjects should be monitored 
closely for signs of toxicity.
FPV and RTV should not be co-administered with carbamazepine, dexamethasone, 
phenobarbital, primidone, rifampin and St. John’s Wort because the PI concentrations 
may be significantly decreased, reducing efficacy. 
Revised Text:
FPV and RTV should not be co-administered with alfuzosin, amiodarone, astemizole, 
bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, 
encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, halofantrine,
lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, 
propafenone, propoxyphene, quinidine, PDE5 inhibitors including sildenafil,
simvastatin, terfenadine and triazolam.  Co-administration may result in competitive 
inhibition of metabolism of these medications and may cause serious or life-threatening 
adverse events.  Co-administration of FPV or FPV/RTV with rifabutin results in 
significant increases in plasma rifabutin levels, therefore the dose of rifabutin should be 
reduced by at least 50% when co-administered with FPV and by at least 75% when co-
administered with FPV/RTV.  Caution should be used and subjects should be monitored 
closely for signs of toxicity.
Systemic corticosteroid effects, including Cushing's syndrome and adrenal 
suppression, have been reported in patients receiving ritonavir and inhaled or 
intranasally administered fluticasone propionate; this interaction is also expected 
with other corticosteroids metabolized via the P450 3A pathway.
Concomitant use of fluticasone propionate and ritonavir should be avoided unless 
the potential benefit to the patient outweighs the risk of systemic corticosteroid side 
effects.
FPV and RTV should not be co-administered with carbamazepine, dexamethasone, 
phenobarbital, primidone, rifampin and St. John’s Wort because the PI concentrations 


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may be significantly decreased, reducing efficacy. FPV and RTV should also not be co-
administered with hepatitis C virus (HCV) protease inhibitors telaprevir and 
boceprevir because both APV and HCV PI concentrations may be significantly 
decreased, with the possibility of sub-therapeutic concentrations.
Change 6:
Amend: 3.3.10.1 GSK Supplied Background NRTI Options, Sections on interactions 
relevant to abacavir and lamivudine added
Interactions Relevant to Abacavir
Based on the results of in vitro experiments and the known major metabolic 
pathways of ABC, the potential for drug interactions involving ABC is low. 
ABC shows no potential to inhibit metabolism mediated by the cytochrome P450 
3A4 enzyme. It has also been shown in vitro not to interact with drugs that are 
metabolised by CYP 3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic 
metabolism has not been observed in clinical studies. Therefore, there is little 
potential for drug interactions with antiretroviral protease inhibitors and other 
drugs metabolised by major P450 enzymes. Clinical studies have shown that there 
are no clinically significant interactions between ABC, zidovudine and 3TC.
Ethanol - The metabolism of ABC is altered by concomitant ethanol resulting in an 
increase in AUC of ABC of about 41%.  Given the safety profile of ABC, these 
findings are not considered clinically significant.  ABC has no effect on the 
metabolism of ethanol.
Methadone - In a PK study, co-administration of 600 mg ABC twice daily with 
methadone showed a 35% reduction in ABC Cmax and a one hour delay in tmax, 
but AUC was unchanged.  The changes in ABC PK are not considered clinically 
relevant.  In this study, ABC increased the mean methadone systemic clearance by 
22%.  This change is not considered clinically relevant for the majority of patients, 
however occasionally methadone dose re-titration may be required.
Retinoids - Retinoid compounds such as isotretinoin, are eliminated via alcohol 
dehydrogenase. Interaction with ABC is possible but has not been studied.
Refer to the local prescribing information for additional information on concurrent 
therapies.
Interactions Relevant to Lamivudine
The likelihood of interactions is low due to limited metabolism and plasma protein 
binding and almost complete renal elimination of unchanged lamivudine.
Lamivudine is predominantly eliminated by active organic cationic secretion. The 
possibility of interactions with other medicinal products administered concurrently 
should be considered, particularly when their main route of elimination is active 


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renal secretion via the organic cationic transport system, e.g. trimethoprim. Other 
medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this 
mechanism and were shown not to interact with lamivudine.
Active substances shown to be predominately excreted either via the active organic 
anionic pathway, or by glomerular filtration are unlikely to yield clinically 
significant interactions with lamivudine.
Zidovudine - A modest increase in Cmax (28%) was observed for zidovudine when 
administered with lamivudine, however overall exposure (AUC) was not 
significantly altered. Zidovudine had no effect on the pharmacokinetics of 
lamivudine. 
Trimethoprim/sulphamethoxazole - Administration of 
trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% 
increase in lamivudine exposure because of the trimethoprim component. However, 
unless the patient has renal impairment, no dosage adjustment of lamivudine is 
necessary (see Dosage and Administration).  Lamivudine has no effect on the 
pharmacokinetics of trimethoprim or sulphamethoxazole. The effect of co-
administration of lamivudine with higher doses of co-trimoxazole for the treatment 
of Pneumocystis carinii pneumonia and toxoplasmosis has not been studied. 
Zalcitabine - Lamivudine may inhibit the intracellular phosphorylation of 
zalcitabine when the two medicinal products are used concurrently.  Lamivudine is 
therefore not recommended to be used in combination with zalcitabine.
Refer to the local prescribing information for additional information on concurrent 
therapies.
Change 7:
Amend: 3.3.10.1 GSK Supplied Background NRTI Options, Packaging and 
Labeling of GSK Supplied Background NRTI Options, Handling of GSK Supplied 
Background NRTI Options, Table
Original Table:
All GSK supplied background NRTIs should be stored until the time of dispensing as 
follows:
Abacavir oral solution
US/Canada/Latin America – Store between 20C - 25C 
(68F - 77F) DO NOT FREEZE. May be refrigerated.
Europe/ South Africa – Store below 30C DO NOT 
FREEZE
Lamivudine oral solution
US/Canada/Latin America – Store in tightly closed bottles 
at 25C (77F)
Europe/ South Africa – Store at or below 25C


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Revised Table:
All GSK supplied background NRTIs should be stored until the time of dispensing as 
follows:
Abacavir oral solution
US/Canada/Latin America – Store between 20C - 25C 
(68F - 77F) DO NOT FREEZE. May be refrigerated.
Europe/ South Africa – Store below 30C DO NOT 
FREEZE
Abacavir tablet*
South Africa – Store at or below 30C.
Lamivudine oral solution
US/Canada/Latin America – Store in tightly closed bottles 
at 25C (77F)
Europe/ South Africa – Store at or below 25C
Lamivudine tablet
South Africa – Store at or below 30C.
*Only supplied when licensed in South Africa.
Change 8:
Amend: 5.7 Bioanalysis and Pharmacokinetic Samples, Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter
Original Text:
All subjects will undergo additional plasma trough PK sampling of 1.0mL of whole blood 
(just prior to receiving a scheduled dose of FPV/RTV BID) at Weeks 12, 16, 24, 36, 48
and every 12 weeks thereafter.  
In addition, at Week 16 (both Cohorts) and Week 36 (Cohort 1 only), subjects will have a 
plasma trough PK sample of 2.0mL whole blood collected (prior to receiving the 
scheduled dose of FPV/RTV BID) to determine the unbound concentration of APV.
Revised Text:
All subjects will undergo additional plasma trough PK sampling of 1.0mL of whole blood 
(just prior to receiving a scheduled dose of FPV/RTV BID) at Weeks 12, 16, 24, 36, 48
and every 12 weeks thereafter.  
In addition, at Week 16 (both Cohorts) and Week 36 (Cohort 1 only), subjects will have a 
plasma trough PK sample of 2.0mL whole blood collected (prior to receiving the 
scheduled dose of FPV/RTV BID) to determine the unbound concentration of APV.
In consultation with the investigator, GSK may discontinue PK sampling and 
monitoring of plasma APV, FPV and RTV concentration on an individual basis 
once a subject has reached and exceeded 2 years and has initiated the 23/3 mg/kg 
BID dosing regimen after Week 48.  Any further dosing changes would follow the 
approved dosing recommendations without PK sampling, including a transition to 
FPV/RTV 18/3 mg/kg BID at 6 years.


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Change 9:
Amend: Section 8.8.
Original Text:
8.8.
Investigator Access to Data and Provision of Study Results
GSK will provide the investigator with a copy of the CRF data collected from the site.  
When a clinical study report is completed, GSK will provide the major findings of the 
study to the investigator.
In addition, details of the study treatment assignment will be provided to the investigator 
to enable him/her to review the data to determine the outcome of the study for his/her 
subject.
A results summary will be posted to a publicly available study register no later than 12 
months after the last subject’s last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV.
Revised Text:
8.8.
Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication
GSK will provide the investigator with a copy of the CRF data collected from the site.  
When a clinical study report is completed, GSK will provide the major findings of the 
study to the investigator.
In addition, details of the study treatment assignment will be provided to the investigator 
to enable him/her to review the data to determine the outcome of the study for his/her 
subject.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit 
(LSLV) [this applies to each data analysis phase for studies with multiple phases, 
e.g., primary analysis, follow up analysis etc]. In addition, the aim is to submit a 
manuscript to a peer-reviewed journal for publication within 18 months of LSLV. 
GSK also aims to publish the full study protocol on the GSK Clinical Study Register 
at the time the results of the study are published as a manuscript in the scientific 
literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further 
study information will be posted to the GSK Clinical Study Register to supplement 
the results summary.


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Change 10:
Amend: 10. TABLES, Revised Flow Chart of Laboratory Scheduled Assessments 
(Per Amendments 5 and 7), Footnote 10
Original Text:
Samples for APV/RTV trough concentration determination collected 12 hours after the 
last dose at Week 8 (Cohort 2 Arm A only) and Weeks 12, 16, 24, 36, 48, and every 12 
weeks thereafter (both cohorts).  
Revised Text:
Samples for APV/RTV trough concentration determination collected 12 hours after the 
last dose at Week 8 (Cohort 2 Arm A only) and Weeks 12, 16, 24, 36, 48, and every 12 
weeks thereafter (both cohorts).  In consultation with the investigator, GSK may 
discontinue PK sampling and monitoring of plasma APV, FPV and RTV 
concentration on an individual basis once a subject has reached and exceeded 2 
years and has initiated the 23/3 mg/kg BID dosing regimen after Week 48.  Any 
further dosing changes would follow the approved dosing recommendations without 
PK sampling, including a transition to FPV/RTV 18/3 mg/kg BID at 6 years.


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11.19.
Appendix 19:  Protocol Amendment 12
Title:  APV20002 - A 48 week phase II, open-label, 2-cohort, multicentre study to 
evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 
and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naïve 
and PI-experienced pediatric subjects aged 4 weeks to <2 years.
This protocol amendment is considered minor as it is being implemented to provide 
additional clarity regarding the optional extended study participation for currently 
enrolled subjects in South Africa who have successfully completed the primary endpoint
in 2011.  The primary change in the protocol is provide additional RTV formulation 
treatment options for the South African subjects because the RTV manufacturer is 
discontinuing sale of the protocol-mandated RTV oral solution.  This amendment will 
apply to the subjects enrolled in APV20002 as of November 1, 2019 at study sites in 
South Africa.
As the protocol was last amended in 2012, in the amended version, in addition to the 
information regarding additional RTV formulations that can be used, and clarification for 
the still-enrolled South African subjects that they may continue  participate in the study 
until they are of a sufficient weight (≥39 Kg) and are able to take FPV tablets, at which 
time they will be withdrawn. Additional updates have been made to the safety and dosing 
sections including updating the FPV and RTV dosing tables for children more than 6 
years of age have been updated, updates to the list of drugs not to be co-administered 
with FPV and RTV have been added, and additional information regarding abacavir 
hypersensitivity.  Minor updates have also been made to ensure that relevant treatment 
guidelines and publications are cited, to indicate that AGN has been discontinued, to 
update the name of the study medical monitor, and to correct grammar and punctuation.
The amendment consists of the following changes shown in order of occurrence in 
the protocol:
1. Update name and contact information for the ViiV Healthcare Medical Monitor 
Reason for the change: For clarification purposes, the Sponsor of the APV20002 
Study is ViiV Healthcare.  ViiV Healthcare engages its affiliate, GlaxoSmithKline, to 
perform certain clinical services on its behalf; the appropriate ViiV Healthcare
medical monitor contact information has subsequently been updated. 
2. Include additional RTV formulation treatment options, descriptions and dosing 
instructions for the additional RTV formulations and update the RTV and FPV 
dosing tables for heavier weight subjects. 
Reason for the change: Sale of the oral RTV solution is being discontinued by the 
manufacturer in South Africa.  Subjects enrolled in South Africa sites who 
successfully completed 48 weeks of treatment are permitted to remain in the study 
until they reach a weight of 39 kg at which time they must be withdrawn (subjects at 
39 kg or more would have commercial access to FPV tablets outside of the 
APV20002 study).  As the study was not originally anticipated to extend for this 


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length of time, the dosing tables were updated for both FPV and RTV to provide 
dosing instructions for these older and larger weight subjects.  The dosing tables have 
been updated for weights through 38 kg for FPV and up to 100 mg BID for RTV
(maximum recommended dose)
3. In Section 1.3.2 FPV Pediatric Clinical Data references to subsequently published 
pediatric study results have been added here (and in the Reference section) as well 
as referring to local labels for summaries of the available data.
Reason for change: The most current information on the primary endpoint results 
from these pediatric studies are available in the individual publications and in the 
local product information:
4. Updated list of drugs not to be co-administered with FPV and RTV
Reason for change: based on recent drug interaction data studies, the list of drugs not 
to be co-administered with FPV and RTV has been amended. Information on drug 
interactions relevant to abacavir and lamivudine has also been updated.
5. Updated the information on Abacavir HSR
Reason for change: Since the last update, new information became available that the 
risk for abacavir HSR to occur is significantly increased for patients who test positive 
for the HLA-B*5701 allele. Additional information regarding HLA-B*5701 testing 
and information regarding suspected abacavir hypersensitivity reactions and rash 
management have been updated.  
6. The section regarding prompt reporting of SAES to GSK was moved to Section 
7.9 and the previous Section 7.9 (Regulatory Reporting Requirements For 
SAEs) was moved to Section 7.8.
Reason for change: to improve flow and understanding.
7. Efficacy: Viral load measurements, after 2013, are being performed using the 
Abbott Realtime HIV-1 assay instead of the Roche Amplicor assay. 
Reason for change: the Roche assay was discontinued by the manufacturer.  The 
Abbott assay has a LLOD of 40 copies/mL.  This change only impacts subjects 
enrolled in the South African sites.
8. Assent forms will also be obtained from subjects still enrolled in the study as of 
Nov 1, 2019.
Reason for change:  Informed consent was originally obtained from the carers as the 
subjects were 2 years or younger at enrolment.  The enrolled subjects who chose to 
participate after successfully completing 48 weeks of treatment at the South African 
sites are now of an age where they can also give assent for study participation.


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Individual Changes
Note: minor punctuation or grammar corrections have not been included in the list of 
changes.  Updated references are indicated in the individual changes for the sections in 
which they are cited. Specific revisions to the text are shown in bold.
Change 1: Medical Monitor Contact Information
Original Text:
, MD
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
Mobile: 
Revised Text 
, MD PhD
ViiV Healthcare 
5 Moore Drive
P.O. 13398
Research Triangle Park USA 27709
Mobile: 
Change 2
Changes within the Protocol Summary Section
2nd Paragraph
Original Text:
Agenerase (AGN, amprenavir, APV) is a protease inhibitor (PI) developed for the 
treatment of HIV disease.  Although AGN has demonstrated antiviral activity and is 
generally safe when given in combination with other antiretroviral agents to subjects at 
all stages of HIV infection, the pill count with the capsule formulation and substantial 
volume of oral solution required (1.5mL/kg BID) are less than optimal and may impact 
long term adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a t 
and oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA™/ 
TELZIR™), the phosphate ester prodrug of APV, have been developed to facilitate 
dosing of adult and pediatric HIV-1 infected patients. The safety and efficacy of FPV-
containing regimens was demonstrated in three Phase III clinical trials in adults.
The use of combination therapy with at least 3 drugs, including either a PI or a non-
nucleoside reverse transcriptase inhibitor (NNRTI), plus a dual nucleoside reverse 
transcriptase inhibitor (NRTI) backbone is the current standard of care and recommended 
for initial treatment of HIV-infected adults and children [US Department of Health and 
Human Services, 2006; Working Group on Antiretroviral Therapy and Medical 
Management of HIV-Infected Children, 2006; South Africa Guidelines, 2005].  There 
PPD
PPD
PPD
PPD
PPD


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remains a need for additional therapies for HIV infected children, in particular there are 
limited choices for a third agent to be given in combination with two NRTIs, and the 
choices are even more limited in children <2 years of age.
Revised Text 
Agenerase (AGN, amprenavir, APV) was a protease inhibitor (PI) developed for the 
treatment of HIV disease.  Although AGN demonstrated antiviral activity and was
generally safe when given in combination with other antiretroviral agents to subjects at 
all stages of HIV infection, the pill count with the capsule formulation and substantial 
volume of oral solution required (1.5mL/kg BID) was less than optimal and could impact 
long term adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a 
tablet and oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA™/ 
TELZIR™), the phosphate ester prodrug of APV, was developed to facilitate dosing of 
adult and pediatric HIV-1 infected patients. The safety and efficacy of FPV-containing 
regimens was demonstrated in three Phase III clinical trials in adults.
The use of combination therapy with 3 drugs, including either a PI or a non-nucleoside 
reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor, plus a dual nucleoside 
reverse transcriptase inhibitor (NRTI) backbone is the current standard of care for and is 
recommended for initial treatment of most HIV-infected adults and children [DHHS, 
2019; EACS, 2018; Panel on Antiretroviral Therapy and Medical Management of 
HIV-Infected Children; 2019].  There remains a need for additional therapies for HIV 
infected children, in particular there are limited choices for a third agent to be given in 
combination with two NRTIs, and the choices are even more limited in children <2 years 
of age.
Protocol Summary, Dose Rationale, 10th Paragraph
Original Text:
None 
Revised Text (paragraph added)
Per Protocol Amendment 12, as sale of RTV oral solution is being discontinued by the 
manufacturer in South Africa, additional RTV formulation options have been added for 
the South African sites.  The RTV dosing is based upon the weight of the child and 
include RTV supplied as 100 mg tablets, capsules or powders/sachets.
Protocol Summary, Study Design, 1st Paragraph
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to <2 
years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 


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until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART.
Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been 
closed.
Recruitment Status for APV20002 – from (FSFV) Oct 03 to Oct 10
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
12 ongoing
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
15 ongoing
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
Revised Text
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to <2 
years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups.  In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. Per 
protocol amendment 12; only subjects at sites in South Africa remain enrolled as 
supplies of oral FPV suspension are not commercially available in South Africa. 
Subjects successfully completing 48 weeks of therapy and receiving clinical benefit 
who weigh less than 39 kg may continue to receive FPV oral suspension provided by 
GSK. Once subjects reach a weight of 39 kg, South African treatment guidelines 


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permit the use of the FPV tablets in children weighing ≥39 kg and these subjects will 
be withdrawn as FPV tablets are commercially available in South Africa.
Single dose PK data for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Enrolment into Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been 
closed.
Recruitment Status for APV20002 – from Oct 2003 (FSFV) to Jul 2011 (cutoff for 48 
week CSR
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
261 enrolled
11 ongoing2
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
281 enrolled
14 ongoing2
1.
A total of 59 patients were enrolled but 5 were discontinued after receiving single dose of FPV; current 
total enrolled patients exceeds the original cohort target because of dose changes in previous amendments
2.
Ongoing as of cutoff for 48 week CSR (July 2011)
Protocol Summary Study Drugs and Dosages 
Original text:
Study drugs are defined as FPV and RTV.  FPV will be administered as a 50mg/mL 
(43.2mg/mL APV molar equivalents) oral suspension.   RTV will be given as an 
80mg/mL oral solution.  Both the FPV and RTV oral formulations should be 
administered with food.  If vomiting or spitting up occurs within 30 minutes of 
administration, parents/guardians should be instructed to re-administer the study 
medications.
Revised Text
Study drugs are defined as FPV and RTV.  FPV will be administered as a 50 mg/mL 
(43.2 mg/mL APV molar equivalents) oral suspension.  RTV will be administered as an 
80 mg/mL oral solution, as a 100 mg capsule or tablet, or as a 100 mg powder 
packet/sachet.  Choice of appropriate formulation will depend on participant’s weight, 
availability of formulation and participant/caregiver preference.  Both the FPV and RTV 
oral formulations should be administered with food.  If vomiting or spitting up occurs 


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within 30 minutes of administration, parents/guardians should be instructed to re-
administer the study medications.  
Protocol Summary Measurements and Evaluations 
Original text:
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.  Subjects will attend the clinic at Screening (within 
approximately 21 days prior to Baseline/Day 1), Day 1 (Baseline), and Weeks 2, 4, 8, 12, 
16, 24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects may continue to receive FPV until they no 
longer derive clinical benefit or according to prior agreements between GSK and 
participating study sites for provision of ART.  A follow-up visit will be performed 
4 weeks after the permanent discontinuation of study drug.
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter. 
Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. 
Revised Text
Schedules showing the timing of study procedures and laboratory evaluations for all 
subjects are shown in Section 10.  Subjects will attend the clinic at Screening (within 
approximately 21 days prior to Baseline/Day 1), Day 1 (Baseline), and Weeks 2, 4, 8, 12, 
16, 24, 36, 48, and every 12 weeks thereafter until commercial supplies of FPV oral 
suspension are available locally and pediatric dosing is approved in the relevant age 
groups.  In countries where local availability is delayed or the drug is not yet available 
through national treatment programs, subjects who successfully complete 48 weeks on 
therapy may continue to receive FPV oral suspension provided by GSK until they no 
longer derive clinical benefit, weigh 39 kg or more, or according to prior agreements 
between GSK and participating study sites for provision of ART.  A follow-up visit will 
be performed 4 weeks after the permanent discontinuation of study drug.
Cohort 1 (6 months to <2 years) Arm A: Plasma samples for evaluation of PK parameters 
will be collected over 4 hours at Week 2 and over 8-12 hours (12 hour sample optional) 
at Week 8.  Plasma trough PK samples will be collected at Weeks 12, 16, 24, 36, 48 and 
every 12 weeks thereafter. Protocol amendment 11 (effective date October 26, 2012) 
provided the option to discontinue PK sampling once a subject had reached and 
exceeded 2 years and had initiated the 23/3 mg/kg FPV/RTV BID dosing regimen.  
PK sampling was discontinued after approval of the amended protocol in South 
Africa.


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Cohort 2 (4 weeks to <6 months) Arm A:  Plasma PK samples will be collected over 8-12 
hours (12 hour sample optional) at Week 2.  Plasma trough PK samples will be collected 
at Weeks 8, 12, 16, 24, 36, 48 and every 12 weeks thereafter. PK sampling was 
subsequently discontinued after approval of APV20002 protocol amendment 11, by 
which time the last enrolled subject had been enrolled in the study for more than 48 
weeks.
Change 3
Amend: Section 1 Introduction
Section 1.1 Background 
Original text:
Agenerase (AGN, amprenavir, APV) is a protease inhibitor (PI) for the treatment of HIV 
disease.  Although AGN has demonstrated antiviral activity and is generally safe when 
given in combination with other antiretroviral agents to subjects at all stages of HIV 
infection, the pill count with the capsule formulation and substantial volume of oral 
solution required (1.5mL/kg BID) are less than optimal and may impact long term 
adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a tablet and 
oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA/ TELZIR), 
the phosphate ester prodrug of APV, have been developed to facilitate dosing of adult 
and pediatric HIV-1 infected patients.
The safety and efficacy of three FPV-containing regimens has been demonstrated in three 
Phase III clinical trials, APV30001 (antiretroviral [ART]-naïve subjects), APV30002 
(ART-naïve subjects), and APV30003 (PI-experienced subjects). [GlaxoSmithKline 
Document Number GM2002/00054/00, Study APV30002; GlaxoSmithKline Document 
Number RM2002/00088/00, Study APV30001; GlaxoSmithKline Document Number 
RM2002/00140/00, Study APV30003].  Based on these studies, three dosing regimens in 
adults are approved in the United States (US); for ART-naïve subjects, FPV 1400mg 
BID, FPV 700mg BID + ritonavir (RTV) 100mg BID or FPV 1400mg QD + RTV 200mg 
QD and for PI-experienced subjects, FPV 700mg BID + RTV 100mg BID.  In Europe, 
the FPV 700mg BID + RTV 100mg BID regimen was approved for PI-naïve or 
experienced HIV-1 infected adults.  A further study in ART-naïve adults (ESS100732, 
KLEAN) demonstrated non-inferiority of FPV 700mg BID + RTV 100mg BID compared 
to lopinavir (LPV)/ RTV (Kaletra) BID [GlaxoSmithKline Document Number 
RM2006/00010/00, Study ESS100732].
Revised Text
Agenerase (AGN, amprenavir, APV) was a protease inhibitor (PI) for the treatment of 
HIV disease.  Although AGN demonstrated antiviral activity and was generally safe 
when given in combination with other antiretroviral agents to subjects at all stages of 
HIV infection, the pill count with the capsule formulation and substantial volume of oral 
solution required (1.5mL/kg BID) were less than optimal and may have impacted long 
term adherence to therapy.  To reduce the pill burden of APV delivered as AGN, a tablet 
and oral suspension formulation of fosamprenavir (FPV, GW433908, LEXIVA/ 


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TELZIR), the phosphate ester prodrug of APV, were developed to facilitate dosing of 
adult and pediatric HIV-1 infected patients. 
The safety and efficacy of three FPV-containing regimens has been demonstrated in three 
Phase III clinical trials, APV30001 (antiretroviral [ART]-naïve subjects), APV30002 
(ART-naïve subjects), and APV30003 (PI-experienced subjects). [GlaxoSmithKline 
Document Number GM2002/00054/00, Study APV30002; GlaxoSmithKline Document 
Number RM2002/00088/00, Study APV30001; GlaxoSmithKline Document Number 
RM2002/00140/00, Study APV30003].  Based on these studies, four dosing regimens in 
adults are approved in the United States (US) for ART-naïve subjects: FPV 1400 mg
BID, FPV 700 mg BID + ritonavir (RTV) 100 mg BID or FPV 1400 mg QD + RTV 200 
mg QD or FPV 1400 mg QD + RTV 100 mg QD and for PI-experienced subjects: FPV 
700 mg BID + RTV 100 mg BID.  In Europe, the FPV 700 mg BID + RTV 100 mg BID 
regimen was approved for PI-naïve or experienced HIV-1 infected adults.  A further 
study in ART-naïve adults (ESS100732, KLEAN) demonstrated non-inferiority of FPV 
700 mg BID + RTV 100 mg BID compared to lopinavir (LPV)/ RTV (Kaletra) BID 
[GlaxoSmithKline Document Number RM2006/00010/00, Study ESS100732].
Change 4
Amend Section 1.2 Rationale
Original text:
The use of combination therapy with at least 3 drugs, including either a PI or a non-
nucleoside reverse transcriptase inhibitor (NNRTI), plus a dual nucleoside reverse 
transcriptase inhibitor (NRTI) backbone is the current standard of care and recommended 
for initial treatment of HIV-infected adults and children [US Department of Health and 
Human Services, 2006; Working Group on Antiretroviral Therapy and Medical 
Management of HIV-Infected Children, 2006; South Africa Guidelines, 2005].  There 
remains a need for additional therapies for HIV infected children, in particular there are 
limited choices for a third agent to be given in combination with two NRTIs, and the 
choices are even more limited in children <2 years of age.
Revised Text
The use of combination therapy with 3 drugs, including either a PI or a non-nucleoside 
reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor, plus a dual nucleoside 
reverse transcriptase inhibitor (NRTI) backbone is the current standard of care for and is 
recommended for initial treatment of most HIV-infected adults and children [DHHS, 
2019; EACS, 2018; Panel on Antiretroviral Therapy and Medical Management of 
HIV-Infected Children; 2019].  There remains a need for additional therapies for HIV 
infected children, in particular there are limited choices for a third agent to be given in 
combination with two NRTIs, and the choices are even more limited in children <2 years 
of age.


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At the time the APV20002 study was collecting the primary outcome data (through 
Week 48), in the NNRTI class, efavirenz (EFZ) and nevirapine (NVP) were available as 
liquid formulations.  NVP is associated with rare but potentially life threatening adverse 
reactions whilst EFZ is associated with neuropsychiatric adverse reactions 
[Viramune Package Insert, 2010] [Sustiva Package Insert, 2010].
Similarly, at the time the APV20002 study was collecting the primary outcome data 
(through Week 48), in the PI class, six agents - APV, indinavir (IDV), nelfinavir (NFV), 
RTV lopinavir/ritonavir (LPV/RTV), and darunavir were approved for use in HIV-1 
infected children.  APV has subsequently been discontinued. The lower age limits for 
which these PIs were approved for use varies between countries. Deleted text: but 
range from >1 month (RTV) or 6 months (LPV/RTV) in some countries, to 2 years 
of age or older for the other currently approved PIs (6 years or older for darunavir).
LPV/RTV is a PI combination frequently used in children.  Several studies support the 
use of LPV/RTV in children.  An early study in children 6 months to 12 years of age 
demonstrated the antiviral activity of LPV/RTV over a 24 week period, with plasma 
HIV-1 RNA levels of <400 copies/mL being achieved in 82% of ART-naïve children and 
66% of children with a mixture of NRTI-experience and NRTI + PI-experience, and 
accompanying improvements in CD4+ lymphocyte counts, after 24 weeks of therapy 
[Violari, 2000].  In a later study, 100 children ages 6 months to 12 years who were either 
ART naïve or ART-experienced but NNRTI naïve, received LPV/RTV as part of an ART 
regimen.  At Week 48, 79% of subjects had plasma HIV-1 RNA levels of <400 
copies/mL with corresponding mean increases in CD4+ cell counts from baseline [Post, 
2010; Ross, 2015; Saez-Llorens, 2003]. Recently, data on the use of LPV/RTV in infants 
<6 weeks of age has been presented.  In this study, 8 infants ages ≥14 days to ≤6 weeks 
received standard dose LPV/RTV over 24 weeks.  LPV/RTV AUCs were significantly 
lower than seen in an older cohort ages 6 weeks to 6 months, yet the regimen resulted in 
virological suppression (plasma HIV-1 RNA <400 copies/mL) in 7/8 subjects [Pinto, 
2007]. 
Although these PI therapies available for the treatment of HIV-1 infected children 
effectively inhibit HIV replication, most display limitations, such as lack of suitable 
formulations, inflexible dosing schedules and clinical side effects. For instance, no liquid 
formulation is available for indinavir and it is more difficult to assure adequate fluid 
intake to avoid renal complications in children than in adults.  The powder formulation of 
nelfinavir is difficult to administer to children, and consequently the adult tablets are used 
which results in a restrictive dosing schedule [Gibb, 2000b].  The major limitations to the 
pediatric formulation of RTV are the taste, vomiting as an adverse event and high alcohol 
content [Panel on Antiretroviral Therapy and Medical Management of HIV-Infected 
Children. Use of Antiretroviral Agents in Pediatric HIV Infection.  Updated April 16, 
2019. Available at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed August 
20, 2019.
Pelton, 1998]. Although Kaletra is now widely used in treating HIV infected children, the 
pediatric liquid formulation of LPV/RTV does have a similar alcohol content (42%) to 


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that in the RTV liquid (43%) [Kaletra Package Insert, 2019; Norvir, Package Insert, 
2017]. Deleted text: ,
Change 5
Amend: 1.3.2.FPV Pediatric Clinical Data
Original Text:
Pharmacokinetic, safety, and antiviral response data in pediatric subjects 2 to 18 years of 
age receiving FPV with or without RTV are available from Study APV29005 (24 week 
data; BID regimens) and Study APV20003 (48 week data; QD regimens).  Additionally, 
48 week data from a small number of pediatric subjects <2 years of age receiving 
FPV/RTV in Study APV20002 have also been reported.  Refer to the Fosamprenavir 
Investigator’s Brochure Supplement for summaries of the available data from these 
studies.
Revised Text
Pharmacokinetic, safety, and antiviral response data in pediatric subjects 2 to 18 years of 
age receiving FPV with or without RTV are available from Study APV29005 [Fortuny, 
2014], and Study APV20003 [Chadwick, 2007].  Additionally, 48 week data from the 
pediatric subjects <2 years of age receiving FPV/RTV in Study APV20002 have also 
been reported [Cotton, 2014; 2014; Ross, 2015].  Overall the safety profile of 
fosamprenavir with and without ritonavir in paediatric patients was comparable to that 
observed in adult clinical studies.  Refer to the local product information for 
summaries of the available data from these studies.
Change 6
Amend: Section 3.1 Study Design
Original Text:
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART. 
Single dose visits (SDVs) for both Cohort 1 Arm A and 2 Arm A are complete.  


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Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  The evaluable PK data for approximately 50 to 60 subjects will be analysed at the end 
of the study and will include subjects who have been on different dosing regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been closed.
Table 6
Recruitment Status for APV20002 – from (FSFV) Oct 03 to Oct. 10
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
12 ongoing
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
291 enrolled
15 ongoing
1.
Current total enrolled patients exceeds the original cohort target because of dose changes in previous 
amendments
Revised Text
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicenter study 
to be conducted in approximately 48 HIV-1 infected pediatric subjects 4 weeks to 
<2 years old.  This study may be performed at study centers in North and South America, 
Europe, and Africa or in other regions as appropriate.  Subjects successfully completing 
48 weeks of therapy in APV20002 may continue in the study with visits every 12 weeks 
until commercial supplies of FPV oral suspension are available locally and pediatric 
dosing is approved in the relevant age groups. In countries where local availability is 
delayed or the drug is not yet available through national treatment programs, subjects 
may continue to receive FPV until they no longer derive clinical benefit or according to 
prior agreements between GSK and participating study sites for provision of ART.  Per 
protocol amendment 12; only subjects at sites in South Africa remain enrolled as 
supplies of oral FPV suspension are not commercially available in South Africa. 
Subjects successfully completing 48 weeks of therapy and receiving clinical benefit 
who weigh less than 39 kg may continue to receive FPV oral suspension provided by 
GSK. Once subjects reach a weight of 39 kg, South African treatment guidelines 
permit the use of the FPV tablets in children weighing ≥39 kg and these subjects will 
be withdrawn as FPV tablets are commercially available in South Africa.  
Single dose visits (SDVs) for both Cohort 1 Arm A and 2 Arm A are complete.  
Dose recommendations have been modified in previous protocol amendments (3, 5, 7 and 
8).  Protocol amendment 10 allows for the discontinuation of collection of samples 
for PK analysis after the age of the subjects exceeds 2 years and the subjects have
successfully completed 48 weeks of treatment.  Therefore, the evaluable PK data for 


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approximately 50 to 60 subjects will be analysed when it is available for all subjects 
successfully completing 48 weeks of therapy and will include subjects who have been 
on different dosing regimens.
Arm B (unboosted FPV cohorts 1 and 2) as per amendment 10 has been closed.
Table 7
Recruitment Status for APV20002 – from Oct 2003 (FSFV) to Jul 2011 
(cutoff for 48 week CSR
Age
(yrs)
Cohorts
No. of Subjects originally 
planned
Cumulative enrolment and 
current status
1A
6 months - <2yr
PI-naïve/exp
FPV/RTV (boosted)
12
261 enrolled
11 ongoing2
2A
4wks - <6mo
PI-naïve/exp
FPV/RTV (boosted)
12
281 enrolled
14 ongoing2
1.
A total of 59 patients were enrolled but 5 discontinued after receiving single dose of FPV; current total 
enrolled patients exceeds the original cohort target because of dose changes in previous amendments
2.
Ongoing as of cutoff for 48 week CSR (July 2011)
Change 7
Amend: Section 3.2.3 Other Study Eligibility Criteria Considerations
Original Text:
In order to assess any potential impact on subject eligibility with regard to safety, the 
investigator must refer to the following document(s) for detailed information regarding 
warnings, precautions, contraindications, adverse events, and other significant data 
pertaining to the study drugs: Such documents may include, but are not limited to, the 
Fosamprenavir Investigator’s Brochure Supplement and local product information or the 
International Product Information.
Revised text:
In order to assess any potential impact on subject eligibility with regard to safety, the 
investigator must refer to the following document(s) for detailed information regarding 
warnings, precautions, contraindications, adverse events, and other significant data 
pertaining to the study drugs: Such documents may include, but are not limited to, the 
Text deleted <Fosamprenavir Investigator’s Brochure Supplement>,  local product 
information or the International Product Information.
Change 8
Amend: Section 3.3.1 Study Drugs; 2-6th paragraphs


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Original Text:
In this study FPV will be provided by GSK.  In all countries, RTV oral solution will be 
obtained locally and reimbursed, if acceptable to regulatory authorities.  GSK will 
provide RTV by other means if reimbursement is not acceptable.  Both FPV and RTV 
will be considered study drugs.  Therefore, in the event that a subject permanently 
discontinues FPV, the subject will discontinue from this protocol and GSK will no longer 
supply FPV or RTV for that subject.
The FPV 50mg/mL (43.2mg/mL APV molar equivalents) suspension is a white to off-
white bubblegum and peppermint flavoured suspension for oral administration using a 
dosing syringe.  Each mL of suspension contains 50mg of FPV, equivalent to 43.2mg/mL 
of APV.  The suspension contains the following inactive ingredients: 
hydroxypropylmethyl cellulose, polysorbate 80, methylparaben, propylparaben, 
propylene glycol (overall 20mg/mL), sucralose, calcium chloride, flavours and purified 
water.  The FPV oral suspension is manufactured by GSK in Mississauga, Ontario, 
Canada.
The RTV oral solution manufactured by Abbott Laboratories contains 80mg/mL of RTV 
in a peppermint and caramel flavoured vehicle and will be administered via a dosing 
syringe.  The RTV solution contains the following inactive ingredients: ethanol, water, 
polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid, saccharin sodium, 
peppermint oil, creamy caramel flavouring and FD&C Yellow No. 6.
Revised text:
In this study, FPV oral suspension will be provided by GSK.  In all countries, RTV oral 
solution, powder, tablets or capsules will be obtained locally and reimbursed if 
acceptable to regulatory authorities.  GSK will provide RTV by other means where 
reimbursement is not acceptable, or GSK may provide RTV if local supplies are not 
available and RTV is able to be obtained from other countries. Both FPV and RTV 
will be considered study drugs.  Therefore, in the event that a subject permanently 
discontinues FPV oral suspension, the subject will discontinue from this protocol and 
GSK will no longer supply FPV or RTV for that subject.
The FPV 50 mg/mL (43.2mg/mL APV molar equivalents) suspension is a white to off-
white bubblegum and peppermint flavoured suspension for oral administration using a 
dosing syringe.  Each mL of suspension contains 50 mg of FPV, equivalent to 43.2
mg/mL of APV.  The suspension contains the following inactive ingredients: 
hydroxypropylmethyl cellulose, polysorbate 80, methylparaben, propylparaben, 
propylene glycol (overall 20 mg/mL), sucralose, calcium chloride, flavours and purified 
water.  The FPV oral suspension is manufactured by GSK in Mississauga, Ontario, 
Canada.
The RTV oral solution manufactured by Abbvie contains 80 mg/mL of RTV in a 
peppermint and caramel flavoured vehicle and will be administered via a dosing syringe.  
The RTV solution contains the following inactive ingredients: ethanol, water, polyoxyl 
35 castor oil, propylene glycol, anhydrous citric acid, saccharin sodium, peppermint oil, 
creamy caramel flavouring and FD&C Yellow No. 6.


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The RTV 100 mg oral powder/sachets manufactured by Abbvie also contains the 
inactive ingredients: copovidone, sorbitan monolaurate, and colloidal silicon 
dioxide, and are sugar-free.
The 100 mg RTV tablets manufactured by Abbvie contains the inactive ingredients 
copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal 
silicon dioxide, and sodium stearyl fumarate. The film coating contains: 
hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, 
talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80. The 100 
mg RTV tablets are white, film-coated, ovaloid tablets and are sugar-free.
The 100 mg soft gelatin RTV capsules manufactured by Abbvie contains ritonavir 
100 mg (SSSS enantiomer); other ingredients include ethanol (12 % v/v), butylated 
hydroxytoluene (antioxidant), oleic acid, polyoxyl 35 castor oil, water, gelatin, sugar, 
sorbitol, glycerin, titianium dioxide, medium chain triglycerides, lecithin and black 
ink.
Change 9
Amend: Section 3.3.2 Background NRTI Options Provided by GlaxoSmithKline; 7th
paragraph
Original Text:
The 3TC tablet contains 150mg of 3TC and the inactive ingredients magnesium stearate, 
microcrystalline cellulose, and sodium starch glycolate. The tablet is coated with a film 
that is made of hypromellose, titanium dioxide, macrogol, and polysorbate 80. 3TC 
tablets are manufactured by GSK in Ware, Hertfordshire, United Kingdom.
Revised text:
The 3TC tablet contains 150 mg of 3TC and the inactive ingredients magnesium stearate, 
microcrystalline cellulose, and sodium starch glycolate. The tablet is coated with a film 
that is made of hypromellose, magnesium stearate, microcrystalline cellulose, 
polyethylene glycol, sodium starch glycolate, titanium dioxide, and polysorbate 80. 
3TC tablets are white, diamond-shaped and scored and manufactured by GSK in Ware, 
Hertfordshire, United Kingdom.
Change 10
Amend: Section 3.3.3 Background ART Not Provided by GlaxoSmithKline
Revised Section Heading: 3.3.3.Background ART Not Provided by 
GlaxoSmithKline/ViiV Healthcare
Original Text:
GSK will not provide or reimburse background ART other than ABC or 3TC.
Revised text:


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GSK/ViiV Healthcare will not provide or reimburse background ART other than ABC 
or 3TC.
Change 11
Amend: Section 3.3.5 Dosages and dosing; 1st and 5th paragraphs
Original Text paragraph 1:
FPV and RTV will be administered according to the doses described in Section 3.3.4.
Revised text paragraph 1:
FPV and RTV will be administered according to the doses described in Section 3.3.4 and 
in Section 3.3.5.1.
Original text paragraph 5
The recommended dose of 3TC solution is 4mg/kg BID (up to a maximum of 
300mg/day).
Revised text paragraph 5
The recommended dose of 3TC solution is currently 4 mg/kg BID (up to a maximum of 
300 mg/day). The dosing recommendation in the local label should be followed.
Change 12
Amend: Section 3.3.5.1 Dosage Regimen Adjustment Criteria in Dose Adjustment 
Due to Subject Age exceeding 2 and 6 years; 1st and 3rd paragraphs
Original Text paragraph 1:
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23mg/kg and 3mg/kg BID respectively, in accordance 
with the  dosage regimen recommended  for this age group in protocol APV29005.  The 
change in dosage can be staged gradually over multiple visits and will be based on 
ongoing viral load, pharmacokinetic and safety assessments, at the investigator’s 
discretion.
Revised text paragraph 1:
Subjects reaching and exceeding 2 years of age during the study should transition to the 
lower dose of FPV and RTV to 23 mg/kg and 3 mg/kg BID respectively <Text deletion: 
in accordance with the  dosage regimen recommended  for this age group in 
protocol APV29005>.  The change in dosage can be staged gradually over multiple visits 
and will be based on ongoing viral load, pharmacokinetic and safety assessments, at the 
investigator’s discretion.
Original Text paragraph 3:


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In consultation with the investigator, GSK may discontinue PK sampling and monitoring 
of plasma APV, FPV and RTV concentration on an individual basis once a subject has 
reached and exceeded 2 years and has initiated the 23/3mg/kg BID dosing regimen after 
Week 48.  Any further dosing changes would follow the approved dosing 
recommendations without PK sampling, including a transition to FPV/RTV 18/3mg/kg 
BID at 6 years.
Revised text paragraph 3:
In consultation with the investigator, GSK may discontinue PK sampling and monitoring 
of plasma APV, FPV and RTV concentration on an individual basis once a subject has 
reached and exceeded 2 years and has initiated the 23/3 mg/kg BID dosing regimen after 
Week 48.  Any further dosing changes would follow the approved dosing 
recommendations without PK sampling, including a transition to FPV/RTV 18/3mg/kg 
BID at 6 years.  Note: after Protocol Amendment 11 became effective, PK sampling 
and monitoring of plasma APV, FPV and RTV concentration on an individual basis 
was discontinued. 
Change 13
Amend: Section 3.3.7.3 Specific Events; 4th-paragraphs
Original Text
The appearance of rash in the absence of other symptoms or signs is not indicative of 
hypersensitivity to ABC.  Subjects receiving ABC who develop rash of any grade should 
be evaluated for the possibility of hypersensitivity as outlined below.
Study treatment should be managed as outlined in the following table:


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Rash Management
Event
Action to be Taken
FPV BID or FPV/RTV BID
ABC
3TC
Grade 1 rash alone
Therapy can continue
Evaluate for the possibility of 
hypersensitivity.  If there is no 
evidence of any other organ system 
involvement and the subject has no 
constitutional symptoms (fever, 
malaise, fatigue, headache), ABC 
may be continued with the warning 
to discontinue immediately and 
permanently if other signs and/or 
symptoms consistent with HSR 
appear.
Therapy can 
continue
Grade 1 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
Therapy can 
continue
Grade 2 rash alone
Therapy can continue
Follow Grade 1 rash alone 
instructions
Therapy can 
continue
Grade 2 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
Discontinue 3TC.  
Therapy should 
not be reinitiated 
unless the 
investigator has 
compelling 
evidence that the 
rash is not caused 
by 3TC.
Grade 3/4 rash alone or 
with symptoms indicating 
multi-organ involvement1
Discontinue FPV BID or 
FPV/RTV BID and do not 
reinitiate therapy3
Discontinue ABC immediately and 
permanently3
Discontinue 3TC3
1.
Symptoms include: systemic symptoms (fever, GI symptoms including nausea, vomiting, diarrhea or abdominal 
pain) or allergic symptoms, or mucosal involvement, or severe tiredness, achiness or generally ill feeling.  
2.
ABC therapy should be permanently stopped and another NRTI therapy should be initiated.
3.
Medications should be permanently stopped and the subject withdrawn from the trial. 
Revised text
The appearance of rash in the absence of other symptoms or signs is not indicative of 
hypersensitivity to ABC.  Subjects receiving ABC as part of their NRTI background 
regimen should be evaluated for the possibility of a clinically suspected ABC HSR and 
managed appropriately as outlined in the local prescribing.  Subjects should be 
instructed to contact the Investigator as soon as possible if they develop a rash while on 
study.
Subjects who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as Stevens-Johnson Syndrome (SJS), 
Toxic Epidermal Necrolysis (TEN) or Erythema Multiforme. SJS, TEN and 
Erythema Multiforme have been reported very rarely in patients taking ABC-
containing products.  These patients generally do not have the cluster of additional 


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symptoms (e.g., gastrointestinal and respiratory) that characterize the ABC HSR, 
but they do have features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s) 
suspected in the Investigators causality assessment) should be discontinued, and the 
subject should not be re-challenged with any ABC-containing medicinal product 
(i.e., TRIUMEQ, ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, 
all other medicinal products that the subject is receiving should also be reviewed 
and discontinued as appropriate.
Study treatment should be managed as outlined in the following table:


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Rash Management
Event
Action to be Taken
FPV BID or FPV/RTV BID
ABC
3TC
Grade 1 rash alone
Therapy can continue
Evaluate for the possibility of 
hypersensitivity.  If there is no 
evidence of any other organ system 
involvement and the subject has no 
constitutional symptoms (fever, 
malaise, fatigue, headache), ABC 
may be continued at the
investigators discretion with the 
warning to discontinue immediately 
and permanently if other signs 
and/or symptoms consistent with 
HSR appear.  The subject should 
be advised to contact the 
Investigator immediately if there 
is any worsening of the rash, if 
any systemic signs or symptoms 
worsen, or if mucosal 
involvement develops.
Therapy can 
continue
Grade 1 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
Subjects should be treated as 
clinically appropriate and 
followed until resolution of the 
AE.
Therapy can 
continue
Grade 2 rash alone
Therapy can continue
Follow Grade 1 rash alone 
instructions
Therapy can 
continue
Grade 2 rash with 
symptoms indicating multi-
organ involvement1
Discontinue FPV BID or 
FPV/RTV BID.  Therapy 
should not be reinitiated 
unless the investigator has 
compelling evidence that 
the rash is not caused by 
FPV.
Discontinue ABC immediately and 
permanently2
The subject should be advised to 
contact the physician 
immediately if rash fails to 
resolve (after more than two 
weeks), if there is any worsening 
of the rash, if any systemic signs 
or allergic symptoms develop, or 
if mucosal involvement develops.
Discontinue 3TC.  
Therapy should 
not be reinitiated 
unless the 
investigator has 
compelling 
evidence that the 
rash is not caused 
by 3TC.
Grade 3/4 rash alone or 
with symptoms indicating 
multi-organ involvement1
Discontinue FPV BID or 
FPV/RTV BID and do not 
reinitiate therapy3
Subjects should be 
treated as clinically 
appropriate and followed 
until resolution of the AE.
Discontinue ABC immediately and 
permanently3
Subjects should be treated as 
clinically appropriate and 
followed until resolution of the 
AE.
Discontinue 3TC3
Subjects should 
be treated as 
clinically 
appropriate and 
followed until 
resolution of the 
AE.
1.
Symptoms include: systemic symptoms (fever, GI symptoms including nausea, vomiting, diarrhea or abdominal 
pain) or allergic symptoms, or mucosal involvement, or severe tiredness, achiness or generally ill feeling.  
2.
ABC therapy should be permanently stopped and another NRTI therapy should be initiated.
3.
Medications should be permanently stopped and the subject withdrawn from the trial. .
Change 14


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Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, 1st paragraph
Original text
In clinical studies, approximately 5% of subjects receiving ABC develop a 
hypersensitivity reaction (HSR) that in rare cases has proved fatal.  However, in the 
PENTA 5 study [Gibb, 2000a] only 1 of the 92 ART-naïve, symptomatic children, aged 3 
months to 16 years who were treated with a regimen containing ABC developed a 
classical hypersensitivity reaction.  In CNAA3006, which utilized an ABC containing 
backbone, ABC HSR was observed in 2% of pediatric subjects.
Revised text
In clinical studies, conducted before the introduction of screening for the HLA-
B*5701 allele, approximately 5% of subjects receiving ABC develop a hypersensitivity 
reaction (HSR) that in rare cases has proved fatal.  However, in the PENTA 5 study 
[Gibb, 2000a] only 1 of the 92 ART-naïve, symptomatic children, aged 3 months to 16 
years who were treated with a regimen containing ABC developed a classical 
hypersensitivity reaction.  In CNAA3006, which utilized an ABC containing backbone, 
ABC HSR was observed in 2% of pediatric subjects. The risk for abacavir HSR to 
occur is significantly increased for patients who test positive for the HLA-B*5701 
allele. However, abacavir HSRs have been reported at a lower frequency in patients 
who do not carry this allele. In the prospective study CNA106030 (PREDICT-1), the 
use of pre-therapy screening for the presence of HLA-B*5701 and subsequently 
avoiding ABC in HLA-B*5701 positive patients, significantly reduced the incidence 
of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803) 
(p<0.0001) [Mallal, 2008]. In clinical studies EPZ108859 (ARIES) and CNA109586 
(ASSERT), 0.8% (4/515) and 3.1% (6/192) of subjects who were HLA-B*5701
negative and who received ABC developed a clinically suspected ABC HSR, 
respectively [Post, 2010; Squires, 2010].
It is recommended that any HIV-infected patient without prior exposure to abacavir 
be screened for HLA-B*5701 allele. Screening is recommended prior to re-initiation 
of abacavir in patients of unknown HLA-B*5701 status who have previously 
tolerated abacavir. Use of abacavir in patients known to carry the HLA-B*5701 
allele is not recommended. In any patient treated with abacavir, the clinical 
diagnosis of suspected hypersensitivity reaction must remain the basis of clinical 
decision making. Even in the absence of the HLAB* 5701 allele, it is important to 
permanently discontinue abacavir and not rechallenge with abacavir if a 
hypersensitivity reaction cannot be ruled out on clinical grounds, due to the 
potential for a severe or even fatal reaction.
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, paragraph 9
Original text
Some subjects with hypersensitivity were initially thought to have onset respiratory 
diseases (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis, or 
reactions to other medications.  This delay in diagnosis of hypersensitivity has resulted in 


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ABC being continued or re-introduced, leading to more severe hypersensitivity reaction 
or death.  Therefore, the diagnosis of hypersensitivity reaction should be carefully 
considered for patients presenting with symptoms of these diseases.  If hypersensitivity 
reaction cannot be ruled out, no medicinal product containing ABC (ZIAGEN, 
TRIZIVIRTM or the ABC/3TC fixed dose combination) should be restarted.
Revised text
Some subjects with hypersensitivity were initially thought to have onset respiratory 
diseases (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis, or 
reactions to other medications.  This delay in diagnosis of hypersensitivity has resulted in 
ABC being continued or re-introduced, leading to more severe hypersensitivity reaction 
or death.  Therefore, the diagnosis of hypersensitivity reaction should be carefully 
considered for patients presenting with symptoms of these diseases.  If hypersensitivity 
reaction cannot be ruled out, no medicinal product containing ABC (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any other ABC-containing product) should be 
restarted.
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, paragraphs 11-13
Original text
Subjects who develop a hypersensitivity reaction must discontinue ABC and must 
NEVER be rechallenged with any medicinal product that contains ABC (ZIAGEN, 
TRIZIVIR or the ABC/3TC fixed dose combination).  Restarting any ABC-containing 
product following a hypersensitivity reaction results in a prompt return of symptoms 
within hours.  This recurrence of the hypersensitivity reaction may be more severe 
than on initial presentation and may include life-threatening hypotension and death.  
There have been infrequent reports of hypersensitivity reactions following reintroduction 
of ABC, where the interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or a respiratory symptom).
On very rare occasions hypersensitivity reactions have been reported in patients who 
have re-started therapy, and who had no preceding symptoms of a hypersensitivity 
reaction.
Revised text
Subjects who develop a hypersensitivity reaction must discontinue ABC and must 
NEVER be rechallenged with any medicinal product that contains ABC (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing product).  Restarting any 
ABC-containing product following a hypersensitivity reaction results in a prompt return 
of symptoms within hours.  This recurrence of the hypersensitivity reaction may be 
more severe than on initial presentation and may include life-threatening 
hypotension and death.  
There have been infrequent reports of hypersensitivity reactions following reintroduction 
of ABC, where the interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or a respiratory symptom).


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On very rare occasions hypersensitivity reactions have been reported in patients who 
have re-started therapy, and who had no preceding symptoms of a hypersensitivity 
reaction (i.e., patients previously considered to be abacavir tolerant).
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, Management of 
Hypersensitivity Reactions, 3rd paragraph
Original text
Subjects who develop a hypersensitivity reaction must discontinue ABC and must 
NEVER be rechallenged with any medicinal product that contains ABC (ZIAGEN, 
TRIZIVIR or the ABC/3TC fixed dose combination).  Restarting any ABC-containing 
product following a hypersensitivity reaction results in a prompt return of symptoms 
within hours.  This recurrence of the hypersensitivity reaction may be more severe 
than on initial presentation and may include life-threatening hypotension and death.
Revised text
Subjects who develop a hypersensitivity reaction must discontinue ABC and must 
NEVER be rechallenged with any medicinal product that contains ABC (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing product).  Restarting any 
ABC-containing product following a hypersensitivity reaction results in a prompt return 
of symptoms within hours.  This recurrence of the hypersensitivity reaction may be 
more severe than on initial presentation and may include life-threatening 
hypotension and death.  
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, Special considerations 
following an interruption of abacavir therapy, 1st-5th paragraph
Original text
If therapy with ABC has been discontinued and restarting therapy is under consideration, 
the reason for discontinuation should be evaluated to ensure that the patient did not have 
symptoms of a hypersensitivity reaction.  If hypersensitivity reaction cannot be ruled 
out, no medicinal product containing ABC (ZIAGEN, TRIZIVIR or the ABC/3TC 
fixed dose combination) should be restarted.
There have been infrequent reports of hypersensitivity reaction following reintroduction 
of an ABC-containing product where the interruption was preceded by a single key 
symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms or a 
respiratory symptom).  If a decision is made to restart any ABC-containing product in 
these patients, this should be done only under direct medical supervision. 
On very rare occasions hypersensitivity reactions have been reported in patients who 
have re-started therapy, and who had no preceding symptoms of a hypersensitivity 
reaction. If a decision is made to re-start an ABC-containing product, this must be done 
only if medical care can be accessed readily by the patient or others.
Revised text


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If therapy with ABC has been discontinued and restarting therapy is under consideration, 
the reason for discontinuation should be evaluated to ensure that the patient did not have 
symptoms of a hypersensitivity reaction.  If hypersensitivity reaction cannot be ruled 
out, no medicinal product containing ABC (ZIAGEN, TRIZIVIR, KIVEXA, 
TRIUMEQ or any ABC-containing fixed dose combination) should be restarted.
There have been infrequent reports of hypersensitivity reaction following reintroduction 
of an ABC-containing product where the interruption was preceded by a single key 
symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms or a 
respiratory symptom).  If a decision is made to restart any ABC-containing product in 
these patients, this should be done only under direct medical supervision. 
Rarely, patients who have stopped ABC for reasons other than symptoms of HSR 
have also experienced life-threatening reactions within hours of re- initiating 
abacavir therapy. Subjects must be made aware that HSR can occur with 
reintroduction of ABC or any other medicinal product containing abacavir and that 
reintroduction of ABC or any other medicinal product containing abacavir should 
be undertaken only if medical care can be readily accessed.
Screening for carriage of the HLA-B*5701 allele is recommended prior to re-
initiation of
ABC in patients of unknown HLA-B*5701 status who have previously tolerated 
ABC. Re-initiation of ABC in such patients who test positive for the HLA B*5701 
allele is not recommended.
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, Essential Patient 
Information, 3rd paragraph
Original text

Parents/legal guardians must be reminded that subjects who are hypersensitive to 
ABC must never take any ABC-containing medicinal product (ZIAGEN, TRIZIVIR 
or the ABC/3TC fixed dose combination) again.
Revised text

Parents/legal guardians must be reminded that subjects who are hypersensitive to 
ABC must never take any ABC-containing medicinal products (ZIAGEN, 
TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing fixed-dose 
combination) again.
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, Reporting of 
Hypersensitivity Reactions
Original text
All cases of potential ABC hypersensitivity should be reported as Serious Adverse Events 
(SAE) (see Section 7.8).  In addition to reporting the case as an SAE, the HSR CRF 
should be completed and faxed to GSK within one week of the onset of the 
hypersensitivity reaction.


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Revised text
All cases of potential ABC hypersensitivity should be reported as Serious Adverse Events 
(SAE) (see Section 7.8). In addition to reporting the case as an SAE, the HSR CRF 
should be completed and sent to GSK within one week of the onset of the 
hypersensitivity reaction. 
Amend: Section 3.3.7.4 Abacavir Hypersensitivity Reaction, Stevens Johnson 
Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme, 2nd paragraph
Original text
If a serious skin reaction develops, the ABC-containing product should be discontinued, 
and the patient should not be rechallenged with any ABC-containing medicinal product 
(ZIAGEN, TRIZIVIR or the ABC/3TC fixed dose combination). 
Revised text
If a serious skin reaction develops, the ABC-containing product should be discontinued, 
and the patient should not be rechallenged with any ABC-containing medicinal product 
(ZIAGEN, TRIZIVIR, KIVEXA, TRIUMEQ or any ABC-containing fixed dose 
combination).
Change 15
Amend: Section 3.3.8 Subject Management Options, 4th paragraph
Original text
If a subject develops an AIDS diagnosis (CDC stage C) or other evidence of disease 
progression such that the treating clinician believes that changing therapy is required 
even though the above criteria have not been met, the investigator should contact GSK 
for further discussion on a case by case basis.
Revised text
If a subject develops an AIDS diagnosis (CDC stage C) or other evidence of disease 
progression such that the treating clinician believes that changing therapy is required 
even though the above criteria have not been met, the investigator should contact ViiV 
Healthcare for further discussion on a case by case basis.
Change 16
Amend: Section 3.3.10, Concurrent Medications and Non-Drug Therapies.
Fosamprenavir and Ritonavir, 1st paragraph
Original text
FPV and RTV are metabolized in the liver by cytochrome P450 3A4 (CYP3A4).  APV 
and RTV are predominantly CYP3A4 inhibitors.  Caution should be used when co-


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administering medications that are substrates, inhibitors, or inducers of CYP3A4.  In 
addition, RTV has an affinity for other cytochrome P450 isozymes including CYP2D6, 
CYP2C9, CYP2C19, CYP2A6, CYP1A2 and CYP2E1, and appears to increase the 
activity of glucuronosyl transferases. 
Revised text
FPV and RTV are metabolized in the liver by cytochrome P450 3A4 (CYP3A4).  APV 
and RTV are predominantly CYP3A4 inhibitors.  When FPV and RTV are co-
administered, the ritonavir metabolic drug interaction profile may predominate 
because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing 
information for ritonavir must therefore be consulted prior to initiation of therapy 
with FPV and RTV.
Amend: Section 3.3.10, Concurrent Medications and Non-Drug Therapies.
Fosamprenavir and Ritonavir, 3rd paragraph
Original text
FPV and RTV should not be co-administered with alfuzosin, amiodarone, astemizole, 
bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, 
encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, halofantrine, 
lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, 
propafenone, propoxyphene, quinidine, PDE5 inhibitors including sildenafil, simvastatin, 
terfenadine and triazolam.  Co-administration may result in competitive inhibition of 
metabolism of these medications and may cause serious or life-threatening adverse 
events.  Co-administration of FPV or FPV/RTV with rifabutin results in significant
increases in plasma rifabutin levels, therefore the dose of rifabutin should be reduced by 
at least 50% when co-administered with FPV and by at least 75% when co-administered 
with FPV/RTV.  Caution should be used and subjects should be monitored closely for 
signs of toxicity
Revised text
FPV and RTV should not be co-administered with alfuzosin, amiodarone, astemizole, 
bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, 
encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, halofantrine, 
lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, 
propafenone, propoxyphene, quinidine, ketaconazole, rifampicin, PDE5 inhibitors 
including sildenafil, simvastatin, terfenadine and triazolam. Co-administration may result 
in competitive inhibition of metabolism of these medications and may cause serious or 
life-threatening adverse events. Co-administration of FPV or FPV/RTV with rifabutin 
results in significant increases in plasma rifabutin levels, therefore the dose of rifabutin 
should be reduced by at least 50% when co-administered with FPV and by at least 75% 
when co-administered with FPV/RTV. Caution should be used and subjects should be 
monitored closely for signs of toxicity.
Amend: Section 3.3.10, Concurrent Medications and Non-Drug Therapies.
Fosamprenavir and Ritonavir, 6th paragraph


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Original text
APV and RTV interact with CYP3A4 and are predominantly CYP3A4 inhibitors.  
Medications which interact with CYP3A4, either as substrates, inhibitors, or inducers of 
the isozyme and which should be used with caution include, but are not limited to:  
alprazolam, amlodipine, atorvastatin, cerivastatin, cimetidine, clarithromycin, 
clindamycin, clonazepam, codeine, dapsone, diltiazem, disopyramide, erythromycin, 
estrogens and progestogens, felodipine, fluvastatin, glucocorticoids, imipramine, 
isradipine, itraconazole, ketoconazole, loratadine, miconazole, nicardipine, nifedipine, 
nimodipine, nisoldipine, pravastatin, verapamil and zolpidem. 
Revised text
APV and RTV interact with CYP3A4 and are predominantly CYP3A4 inhibitors.  
Medications which interact with CYP3A4, either as substrates, inhibitors, or inducers of 
the isozyme, or medicinal products with narrow therapeutic windows that are 
substrates of cytochrome P450 3A4 (CYP 3A4) should be used with caution include, 
but are not limited to:  alprazolam, amlodipine, atorvastatin, cerivastatin, cimetidine, 
clarithromycin, clindamycin, clonazepam, codeine, dapsone, diltiazem, disopyramide, 
erythromycin, estrogens and progestogens, felodipine, fluvastatin, glucocorticoids, 
imipramine, isradipine, itraconazole, loratadine, miconazole, nicardipine, nifedipine, 
nimodipine, nisoldipine, pravastatin, verapamil and zolpidem. 
Amend: Section 3.3.10, Concurrent Medications and Non-Drug Therapies.
Fosamprenavir and Ritonavir, 8-10th paragraphs
Original text
RTV is an inhibitor of CYP2D6 and an inducer of CYP1A2, CYP2C9 and glucuronosyl 
transferase.  Medications which interact with CYP2D6, CYP1A2, CYP2C9, and/or 
glucuronosyl transferase should be used with caution and include but are not limited to: 
bisoprolol, codeine, chlorpromazine, cyclobenzaprine, desipramine, doxepin, 
fluphenazine, fluoxetine, haloperidol, hydrocodone, methamphetamine, metoprolol, 
mexilitine, morphine, propranolol, oxycodone, paroxetine, perphenazine, risperidone, 
thioridazine, timolol, tramadol, trazodone, and venlafaxine.  
Because RTV oral solution contains alcohol, drugs such as metronidazole that may 
inhibit alcohol metabolism should be avoided.
IMPORTANT: For further information refer to Fosamprenavir Investigator’s Brochure 
Supplement and local product information or the International Product Information for 
more complete information.
Revised text
RTV is not recommended for use with digoxin, voriconazole, blonanserin, 
salmeterol and other drugs not recommended for use with FPV above.  RTV is an 
inhibitor of CYP2D6 and an inducer of CYP1A2, CYP2C9 and glucuronosyl transferase. 
Medications which interact with CYP2D6, CYP1A2, CYP2C9, and/or glucuronosyl 
transferase should be used with caution and include but are not limited to: bisoprolol, 


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codeine, chlorpromazine, cyclobenzaprine, desipramine, doxepin, fluphenazine, 
fluoxetine, haloperidol, hydrocodone, methamphetamine, metoprolol, mexilitine, 
morphine, propranolol, oxycodone, paroxetine, perphenazine, risperidone, thioridazine, 
timolol, tramadol, trazodone, and venlafaxine.  
Because RTV oral solution contains alcohol, drugs such as metronidazole that may 
inhibit alcohol metabolism should be avoided.
IMPORTANT: For further information refer <deleted text Fosamprenavir 
Investigator’s Brochure Supplement and> to local product information or the 
International Product Information for more complete information.
Change 17
Amend: Section 3.3.10.1, GSK Supplied Background NRTI Options, Interactions 
Relevant to Lamivudine, 7th paragraph
Original text
None
Added text
Emtricitabine: Lamivudine may inhibit the intracellular phosphorylation of 
emtricitabine when the two medicines are used concurrently. Additionally, the 
mechanism of viral resistance for both lamivudine and emtricitabine is mediated via 
mutation of the same viral reverse transcriptase gene (M184V) and therefore the 
therapeutic efficacy of these medicines in combination therapy may be limited. 3TC 
is not recommended for use in combination with emtricitabine.
Change 18
Amend: Section 4.1, Study Drug Packaging and Labeling, 3rd paragraph
Original text
RTV oral solution will be provided locally by the investigator as required and should be 
stored according to the local product information.
Revised text
RTV oral solution will be provided locally by the investigator as required and should be 
stored according to the local product information. GSK will provide RTV by other 
means where reimbursement is not acceptable, or GSK may provide RTV if local 
supplies are not available and RTV is able to be obtained from other countries.  
Change 19
Amend: Section 4.2, Study Drug Handling, 2nd paragraph


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Original text
FPV will be shipped to the investigational sites by GSK.  In all countries, RTV oral 
solution will be obtained locally and reimbursed if acceptable to regulatory authorities.  
GSK will provide RTV by other means where reimbursement is not acceptable. At each 
visit, the investigator or designated site staff should dispense sufficient amount of study 
drug to provide adequate supply for each subject until the next scheduled visit.  All study 
drug that is not utilized during the study will be destroyed at the completion of the trial.  
Drug disposition records will be regularly reviewed by the study monitor.
Revised text
FPV will be shipped to the investigational sites by GSK.  In all countries, RTV oral 
solution, powder, tablets or capsules will be obtained locally and reimbursed if acceptable 
to regulatory authorities.  GSK will provide RTV by other means where reimbursement is 
not acceptable, or GSK may provide RTV if local supplies are not available and RTV is 
able to be obtained from other countries. At each visit, the investigator or designated site 
staff should dispense sufficient amount of study drug to provide adequate supply for each 
subject until the next scheduled visit.  All study drug that is not utilized during the study 
will be destroyed at the completion of the trial.  Drug disposition records will be regularly 
reviewed by the study monitor.
Amend: Section 4.2, Study Drug Handling, 6th paragraph
Original text
None
Revised text
Note per Amendment 12; for subjects weighing less than 33 kg, if RTV oral solution 
is not available, the RTV powder can be substituted.  For doses less than 100 mg or 
partial doses between 100 mg increments the following instructions should be 
followed. Mix 1 packet/sachet of oral powder (100 mg) with 9.4 mL of liquid (such 
as water, chocolate milk, or infant formula) in a mixing cup. Once mixed, use an 
oral dosing syringe to measure and administer the prescribed volume.  Once the 
powder is mixed, the dosage must be consumed within 2 hours. Discard any mixture 
remaining in the mixing cup. Additional guidance is provided in Section 11.6.
Amend: Section 4.2, Study Drug Handling, 8th paragraphs
Original text
Study medications should be stored until the time of dispensing as follows:
FPV 50 mg/mL oral suspension
Store below 30C (86F) DO NOT FREEZE
RTV 80 mg/mL oral solution
Store according to local product information
Revised text
Study medications should be stored until the time of dispensing as follows:


GD2001/00007/12
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FPV 50 mg/mL oral suspension
Store below 30C (86F) DO NOT FREEZE
RTV 80 mg/mL oral solution
Store according to local product information
RTV oral powder
Store according to local product information
RTV 100 mg tablet
Store according to local product information
RTV 100 mg soft gelatin capsules
Store according to local product information
Change 20
Amend: Section 5.5, Efficacy, 2nd paragraph
Original text

Quantitative plasma HIV-1 RNA (Roche Amplicor HIV-1 Monitor Test; version 1.5, 
ultrasensitive limit of detection (LOD) = 50copies/mL).  Samples with 
>75,000copies/mL will be retested using the Roche Amplicor HIV-1 Monitor Test, 
version 1.5, standard assay LOD = 400copies/mL.  (NOTE:  At the Screening and 
Baseline (Day 1) visits, the Roche Amplicor HIV-1 Monitor Test, version 1.5, 
standard assay will be used).
Revised text

Quantitative plasma HIV-1 RNA (Roche Amplicor HIV-1 Monitor Test; version 1.5, 
ultrasensitive limit of detection (LOD) = 50 copies/mL).  Samples with >75,000
copies/mL will be retested using the Roche Amplicor HIV-1 Monitor Test, version 
1.5, standard assay LOD = 400 copies/mL.  (NOTE:  At the Screening and Baseline 
(Day 1) visits, the Roche Amplicor HIV-1 Monitor Test, version 1.5, standard assay 
will be used). Per Protocol Amendment 12: the Roche Amplicor HIV-1 Monitor 
Test Version 1.5 was subsequently discontinued after the July 2011 cut-off date 
for the week 48 CSR.  By January 2013, only two APV20002 study sites, both in 
South Africa had actively enrolled subjects; and efficacy for these subjects was 
evaluated using the Abbott Realtime HIV-1 Test, which has a LOD of 40 
copies/mL.
Change 21
Amend: Section 5.9.1, Withdrawal, 1st paragraph
Original text
Subjects who prematurely discontinue from the study, whether voluntarily or not, should 
have the Withdrawal visit assessments performed (refer to Section 10).  A Follow-up visit 
will be performed 4 weeks after the Withdrawal visit.
Revised text
Subjects who prematurely discontinue from the study, whether voluntarily or not, should 
have the Withdrawal visit assessments performed (refer to Section 10).  Once a subject’s 
weight has increased to 39 kg or more, they should be withdrawn from the study 


GD2001/00007/12
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300
(refer to Section 3.1).  A Follow-up visit will be performed 4 weeks after the 
Withdrawal visit.
Change 22
Amend: Section 7.8, Prompt Reporting of SAEs to GSK moved to Section 7.9
Original text
7.8. Prompt Reporting of SAEs to GSK
SAEs must be reported promptly to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition of an SAE.
7.8.1 Timeframes for Submitting SAE Reports to
Initial SAE Reports
Additional Information on a 
Previously Reported SAE
Type of SAE
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hrs
“SAE” CRF pages
24 hrs
Updated “SAE” 
CRF pages
7.8.2. Transmission of the SAE Reports
Facsimile transmission of the “SAE” CRF is the preferred method to transmit this 
information to the project contact for SAE receipt.  In the absence of facsimile 
equipment, notification by telephone is acceptable for deaths and life-threatening events, 
with a copy of the “SAE” CRF sent by overnight mail. For SAEs that are not deaths or 
life-threatening events, telephone notification, in the absence of facsimile equipment, is 
not acceptable.  Instead, a copy of the “SAE” CRF will be sent by overnight mail.  GSK 
will provide separately a list of project contacts for SAE receipt, fax numbers, and 
mailing addresses.
Revised text
This section regarding reporting of SAES was moved to Section 7.9 and the previous 
Section 7.9 (Regulatory Reporting Requirements For SAEs) was moved to Section 7.8.
Change 23
Amend: Section 8.2.4 Subject Informed Consent, Paragraph 3  
Original text
None 
Revised text
Per protocol amendment 12: Assent forms will also be obtained from subjects still 
enrolled in the study as of Nov 1, 2019. 


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Change 24
Amend: Appendix 5:  Dosing Table for FPV Oral Suspension
Original text
New tables for higher weight subjects were added
Revised text
Appendix 5:  Dosing Table for FPV Oral Suspension
As per Section 3.3.5.1, for subjects exceeding 6 years of age, the following weight-based 
dosing for FPV should be used:
FPV 18 mg/kg BID (>6 years old)
Weight (kg)
Dose (mg): 18 mg/kg
Amount of 50 mg/mL 
suspension (mL) per Dose
No. Bottles (225mL) 
Needed Per Month
25
450
9
3
26
468
9.4
3
27
486
9.7
3
28
504
10.1
3
29
522
10.4
3
30
540
10.8
3
31
558
11.2
3
32
576
11.5
4
33
594
11.9
4
34
612
12.2
4
35
630
12.6
4
36
648
13
4
37
666
13.3
4
38
684
13.7
4
Change 25
Amend: Appendix 6:  Dosing Table for RTV Oral Solution, Powder, Capsules and
Tablets 
Original text
New tables for higher weight subjects were added
Additional table and text:


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RTV Oral Solution 7 mg/kg BID (<2 years old)
Weight (kg)
Dose (mg): 7 
mg/kg
Amount of 80 mg/mL solution 
(mL) per Dose
3
21
0.26
3.5
24.5
0.31
4
28
0.35
4.5
31.5
0.39
5
35
0.44
5.5
38.5
0.48
6.0
42
0.53
6.5
45.5
0.57
7.0
49
0.61
7.5
52.5
0.66
8
56
0.70
8.5
59.5
0.74
9
63
0.79
9.5
66.5
0.83
10
70
0.88
10.5
73.5
0.92
11
77
0.96
11.5
80.5
1.01
12
84
1.05
12.5
87.5
1.09
13
91
1.14


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As per Section 3.3.5.1, for subjects exceeding 6 years of age, the following weight-
based dosing for RTV oral solution should be used:
RTV Oral Solution 3 mg/kg BID (>6 years old)
Weight (kg)
Dose (mg): 3 mg/kg
Amount of 80 mg/mL 
suspension (mL) per Dose
25
75
0.9
26
78
1.0
27
81
1.0
28
84
1.1
29
87
1.1
30
90
1.1
31
93
1.2
32
96
1.2
≥33a
99
1.2
a Subjects who are ≥33kg and are receiving RTV oral solution at a dose of 3mg/kg 
should remain at the recommended optimal dose for ≥33kg (99mg BID for 3mg/kg 
dosing) even as their weight increases above 33kg. The maximum allowed total daily 
dose for RTV oral solution is 200mg.
The following weight-based dosing for RTV oral powder can be used if RTV oral 
solution is not available.  For doses less than 100 mg or partial doses between 100 
mg increments: Mix 1 packet/sachet of oral powder (100 mg) with 9.4 mL of liquid 
(such as water, chocolate milk, or infant formula) in a mixing cup. Once mixed, use 
an oral dosing syringe to measure and administer the prescribed volume.  Once the 
powder is mixed, the dosage must be consumed within 2 hours. Discard any mixture 
remaining in the mixing cup.
RTV Oral Powder (100 mg sachets) 3 mg/kg BID (>6 year old)
Weight (kg)
Dose (mg): 3 mg/kg
Amount of liquid per dose 
once the sachet with 100 mg 
powder is dissolved in 9.4 
mL of liquid (10 mg/mL)
25
75
7.5 mL
26
78
7.8 mL
27
81
8.1 mL
28
84
8.4 mL
29
87
8.7 mL
30
90
9.0 mL
31
93
9.3 mL
32
96
9.6 mL
≥33a
99
10.0 mL


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As per Section 3.3.5.1, for subjects exceeding 6 years of age who weigh ≥33kg and 
can swallow capsules or tablets whole, the following weight-based dosing for RTV 
oral 100 mg tablets or 100 mg capsules should be used: 1 capsule or tablet (dose of 
100 mg) BID.  The maximum allowed total daily dose of RTV capsules or tablets is 
200 mg. 

SAP_001.pdf: 
Reporting and Analysis Plan 
Study ID:  APV20002
Official Title of Study:  A 48 Week Phase II, Open-label, 2-cohort, Multicentre 
Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral Activity 
of GW433908 and GW433908/RTV When Administered to HIV-1 Infected 
Protease Inhibitor (PI) Naïve and PI-Experienced Pediatric Subjects aged 4 weeks 
to <2 years.
Date of Document: 21-Mar-2022  


CONFIDENTIAL 
QM2005/00016/01 
ViiV Healthcare and the GlaxoSmithKline group of companies 
APV20002 
1 
Division: World Wide Development 
Retention Category: GRS019 
Information Type: Reporting and Analysis Plan 
Title: 
Reporting and Analysis Plan for APV20002 (Protocol Number 
GD2001/00007/03):  A 48 Week Phase II, Open-label, 2-cohort, 
Multicentre Study to Evaluate the Pharmacokinetics, Safety, 
Tolerability and Antiviral Activity of GW433908 and 
GW433908/RTV When Administered to HIV-1 Infected 
Protease Inhibitor (PI) Naïve and PI-Experienced Pediatric 
Subjects aged 4 weeks to <2 years 
Compound Number: GW433908 
Effective Date: 
Refer to document date 
Identifier/Version Number:  QM2005/00016/01 
Author’s Name, Title and Functional Area:  
, Senior Statistician, GSK Biostatistics 
, 
, Mature Marketed Products, ViiV Healthcare 
, Manager, Mature Marketed Products, ViiV Healthcare 
Copyright 2022 ViiV Healthcare and the GlaxoSmithKline group of companies. All 
rights reserved.  Unauthorised copying or use of this information is prohibited. 
PPD
PPD
PPD
PPD


CONFIDENTIAL 
QM2005/00016/00 
APV20002 
2 
TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ........................................................................................................... 4 
1.
INTRODUCTION ...................................................................................................... 7 
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S) ........................................................... 7 
2.1. 
Study Objective(s) ........................................................................................ 7 
2.1.1. 
Primary Study Objectives ............................................................... 8 
2.1.2. 
Secondary Study Objectives .......................................................... 9 
2.2. 
Study Endpoint(s) ......................................................................................... 9 
2.2.1. 
Primary Study Endpoints ............................................................... 9 
2.2.2. 
Secondary Study Endpoints ......................................................... 10 
2.3. 
Statistical Hypotheses................................................................................. 11 
3.
STUDY DESIGN .................................................................................................... 11 
4.
PLANNED ANALYSES .......................................................................................... 12 
4.1. 
Abbreviated Interim Analysis....................................................................... 13 
4.2. 
24-Week Analysis ....................................................................................... 13
4.3. 
48-Week Analysis ....................................................................................... 13
4.4. 
Final Analysis ............................................................................................. 13 
5.
SAMPLE SIZE CONSIDERATIONS ....................................................................... 13 
7.
ANALYSIS POPULATIONS ................................................................................... 14 
7.1. 
Safety Population ........................................................................................ 14 
7.2. 
Baseline Virology Population ...................................................................... 14 
7.3. 
Virological Failure Population...................................................................... 14 
7.4. 
Total Virology Population ............................................................................ 15 
7.5. 
Data Display Treatment and Other Sub-group Descriptors ......................... 15 
7.6. 
Examination of Subgroups .......................................................................... 16 
7.7. 
HIV-1 Genotypic and Phenotypic Data ........................................................ 17 
7.7.1. 
Genotype ..................................................................................... 17 
7.7.2. 
Phenotypic Data .......................................................................... 18 
8.
DATA HANDLING CONVENTIONS ....................................................................... 19 
8.1. 
Premature Withdrawal and Missing Data .................................................... 19 
8.1.1. 
Methods for Proportion Endpoints Based on Plasma HIV-1 
RNA ............................................................................................. 19 
8.1.2. 
Methods for continuous endpoints based on plasma HIV-1 
RNA ............................................................................................. 20 
8.1.3. 
Methods for Other Laboratory Data.............................................. 20 
8.1.4. 
Methods for PK Data ................................................................... 20 
8.1.5. 
Methods for Missing Dates .......................................................... 20 
8.2. 
Derived and Transformed Data ................................................................... 21 
8.2.1. 
Assessment Windows .................................................................. 22 
8.3. 
Values of Clinical Concern .......................................................................... 23 
9.
STUDY POPULATION ........................................................................................... 23 


 
CONFIDENTIAL 
QM2005/00016/00 
 
 
APV20002 
 
3 
 
9.1. 
Disposition of Subjects ................................................................................ 24 
9.2. 
Demographic and Baseline Characteristics ................................................. 24 
9.3. 
Concurrent Medications .............................................................................. 25 
9.4. 
Prior and Concomitant Antiretroviral Therapy ............................................. 25 
10. ANTIVIRAL RESPONSE ANALYSES .................................................................... 26 
10.1. 
Protocol Deviations ..................................................................................... 26 
10.2. 
Proportion of Subjects with Plasma HIV-1 RNA levels Below 400 
copies/mL at each Visit ............................................................................... 26 
10.3. 
Proportion of Subjects with Plasma HIV-1 RNA levels Below 50 
copies/mL at each Visit ............................................................................... 26 
10.4. 
Measured values and change from baseline in plasma HIV-1 RNA 
log10 copies/mL ........................................................................................... 26 
10.5. 
Measured values and change from baseline in CD4+ cell counts ............... 27 
10.6. 
HIV Associated Conditions ......................................................................... 27 
10.7. 
HIV Disease Progression ............................................................................ 27 
11. SAFETY ANALYSES ............................................................................................. 27 
11.1. 
Extent of Exposure ..................................................................................... 27 
11.2. 
Adverse Events........................................................................................... 28 
11.3. 
Deaths and Serious Adverse Events ........................................................... 33 
11.4. 
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events........................................................................................... 33 
11.5. 
Clinical Laboratory Evaluations ................................................................... 33 
11.6. 
Other Safety Measures ............................................................................... 34 
12. CLINICAL PHARMACOLOGY DATA ANALYSES .................................................. 34 
12.1. 
Bioanalysis ................................................................................................. 35 
12.2. 
Pharmacokinetic Analyses .......................................................................... 35 
13. VIRAL GENOTYPING/PHENOTYPING ................................................................. 35 
14. COVID - 19 ANALYSIS .......................................................................................... 39 
15. REFERENCES ....................................................................................................... 40 
16. ATTACHMENTS .................................................................................................... 41 
16.1. 
Table of Contents for Data Display Specifications ....................................... 41 
16.2. 
Data Display Specifications ........................................................................ 52 


CONFIDENTIAL 
QM2005/00016/00 
APV20002 
4 
ABBREVIATIONS 
3TC 
Lamivudine, EPIVIR 
AAG 
alpha-1 acid glycoprotein 
ABC 
Abacavir, ZIAGEN 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
APV 
Amprenavir 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase (SGOT) 
ATC 
Anatomical therapeutic chemical 
ATV 
Atazanavir 
ATV/r 
ATV boosted with RTV 
AUC(0-τ) 
area under the concentration versus time curve during a 
dosing interval, τ, at steady state 
AUC(0-∞) 
area under the plasma concentration versus time curve 
from time 0 and extrapolated to infinity 
%AUCex 
percent of AUC(0-∞) that is extrapolated beyond the last 
quantified concentration 
AUC(0-t) 
area under the plasma concentration versus time curve 
from time 0 to the time of the last quantifiable 
concentration 
AUCτ,ss 
AUC for the dosing interval at steady state 
BID 
twice daily 
CD4+ 
helper-inducer T-lymphocyte surface antigen 
Cavg 
average concentration during the dosing interval at steady-
state 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CL/F 
apparent clearance of drug from plasma following 
extravascular administration 
Cmax 
maximum concentration 
Cmax,ss 
Cmax at steady state 
CPMS 
clinical pharmacology modelling and simulation 
CRF 
Case report form 
CSR 
Clinical study report 
Cτ 
concentration at the end of a dosing interval, τ, at steady 
state 
CV 
coefficient of variation for the arithmetic mean 
CVb 
coefficient of variation for the geometic mean 
d4T 
Stavudine 
ddl 
Didanosine 
DLV 
Delavirdine  
DRV/r 
Darunavir boosted with RTV 
EFV 
Efavirenz 
ETV 
Etravirine 


CONFIDENTIAL 
QM2005/00016/00 
APV20002 
5 
FC 
Fold Change 
FDA 
Food and Drug Administration (US) 
FPV 
Fosamprenavir, TELZIR, LEXIVA 
FPV/RTV 
FPV boosted with RTV, FPV/r 
FR 
Fold reduction 
FSFV 
First subject first visit 
FTC 
Emtricitabine 
GLS 
geometric least squares mean 
GSK 
Glaxo SmithKline 
h 
Hour 
HDL 
high density lipoprotein 
HIV-1 
human immunodeficiency virus type 1 
IAS 
International AIDS Society 
IC50 
Inhibitory Concentration, 50% 
IDV 
Indinavir 
IDV/r 
Indinavir boosted with RTV 
ITT(E) 
Intent-to-Treat Exposed 
λz 
terminal phase rate constant 
LDL 
low density lipoprotein 
LFT 
liver function test 
LOCF 
last observation carried forward 
LOD 
limit of detection 
LPV/r 
Lopinavir/Ritonavir 
MSD=F 
missing, switch or discontinuation equals failure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Millilitre 
NFV 
Nelfinavir, Viracept 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NRTI 
nucleoside reverse transcriptase inhibitor 
NVP 
Nevirapine 
Obs 
Observed 
OS 
Oral suspension 
PCR 
polymerase chain reaction 
PD 
Pharmacodynamics 
PI 
protease inhibitor 
PK 
Pharmacokinetics 
PR 
Protease 
RAP 
Reporting Analysis Plan  
RPV 
Rilpivirine 
RNA 
Ribonucleic acid 
RT 
Reverse transcriptase 
RTV 
ritonavir, /r, 
SAE 
serious adverse event 
SD 
Standard deviation 
SDV 
single dose visit 
SOP 
Standard Operating Procedure 
SQV 
Saquinavir 


CONFIDENTIAL 
QM2005/00016/00 
APV20002 
6 
SQV/r 
Saquinavir boosted with RTV 
t1/2 
apparent plasma half-life 
TAM 
Thymidine analogue mutation 
TFV 
Tenofovir 
tlag 
lag time before observation of drug concentrations in 
plasma 
TLOVR 
time to loss of virologic response 
tmax 
first time of occurrence of Cmax 
TPV 
Tipranavir 
ZDV 
Zidovudine, RETROVIR 
Trademark Information 
Trademarks of the ViiV Healthcare group 
of companies 
Trademarks not owned by the ViiV 
Healthcare group of companies 
COMBIVIR 
SAS 
EPIVIR 
UNIX 
LEXIVA 
QUEST 
RETROVIR 
Winnonln 
TELZIR 
Monogram 
TRIZIVIR 
PhenoSense 
VIRACEPT 
UltraSensitive Monitor 
ZIAGEN 
Geneseq 


 
CONFIDENTIAL 
QM2005/00016/00 
 
 
APV20002 
 
7 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to provide details of planned 
analyses and data displays for reporting the safety, antiviral response, global health 
outcome and virology results of study APV20002. These analyses will be used in study 
reports and publications. 
The analyses detailed in this document are based on the latest version of the APV20002 
protocol (Document Code GD2001/00007/12) issued on 20th Nov 2019. This is the 
twelfth amendment to the original protocol (Document Code GD2001/00007/00) issued 
on 20th September 2002 (see Section 2.1). 
The original RAP is based on the standard operating procedure SOP_000000548383 (4.0) 
Development, Review and Approval of Reporting and Analysis Plans. It was written 
using the document standard DS-WWD-4000 v03 issued on 11th November 2005. It 
covered the analyses produced for the primary analysis at Week 48 and prior interim 
analyses. The original RAP included pharmacokinetic sampling assessments and Health 
Outcomes and Compliance questionnaires performed at the Week 48 visit or by the cut-
off date of 05July2011. Virology analyses in the original analysis were censored to 
include only those subjects who had met confirmed virologic failure criteria by Week 48. 
The amended RAP will cover a subset of the endpoints to further describe the data 
collected after the Week 48 data cut-off for the primary analysis for the safety endpoints, 
the observed efficacy endpoint, a limited analysis of pharmacokinetic (PK) data collected 
after 05July2011 cut-off and the virology results for those subjects who met confirmed 
virologic failure criteria after 48 weeks. These results will be described in the abbreviated 
Clinical Study Report (CSR) that will be produced for the results collected after the 
05July2011 cut-off for the Week 48 analysis.  
In this document, fosamprenavir/GW433908 will be referred to as FPV, amprenavir as 
APV and ritonavir as RTV. 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
2.1. 
Study Objective(s) 
APV20002 was planned to evaluate the PK, safety, tolerability and antiviral activity of 
FPV oral suspension (OS) when administered to HIV-1 infected protease inhibitor (PI)-
naïve and PI-experienced pediatric subjects aged 4 weeks to <2 years. Enrolment into 
cohorts evaluating unboosted FPV was closed, and FPV was only administered in 
combination with low dose RTV (used as a pharmacokinetic enhancer). In addition to 
FPV/RTV, study participants also received two nucleoside reverse transcriptase inhibitors 
(NRTIs), where the choice of NRTIs was determined by the site physician, as part of 
their antiretroviral therapy (ART). Subjects in this study were enrolled into two age 
cohorts (Cohort 1: 6 months to <2 years, and Cohort 2: 4 weeks to <6 months) to 
determine the FPV/RTV dosage regimens for pediatric subjects at various stages of 
physiologic development. An abbreviated interim analysis with a cut-off date of March 
31, 2006 was published in September 2006 [GlaxoSmithKline Document Number 


 
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RM2006/00360/00], while a 24 week analysis with a cut-off date of November 2011 was 
published in June 2011 [GlaxoSmithKline Document Number 2010N107734_01] and a 
48-week analysis of data collected through 05July2011 [GlaxoSmithKline Document 
Number 2011N127273_00_01]. 
The APV20002 study included an optional extension phase for subjects enrolled in sites 
in South Africa as fosamprenavir oral suspension (FPV OS) was not commercially 
available in South Africa after the last enrolled subject reached 48 weeks on treatment on 
05July2011, the cut-off for the Week 48 analysis to provide them with access to FPV OS. 
The most recent protocol amendment 12 was minor as it was implemented to provide 
additional RTV formulation treatment options for the South African subjects because the 
RTV manufacturer discontinued sale of the protocol mandated RTV oral solution. This 
amendment applied to those subjects enrolled in APV20002 as of November 1, 2019 at 
study sites in South Africa. The study is expected to end in March 2022, when the final 
subject will be withdrawn.   
For this RAP amendment, as many of the primary and secondary objectives were met in 
the 48 week primary analysis, the final study analysis will focus on the incidence and 
frequency of adverse events and laboratory abnormalities, the virologic efficacy and 
immunologic impact of this ART regimen through the end of study (EoS), genotypic and 
phenotypic resistance in subjects who met protocol-defined virologic failure criteria after 
48 weeks. All PK objectives were met through previous analyses. The additional PK data 
past 05July2011 (week 48 reporting) is less than 10% of the total pharmacokinetic (PK) 
data and were sparse samples taken for routine clinical follow-up. These data are  not 
expected to change any of the conclusions drawn previously on the objectives, nor 
provide new insights into the PK of the investigated treatments. Therefore, instead of a 
full PK analysis, only summary statistics will be performed on the remaining PK data 
collected after 05July2011.  
2.1.1. 
Primary Study Objectives 
The bulleted primary study objectives were completed at the time of the Week 48 
primary analysis, which included data collected up to the cut-off of 05July2011.  
• To define the FPV/RTV twice daily (BID) dosage regimens which will provide 
target steady-state plasma APV exposure to HIV-1 infected paediatric subjects 
aged 4 weeks to <2 years 
• To evaluate the safety and tolerability of FPV (deferred per amendment 5) and 
FPV/RTV when administered as a component of combination therapy in HIV-1 
infected subjects aged 4 weeks to <2 years.  
The safety and efficacy of FPV OS-containing ART continued to be evaluated for the 
subset of subjects who continued in the study after the 05July2011 data cut-off for the 
week 48 analysis. Safety events will be summarized in two groups: those reported 
cumulatively throughout the study and those reported after 05July2011 until study 
completion (EoS). Due to the small number of subjects (n=25) who continued in the 
study past 05July2011, a comparison will be made between the two groups to determine 
if any safety events were reported in both groups and these will be identified in the 


 
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report. All cumulative safety events will be listed for this study. As described previously, 
a full analysis of the PK data after the timepoint of 05July2011 (week 48 reporting) is not 
considered relevant and thus only summary statistics of drug concentrations collected 
after 05July2011will be included in the CSR. 
2.1.2. 
Secondary Study Objectives 
The bulleted secondary objectives have already been met and reported in week 48 CSR.  
• The antiviral activity was evaluated for the on treatment population that 
completed 48 weeks of treatment in APV20002 and continues to receive 
FPV/RTV in combination with NRTI therapy  
• The immunologic activity was evaluated for the on treatment population that 
completed 48 weeks of treatment in APV20002 and continued to receive 
FPV/RTV in combination with NRTI therapy up to the 48 week analysis data cut-
off of 05July2011   
• The systemic exposure to FPV was evaluated for the on treatment population that 
completed 48 weeks of treatment in APV20002 and continued to receive 
FPV/RTV in combination with NRTI therapy up to the 48 week analysis data cut-
off of 05July2011  
• Assessed plasma RTV AUCτ,ss, Cmax,ss and Cτ,ss following multiple dose 
administration of FPV/RTV twice daily BID for samples obtained up to the 48 
week analysis data cut-off of 05July2011 
• Investigated the relationship of steady state plasma APV PK parameters to 
changes in plasma HIV-1 RNA concentrations, CD4+ percentages and / or the 
occurrence of adverse events for samples obtained up to the 48 week analysis data 
cut-off of 05July2011 
• Assessed viral resistance patterns and compared these patterns with treatment 
outcome (where permissible by blood volumes) for subjects who met the 
definition of confirmed virologic failure after 48 weeks of treatment with 
FPV/RTV in combination with NRTI therapy  
For the EoS report, the safety, efficacy and assessment of virologic failure for HIV-1 
infected paediatric subjects who were 4 weeks to <2 years at study enrolment and treated 
with FPV/RTV in combination with NRTIs were evaluated until the subjects 
discontinued, completed the 48 weeks on treatment, or until the subjects reached 39 
kilograms and were withdrawn from the study or at study closure (by not later than April 
29, 2022). 
2.2. 
Study Endpoint(s) 
2.2.1. 
Primary Study Endpoints 
The bulleted primary study endpoints were completed at the time of the Week 48 primary 
analysis: 


 
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• Plasma APV AUCτ,ss, Cmax,ss and Cτ,ss following multiple dose administration of 
FPV BID (deferred per amendment 5). This endpoint was removed along with 
closure of enrolment into the unboosted cohorts (Cohort 1 Arm B and Cohort 2 
Arm B)  per Protocol Amendment 10. 
• Plasma APV AUCτ,ss, Cmax,ss and Cτ,ss following multiple dose administration of 
FPV/RTV twice daily (BID) 
• The incidence and nature of adverse events, laboratory abnormalities, and 
treatment limiting toxicities 
• Proportion of subjects who permanently discontinued FPV (deferred per 
amendment 5) or FPV/RTV due to adverse events 
For the EoS report, safety endpoints as bulleted below will continue to be evaluated:  
• The incidence and nature of adverse events, laboratory abnormalities, and 
treatment limiting toxicities will be evaluated for the subset of subjects who 
continued in the study after the 05July2011 data cut-off for the 48 Week data 
analysis. 
• For the subset of subjects who continued in the study after the 05July2011 data 
cut-off for the 48 Week data analysis, the proportion of subjects who permanently 
discontinue FPV/RTV due to adverse events will be evaluated.  
2.2.2. 
Secondary Study Endpoints 
The original secondary endpoints were completed at the time of the Week 48 primary 
analysis: 
• Proportions of subjects with plasma HIV-1 RNA levels < 400 copies/mL at each 
study visit 
• Change from Baseline in plasma HIV-1 RNA at each study visit (absolute values 
and time-averaged) 
• Proportion of subjects with ≥ 1.0 log10 decrease in plasma HIV-1 RNA at each 
study visit 
• Change from Baseline in the percentage of  CD4+ lymphocytes at each study visit 
(absolute values and time-averaged) 
• Plasma FPV concentrations 
• Plasma RTV AUCτ,ss, Cmax,ss and Cτ,ss following multiple dose administration of 
FPV/RTV BID 
• Relationship of steady state plasma APV PK parameters to changes in plasma 
HIV-1 RNA concentrations, CD4+ percentages and / or the occurrence of adverse 
events 
• Subject adherence, and parent/guardian perceptions of study medications 
• Incidence of viral resistance (where permissible by blood volumes) 
For the EoS analysis, these endpoints will be evaluated using the data obtained after 
05July2011, the cut-off date for the Week 48 primary analysis: 


 
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• Proportions of subjects with plasma HIV-1 RNA levels < 400 copies/mL at each 
study visit 
• Change from Baseline in plasma HIV-1 RNA at each study visit (absolute values 
and time-averaged) 
• Change from Baseline in the percentage of CD4+ lymphocytes at each study visit 
(absolute values and time-averaged) 
• Plasma FPV concentrations collected after the 05July2011 data lock will be 
summarized (mean and standard deviation, median and 95% percentiles). 
• Incidence of viral mutations and phenotypic resistance patterns for subjects who 
met the protocol definition of confirmed virologic failure after Week 48. 
2.3. 
Statistical Hypotheses 
No formal statistical hypothesis testing will be performed in this EoS analysis. Only 
descriptive methods will be used in any analysis of the data obtained from this study after 
05July2011. 
3. 
STUDY DESIGN 
APV20002 is an international, 48-week, Phase II, open-label, 2–cohort, multicentre study 
conducted in HIV-1 infected pediatric subjects 4 weeks to <2 years old. This study was 
conducted in seven centres, three in South Africa, two in Mexico and one each in 
Argentina and Portugal. Subjects successfully completing 48 weeks of therapy in 
APV20002 had the option to continue in the study with visits every 12 weeks until 
commercial supplies of FPV OS were available locally and paediatric dosing was 
approved in the relevant age groups. In countries where local availability was delayed or 
the drug was not yet available through national treatment programs, subjects could 
continue to receive FPV until they no longer derived clinical benefit, the carers/legal 
guardians withdrew consent or the subjects were discontinued according to prior 
agreements between GSK and the participating study sites regarding provision of ART.  
As per Amendments 7 and 8, the approximate number of additional subjects required in 
APV20002 is illustrated in Table 1. Cohort 1 Arm A (FPV/RTV, 6 months to <2years) 
and Cohort 2 Arm A (FPV/RTV, 4 weeks to <6 months) were open in parallel. Cohort 1 
Arm A and Cohort 2 Arm A recruited either PI-naïve or experienced subjects. Enrolment 
into Arm B (unboosted FPV cohorts 1 and 2) was closed and no subjects received 
unboosted FPV as per amendment 10 (effective 28-MAR-2011). Recruitment status as of 
the week 48 CSR is provided below in Table 1. 
Dose recommendations have been modified in this and previous protocol amendments (3, 
5, 7 and 8). The remaining evaluable PK data collected after 05July2011 will be analysed 
at the end of the study and will include subjects who have been on different dosing 
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Table 1 
Recruitment Status for APV20002 – from Oct 2003 (FSFV) to 05 Jul 
2011 (cutoff for 48 week CSR) 
Age 
(yrs) 
 
Cohorts 
 
No. of Subjects originally 
planned 
 
Cumulative enrolment and 
current status1 
1A 
6months - <2yr 
PI-naïve/exp 
FPV/RTV (boosted) 
 
12 
 
28 enrolled2 
 
2A 
4wks - <6mo 
PI-naïve/exp 
FPV/RTV (boosted) 
 
12 
 
 
26 enrolled2 
 
1. A total of 59 patients were enrolled but 5 were discontinued after receiving single dose of FPV; the total enrolled number of 
patients exceeds the original cohort target because of dose changes in previous amendments 
Source data: Table 6.3 APV20002 48 week study report GSK Document 2011N127273_00 
Cohort 1 Arm A (FPV/RTV, 6 months to <2years) and Cohort 2 Arm A (FPV/RTV, 
4 weeks to <6 months) were open in parallel. Cohort 1 Arm A and Cohort 2 Arm A 
recruited either PI-naïve or experienced subjects.   
Dose recommendations were modified in protocol amendments 3, 5, 7 and 8. The 
evaluable PK data for approximately 50 to 60 subjects was analysed at the Week 48 data 
lock (05July2011) and included subjects who were on different dosing regimens. 
The initial group of subjects who were enrolled into the study underwent a single dose 
visit (SDV) before commencing multiple dosing with for example FPV/RTV at Baseline 
and were referred to as Arm A SDV. As per Amendments 5 and 7, no additional subjects 
were required to undergo SDV assessments. 
For more details on the study design, please refer to Section 3 in the latest version of 
protocol, Protocol Amendment 12 [GlaxoSmithKline Document Number 
GD2001/00007/12]. 
4. 
PLANNED ANALYSES 
Evaluation of APV PK following single dose administration of FPV and FPV/RTV was 
performed for the first 6-10 subjects enrolled in each cohort in order to provide individual 
dosage regimen recommendations to investigators, because APV had not been studied in 
children <2 years of age and data for other HIV-1 PIs has demonstrated that children <2 
years require much higher mg/kg doses than older children and adults. In addition, it was 
possible to undertake expedited analysis of plasma APV, RTV and FPV on a case by case 
basis on PK trough samples collected to allow for dose regimen adjustment due to the 
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4.1. 
Abbreviated Interim Analysis 
An abbreviated interim analysis of APV20002 including data for subjects enrolled in 
Arm A was conducted and included as part of a regulatory submission. All data up to and 
including the 31st of March 2006 was included in the analysis and contained data through 
48 Weeks for 10 subjects. The abbreviated interim analysis is included in the CSR 
[RM2006/00360/00] issued on 20th September 2006. 
4.2. 
24-Week Analysis 
Data up to the cut-off date of 24th November 2010 was included in this analysis. This 
included 24 week safety, PK, and efficacy data for 54 subjects. The 24 week analysis is 
included in the CSR [GlaxoSmithKline Document Number 2010N107734_00] issued on 
June 8, 2011. 
4.3. 
48-Week Analysis 
Data up to and including the 05July2011 cut-off date was included in the week 48 
analysis. The Week 48 CSR was generated after the database was cleaned and included 
all subjects who had not withdrawn prior to week 48 and was issued April 24, 2012 
[GlaxoSmithKline Document Number 2011N127273_00_01]. 
4.4. 
Final Analysis 
A final analysis will be performed when all subjects discontinued, completed the 48 
weeks on treatment, or until the subjects reached 39 kilograms and were withdrawn from 
the study or at study closure (by not later than April 29, 2022). This closeout appendix 
RAP will provide the details of planned analyses and data displays for APV20002 EoS 
reporting for the EoS CSR. 
5. 
SAMPLE SIZE CONSIDERATIONS 
The sample size of 48 subjects was selected as an appropriate number to allow an 
accurate description of plasma APV PK, safety and tolerability of FPV BID, Arm B 
(n=24 for PK and safety; enrolment closed per Amendment 10; effective 28Mar-2011] 
and FPV/RTV BID, Arm A (n=24 for PK and safety). Safety and tolerability assessment 
of the FPV/RTV BID regimen (Arm A) was assessed for the duration of the study or until 
a subject permanently discontinues the study drug.  
 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
This appendix RAP is written additionally to support the main RAP (effective on 29-
SEP-2011). Since the primary analyses have been completed based on the main RAP, the 
present RAP is written to cover only analyses included in the final reporting. Only those 
definitions and derivations that have changed since previous interim analyses will be 


 
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included in the current RAP, i.e. for derivation of analysis windowing, how to deal with 
missing dates, definition of concomitant medications, etc. refer to the main RAP. This 
RAP summarizes only the key endpoints of interest for the final analysis and explains any 
deviations from the main RAP.  
Since the analysis in the main RAP censored the virology data to include only those 
subjects who met the criteria for confirmed virologic failure by Week 48, additional 
descriptions of those analysis populations are included here for the EoS report.  
7. 
ANALYSIS POPULATIONS 
7.1. 
Safety Population 
All subjects receiving FPV or FPV/RTV at any dose will be included in the safety 
population. Safety events will be summarized in two groups: those reported cumulatively 
throughout the study and those reported after 05July2011 until study completion (EoS). 
The EoS population continuing in the study following the July 5 2011 cut-off date will be 
the primary population for any safety analyses in this amended RAP and all cumulative 
safety events will be listed for this study. 
7.2. 
Baseline Virology Population 
All subjects enrolled into the study with data from Day 1 (Baseline) or Screening HIV 
Resistance Testing (Geneseq and PhenoSense, Monogram Biosciences Inc.) will be 
included in this population. This population will be used for the virology analysis. 
7.3. 
Virological Failure Population 
A specific comprehensive definition for virologic failure was not included in the original 
protocol. Therefore, to be consistent with current standard practice, for the Week 24 
analysis virologic failure was defined as failure to achieve a plasma HIV-RNA value of < 
400 copies/mL by Week 24 or two consecutive values of HIV-RNA rebound to ≥400 
copies/mL after initially achieving a plasma HIV-RNA of  <400 copies/mL. If a subject 
had a single viral load rebound ≥400 copies/mL at Week 24 and it was their last available 
visit and hence virological failure could not be confirmed, they were not included in the 
Week 24 Virological Failure Population. The Week 48 analysis included those subjects 
defined as virological failures in the Week 24 analysis along with subjects who had two 
consecutive values of HIV-RNA rebound to ≥400 copies/mL after achieving a plasma 
HIV-1 RNA of  <400 copies/mL between Week 24 and Week 48. Therefore, if a subject 
had a single viral load rebound HIV-1 RNA ≥400 copies/mL at Week 48 and it was their 
last available visit so virological failure could not be confirmed, they were not included 
in the Virological Failure Population for the Week 48 CSR. 
Plasma samples from subjects with plasma HIV-1 RNA >400 copies/mL, when available, 
were sent for HIV Resistance Testing (Geneseq and PhenoSense, Monogram Biosciences 
Inc.) if the subject had met the criteria for confirmed virologic failure together with the 
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Resistance Testing for some subjects at study start to assist investigators with selection of 
appropriate NRTI ART. Samples with plasma HIV-1 RNA >400 copies/ml were also sent 
for analysis at additional timepoints during the study at the request of investigators to aid 
patient management. 
Since the confirmed virologic failure results presented in the Week 48 CSR were 
censored to include only subjects with confirmed virologic failure by Week 48, the EoS 
virology analysis will include summary tables for subjects who had two consecutive 
values of HIV-RNA ≥400 copies/mL after achieving a plasma HIV-1 RNA of <400 
copies/mL at any time after Week 48 through the EoS. Subjects who met confirmed 
virologic failure criteria by Week 48 and were included in the Week 48 CSR will not be 
included in these EoS tables describing subsequent confirmed virologic failures and 
treatment emergent changes in drug resistance or resistance associated mutations. In the 
event that a subject had a single HIV-1 RNA value of ≥400 copies/mL at Week 48 and it 
was their last available visit at the July 5 2011 data cut-off so that virologic failure was 
unconfirmed and the subject had a second consecutive HIV-1 RNA ≥400 copies/mL at 
their next study visit, then the subject would be deemed a virological failure and the 
results for this subject will be included in the summary tables for Virological Failure 
Population for the EoS report. Treatment emergent resistance associated mutations and 
treatment emergent changes in phenotypic resistance will be calculated for subjects 
meeting confirmed virologic failure at any time after Week 48 and the EoS for all 
confirmed virologic failure subjects with baseline genotypic or phenotypic data. This will 
be the primary population for genotypic and phenotypic analyses. However, a disposition 
table will also summarize how many subjects met confirmed virologic failure criteria by 
Week 48 and how many additional subjects met this criterion after Week 48 through EoS.   
7.4. 
Total Virology Population 
All subjects with HIV resistance testing data will be included in this population, 
including those with genotypic and phenotypic data obtained post-baseline where the 
subject is not considered a virological failure. This population will be used for the listings 
of virology data for all subjects with genotypic and/or phenotypic data collected from 
study start through EoS. 
7.5. 
Data Display Treatment and Other Sub-group Descriptors 
In data displays, treatment groups, dose regimen groups and age groups will be identified 
as described in Table 2 and footnotes will be provided in the PK summary tables. All of 
the dose regimens will be summarised and listed, but only the regimens with n ≥6 
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Table 2 
Group Descriptors 
Treatment Group 
Descriptor 
FPV 30mg/kg single dose alone 
FPV SD 
FPV 30mg/kg + RTV 6mg/kg single dose 
FPV/RTV SD 
FPV/RTV BID  
FPV/RTV BID 
Age Group 
  
6 months-<24 months at PK profile 
6-<24m 
4week-<6months at PK profile 
1-<6m 
Dose Group 
Description 
Value 
FPV/RTV where FPV was dosed within 40.5-
49.5mg/kg 
FPV/RTV 
45/7mg/kg BID 
45/7 
FPV/RTV where FPV was dosed within 40.5-
49.5mg/kg 
FPV/RTV 45/10 
mg/kg BID 
45/10 
FPV was dosed within 27-33 mg/kg  
FPV/RTV 30 mg/kg 
BID 
30 
FPV was dosed within 27-33 mg/kg  
FPV/RTV 30/7 
mg/kg BID 
30/7 
FPV/RTV where FPV was dosed within 
54~66mg/kg 
FPV/RTV 60/7 
mg/kg BID 
60/7 
FPV/RTV where FPV was dosed within 
54~66mg/kg 
FPV/RTV 60/10 
mg/kg BID 
60/10 
 
7.6. 
Examination of Subgroups 
Some Study Population, Efficacy and Safety summaries may be presented by age group 
at entry. The age group categories will be 4 weeks to <6months and 6 months to 2 years. 
Some summaries may also be presented by PI status (PI-experienced or PI-naïve), gender 
and race. 
The following baseline viral load categories will be used in summaries; 400 to-<5,000 
copies/mL, 5,000 to-<100,000 copies/mL, 100,000 to-<250,000 copies/mL, 250,000 to-
<500,000 copies/mL and ≥500,000 copies/mL. Similarly, the following baseline CD4+ 
categories will be used; <100 cells/cu mm3, 100to-<200 cells/cu mm3, 200 to-<350 
cells/cu mm3, 350 to-<500 cells/cu mm3 and ≥500 cells/cu mm3.  


 
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PK summaries may be presented by dose and age group at the time of the PK assessment, 
and for combined age groups. The age group categories will be 4 weeks to– <6 months 
and 6 months to- <2 years. 
7.7. 
HIV-1 Genotypic and Phenotypic Data 
7.7.1. 
Genotype 
Genotypic summaries are based on differences in the plasma HIV-1 sequence from the 
molecular wild-type strain NL-43. An assessment will be made of the total number of 
changes across all amino acids within the reverse transcriptase (RT) and protease (PRO) 
regions, as well as an assessment of specific amino acid changes associated with the 
development of resistance to antiretrovirals. The specific protease and reverse 
transcriptase mutations which are associated with the development of resistance as 
currently defined by the IAS-USA as listed in Table 3. Mutations as defined in the most 
current version of the IAS-USA guidelines available at the time of data analysis will be 
used and included in analyses described in this report. 
Table 3 
Specific Protease and RT mutations associated with the 
Development of Resistance 
NRTI Associated Mutations 
M41L, A62V, K65R/E/N, D67N, T69insert, K70R, L74V, V75I, F77L, Y115F, F116Y, Q151M, M184V/I, 
L210W, T215Y/F, K219Q/E 
Thymidine Analogue Mutations (TAMs) 
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E 
NNRTI Analogue Mutations: Major 
L100I, K101E/P, K103N, V106A/M, V108I, E138A/G/K/Q, Y181C/I/V, Y188C/L/H, G190A/S, P225H, 
F227C, M230I/L 
NNRTI Analogue Mutations: Minor 
V90I, A98G, K101H, V106I/T, V179D/F/T, G190E, F227L/R, L234I 
Protease Mutations:  Major 
D30N, V32I, M46I/L, I47V/A, G48V, I50V/L, I54L/M, Q58E, T74P, L76V, V82A/F/T/S/L, N83D, I84V, 
N88S, L90M 
Protease Mutations: Minor 


 
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L10F/I/R/V/C, V11I, G16E, K20M/R/I/T/V, L24I, L33I/F/V, E34Q, M36I/L/V, K43T, F53L/Y, I54V/A/T/S, 
D60E, I62V, L63P, I64L/M/V, H69K/R, A71V/I/L/T, G73S/A/C/T, V77I, V82I, I85V, N88D, L89I/M/V, 
I93L/M 
Taken from the IAS guideline published in Topics in HIV Medicine: Update of the Drug Resistance Mutations in 
HIV-1: December 2019 Volume 27 Issue 3 pages 111-121  
 
7.7.2. 
Phenotypic Data 
Phenotypic susceptibility to all licensed antiretroviral drugs will be determined and will 
be reported as fold change in IC50 relative to wild-type control virus (FC). Susceptibilities 
will be categorised according to FC based on the susceptibility cut-offs published by 
Monogram as shown in Table 4 or as in the most current cut-offs on the Monogram 
website at the time of analysis. 
Table 4 
Fold Change Used to Classify Virus as Sensitive or Resistant: in the 
Monogram PhenoSense Assay 
Drug 
Class 
Reduced Susceptibility Lower 
Cut-offa 
Reduced Susceptibility 
Upper Cut-offa 
 
ABC 
NRTI 
4.5a 
6.5 
ddI 
NRTI 
1.3a 
2.2 
3TC 
NRTI 
3.5a 
 
d4T 
NRTI 
1.7a 
 
TFV 
NRTI 
1.4a 
4 
FTC 
NRTI 
3.5b 
 
ZDV 
NRTI 
1.9 b 
 
DLV 
NNRTI 
6.2 
 
EFV 
NNRTI 
3 b 
 
ETV 
NNRTI 
2.9a 
10 
NVP 
NNRTI 
4.5 b 
 
ATV 
PI 
2.2 
 
ATV/r 
PI 
5.2 
 
DRV/r 
PI 
10 
90 
FPV 
PI 
2 b 
 
FPV/r 
PI 
4 
11 
IDV/r 
PI 
10a 
 


 
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LPV/r 
PI 
9a 
55 
NFV 
PI 
3.6 b 
 
RTV 
PI 
2.5 b 
 
SQV 
PI 
1.7 b 
 
SQV/r 
PI 
2.3 
12 
TPV 
PI 
2.0a 
8 
a. 
Cut-off determined by clinical evaluation as per Monogram web site, accessed on January 2021 using an 
advanced proprietary algorithm (version 12) 
b. 
Biologic cut-off as per Monogram web site accessed on January 2021 using an advanced proprietary algorithm 
(version 12) 
8. 
DATA HANDLING CONVENTIONS 
All data manipulations, tabulations, and calculations will be performed using SAS™ 
Version 9.1.3 on a system of UNIX™ computers. 
8.1. 
Premature Withdrawal and Missing Data 
Data recorded at early withdrawal visits will be handled in the same way as scheduled 
data and will be slotted using the pre-defined visit windows (see Section 9.3). 
The method for dealing with premature withdrawals and missing data will depend on the 
endpoint being analysed. In the following sections, methods are outlined and the ‘analysis 
strategies’ described. A subject will be considered a completer in the analysis if they 
remain in the study until Week 48 or until the study it is closed. 
8.1.1. 
Methods for Proportion Endpoints Based on Plasma HIV-1 RNA 
For proportion based analyses of plasma HIV-1 RNA data the following methods will be 
employed: 
Observed (Obs) 
For the EoS analysis, an observed analysis will be performed to evaluate regiment 
efficacy. For each scheduled assessment time, the rate is defined as follows, where a 
positive response is defined as plasma HIV-1 RNA response <400 copies/mL (or <50 
copies/mL or ≥ 1 log10 copies/mL below baseline): 
 
 
Number of subjects with a positive response where the  
Obs 
= 
subject is still receiving study medication  
 
 
Number of subjects in the ITT(E) population with an assessment in the visit Window 
 


 
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8.1.2. 
Methods for continuous endpoints based on plasma HIV-1 RNA 
For continuous endpoints based on plasma HIV-1 RNA data the following methods will 
be employed: 
Observed 
Only subjects who are still receiving investigational product and have data at a visit will 
be included in the analysis, and no missing values will be imputed. For observed analyses 
of changes from baseline or actual values, the number of subjects in the analysis at each 
assessment window may change. 
8.1.3. 
Methods for Other Laboratory Data 
For other laboratory data (CD4+ cell counts, haematology and clinical chemistry) the 
following methods will be employed: 
Observed 
Only subjects who are still receiving investigational product and have data at a visit will 
be included in the analysis, and no missing values will be imputed. For observed analyses 
of actual values, the number of subjects in the analysis at each assessment window may 
change. 
8.1.4. 
Methods for PK Data 
No imputations will be made for missing PK data. 
8.1.5. 
Methods for Missing Dates 
In the event that only partial dates are collected in running log pages (e.g. AEs, 
concurrent medications, background antiretroviral therapy) when full dates are expected 
and necessary for analyses, the following conventions will apply: 
• If the year is missing and cannot be captured, the date will remain missing. 
• If start day is missing and cannot be captured, but the month is available, the day 
will be assigned to the 1st of the month, unless this takes the start date to before 
treatment start date. In this case the treatment start date will be used. If start day 
and month is missing and cannot be captured, the day will be assigned to the 1st of 
January that year, unless this takes the start date to before treatment start date. 
Again in this case the date of treatment start will be used. 
• If stop day is missing and cannot be captured, but the month is available, the day 
will be assigned to the last day of that month, unless this estimated date comes 
after the treatment stop date. In this case the treatment stop date is used. If stop 
day and month is missing and cannot be captured, the day will be assigned to the 
31st of December that year, unless this estimated date comes after the treatment 
stop date. Again in this case the treatment stop date is used. 


 
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The 24 week and the 48 week analyses were performed using data from subjects who had 
not yet completed the study, so a number of subjects had missing treatment stop dates. 
For this EoS analysis: 
• If the treatment stop date is missing, and there is no record of the subject having 
discontinued then the last assessment date will be used as treatment stop date. 
In the event that only partial treatment stop dates are collected when full dates are 
expected and necessary for analyses, the following conventions will apply: 
• Where a month is entered, the imputed treatment stop date is the most relevant 
date in that month. Where only a year is entered, the imputed treatment stop date 
is the most relevant date in that year. For example: 
• If the investigational product is discontinued due to lost to follow-up, then the last 
assessment date will be used as treatment stop date, if it falls in the same 
month/year as the partial date. If it is not in the same month, the last day of the 
month will be used. 
• If the investigational product is discontinued due to virological failure, then the 
date of the last lab/PCR assessment is used a treatment stop date, if it falls in the 
same month/year as the partial date.  If it is not in the same month, the last day of 
the month will be used. 
• If the investigational product is discontinued and the reason is missing, then the 
last assessment date will be used as treatment stop date, if it falls in the same 
month/year as the partial date. If it is not in the same month, the last day of the 
month will be used. 
If an adverse event onset date is completely missing, the adverse event is assumed to 
have started during treatment and is therefore included in the adverse event summaries. 
If the missing date is associated with a scheduled visit (e.g., Week 4) then the missing 
date will be assigned the target date. The target date will be derived from the subject’s 
treatment start date and the target study day for the scheduled visit as specified in 
Section 9.3. 
For investigational product exposure dates, if the FPV and RTV dates differ, the date for 
FPV will be used. 
8.2. 
Derived and Transformed Data 
Baseline 
For Plasma HIV-1 RNA, lymphocyte subsets, genotypic and phenotypic data and all 
other parameters for which baseline values or changes from baseline are calculated, the 
baseline value is defined as the value observed at the Day 1 visit or if this value is 
missing the last value observed before the start of investigational product. 


 
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Plasma HIV-1 RNA data 
For analyses which use HIV-1 RNA levels as a continuous measure the values will be 
logged to the base 10. 
Quantitative plasma HIV-1 RNA PCR is measured using the Roche Ultrasensitive HIV-1 
Monitor Test  (Version 1.5, LOD [limit of detection]=50 copies/mL) which can detect 
HIV-1 RNA values within the range 50-75,000 copies/mL. Samples with HIV-1 RNA 
results >75,000 copies/mL will be retested using the Roche HIV-1 Monitor Test, version 
1.5, standard LOD=400 copies/mL, which can detect HIV-1 RNA values within the range 
400-750,000 copies/mL. 
In cases where the sample has been retested, the retest value will be used in the analysis. 
However, in the case that there is only a value reported as <50, <400, >75,000, >750,000 
or >7,500,000 copies/mL, the value will be replaced by 49, 399, 75,001, 750,001 or 
7,500,001 copies/mL for the purpose of calculating summary statistics, but <50, <400, 
>75,000, >750,000 or >7,500,000 will be shown in listings. 
Due to discontinuation of the Roche Ultrasensitive HIV-1 Monitor Test  (Version 1.5, 
LOD [limit of detection]=50 copies/mL) during the EoS timeframe after the primary 
endpoint was completed, the assay for determination of HIV-1 RNA viral loads was 
changed to the Abbott RealTime HIV-1 VL assay. When using the 0.6 mL plasma 
protocol the linear detection/quantification range is 40 to 10,000,000 copies/mL.   
PK Data 
No transformations will be made of plasma APV and RTV concentrations. 
For FPV and RTV doses where data was captured as ml, these data will be converted to 
mg/kg as (FPV dose in ml*50(mg/ml))/weight(kg) for FPV and (RTV dose in 
ml*80mg/ml)/weight(kg) for RTV. 
8.2.1. 
Assessment Windows 
For summaries of PK, safety and antiviral activity, data will be assigned to assessments 
according to the actual visit dates rather than the nominal dates as recorded on the CRF or 
in the laboratory database. A window around an assessment will include all dates from 
the midpoints between the target day and that of the previous and proceeding visits and, 
in general, the nominal target day for week (w) will be (7*w)+1. This visit slotting will 
be performed according to the time intervals shown in Table 5 with days relative to the 
date of first dose of FPV/RTV BID investigational product (Day 1). 


 
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Table 5 
Visit Slotting Intervals 
Randomised Period 
Scheduled Visit 
First Day* 
Target Study Day 
Last Day* 
Screening 
not applicable 
-28  
-4 
Day 1 
-3 
1 
1 
Week 2 
2 
15 
22 
Week 4 
23 
29 
43 
Week 8 
44 
57 
71 
Week 12 
72 
85 
99 
Week 16 
100 
113 
141 
Week 24 
142 
169 
211 
Week 36 
212 
253 
295 
Week 48 
296 
337 
379 
Week 60 
380 
422 
463 
Week 72 
464 
506 
546 
Etc. 
Etc. 
Etc. 
Etc. 
Follow-up 
> (Study Day of last 
dose + 1) 
Study Day of last dose 
+ 28 
> (Study Day of last 
dose + 1) 
* Date of assessment – date of first dose + 1 
If an assessment window contains more than one value, the value collected closest in 
time to the target study day will be used for analyses, but all data will be listed. If more 
than one value is collected the same number of days away from the target study day, the 
arithmetic mean (geometric mean for HIV-1 RNA data) will be assigned, and for 
categorical data the worst case scenario will be taken. 
The window based method presented above applies to data collected at all scheduled 
visits (e.g. plasma HIV-1 RNA, other clinical laboratory parameters). Some assessments 
are not scheduled to be performed at every visit (e.g. health outcomes questionnaires and 
PK sampling) and for these parameters the windows will be widened if necessary to 
avoid missing data. 
8.3. 
Values of Clinical Concern 
Systems for grading severity of laboratory abnormalities and clinical AEs were included 
in the protocol. These grades will be utilized in the presentation of the data as described 
in Section 12. 
9. 
STUDY POPULATION 
All tables referred to in this section will be presented on the ITT(E) population, unless 
otherwise specified. All subjects will be included in listings as appropriate. 


 
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9.1. 
Disposition of Subjects 
In general, disposition tables summarizing the disposition of subjects at screen or at 
baseline for which the data will not have changed since the Week 48 analysis will not be 
reanalysed for the EoS report; the report will refer back to the results presented in the 
Week 48 CSR. Subject disposition tables that include additional data collected or 
representation of the data to account for subjects who continued in the study after Week 
48 will be re-analysed for the EoS report.   
The following disposition tables will be generated for the EoS report; minor modification 
to these tables which were included in the Week 48 CSR will be made so that the 
summaries will describe and differentiate between subjects who continued in the study 
after Week 48 versus the population who withdrew before or on completion of the Week 
48 July 5 2011 cut-off: 
• Summary of Investigational Product Status by Age Group at entry for all subjects 
(h_sp_t001_age) 
• Summary of Investigational Product Status by Age Group at entry for subjects 
who continued after 05July2011 (h_sp_t001_age) 
• Summary of Investigational Product Status by Visit (h_sp_t002) including an 
asterisk for any values obtained after 05July2011 
• Summary of End of Study Record for all subjects (h_ds_t001) 
•  Summary of End of Study Record for subjects who continued after 05July2011 
(h_ds_t001) 
• Summary of End of Study Record by Visit including an asterisk for any values 
obtained after 05July2011 (s_ds_t001) 
A summary of the number and percentage of subjects who completed the study as well as 
subjects who withdrew prematurely from the study as recorded in the CRF Study 
Conclusion page will be produced overall and by visit. A listing of the Study Conclusion 
page will be produced for the ‘All Subjects Enrolled Population’. 
9.2. 
Demographic and Baseline Characteristics 
The demographic data tables noted below were generated for the Week 48 report and 
only demographic analyses which have updates after the 05July2011 data cut-off for the 
primary analysis will be re-analysed for the EoS report. 
Demographic characteristics (gender, age, ethnicity), collected at screening or baseline 
will be summarised overall and by age group at entry. Date of birth, the screening 
assessment date, age, gender and ethnicity will be included in the listing of demographic 
data. Race will be summarised, and a by-subject listing of race will also be produced. 
Number and percent of subjects with CDC Classification of HIV Infection Categories N, 
A, B and C at baseline will be summarised and listed.   
HIV risk factor/mode of transmission and current medical conditions at entry will be 
summarised. 


 
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Summary statistics and the distribution of both plasma HIV-1 RNA and CD4+ cell count 
data (cells/mm3 and %) at screening and baseline will be presented by age group at entry 
for subjects who continue after 05July2011. 
9.3. 
Concurrent Medications 
For reporting purposes, prior, concomitant and follow-up medications will be defined 
using the start and stop dates and ongoing fields recorded in the CRF, relative to the first 
and last dose dates of randomised study medication. 
Concurrent medications administered during the study will be coded using the GSK Drug 
coding dictionary and the following table will be generated: 
• Summary of Concomitant Medication Ingredient Combinations for subjects who 
continue after 05July2011 (h_cm_t003). 
A by subject listing of concomitant medications will be produced. The hierarchical 
relationship between the ATC level 1, ingredient and verbatim text will be listed. 
9.4. 
Prior and Concomitant Antiretroviral Therapy 
All prior and concomitant antiretroviral therapy (ART) will be presented including GSK 
Drug (ATC) classification level 4 (which will provide ART class), ingredient and 
verbatim text. In the case of multiple ingredients, drugs will be recombined into the 
combination product if possible (e.g., COMBIVIR, TRIZIVIR). 
For reporting purposes, prior, concomitant and follow-up ART medications will be 
defined using the start and stop dates and ongoing fields recorded in the CRF, relative to 
the first and last dose dates of randomised study medication. The following tables that 
summarize concomitant ART or changing NRTIs during the study by PI status in subjects 
who continued after 05July2011 will be generated: 
• Summary of Concomitant Antiretroviral Therapy by PI Status for subjects who 
continued after 05July2011 (h_cm_t007) 
• Summary of Number of Subjects Changing NRTIs During the Study by PI Status 
for subjects who continued after 05July2011 (s_cm_t004).  
Prior and concomitant ART will be listed. Summary tables were generated for the 48 
week report and therefore only tables that deal with concomitant (or follow-up) 
antiretroviral therapy after 05July2011 will be updated for the EoS report.  
Listings will be generated for subject disposition as follows though the end of study and 
will differentiate between subjects who continued in the study after 05July2011 (week 48 
data cut-off date) with the addition of an asterisk vs those who did not:  
• Listing of Investigational Product Discontinuation and reason for 
discontinuation(h_sp_l001)  
• Listing of End of Study Record (h_ds_l002) 


 
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• Listing of Demographic Characteristics (h_dm_l001)  
• Listing of Race (h_dm_l002)  
• Listing of Concomitant Medications (h_cm_l001) 
• Listing of Concomitant Antiretroviral Therapy (h_cm_l004) 
• Listing of Study Populations (h_pn_1001) 
• Listing of Concomitant medication Relationship between ATC Level 1, 
Ingredient and Verbatim Text (h_cm_1002) 
• Listing of Prior Antiretroviral Therapy (h_cm_1003) 
• Listing of Important Protocol Deviations 
10. 
ANTIVIRAL RESPONSE ANALYSES 
All antiviral response analyses will be performed on the ITT(E) Population, unless 
otherwise stated. All subjects will be included in listings as appropriate. 
10.1. 
Protocol Deviations 
All violations of inclusion/exclusion criteria will be  listed. 
10.2. 
Proportion of Subjects with Plasma HIV-1 RNA levels Below 
400 copies/mL at each Visit 
For the EoS analysis, the proportion of subjects with plasma HIV-1 RNA level below 400 
copies/mL will be presented for each visit using the Observed analysis strategy.  
10.3. 
Proportion of Subjects with Plasma HIV-1 RNA levels Below 
50 copies/mL at each Visit 
For the EoS analysis, the proportion of subjects with plasma HIV-1 RNA level below 50 
copies/mL will be presented for each visit. This analysis will be performed using the 
Observed analysis strategy (see Section 8.1.1). 
In addition to the above, the viral load data will be listed by subject and by visit. 
10.4. 
Measured values and change from baseline in plasma HIV-1 
RNA log10 copies/mL 
The actual values and changes from baseline in plasma HIV-1 RNA log10 copies/mL will 
be summarised and will be presented for each visit. This analysis will be performed using 
the Observed analysis strategy (see Section 8.1.1) and the data will be listed. The actual 
values will also be presented by age group at entry, gender and race. 


 
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10.5. 
Measured values and change from baseline in CD4+ cell 
counts 
The actual values and changes from baseline in CD4+ cell count (cells/mm3 and %) will 
be summarised by age group at entry and presented by visit for the Observed analysis 
strategy (see Section 8.1.1) and the data will also be listed.  
10.6. 
HIV Associated Conditions 
All data collected on HIV associated conditions will be listed. 
A summary of all treatment emergent HIV associated conditions including those which 
are a recurrence of a previous condition will be presented for subjects with data after the 
05July2011 cut-off. Similar summaries will be presented which exclude those HIV 
associated conditions which are a recurrence of a previous condition.  
10.7. 
HIV Disease Progression 
Proportions of subjects experiencing clinical disease progression or death after the 
05July2011 data cut-off for the Week 48 analysis will be presented. 
Clinical disease progression is defined as the progression from baseline HIV disease 
status as follows: 
• CDC Category N at baseline to CDC Category C event 
• CDC Category A at baseline to CDC Category C event  
• CDC Category B at baseline to CDC Category C event 
• CDC Category C at baseline to new CDC Category C event 
• CDC Category N, A, B or C at baseline to death  
 
11. 
SAFETY ANALYSES 
All safety tables are based on the Safety Population. All subjects will be included in 
listings as appropriate. 
11.1. 
Extent of Exposure 
For the EoS population continuing treatment following the week 48 report cut-off date 
(05July2011), the date a subject discontinued together with details of the reason for those 
subjects who discontinued will be listed (as collected on the Investigation Product Record 
and Investigation Product Discontinuation Record pages). 


 
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11.2. 
Adverse Events 
Adverse events will be coded using the MedDRA coding dictionary, to give a preferred 
term and a system organ class. These preferred terms and system organ classes will be 
used when summarising the data. The verbatim text will be used in listings together with 
the lower level term, preferred term and system organ class. A listing of the relationship 
of preferred term to lower level terms and investigator text will be presented ordered by 
system organ class. 
The following sets of treatment emergent adverse events (i.e. those with onset date on or 
after initiation of investigational product, and up to the day of the last dose of 
investigational product) will be tabulated. A cumulative summary of treatment emergent 
adverse events in all subjects will be generated and a summary of treatment emergent 
AEs for subjects who continued after 05July2011 (week 48 data cut-off date) through 
EoS will be generated. In order to account for any duplication of the same AE reported in 
both the week 48 report and in the EoS population, a comparison will be performed for 
AEs in the subjects remaining on treatment after 05July2011 (as there were 25 subjects in 
the study on July 5, 2011, it is estimated that this n=25) and any duplication will be noted 
in the EoS report. For AEs captured more than once, the most severe intensity will be 
included in summaries, and all events will be included in the following listings: 
• Table 3.01 Summary of All Treatment Emergent Adverse Events by System 
Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_all) 
• Table 3.02 Summary of All Treatment Emergent Adverse Events by System 
Organ Class for all study participants (h_ae_t001_all) 
• Table 3.11 Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Maximum Toxicity/Intensity for subjects who remained on 
treatment after 05July2011 (h_ae_t004_all) 
• Table 3.12 Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Maximum Toxicity/Intensity for all study participants 
(h_ae_t004_all) 
• Table 3.21 Summary of All Treatment Emergent Adverse Events by System 
Organ Class by Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_ae_t002_age) 
• Table 3.22 Summary of All Treatment Emergent Adverse Events by System 
Organ Class by Age Group at Entry for all study participants (h_ae_t002_age) 
• Table 3.31 Summary of All Treatment Emergent Adverse Events by Frequency 
for subjects who remained on treatment after 05July2011 (h_ae_t003) 
• Table 3.32 Summary of All Treatment Emergent Adverse Events by Frequency 
for all study participants (h_ae_t003) 
• Table 3.41 Summary of Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_24) 


 
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• Table 3.42 Summary of Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class for all study participants (h_ae_t001_24) 
• Table 3.51 Summary of Treatment Emergent Grade 2-4 Adverse Events by 
Frequency for subjects who remained on treatment after 05July2011 
(h_ae_t003_24) 
• Table 3.52 Summary of Treatment Emergent Grade 2-4 Adverse Events by 
Frequency for all study participants (h_ae_t003_24) 
• Table 3.61 Summary of Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class and Age Group at Entry for subjects who remained on 
treatment after 05July2011 (h_ae_t001_24_age) 
• Table 3.62 Summary of  Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class and Age Group at Entry for all study participants 
(h_ae_t001_24_age) 
• Table 3.71 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_dr) 
• Table 3.72 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class for all study participants (h_ae_t001_dr) 
• Table 3.81 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class and Maximum Toxicity for subjects who remained on 
treatment after 05July2011 (h_ae_t004_dr) 
• Table 3.82 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class and Maximum Toxicity for all study participants 
(h_ae_t004_dr) 
• Table 3.91 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class and Age Group at Entry for subjects who remained on 
treatment after 05July2011 (h_ae_t004_dr_age) 
• Table 3.92 Summary of Drug Related Treatment Emergent Adverse Events by 
System Organ Class and Age Group at Entry for all study participants 
(h_ae_t004_dr_age) 
• Table 3.101 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by System Organ Class for subjects who remained on treatment after 
05July2011 (h_ae_t001_dr_24) 
• Table 3.102 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by System Organ Class for all study participants (h_ae_t001_dr_24) 
• Table 3.111 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by Frequency for subjects who remained on treatment after 05July2011 
(h_ae_t003_dr_24) 
• Table 3.112 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by Frequency for all study participants (h_ae_t003_dr_24) 


 
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• Table 3.121 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by System Organ Class and Age Group at Entry for subjects who 
remained on treatment after 05July2011 (h_ae_t001_dr_24_age) 
• Table 3.122 Summary of Drug Related Treatment Emergent Grade 2-4 Adverse 
Events by System Organ Class and Age Group at Entry for all study participants 
(h_ae_t001_dr_24_age) 
• Table 3.131 Summary of Treatment Emergent Grade 3/4 Adverse Events by 
Frequency for subjects who remained on treatment after 05July2011 
(h_ae_t001_34) 
• Table 3.132 Summary of Treatment Emergent  Grade 3/4 Adverse Events by 
Frequency for all study participants (h_ae_t001_34) 
• Table 3.141 Summary of Treatment Emergent Serious Adverse Events by System 
Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_ser)  
• Table 3.142 Summary of Treatment Emergent Serious Adverse Events by System 
Organ Class for all study participants (h_ae_t001_ser) 
• Table 3.151 Summary of Treatment Emergent Serious Adverse Events by System 
Organ Class and Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_ae_t001_ser_age) 
• Table 3.152 Summary of Treatment Emergent Serious Adverse Events by System 
Organ Class and Age Group at Entry for all study participants 
(h_ae_t001_ser_age) 
• Table 3.161 Summary of Drug Related Treatment Emergent Serious Adverse 
Events by System Organ Class for subjects who remained on treatment after 
05July2011 (h_ae_t001_dr_ser) 
• Table 3.162 Summary of Drug Related Treatment Emergent Serious Adverse 
Events by System Organ Class for all study participants (h_ae_t001_dr_ser) 
• Table 3.171 Summary of Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Chronic FPV for subjects who remained on 
treatment after 05July2011 (h_ae_t001_disc) 
• Table 3.172 Summary of Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Chronic FPV for all study participants 
(h_ae_t001_disc) 
• Table 3.181 Summary of Treatment Emergent Adverse Events Leading to 
Withdrawal from the Study for subjects who remained on treatment after 
05July2011 (h_ae_t001_wdw) 
• Table 3.182 Summary of Treatment Emergent Adverse Events Leading to 
Withdrawal from the Study for all study participants (h_ae_t001_wdw) 
• Table 3.191 Summary of All Episodes of Selected Drug Related Treatment 
Emergent AEs by Days to Onset, Duration, Status, Intensity and Action Taken for 
subjects who remained on treatment after 05July2011 (s_ae_t003) 


 
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• Table 3.192 Summary of All Episodes of Selected Drug Related Treatment 
Emergent AEs by Days to Onset, Duration, Status, Intensity and Action Taken for 
all study participants (s_ae_t003) 
• Table 3.201 Summary of Treatment Emergent Rash Adverse Events by System 
Organ Class for subjects who remained on treatment after 05July2011 
(t_ae_t002_rash) 
• Table 3.202 Summary of Treatment Emergent Rash Adverse Events by System 
Organ Class for all study participants (t_ae_t002_rash)  
• Table 3.211 Summary of Clinical Chemistry by Visit – Parameters of Special 
Interest by Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_lb_t001_chem_sp_age)  
• Table 3.212 Summary of Clinical Chemistry by Visit – Parameters of Special 
Interest by Age Group at Entry for all study participants 
(h_lb_t001_chem_sp_age) 
• Table 3.221 Summary of Clinical Chemistry by Visit – All Other Parameters for 
subjects who remained on treatment after 05July2011 (h_lb_t001_chem_oth) 
• Table 3.222 Summary of Clinical Chemistry by Visit – All Other Parameters for 
all study participants (h_lb_t001_chem_oth) 
• Table 3.231 Summary of Haematology by Visit for subjects who remained on 
treatment after 05July2011 (h_lb_t001_hem) 
• Table 3.232 Summary of Haematology by Visit for all study participants 
(h_lb_t001_hem) 
• Table 3.241 Summary of Clinical Chemistry Toxicities – Total for subjects who 
remained on treatment after 05July2011 (s_lb_t003_chem) 
• Table 3.242 Summary of Clinical Chemistry Toxicities – Total for all study 
participants (s_lb_t003_chem) 
• Table 3.251 Summary of Clinical Chemistry Toxicities – Parameters of Special 
Interest for subjects who remained on treatment after 05July2011 
(s_lb_t003_chem_sp) 
• Table 3.252 Summary of Clinical Chemistry Toxicities – Parameters of Special 
Interest for all study participants (s_lb_t003_chem_sp) 
• Table 3.261 Summary of Clinical Chemistry Toxicities – All Other Parameters for 
subjects who remained on treatment after 05July2011 (s_lb_t003_chem_othf) 
• Table 3.262 Summary of Clinical Chemistry Toxicities – All Other Parameters for 
all study participants (s_lb_t003_chem_othf) 
• Table 3.271 Summary of Haematology Toxicities for subjects who remained on 
treatment after 05July2011 (s_lb_t003_hem) 
• Table 3.272 Summary of Haematology Toxicities for all study participants 
(s_lb_t003_hem) 


 
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• Table 3.281 Summary of Vital Signs Data by Visit for subjects who remained on 
treatment after 05July2011 (h_vs_t001) 
• Table 3.282 Summary of Vital Signs Data by Visit for all study participants 
(h_vs_t001) 
• Table 3.291 Summary of Abacavir Hypersensitivity Record for subjects who 
remained on treatment after 05July2011 (h_abc_t001) 
• Table 3.292 Summary of Abacavir Hypersensitivity Record for all study 
participants (h_abc_t001) 
• Table 3.301 Summary of Common (≥5% Frequency) Non Serious Treatment 
Emergent Adverse Events by Overall Frequency for subjects who continued 
treatment after 05July2011 (h_ae_fdaaa) 
• Table 3.302 Summary of Common (≥5% Frequency) Non Serious Treatment 
Emergent Adverse Events by Overall Frequency for all study participants 
(h_ae_fdaaa) 
• Table 3.310 Summary of COVID-19 Assessment for Subjects with COVID-19 
Adverse Events(PAN1) 
• Table 3.320 Summary of COVID-19 Symptoms for Subjects with COVID-19 
Adverse Events(PAN3)  
These adverse event incidence rates will be calculated using the total number of subjects 
in the Safety Population as the denominator. 
A summary of common (≥5%) non-serious adverse events will be provided for use in the 
FDAAA template. Serious adverse events will be excluded from the summary and the 
denominator will be the number of subjects reported at least one of the most common 
(≥5%) non-serious adverse events. 
The following safety figures will be included: 
• Figure displaying the time to onset, duration, severity and outcome of the first 
occurrence of the selected drug-related AEs of special interest (above) will be 
presented. 
• Individual patient profile plots of LFTs for Subjects who Experience a Grade 3 or 
4 LFT Toxicity 
• Individual patient profile plots of Neutrophils, Lymphocytes and White Blood 
Cells for Subjects who Experience a Grade 3 or 4 Neutrophil Toxicity 
The following listings will also be listed with the addition of an asterisk to indicate that 
the adverse event occurred after 05July2011: 
• Listing of Exposure Data 
• Listing of all adverse events  
• Listing of fatal adverse events  
• Listing of non-fatal serious adverse events  
• Listing of subject numbers for individual adverse events 


 
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• Listing of clinical chemistry data for subjects with laboratory abnormalities 
• Listing of haematology data for subjects with laboratory abnormalities 
• Listing of subjects who discontinued 
Listing of adverse events leading to permanent discontinuation of investigational 
product 
• Listing of adverse events leading to withdrawal from the study Listing of all 
adverse events for subjects who experienced any rash 
• Listing of Relationship of MedDRA Preferred Terms to Lower Level Terms and 
Adverse Event Investigator Text 
• Listing of Clinical Chemistry Data 
• Listing of Haematology Data 
• Listing of Laboratory Data from Local Labs 
• Listing of Vital Signs Data 
• Listing of Clinical Chemistry Laboratory Data for Subjects with Laboratory 
Abnormalities of Potential Clinical Concern(LB5) 
• Listing of Haematology Laboratory Data for Subjects with Laboratory 
Abnormalities of Potential Clinical Concern(LB5) 
• Listing of the relationship of adverse event system organ classes, preferred terms 
and verbatim text 
11.3. 
Deaths and Serious Adverse Events 
Deaths and serious adverse events will be reported as detailed in the Section 11.2. 
11.4. 
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events 
Adverse events leading to discontinuation of investigational product and/or withdrawal 
from the study will be reported as detailed in the section 11.2. 
Any subjects experiencing an Abacavir Hypersensitivity Reaction (ABC HSR) were 
required to complete the ABC HSR Record in the CRF. The number of subjects 
experiencing an ABC HSR will be summarized and all data will be listed. 
11.5. 
Clinical Laboratory Evaluations 
Laboratory data are given in standard units by the central laboratory (see protocol for a 
list), and only these values will be presented in summaries and listings. Non-numeric 
values that contain an embedded number (e.g. ‘>100’, ‘<1.9’) will be interpreted as 


 
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having a value equal to the numeric portion for data analysis plus/minus a meaningful 
quantity, but presented ‘as is’ in the listings. 
Individual haematology, clinical chemistry and lipid data are flagged as above (H) or 
below (L) the appropriate normal range of the central laboratory and with respect to 
toxicity grades according to the toxicity scales. Some flags may be calculated during the 
analysis using the ranges provided in the protocol. These flags and toxicity grades will be 
included in the listings of clinical chemistry and haematology data, which will be by 
treatment, investigator number, subject number and visit. 
All parameters e will be presented using summary statistics by visit. Separate summaries 
will be displayed for clinical chemistry parameters of special interest (ALT, AST, 
triglycerides, HDL, LDL, total cholesterol, lipase, hyperglycaemia and hypoglycaemia), 
clinical chemistry for all other parameters and haematology. Clinical chemistry data and 
haematology data will be listed. The summary of actual values for the clinical chemistry 
parameters of special interest will be presented by age group at entry. For the EoS report, 
summaries will distinguish between data that was reported after 05July2011 (Week 48 
data cut-off) through EoS versus results reported cumulatively throughout the study. 
Summaries of all treatment emergent clinical chemistry and hematology toxicities will be 
produced. A summary of clinical chemistry toxicities will also be produced separately for 
the parameters of special interest and all other parameters. A graded toxicity is 
considered treatment emergent if it develops or increases post baseline in intensity (and 
prior to last dose of investigational product). Listings of subjects reporting at least one 
Grade 3 or 4 laboratory abnormality of potential clinical concern will be presented. 
Individual patient profile plots for liver function tests (LFTs) will be produced for all 
subjects who experience a Grade 3 or 4 toxicity in at least of the LFTs during the study; 
LFTs are AST, ALT, Bilirubin and Alkaline Phosphatase. Individual patient profile plots 
for neutrophils, lymphocytes and white blood cells will be produced for all subjects who 
experience a Grade 3 or 4 neutrophil toxicity. 
Data from local laboratories will be listed separately from the central laboratory data and 
will not be included in the summaries unless there is significant missing data in which 
case local and central laboratory data may be combined. 
11.6. 
Other Safety Measures 
Summary statistics of actual values in blood pressure, heart rate, height, and weight and 
head circumference during the study will be presented by visit and the data listed.  
12. 
CLINICAL PHARMACOLOGY DATA ANALYSES 
The EoS report will not contain a formal pharmacokinetic analysis. Generation of 
summary statistics and listings for the remaining pharmacokinetic samples will be the 
responsibility of stats and programming (SMP) 


 
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12.1. 
Bioanalysis 
Drug analysis was the responsibility of the Department of Worldwide Bioanalysis, Drug 
Metabolism and Pharmacokinetics. Plasma PK samples were analysed for APV, FPV, 
and RTV concentrations using a validated analytical method.  
12.2. 
Pharmacokinetic Analyses 
The previous Week 48 PK analysis of the plasma APV and RTV concentration-time data 
using non-compartmental methods was conducted by the GSK Department of CPMS 
using Winnonlin™ Version 4.1 or higher (Pharsight Corporation, Mountain View, CA, 
USA) for the Week 48 CSR.  Actual plasma PK sample collection times were  used in the 
PK analysis.   
For the APV20002 study, primary analysis of PK data from subjects was completed at 
week 48 and 05July2011 was the cut off point for data used in the original report. A small 
number of additional PK samples (<10% of the total PK data) was collected and 
approved after the 05July2011 cut-off date up to a timepoint of September 26, 2011.   
Since 2012, weight based dosing has been implemented for FPV OS based on the Week 
48 PK analysis in countries where this FPV OS is marketed and no new safety concerns 
have arisen regarding the use of the dosage recommended in the 48 week CSR. Given 
that the FPV OS paediatric dosing regimen for this age and weight group has been 
available since 2012, it is unlikely that the reanalysis of all PK data to include this small 
number of additional PK samples would increase our understanding or change current 
FPV OS dosing recommendations. Therefore, two tables of descriptive statistics (see 
Section 16.1) summarizing the PK data will be produced for the additional PK samples 
collected between July 6 and Sept 26, 2011. The tables and listings will include the 
following:   
• 
10.1 , Summary of APV concentrations (mean and standard deviation, median and 
95% percentile)   
• 
10.2 , Summary of RTV concentrations (mean and standard deviation, median and 
95% percentile)   
• 
10.3 , Listing of Plasma APV Concentration Data (mg/mL) (by Subject and 
Visit)   
• 
10.4 , Listing of Plasma RTV Concentration Data (mg/mL) (by Subject and 
Visit)  
 
13. 
VIRAL GENOTYPING/PHENOTYPING 
Plasma samples for HIV viral resistance testing (PhenosenseGT, Monogram Biosciences 
Inc) were collected from all subjects at baseline (Day 1) for evaluation of baseline reverse 
transcriptase (RT) and protease (PR) mutations, and phenotypic resistance.   
A specific comprehensive definition for virologic failure was not included in the original 
APV20002 protocol. In subsequent protocol amendments, to be consistent with the then 
current standard practice, for the 24 Week analysis, virologic failure was defined as 


 
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failure to achieve a plasma HIV-RNA by Week 24 or confirmed HIV-RNA rebound to 
≥400 copies/mL after achieving a plasma HIV-RNA of  <400 copies/mL. The Week 48 
analysis included subjects defined as virological failures in the Week 24 interim analysis 
along with subjects who had a confirmed HIV-RNA rebound to ≥400 copies/mL after 
achieving a plasma HIV-RNA of <400 copies/mL between Week 24 and Week 48. If a 
subject had a single viral load rebound ≥400 copies/mL at Week 48 and it was their last 
available visit at the time of the 05July2011 data cut, virological failure could not be 
confirmed, and those subjects were not included in the Virological Failure Population for 
the 48 week analysis.   
For the EoS analysis, the same definition of virologic failure (confirmed HIV-RNA 
rebound to ≥400 copies/mL after achieving a plasma HIV-RNA of  <400 copies/mL) will 
be applied for subjects who continued in the study after Week 48. Given the limited 
sample material available for analysis any result obtained up to 12 weeks after the 
virologic failure analysis point will be used in the analysis (if there are 2 results within 
this time window, the closest to the initial virologic failure timepoint will be used).  
A summary of the number of subjects who have provided genotypic and phenotypic data 
from their HIV-1 isolates will be presented for both the Baseline Virology and 
Virological Failure Populations. However, any genotypic and phenotypic data obtained 
for subjects who are unconfirmed virologic failures will be included in the listings along 
with data from subjects who met confirmed virologic failure, but data from subjects who 
are unconfirmed virologic failures will not be further analyzed.  
Mutations included in the virology analyses are those in the RT and PRO regions of the 
HIV genome which are NRTI, NNRTI, or PI resistance-associated amino acid 
substitutions (see Section 8.4). 
Subjects with confirmed virological failure after Week 48 will be summarized separately 
from any summary of subjects who met the criteria for confirmed virologic failure by 
Week 48 in summary tables generated for the EoS analysis. To better describe the 
virologic failures that occurred after the Week 48 analysis  data cut-off (05July2011) 
compared to those that occurred by Week 48, the tables describing the two populations 
will include the following: 
• Table 11.01 A Summary of Subject Accountability by Age Group: Populations 
describing the total virology population, the baseline virology population, the total 
confirmed virologic failure population and the confirmed virologic failure 
population after Week 48 to EoS  
• Table 11.02 A Summary of Subject Accountability Genotypic Data Available –
baseline virology population summarizing the number of subjects with HIV RT 
and PRO mutation data at baseline, the number of subjects with baseline data; all 
subjects with virologic failure timepoint data, all subjects with matched baseline 
and virologic failure timepoint samples all subjects with virologic failure (after 
week 48 through EoS) data and subjects with virologic failure (after week 48 
through EoS) with matched baseline and failure timepoint data   
• Table 11.03 A Summary of Subject Accountability Genotypic Data Available –
Virological Failure Population summarizing the number of subjects with HIV RT 


 
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and protease (PR) mutation data  at virologic failure for the confirmed virologic 
failure population; including the total numbers of subjects with confirmed 
virologic failure, the number of these subjects with baseline data, all subjects with 
matched baseline and virologic failure timepoint data; those subjects with 
virologic failure (after week 48 through EoS) and those subjects with virologic 
failure (after week 48 through EoS) with matched baseline and failure timepoint 
sample data  
• Table 11.04 A Summary of Subject Accountability Phenotypic Data Available –
baseline virology population summarizing the number of subjects with phenotypic 
data (for each drug class NRTI, NNRTI and PI) at baseline, for all subjects with 
virologic failure data; all subjects with matched baseline and virologic failure 
timepoint data and those with data at both baseline and virologic failure (after 
week 48 through EoS) and those subjects with virologic failure (after week 48 
through EoS) with matched baseline and failure sample data  
• Table 11.05 Summary of Subject Accountability Phenotypic Data Available – 
Virological Failure Population summarizing the number of subjects with 
phenotypic drug resistance data for each drug class NRTI, NNRTI and PI for  the 
confirmed virologic failure population through and the confirmed virologic failure 
population after Week 48 to EoS. including the total numbers of subjects with 
confirmed virologic failure, the number of these subjects with baseline data, all 
subjects with matched baseline and virologic failure timepoint data; those subjects 
with virologic failure (after week 48 through EoS) and those subjects with 
virologic failure (after week 48 through EoS) with matched baseline and failure 
timepoint sample data 
• Table 11.11 Summary of End of Study Record - Virological Failure Population 
for two groups- the confirmed virologic failure population for all subjects with 
confirmed virologic failures  
• Table 11.12 Summary of End of Study Record - Virological Failure Population 
for the the confirmed virologic failure population after Week 48 to EoS 
• Table 11.21 Summary of Baseline Characteristics - Virological Failure Population 
for all subjects with confirmed virologic failure 
• Table 11.22 Summary of Baseline Characteristics - Virological Failure Population 
for the confirmed virologic failure population after Week 48 to EoS 
NRTI, NNRTI and PI resistance associated genotypic mutations in the HIV RT and PR 
regions will be summarized for both the Baseline Virology and Virological Failure 
populations by ART/PI status (ART naïve vs. ART experienced with ART experienced 
subjects further subdivided into PI naïve vs PI experienced. These summary tables will 
differentiate between confirmed virologic failures that occurred by Week 48 versus 
confirmed virologic failures which occurred after Week 48. Baseline is defined as the 
Day 1 result unless this is missing in which case the screening result will be used. These 
summary tables will include: 
• Table 11.31 Summary of PR and RT Genotypic Mutations at Failure Timepoint 
by ART/PI Status – Virological Failure Population for the confirmed virologic 
failure population after Week 48 to EoS 
• Table 11.32-Summary of PR and RT Genotypic Mutations at Failure Timepoint 
by ART/PI Status – Virological Failure Population for all Virologic Failure 


 
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• Table 11.41 Summary of Baseline RT and PR Mutations Associated with Each 
Drug Class at the virologic failure timepoint for confirmed virologic failures after 
Week 48 to EoS – Virological Failure Population 
• Table 11.42 Summary of Baseline RT and PR Mutations Associated with Each 
Drug Class at the virologic failure timepoint for all Virologic failures – 
Virological Failure Population 
• Table 11.50 Summary of RT and PR Mutations by Subject and Visit – Virological 
Failure Population.  Footnotes to be included * Indicates that the sample was used 
as part of a virological failure paired sample; # Indicates a treatment emergent 
mutation and ^^ after the Subject ID indicates the subject met confirmed virologic 
failure after Week 48 through EoS  
• Table 11.61 Summary of Treatment Emergent PRO and RT Genotypic Mutations 
by ART/PI Status – Virological Failure Population after Week 48 to EoS. 
Treatment emergent mutations are defined as mutations detected post baseline at 
the virologic failure timepoint that were not present in the baseline sample. 
• Table 11.62 Summary of Treatment Emergent PRO and RT Genotypic Mutations 
by ART/PI Status – Virological Failure Population (s_geno_te) 
• Table 11.71 Summary of Treatment Emergent RT and PR Mutations at Failure 
Timepoint Associated with Each Drug Class – Virological Failure Population 
after Week 48 through EOS 
• Table 11.72 Summary of Treatment Emergent RT and PR Mutations at Failure 
Timepoint Associated with Each Drug Class – Entire Virological Failure 
Population 
• Table 11.81 Summary of Genotypic Resistance defined by IAS-USA guidelines at 
Baseline and Failure Timepoint  by Treatment, ART/PI Status and Subject  – 
Virological Failure Population (s_geno_IAS pi_fail).  Note: ^^ after the Subject 
ID indicates the subject met confirmed virologic failure after Week 48 through 
EoS 
• Table 11.82 Summary of Genotypic Resistance defined by IAS-USA guidelines at 
Baseline and Failure Timepoint  by Treatment, Age Group at Entry Status and 
Subject  – Virological Failure Population (s_geno_IAS_age_fail) Note: ^^ after 
the Subject ID indicates the subject met confirmed virologic failure after Week 48 
through EoS 
For the Phenotypic resistance data, a table summarizing phenotypic Fold Resistance by 
Subject and Visit for the Virological Failure Population for each drug tested in the 
Monogram assay will be generated. One table will summarize fold resistance by subject 
and visit for those subjects who met virologic failure criteria after Week 48 through EoS, 
while the second table will summarize fold resistance by subject and visit from all 
subjects who met confirmed Virologic Failure criteria throughout the entire study. visit 
distinguish between subjects who became confirmed virologic failures by Week 48 vs 
those that occurred after Week 48.  
• Table 11.91 Summary of Fold Resistance by Subject and Visit - Virological 
Failure Population after Week 48 through EoS (s_fr_subj_fail) Footnote to be 
included * Indicates that the sample was used as part of a virological failure 
paired sample 


 
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• Table 11.92 Summary of Fold Resistance by Subject and Visit -  Entire 
Virological Failure Population (s_fr_subj_fail) Footnote to be included * 
Indicates that the sample was used as part of a virological failure paired sample 
Treatment Emergent reduced susceptibility (resistance) at the Failure Timepoint by 
ART/PI Status – Virological Failure Timepoint will be generated that distinguishes 
between confirmed virologic failures that occurred by Week 48 vs those that occurred 
after Week 48 
• Table 11.101 Summary of Treatment Emergent Susceptibility at Failure 
Timepoint by ART/PI Status – Virological Failure Timepoint Virologic Failure 
Population after Week 48 through EoS 
• Table 11.102 Summary of Treatment Emergent Susceptibility at Failure 
Timepoint by ART/PI Status – Virological Failure Timepoint -Entire Virologic 
Failure Population 
The total Virology Population will be listed. All genotypic data collected will be included 
in separate listings of RT and PR mutations. All phenotypic data will be listed. The 
phenotypic data will also be listed by the on-therapy background drugs. Clade assignment 
and replicative capacity data will also be listed. These listings will also include the 
Subject ID, sample date and actual relative time, as appropriate. All listings will be 
presented as bulleted below: 
• Listing of Subject Accountability: Populations  
• Listing of Reverse Transcriptase Mutations) 
• Listing of Protease Mutations  
• Listing of Phenotypic Data  
• Summary of Phenotypic Data for On-Therapy drugs by Subject  
• Listing of Clade assignment  
• Listing of Replicative Capacity Data  
14. 
COVID - 19 ANALYSIS 
This study was started in 2012 and is being continued during the outbreak of the ongoing 
COVID -19 pandemic. The information regarding the number of subjects affected by 
COVID-19 and its symptoms will be reported according to GSK core standards. Any 
visits impacted due to the pandemic outbreak will be reported. Protocol deviations or 
adverse events related to COVID-19 if any, will also be reported according to GSK core 
standards.  
 


 
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15. 
REFERENCES 
GlaxoSmithKline Document Number GD2001/00007/00 Study ID: APV20002. A 48 
Week Phase II,  Open-label, 2-cohort, Multicentre Study to Evaluate the 
Pharmacokinetics, Safety, Tolerability and Antiviral Activity of GW433908 and 
GW433908/RTV When Administered to HIV-1 Infected Protease Inhibitor (PI) Naïve 
and PI-Experienced Pediatric Subjects aged 6 weeks to <2 years. Effective date:20 Sept-
2002. 
GlaxoSmithKline Document Number GD2001/00007/12.  Protocol Amendment 12.  
APV20002: A 48 Week Phase II, Open-label, 2-cohort, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, Tolerability and Antiviral Activity of GW433908 and 
GW433908/RTV When Administered to HIV-1 Infected Protease Inhibitor (PI) Naïve 
and PI-Experienced Paediatric Subjects aged 4 weeks to <2 years. Effective date:30 Nov-
2019. 
GlaxoSmithKline Document Number RM2006/00360/00. A 48 Week Phase II, Open-
label, 2-cohort, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability 
and Antiviral Activity of GW433908 and GW433908/RTV When Administered to HIV-1 
Infected Protease Inhibitor (PI) Naïve and PI-Experienced Paediatric Subjects aged 4 
weeks to <2 years. Effective date:20-SEP-2006. 
GlaxoSmithKline Document Number 2010N107734_00. A 48 Week Phase II, Open-
label, 2-cohort, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability 
and Antiviral Activity of GW433908 and GW433908/RTV When Administered to HIV-1 
Infected Protease Inhibitor (PI) Naïve and PI-Experienced Paediatric Subjects aged 4 
weeks to <2 years. Effective date:08-JUN-2011. 
GlaxoSmithKline Document Number 2010N107734_01. A 48 Week Phase II, Open-
label, 2-cohort, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability 
and Antiviral Activity of GW433908 and GW433908/RTV When Administered to HIV-1 
Infected Protease Inhibitor (PI) Naïve and PI-Experienced Paediatric Subjects aged 4 
weeks to <2 years. Effective date: 30-JUN-2011. 
GlaxoSmithKline Document Number 2011N127273_00_01. A 48 Week Phase II, Open-
label, 2-cohort, Multicenter Study to Evaluate the Pharmacokinetics, Safety, Tolerability 
and Antiviral Activity of GW433908 and GW433908/RTV When Administered to HIV-1 
Infected Protease Inhibitor (PI) Naïve and PI-Experienced Paediatric Subjects aged 4 
weeks to <2 years. Effective date:24-APR-2012. 


 
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16. 
ATTACHMENTS 
16.1. 
Table of Contents for Data Display Specifications 
Study Population and Baseline Characteristic Tables 
Table  
Title 
1.01 
 
Summary of Investigational Product Status by Age Group at entry (h_sp_t001_age) for 
all subjects 
1.02 
 
Summary of Investigational Product Status by Age Group at entry (h_sp_t001_age) for 
subjects who continued after 05July2011 
1.03 
 
Summary of Investigational Product Status by Visit (h_sp_t002) with asterisk for any 
subject after 05July2011 
1.04 
 
Summary of End of Study Record (h_ds_t001) for all subjects 
1.05 
 
Summary of End of Study Record (h_ds_t001) for subjects included after 05jul2011  
1.06 
 
Summary of End of Study Record by Visit (s_ds_t001) with asterisk for values obtained 
after 05July2011 
1.07 
 
Distribution of Quantitative Plasma HIV-1 RNA Results at Screening and Baseline by 
Age Group at entry for subjects who continued after 05July2011(s_vl_t001_age) 
1.08 
 
Distribution of CD4+ Cell Count (cells/cu mm) Results at Screening and Baseline by 
Age Group at entry for subjects who continued after 05July2011(s_cd_t001_ct_age) 
1.09 
 
Summary of Concomitant Medication Ingredient Combinations for subjects who 
continued after 05july2011 (h_cm_t003)  
1.11 
Summary of Concomitant Antiretroviral Therapy by PI Status for subjects who 
continued after 05july2011 (h_cm_t007)  
1.12 
Summary of Number of Subjects Changing NRTIs During the Study by PI Status for 
subjects who continued after 05July2011 (s_cm_t004)  
 


 
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Study Population and Baseline Characteristics ICH Listings (Note: subjects 
who continued after 05July2011 will be denoted with an asterisk) 
Listing  Title 
1.  Listing of Investigational Product Discontinuation (h_sp_l001)  
2.  Listing of End of Study Record (h_ds_l002) 
3.  Listing of Demographic Characteristics (h_dm_l001)  
4.  Listing of Race (h_dm_l002)  
5.  Listing of Concomitant Medications (h_cm_l001) 
6.  Listing of Concomitant Antiretroviral Therapy (h_cm_l004) 
 
Study Population and Baseline Characteristic Other Listings (Note: subjects 
who continued after 05July2011 will be denoted with an asterisk) 
Listing  Title 
1 
Listing of Study Populations (h_pn_l001) 
2 
Listing of Concomitant Medication Relationship between ATC Level 1, Ingredient and 
Verbatim Text (h_cm_l002) 
3 
Listing of Prior Antiretroviral Therapy (h_cm_l003) 
4 
Listing of Important Protocol Deviations 
 
 
 


 
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Antiviral Response Tables 
Table 
Title 
2.01 
Proportion of Subjects with Quantitative Plasma HIV-1 RNA <400 copies/ml by 
Visit – Observed (h_prp_t001_400_obs) 
2.02 
Proportion of Subjects with Quantitative Plasma HIV-1 RNA <50 copies/ml by 
Visit – Observed (h_prp_t001_50_obs) 
2.03 
Proportion of Subjects with Quantitative Plasma HIV-1 RNA at Least 1.0log10 
copies/ml below Baseline by Visit – Observed (h_prp_t001_1log_obs) 
2.04 
Summary of Quantitative Plasma HIV-1 RNA Results by Visit (log10 copies/ml) – 
Observed (h_vl_t002) 
2.05 
Summary of Quantitative Plasma HIV-1 RNA Results by Visit and Age Group 
(log10 copies/ml) – Observed (h_vl_t002_age) 
2.06 
Summary of Quantitative Plasma HIV-1 RNA Results by Visit and Gender (log10 
copies/ml) – Observed (h_vl_t002_sex) 
2.07 
Summary of Quantitative Plasma HIV-1 RNA Results by Visit and Race (log10 
copies/ml) – Observed (h_vl_t002_race) 
2.08 
Summary of Quantitative Plasma HIV-1 RNA Changes from Baseline by Visit 
(log10 copies/ml) – Observed (h_vl_t002_chg) 
2.09 
Summary of CD4+ Cell Count (cells/cu mm) – Results by Visit and Age Group 
Observed (h_cd_t002_4_ct_age) 
2.10 
Summary of HIV Associated Conditions Including Recurrences for Children 
(h_cdc_t001_inc_child) 
       2.11 
Summary of HIV Associated Conditions Excluding Recurrences for Children 
(h_cdc_t001_ex_child) 
       2.12 
Summary of HIV Disease Progressions for Children (t_cdc_t002_child) 
       2.13 
Summary of Last On-treatment CD4+ Cell Count Values (cell/cu mm & %) for 
Subjects who Prematurely Discontinue (h_cd4_disc) 
 
Antiviral Response ICH Listings (Note: subjects who continued after 05July2011 will 
be denoted with an asterisk)  
Listing Title 
7 
Listing of Quantitative Plasma HIV-1 RNA Data (h_vl_l001)  
Antiviral Response Other Listings (Note: subjects who continued after 05July2011 
will be denoted with an asterisk) 
Listing Title 
5 
Listing of CD4+ Cell Count Data (s_cd_l001)  
6 
Listing of HIV Associated Conditions for Children Age <13 Years (h_cdc_l002_child)  
 
 
 


 
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Safety Tables 
Table 
Title 
3.01 
Summary of All Treatment Emergent Adverse Events by System Organ Class for 
subjects who remained on treatment after 05July2011 (h_ae_t001_all) 
3.02 
Summary of All Treatment Emergent Adverse Events by System Organ Class for 
all study participants (h_ae_t001_all) 
3.11 
Summary of All Treatment Emergent Adverse Events by System Organ Class and 
Maximum Toxicity/Intensity for subjects who remained on treatment after 
05July2011 (h_ae_t004_all) 
3.12 
Summary of All Treatment Emergent Adverse Events by System Organ Class and 
Maximum Toxicity/Intensity for all study participants (h_ae_t004_all) 
3.21 
Summary of All Treatment Emergent Adverse Events by System Organ Class by 
Age Group at Entry for subjects who remained on treatment after 05July2011 
(h_ae_t002_age) 
3.22 
Summary of All Treatment Emergent Adverse Events by System Organ Class by 
Age Group at Entry for all study participants (h_ae_t002_age) 
3.31 
Summary of All Treatment Emergent Adverse Events by Frequency for subjects 
who remained on treatment after 05July2011 (h_ae_t003) 
3.32 
Summary of All Treatment Emergent Adverse Events by Frequency for all study 
participants (h_ae_t003) 
3.41 
Summary of Treatment Emergent Grade 2-4 Adverse Events by System Organ 
Class for subjects who remained on treatment after 05July2011 (h_ae_t001_24) 
3.42 
Summary of Treatment Emergent Grade 2-4 Adverse Events by System Organ 
Class for all study participants (h_ae_t001_24) 
3.51 
Summary of Treatment Emergent Grade 2-4 Adverse Events by Frequency for 
subjects who remained on treatment after 05July2011 (h_ae_t003_24) 
3.52 
Summary of Treatment Emergent Grade 2-4 Adverse Events by Frequency for all 
study participants (h_ae_t003_24) 
3.61 
Summary of Treatment Emergent Grade 2-4 Adverse Events by System Organ 
Class and Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_ae_t001_24_age) 
3.62 
Summary of Treatment Emergent Grade 2-4 Adverse Events by System Organ 
Class and Age Group at Entry for all study participants (h_ae_t001_24_age) 


 
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3.71 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class for subjects who remained on treatment after 05July2011 (h_ae_t001_dr) 
3.72 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class for all study participants (h_ae_t001_dr) 
3.81 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class and Maximum Toxicity for subjects who remained on treatment after 
05July2011 (h_ae_t004_dr) 
3.82 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class and Maximum Toxicity for all study participants (h_ae_t004_dr) 
3.91 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class and Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_ae_t004_dr_age) 
3.92 
Summary of Drug Related Treatment Emergent Adverse Events by System Organ 
Class and Age Group at Entry for all study participants (h_ae_t004_dr_age) 
3.101 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_dr_24) 
3.102 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class for all study participants (h_ae_t001_dr_24) 
3.111 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
Frequency for subjects who remained on treatment after 05July2011 
(h_ae_t003_dr_24) 
3.112 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
Frequency for all study participants (h_ae_t003_dr_24) 
3.121 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class and Age Group at Entry for subjects who remained on 
treatment after 05July2011 (h_ae_t001_dr_24_age) 
3.122 
Summary of Drug Related Treatment Emergent Grade 2-4 Adverse Events by 
System Organ Class and Age Group at Entry for all study participants 
(h_ae_t001_dr_24_age) 
3.131 
Summary of Treatment Emergent Grade 3/4 Adverse Events by Frequency for 
subjects who remained on treatment after 05July2011 (h_ae_t001_34) 
3.132 
Summary of Treatment Emergent Grade 3/4 Adverse Events by Frequency for all 
study participants (h_ae_t001_34) 


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3.141 
Summary of Treatment Emergent Serious Adverse Events by System Organ 
Class for subjects who remained on treatment after 05July2011 (h_ae_t001_ser) 
3.142 
Summary of Treatment Emergent Serious Adverse Events by System Organ 
Class for all study participants (h_ae_t001_ser) 
3.151 
Summary of Treatment Emergent Serious Adverse Events by System Organ 
Class and Age Group at Entry for subjects who remained on treatment after 
05July2011 (h_ae_t001_ser_age) 
3.152 
Summary of Treatment Emergent Serious Adverse Events by System Organ 
Class and Age Group at Entry for all study participants (h_ae_t001_ser_age) 
3.161 
Summary of Drug Related Treatment Emergent Serious Adverse Events by 
System Organ Class for subjects who remained on treatment after 05July2011 
(h_ae_t001_dr_ser) 
3.162 
Summary of Drug Related Treatment Emergent Serious Adverse Events by 
System Organ Class for all study participants (h_ae_t001_dr_ser) 
3.171 
Summary of Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Chronic FPV for subjects who remained on treatment after 
05July2011 (h_ae_t001_disc) 
3.172 
Summary of Treatment Emergent Adverse Events Leading to Permanent 
Discontinuation of Chronic FPV for all study participants (h_ae_t001_disc) 
3.181 
Summary of Treatment Emergent Adverse Events Leading to Withdrawal from the 
Study for subjects who remained on treatment after 05July2011 (h_ae_t001_wdw) 
3.182 
Summary of Treatment Emergent Adverse Events Leading to Withdrawal from the 
Study for all study participants (h_ae_t001_wdw) 
3.191 
Summary of All Episodes of Selected Drug Related Treatment Emergent AEs by 
Days to Onset, Duration, Status, Intensity and Action Taken for subjects who 
remained on treatment after 05July2011 (s_ae_t003) 
3.192 
Summary of All Episodes of Selected Drug Related Treatment Emergent AEs by 
Days to Onset, Duration, Status, Intensity and Action Taken for all study 
participants (s_ae_t003) 
3.201 
Summary of Treatment Emergent Rash Adverse Events by System Organ Class 
for subjects who remained on treatment after 05July2011 (t_ae_t002_rash) 
3.202 
Summary of Treatment Emergent Rash Adverse Events by System Organ Class 
for all study participants (t_ae_t002_rash) 


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3.211 
Summary of Clinical Chemistry by Visit – Parameters of Special Interest by Age 
Group at Entry for subjects who remained on treatment after 05July2011 
(h_lb_t001_chem_sp_age) 
3.212 
Summary of Clinical Chemistry by Visit – Parameters of Special Interest by Age 
Group at Entry for all study participants (h_lb_t001_chem_sp_age) 
3.221 
Summary of Clinical Chemistry by Visit – All Other Parameters for subjects who 
remained on treatment after 05July2011 (h_lb_t001_chem_oth) 
3.222 
Summary of Clinical Chemistry by Visit – All Other Parameters for all study 
participants (h_lb_t001_chem_oth) 
3.231 
Summary of Haematology by Visit for subjects who remained on treatment after 
05July2011 (h_lb_t001_hem) 
3.232 
Summary of Haematology by Visit for all study participants (h_lb_t001_hem) 
3.241 
Summary of Clinical Chemistry Toxicities – Total for subjects who remained on 
treatment after 05July2011 (s_lb_t003_chem) 
3.242 
Summary of Clinical Chemistry Toxicities – Total for all study participants 
(s_lb_t003_chem) 
3.251 
Summary of Clinical Chemistry Toxicities – Parameters of Special Interest for 
subjects who remained on treatment after 05July2011 (s_lb_t003_chem_sp) 
3.252 
Summary of Clinical Chemistry Toxicities – Parameters of Special Interest for all 
study participants (s_lb_t003_chem_sp) 
3.261 
Summary of Clinical Chemistry Toxicities – All Other Parameters for subjects who 
remained on treatment after 05July2011 (s_lb_t003_chem_othf) 
3.262 
Summary of Clinical Chemistry Toxicities – All Other Parameters for all study 
participants (s_lb_t003_chem_othf) 
3.271 
Summary of Haematology Toxicities for subjects who remained on treatment after 
05July2011 (s_lb_t003_hem) 
3.272 
Summary of Haematology Toxicities for all study participants (s_lb_t003_hem) 
3.281 
Summary of Vital Signs Data by Visit for subjects who remained on treatment after 
05July2011 (h_vs_t001) 
3.282 
Summary of Vital Signs Data by Visit for all study participants (h_vs_t001) 
3.291 
Summary of Abacavir Hypersensitivity Record for subjects who remained on 
treatment after 05July2011 (h_abc_t001) 


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3.292 
Summary of Abacavir Hypersensitivity Record for all study participants 
(h_abc_t001) 
3.301 
Summary of Common (≥5% Frequency) Non-Serious Treatment Emergent 
Adverse Events by Overall Frequency for subjects who continued treatment after 
05July2011 (h_ae_fdaaa) 
3.302 
Summary of Common (≥5% Frequency) Non-Serious Treatment Emergent 
Adverse Events by Overall Frequency for all study participants (h_ae_fdaaa) 
3.310 
Summary of COVID-19 Assessment for Subjects with COVID-19 Adverse Events 
(PAN1) 
3.320 
Summary of COVID-19 Symptoms for Subjects with COVID-19 Adverse Events 
(PAN3) 
Safety ICH Listings (Note: subjects who continued after 05July2011 will be denoted 
with an asterisk) 
Listing Title 
8 
Listing of Exposure Data (h_ex_l001) 
9 
Listing of All Adverse Events (h_ae_l001_all) 
10 
Listing of Fatal Adverse Events (h_ae_l001_ft) 
11 
Listing of Non-Fatal Serious Adverse Events (h_ae_l001_ser) 
12 
Listing of Subject Numbers for Individual Adverse Events (h_ae_l003) 
13 
Listing of Clinical Chemistry Data for Subjects with Laboratory Abnormalities 
(h_lb_l001_chem_abn) 
14 
Listing of Haematology Data for Subjects with Laboratory Abnormalities 
(h_lb_l001_hem_abn)  


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Safety Other Listings (Note: subjects who continued after 05July2011 will be denoted 
with an asterisk) 
Listing Title 
7 
Listing of Adverse events Leading to Permanent Discontinuation of Investigational 
Product (h_ae_l001_disc) 
8 
Listing of Adverse Events Leading to Withdrawal from the Study (h_ae_l001_wdw) 
9 
Listing of Adverse Events for Subjects who Experienced a Rash (h_ae_l001_rash) 
10 
Listing of Relationship of MedDRA Preferred Terms to Lower Level Terms and 
Adverse Event Investigator Text (h_ae_l002) 
11 
Listing of Clinical Chemistry Data (h_lb_l001_chem) 
12 
Listing of Haematology Data (h_lb_l001_hem) 
13 
Listing of Laboratory Data from Local Labs (h_lb_l002) 
14 
Listing of Vital Signs Data (h_vs_l001) 
15 
Listing of Clinical Chemistry Laboratory Data for Subjects with Laboratory 
Abnormalities of Potential Clinical Concern(LB5) 
16 
Listing of Hematology Laboratory Data for Subjects with Laboratory Abnormalities of 
Potential Clinical Concern(LB5) 
Safety Figures 
Figure 
Title 
3.1 
Onset, Duration, Severity and Outcome of First Occurrence of AEs of Special Interest 
(s_ae_f001) 
3.2 
Individual patient profile plots of LFTs for Subjects who Experience a Grade 3 or 4 
LFT Toxicity (s_ae_f002) 
3.3 
Individual patient profile plots of Neutrophils, Lymphocytes and White Blood Cells for 
Subjects who Experience a Grade 3 or 4 Neutrophil Toxicity (s_ae_f003) 


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Clinical Pharmacology Tables 
Table 
Title 
Format /QC level 
10.01 
Summary of APV concentrations (mean and standard deviation, 
median and 95% percentile) 
Table 10.1 
10.02 
Summary of RTV concentrations (mean and standard deviation, 
median and 95% percentile) 
Table 10.2 
10.03 
Listing of Plasma APV Concentration Data (mg/mL) (by Subject 
and Visit) 
Table 10.3 
10.04 
Listing of Plasma RTV Concentration Data (mg/mL) (by Subject 
and Visit) 
Table 10.4 
Viral Genotyping/Phenotyping Tables 
Table 
Description 
Programming Note 
11.01 Summary of Subject Accountability by age group: Populations 
(s_vir_t001) 
11.02 Summary of Subject Accountability Genotypic Data Available 
– Baseline Virology Population (s_vir_t002_base)
11.03 Summary of Subject Accountability Genotypic Data Available 
– Virological Failure Population (s_vir_t002_fail)
11.04 Summary of Subject Accountability Phenotypic Data Available 
– Baseline Virology Population (s_vir_t003_base)
11.05 Summary of Subject Accountability Phenotypic Data Available 
– Virological Failure Population (s_vir_t003_fail)
      11.11 
Summary of End of Study Record - Virological Failure 
Population for two groups- the confirmed virologic failure 
population for all subjects with confirmed virologic failures 
(h_ds_t001_fail) 
11.12 Summary of End of Study Record - Virological Failure 
Population for the confirmed virologic failure population after 
Week 48 to EoS 
11.21 Summary of Baseline Characteristics - Virological Failure 
Population for all subjects with Confirmed Virologic Failure 
(h_dm_char_fail) 
11.22 Summary of Baseline Characteristics - Virological Failure 
Population for all subjects with Confirmed Virologic Failure 
after Week 48 to EoS  
11.31 
Summary of PR and RT Genotypic Mutations at Failure 
Timepoint by ART/PI Status – Virological Failure Population 
for the confirmed virologic failure population after Week 48 to 
EoS  
      11.32 
Summary of PR and RT Genotypic Mutations at Failure 
Timepoint by ART/PI Status – Virological Failure Population 
for all Virologic Failure(s_geno_ft_fail) 


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11.41 Summary of Baseline RT and PR Mutations Associated with 
Each Drug Class at the virologic failure timepoint for confirmed 
virologic failures after Week 48 to EoS – Virological Failure 
Population  
11.42 Summary of Baseline RT and PR Mutations Associated with 
Each Drug Class at the virologic failure timepoint for all 
Virologic failures – Virological Failure Population 
(s_geno_drg_bl_fail) 
11.50 Summary of RT and PR Mutations by Subject and Visit – 
Virological Failure Population (s_geno_subj_fail)   
Note: Footnotes to be 
included * Indicates 
that the sample was 
used as part of a 
virological failure 
paired sample; # 
Indicates a treatment 
emergent mutation 
and ^^ after the 
Subject ID indicates 
the subject met 
confirmed virologic 
failure after Week 48 
through EoS 
11.61 Summary of Treatment Emergent PR and RT Genotypic 
Mutations by ART/PI Status – Virological Failure Population 
after Week 48 to EoS 
11.62 Summary of Treatment Emergent PR and RT Genotypic 
Mutations by ART/PI Status – Virological Failure Population 
(s_geno_te) 
11.71 Summary of Treatment Emergent RT and PR Mutations at 
Failure Timepoint Associated with Each Drug Class – 
Virological Failure Population after Week 48 through EOS 
11.72 Summary of Treatment Emergent RT and PR Mutations at 
Failure Timepoint Associated with Each Drug Class – Entire 
Virological Failure Population (s_geno_drg_ft) 
11.81 Summary of Genotypic Resistance defined by IAS-USA 
guidelines at Baseline and Failure Timepoint  by Treatment, 
ART/PI Status and Subject  – Virological Failure Population 
(s_geno_IAS pi_fail)  
Note: ^^ after the 
Subject ID indicates 
the subject met 
confirmed virologic 
failure after Week 48 
through EoS 
11.82 Summary of Genotypic Resistance defined by IAS-USA 
guidelines at Baseline and Failure Timepoint  by Treatment, 
Age Group at Entry Status and Subject  – Virological Failure 
Population (s_geno_IAS_age_fail)  
Note: ^^ after the 
Subject ID indicates 
the subject met 
confirmed virologic 
failure after Week 48 
through EoS 


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11.91 Summary of Fold Resistance by Subject and Visit - Virological 
Failure Population after Week 48 through EoS (s_fr_subj_fail)  
Note: * indicates the 
sample was used as 
a virological failure 
paired sample 
11.92 Summary of Fold Resistance by Subject and Visit -  Entire 
Virological Failure Population (s_fr_subj_fail)  
Note: * indicates the 
sample was used as 
a virological failure 
paired sample 
11.101 Summary of Treatment Emergent Susceptibility at Failure 
Timepoint by ART/PI Status – Virological Failure Timepoint 
Virologic Failure Population after Week 48 through EoS 
    11.102 
Summary of Treatment Emergent Reduced Susceptibility at 
Failure Timepoint by ART/PI Status – Virological Failure 
Timepoint -Entire Virologic Failure Population 
Viral Genotyping/Phenotyping Listings 
Listing 
Title 
17 
Listing of Subject Accountability: Populations (h_pn_t001_vir) 
18 
Listing of Reverse Transcriptase Mutations (h_vir_l001) 
19 
Listing of Protease Mutations (h_vir_l002) 
20 
Listing of Phenotypic Data (h_vir_l003) 
21 
Summary of Phenotypic Data for On-Therapy drugs by Subject (s_phen_drug_l001) 
22 
Listing of Clade assignment (s_clade_l001) 
23 
Listing of Replicative Capacity Data  (s_rc_l001) 
16.2. 
Data Display Specifications 
Available upon request.