An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients With Advanced HIV Disease
Phase: PHASE3
Conditions: HIV/AIDS
Sponsor: NEAT ID Foundation

 
1 
 
Appendix 
Study Protocol and SAP for: Georg M.N. Behrens, Lambert Assoumou, Geoffrey Liegeon, 
Andrea Antinori, Rafael Micán et al. Integrase versus protease inhibitor therapy in advanced 
HIV disease: The Late Presenter Treatment Optimization (LAPTOP) Randomized Trial 
 
All documents are for the LAPTOP Study 
 
1. Study Protocol v1.5 (08 Jan 2019) 
2. Study Protocol v5.0 (11 March 2024) 
3. Statistical Analysis Plan (SAP) v0.3 (22.11.2023) 
 
Changes in the protocol, which was initially approved by the ethics committee (UK), are 
summarized on page 2-13 
 
 
 

 
2 
 
Protocol v1.4 to v1.5 (UK only)  
This amendment was only in the UK. EU territories initiated on Protocol v1.5 or later. 
1. A change of vendor from Covance to ACM Global for the shipment and storage of 
resistance samples for deep sequencing. This change has also been incorporated into 
the patient information sheet and informed consent form. Updates to other addresses 
have also been incorporated. 
2. Addition of a weight assessment at week 24 and 48 in the schedule of assessment table. 
This addition has been included due to scientific evidence that the IMPs used for the 
study may have a minor effect on patient's weight. 
3. Section 6.1.3 required clarification regarding treatment switching 
4. Update to one of the secondary outcomes which required additional wording regarding 
resistance mutations at baseline as patients may switch treatment due to resistance 
testing results or discontinue medication completely. Although this is not new, it should 
have been incorporated into the outcome in the previous versions of the protocol. 
Protocol v1.5 to v2.0 
Comparative table with description of change and rationale for change to the protocol from 
version 1.5 to version 2.0 (Substantial Amendment 2) 
Change 
No. 
Description of Change 
Rationale for Change 
1.  
Study Synopsis- Treatment Arm 2 is 
referred to as the “comparator arm” 
to Treatment Arm 1. 
This wording was added to ensure that the 
naming of treatment arm 2 is consistent with 
how it is described in the Development Safety 
Update Report. 
2.  
Section 1.2.1- “Urticaria” has been 
added as a new uncommon side 
effect of Biktarvy® and “Changes in 
Serum Creatinine” and “Changes in 
Billirubin” contains stability data of 
up to week 96 (previous data went 
up to week 48). 
These changes reflect the updates contained 
in the latest version of the Reference Safety 
Information for Biktarvy® (02 April 2020) 
3. 
Section 5.1. Inclusion criteria 4b- 
Window for severe bacterial 
infection and CD4 cell count 
changed from “30 days” to “28 days” 
This was changed to be consistent with the 
time window allowed for the use of historic 
test results (28 days) as screening results  
4. 
Section 5.1. Inclusion criteria 4c- 
Sentence changed from “Are 
asymptomatic with a CD4 cell count 
< 100/µL within 30 days” to “Any 
symptoms or no symptoms and 
must have a CD4 cell count < 100/µL 
within 28 days’’ 
This sentence was modified because of 
feedback from several sites who commented 
that the wording in protocol version 1.5 was 
not clear. Time window changed from 30 days 
to 28 days for consistency 

 
3 
 
Change 
No. 
Description of Change 
Rationale for Change 
5. 
Section 5.1. Footnote added to the 
following: 
Inclusion criteria 2: “Male and 
female sex are defined as sex at 
birth. For transgender participants 
≥13 years of age who have been on 
hormone therapy for more than 6 
consecutive months, grade 
haemoglobin based on the gender 
with which they identify (i.e. a 
transgender female should be 
graded using the female sex at birth 
hemoglobin laboratory values)” 
This sentence was added to clarify the gender 
being collected for transgender participants. 
6. 
Section 5.1. Additional wording was 
added to the following footnote for: 
Inclusion criteria 3: “(severe or 
medically significant but not 
immediately life-threatening, see 
Appendix 2)”  
The sentence in brackets was added to 
provide a definition for “grade 3 severity”. 
7. 
Section 5.1. Footnote added to the 
following: 
Inclusion criteria 4b: “Study entry is 
defined as the start of the screening 
process” 
This sentence was added to clarify what is 
meant by “study entry”. 
8.  
Section 5.1. Inclusion criteria 4d) ii: 
The sentence has been modified to 
the following “Current OI treatment 
can have been discontinued prior to 
start of ART” 
The modification was made to remove the 
following sentence” Current OI treatment 
must have been started ≤ 14 days prior to 
study entry”; this was reviewed and 
considered none- mandatory for a patient to 
be eligible for the study. 
9.  
Section 5.1. Inclusion criteria 5 
added: 
“Have an entry HIV viral load > 1000 
copies/mL” 
This sentence was added to clarify that 
participants must have an entry HIV viral load 
> 1000 copies/mL to be eligible for the study 
 
10.  
Section 5.2 Exclusion criteria 1: 
Sentence modified to read the 
following “Any therapeutic ARV 
which commenced less than 2 
weeks prior to screening and which 
This sentence was modified to allow patients, 
who have been treated with ARV for other 
indications (such as patients infected with 
COVID-19) to still be eligible to enter the 
study, provided that their ARV commenced 

 
4 
 
Change 
No. 
Description of Change 
Rationale for Change 
study entry was taken for more than 
48 hours” 
less than 2 weeks prior to screening and was 
not taken for more than 48 hours 
11.  
The following changes have been 
made to Section 8- 
Pharmacovigilance: 
 
Section 8.1 Definitions table: 
The following has been removed 
from the definition of a SUSAR “in 
question set out: -in the case of a 
product with a marketing 
authorisation, in the SmPC for that 
product -in the case of any other 
investigational medicinal product, in 
the IB relating to the trial in 
questions” 
Section 8.2: 
Removal of the following paragraph 
“An AE is any untoward medical 
occurrence in a subject 
administered a pharmaceutical 
product and which does not 
necessarily have a causal 
relationship with the study 
treatments. An AE can therefore be 
any unfavorable and/or unintended 
sign (including an abnormal 
laboratory finding), symptom, or 
disease temporally associated with 
the use of an IMP, whether or not 
considered related to the IMP.” 
8.2.3 Collection and Follow up of 
Adverse Events 
Removal of the sentence “AEs not 
already reported in the RSI for the 
study drugs will be considered 
unexpected.” 
8.2.4 Recording and Reporting of 
SAEs and SUSARs 
These changes have been made to ensure 
that the protocol is in line with the 
pharmacovigilance processes and 
procedures of the Sponsor. 

 
5 
 
Change 
No. 
Description of Change 
Rationale for Change 
Removal of “8.3 Serious Adverse 
Events (SAEs)” heading and addition 
of new subheading “8.2.4 Recording 
and Reporting of SAEs and SUSARs” 
Paragraph one modified to read the 
following “The SAE should be 
reported to the sponsor using the 
study Safety Event Reporting Form 
(SERF), within 24 hours of a member 
of the study team becoming aware 
of the event via e-mail to 
Safety@rokcservices.com or via the 
fax number provided on the SERF.” 
Removal of subheading section 
“8.3.1 Recording and Reporting of 
SAEs and SUSARs” 
8.8.3 Responsibilities 
Re-numbering of subheadings in this 
section and insertion of 
safety@rokcservices.com email 
address for safety reporting. 
12 
Appendix 1- Study Flowchart. The 
following changes have been made 
to the schedule of assessments and 
assessment sub-notes: 
Physical examination (height and 
weight) to be carried out from 
screening through to week 48 visit. 
Previous schedule only required this 
at baseline, week 24 and week 48 
visit. 
Urinalysis no longer required at 
baseline, week 4 and week 8 visits. 
Assessment sub note 1- The 
following text has been added: 
“The maximum time between 
screening visit and baseline visit is 
28 days; however, participants 
should be invited for their baseline 
These changes have been made to: 
a) Reflect any updates made to the Inclusion 
and Exclusion criteria of the protocol 
b) To define which historic test results can be 
used for screening 
c) To allow for the use of certain screening 
test results to be used as baseline results and 
to clarify which ones these are 
d) To address common questions which have 
been asked since the study commenced and 
to provide clarity on certain assessment 
criteria 
  

 
6 
 
Change 
No. 
Description of Change 
Rationale for Change 
visit as soon as reasonably possible 
in order to start their treatment. 
Only the following laboratory 
assessments are required for 
screening and historic (up to 28 days 
old) tests results may be used for 
screening: 
• HBV and HCV testing 
• TB test 
• CD4 & CD8 testing 
• Platelet count testing 
• Clinical chemistry (only 
creatinine, creatinine clearance, 
eGFR, potassium, sodium, ALT, AST 
is required) 
• Viral load testing 
• Resistance testing (the last 
resistance test carried out can be 
used)” 
 
“A serum pregnancy test is 
mandatory at the screening visit for 
women of childbearing potential” 
Urinary proteins has been removed 
from the above list. 
Assessment sub note 2 
The following baseline visit sub note 
has been added “For baseline 
results, all screening tests carried 
out within 10 days before baseline 
can be used. This includes historic 
screening results, as long as they fall 
within the 10 day window before 
baseline. Screening data obtained 
more than 10 days from baseline, 
must be repeated at baseline” 
Assessment sub note 5 
The following text has been added “If 
an ECG is not performed at 
screening, it must be performed by 
the time of the baseline visit.” 

 
7 
 
Change 
No. 
Description of Change 
Rationale for Change 
Assessment sub note 6 
The following text has been added 
“For screening, test results 28 days 
prior to the screening visit can be 
used.” 
Assessment sub note 7 
The following text has been added 
“For screening, test results 28 days 
prior to the screening visit can be 
used.  
Patients can be randomised into the 
study without having the latent TB 
screening results available at 
randomisation” 
Assessment sub note 8 
The following text has been added “If 
a HIV resistance test was done 
previously and results are available, 
the last resistance test carried out 
shall be considered.” 
Assessment sub note 10 
The following text in bold has been 
added: 
“Including: 
• Urinary creatinine* 
• Urinary glucose (dipstick test 
sufficient) * 
• Urinary proteins* 
• Albumin (can be obtained from 
‘spot’ urine test) * 
• Nitrites (dipstick test sufficient) * 
• Albumin: Creatinine Ratio (ACR) 
and Protein: Creatinine Ratio 
(PCR) 
• Urinary phosphate 
• Beta-2 microglobulin 
• Leukocytes (dipstick test 
sufficient) 
Assessments should be performed 
as per local site procedure; however, 

 
8 
 
Change 
No. 
Description of Change 
Rationale for Change 
assessments marked with an 
asterisk are mandatory for the study 
at and after baseline. 
Assessment sub note 11 
In addition to some of the tests 
already marked with an asterix, the 
following assessments also now 
have asterixis: 
• RBC Count (indices MCV & 
MCH)* 
• WBC count (absolute)* 
• MCV* 
• MCH* 
• Monocytes* 
• Eosinophils* 
• Basophils* 
The following text has been added 
“Assessments that have been 
underlined are required at screening 
(results up to 28 days old can be 
used).” 
Assessment sub note 12 
The following text in bold has been 
added “Assessments should be 
performed as per local site 
procedure; however, assessments 
marked with an asterisk are 
mandatory for the study at and after 
baseline. 
Assessments that have been 
underlined are required at screening 
(results up to 28 days old can be 
used.” 
Assessment sub note 13 
The following text in bold has been 
added “HIV RNA viral load-results 
obtained 28 days prior to screening 
can be used” 
Assessment sub note 18 

 
9 
 
Change 
No. 
Description of Change 
Rationale for Change 
The following text has been added “If 
a urine pregnancy test is not 
possible, a serum pregnancy test 
can replace this.” 
Assessment sub note 19 
The description here has been 
modified to read “Weight is required 
at all visits, as detailed in the 
appendix 1, however height is only 
required at baseline.” 
13. 
Removal of subheading 13.7 from 
Protocol Version 1.5 which read: 
“2.1 Financial and other competing 
interests for the CI, PIs at each site 
and committee members for the 
overall trial management. The 
sponsor will identify and collect the 
following disclosure information: 
• Ownership interests that may be 
related to products, services, or 
interventions considered for use in 
the trial or that may be significantly 
affected by the trial 
• Commercial ties requiring 
disclosure include, but are not 
restricted to, any pharmaceutical, 
behaviour modification, and/or 
technology company 
• Any non-commercial potential 
conflicts e.g. professional 
collaborations that may impact on 
academic promotion.’’ 
This was removed as financial and competing 
interests is covered in the site agreements (PI 
Declaration section). 
 
 
 

 
10 
 
Protocol v2.0 to v4.0 (UK only) 
Comparative table with description of change and rationale for change to the protocol from 
version 2.0 to version 4.0. 
Please note version 3.0 was never fully approved in any territory due to an error in the document. 
V4.0 re-incorporates all approved changes made previously and also includes the following:  
Chang
e No. 
Description of Change 
Rationale for Change 
3.  
Changes made to reference the 
compliance with Clinical Trial 
Regulation (EU) No 536/2014 in the 
statements the CI, Sponsor, 
statistician, and PIs sign. 
Addition of EUCT number to title page. 
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 
4.  
Protocol summary: 
Number of sites and countries 
changed from 45 to 61, and 7 to 11, 
respectively. 
Expansion of trial sites and territories is 
ongoing. 
5.  
Section 1.2.1: Therefore, in cases 
when needs ART needs to be initiated 
before genotypic testing results are 
available 
Typographical error on in the background and 
rationale section 
 
6.  
Section 1.2.1, Section 7.1 and Section 
7.7: Change to the language regarding 
the referenced RSI provided by the 
sponsor in  
Changed to emphasize that the study team 
should refer to the particular SmPC provided 
and authorised as the RSI in the study, even if 
this is not the local country version or most 
current.  
7.  
Section 5.2: Exclusion Criteria: 
Removal of the requirement that 
forbidden concomitant medications 
should have been stopped at least 30 
days ahead of baseline. 
30 days was added initially at the start of the 
trial when there was less safety data available 
for Biktarvy, in particular, as it was not yet 
authorised when the protocol was written. 
Therefore, it was thought to exclude all 
contraindicated medication for 30 days as a 
safety precaution. However, it is now thought 
this is unnecessary and the sites should 
follow any recommendations in the SmPC. 
8.  
Section 5.2 and Appendix 1: 
A latent TB test may be performed. 
Previously a TB test will be performed 
To clarify that the test is to confirm if latent TB 
is present. 
Additionally, TB testing has always been 
intended to be done in those patients in who 
it may be suspected. This wording has been 
changed to clarify that.  

 
11 
 
Chang
e No. 
Description of Change 
Rationale for Change 
9.  
Removal of “Investigator Brochure” 
from the title of section 7.1 
There is no Investigator Brochure used for the 
trial.  
10.  
Section 8.2.4 and Section 8.3.3.: 
1. 
Additional text to state that 
details of reporter included on 
the Safety Event Report Form 
2. 
Addition of text to mention the 
pharmacovigilance 
management plan (PVMP) will 
be used by the CI and sponsor 
in assessment of safety 
reporting 
Addition in line with change to Sponsor’s 
safety event reporting form to include the 
pharmacovigilance management plan 
(PVMP). 
11.  
Section 8.2.4 Recording and 
Reporting of SAEs and SUSARs 
Statement made that the Sponsor will 
update the Eudrvigilance database.  
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 
12.  
Section 8.3.6 and Section 12 
Addition of details regarding Endpoint 
committee review  
An endpoint committee may be requested 
ahead of any data analysis required by the 
DSMB or the TSC. 
13.  
8.8 Development Safety Update 
Reports 
Statement of intent for the sponsor to 
submit a single safety report for both 
IMP 
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 
14.  
9.5 Interim analysis and criteria for 
the premature termination of the trial 
Statement that there are no specific 
trial stopping criteria  
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 
15.  
13.3 Regulatory Compliance 
Change to reflect the trial will be 
conduct in compliance with Clinical 
Trial Regulation (EU) No 536/2014  
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 
16.  
13.6 Data protection and patient 
confidentiality 
Updated to comply with the Clinical 
Trial Regulation (EU) No 536/2014 
Compliance with Clinical Trial Regulation 
(EU) No 536/2014 

 
12 
 
Chang
e No. 
Description of Change 
Rationale for Change 
17.  
Section 13.5: 
Change to the definition of serious 
breach and reporting timelines  
The previously included strictly MHRA 
definition has hence been modified to include 
the Clinical Trial Regulation wording. 
18.  
Appendix 1: Study Flowchart 
Removal of “including urinary 
chemistry” after “Clinical Chemistry” 
in the description of this assessment 
The words are superfluous as the actual tests 
required are described in the footnote 12 – 
removing them for clarity for the sites.  
19.  
Appendix 1:  
Change to the footnote 10 wording 
after the asterisk: regarding when 
assessments should be taken. 
Changing from “after baseline” to “at 
all visits required” 
Changing this for clarity as it is ambiguous 
about whether urinalysis assessments 
should be done at all visits.  
20.  
Appendix 1: 
Additional wording to state that either 
urinary creatinine or ACR and PCR are 
mandatory, not both 
As it is the ACR and PCR which are required, 
and these are calculated from the urinary 
creatinine, if the ACR and PCR are provided 
by the site directly and the site do not 
routinely also provide the urinary creatinine in 
lab reports, this is acceptable. 
21.  
Appendix 1: 
Change to clarify that, as CD4 and 
CD8 can be calculated from total 
lymphocytes and CD4% and CD8%, 
CD4 and CD8 count are not 
mandatory 
CD4% and CD8% and lymphocytes are 
already mandatory.  
22.  
Appendix 1: 
Urinary nitrites are no longer 
mandatory 
It is considered that urinary nitrites are not a 
necessary safety test that is needed.  
 
 
 

 
13 
 
Protocol v4.0 to v5.0 (EU only) 
Comparative table with Description of Change and Rationale for change to the Protocol 
from Version 4.0 to Version 5.0.  
Protocol v4.0 was submitted in the EU but subsequently updated to v5.0 during the approval 
process due to the requirement for updated data protection wording. V5.0 is the same as v4.0 in 
almost all aspects. V5.0 is the final version for EU territories. 
 
Change 
No.  
Description of Change  
Rationale for Change  
1.  
Section 13.6:  
Additional wording to clarify how 
data is stored and processed at the 
end of the study, and in what 
format  
Compliance with Clinical Trial Regulation 
(EU) No 536/2014  
 

 
 
NEAT44 PROTOCOL | NEAT ID 
LAPTOP Study Protocol 
EudraCT: 2018-003481-13 
                       Version 1.5 – 08 January 2019 
Page 1 of 83 
 
 
 
An Open-Label, Multi-Centre, Randomised Study to Investigate 
Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral 
Therapy for Patients with Advanced HIV Disease 
-The Late Presenter Treatment Optimisation Study (LAPTOP)- 
Version 1.5 dated 08 January 2019 
 
SPONSOR: NEAT ID Foundation 
 
Sponsor code: NEAT44 
EudraCT: 2018-003481-13 
 
 
PLEASE RETAIN ONE COPY FOR THE SITE FILE 
 
 
 
 
 
 
 
Private & Confidential 
 
 
 
GCP Compliance Statement: 
This trial will be conducted in compliance with the protocol, the principles that have their origin in the Declaration of 
Helsinki and all applicable regulatory requirements 

 
 
NEAT44 PROTOCOL | NEAT ID 
LAPTOP Study Protocol 
EudraCT: 2018-003481-13 
                       Version 1.5 – 08 January 2019 
Page 2 of 83 
 
SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to 
the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 
2004/1031), amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial 
regulations, GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
For and on behalf of the trial Sponsor: 
Signature:  
Date: ____ / _____ / ________ 
 
 
 
Name (print): 
 
 
 
 
Chief Investigator: 
Signature:  
Date: ____ / _____ / ________ 
 
 
 
Name (print): 
 
 
 
 

 
 
NEAT44 PROTOCOL | NEAT ID 
LAPTOP Study Protocol 
EudraCT: 2018-003481-13 
                       Version 1.5 – 08 January 2019 
Page 3 of 83 
 
STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Statistician or Study Analyst agrees to conduct the trial in compliance with the approved protocol, 
Statistical Principles for Clinical Trials, ICH E10 and will adhere to the principles outlined in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 
2006/1928) and any subsequent amendments of the clinical trial regulations, GCP guidelines, the 
Sponsor’s SOPs and other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
 
Statistician or Study analyst 
Signature:  
Date: ____ / _____ / ________ 
 
 
 
Name (print): 
 
 
 
 

 
 
NEAT44 PROTOCOL | NEAT ID 
LAPTOP Study Protocol 
EudraCT: 2018-003481-13 
                       Version 1.5 – 08 January 2019 
Page 4 of 83 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the trial in accordance with ICH-GCP and the applicable regulatory requirements 
and with the approved protocol. 
I agree to comply with the procedures for data recording/reporting 
I agree to permit monitoring, auditing and inspection at this site and to retain all trial related essential 
documentation for the duration of the study as required according to ICH-GCP. 
 
 
Principal Investigator: 
Signature:  
Date: ____ / _____ / ________ 
Name (print): 
 
 
 
 
 

 
 
NEAT44 PROTOCOL | NEAT ID 
LAPTOP Study Protocol 
EudraCT: 2018-003481-13 
                       Version 1.5 – 08 January 2019 
Page 5 of 83 
 
TABLE OF CONTENTS 
SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE ..................................................................................2 
STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE ......................................................................................3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................................................................4 
TABLE OF CONTENTS ........................................................................................................................................5 
KEY TRIAL CONTACTS .......................................................................................................................................8 
FUNDING AND SUPPORT .................................................................................................................................9 
STUDY SYNOPSIS ........................................................................................................................................... 10 
LIST OF ABBREVIATIONS ................................................................................................................................ 12 
1. 
BACKGROUND AND RATIONALE ............................................................................................................ 15 
1.1 
FUNDING AND COLLABORATORS.................................................................................................................. 16 
1.2 
ASSESSMENT AND MANAGEMENT OF RISK ..................................................................................................... 16 
1.2.1 
B/F/TAF ........................................................................................................................................... 16 
1.2.2 
Risk/Benefit Assessment for the Study............................................................................................ 20 
1.2.3  
Rationale for Dose Selection ....................................................................................................... 21 
2. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ........................................................................... 21 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................. 21 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................ 21 
2.3 
EXPLORATORY OBJECTIVES ......................................................................................................................... 21 
2.4 
OUTCOME MEASURES/ENDPOINTS .............................................................................................................. 21 
2.4.1 
Primary endpoint/outcome ............................................................................................................. 21 
2.4.2 
Secondary endpoints/outcomes...................................................................................................... 22 
2.4.3 
Exploratory endpoints/outcomes .................................................................................................... 22 
3 
TRIAL DESIGN ........................................................................................................................................ 23 
3.1 
STUDY SCHEMA ....................................................................................................................................... 23 
4 
STUDY SETTING ..................................................................................................................................... 23 
5 
ELIGIBILITY CRITERIA ............................................................................................................................. 24 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 24 
5.2 
EXCLUSION CRITERIA ................................................................................................................................. 25 
6 
TRIAL PROCEDURES ............................................................................................................................... 26 
6.1 
RECRUITMENT ......................................................................................................................................... 26 
6.1.1 
Patient identification ...................................................................................................................... 26 
6.1.2 
Screening......................................................................................................................................... 26 
6.1.3 
Resistance Testing and Results ....................................................................................................... 27 
6.1.4 
Consent ........................................................................................................................................... 28 
6.1.5 
The randomisation scheme ............................................................................................................. 28 
6.1.6 
Method of implementing the allocation sequence ......................................................................... 28 
6.2 
BASELINE DATA ........................................................................................................................................ 28 
6.3 
TREATMENT PHASE ASSESSMENTS ............................................................................................................... 28 
6.4 
FOLLOW-UP/EARLY TERMINATION VISIT (ETV) ............................................................................................. 29 
6.5 
WITHDRAWAL CRITERIA ............................................................................................................................. 29 
6.6 
STORAGE AND ANALYSIS OF SAMPLES ........................................................................................................... 29 
6.6.1 
Resistance testing ........................................................................................................................... 29 
6.7 VIROLOGICAL FAILURE ...................................................................................................................................... 30 
6.8 END OF TRIAL .................................................................................................................................................. 30 

 
 
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7 
TRIAL MEDICATION ............................................................................................................................... 30 
7.1 
SUMMARY OF PRODUCT CHARACTERISTICS (SMPC), INVESTIGATOR’S BROCHURE (IB) AND REFERENCE SAFETY 
INFORMATION (RSI) .............................................................................................................................................. 31 
7.2 
DRUG STORAGE AND SUPPLY ...................................................................................................................... 32 
7.3 
PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT .......................................................... 32 
7.4 
DOSAGE SCHEDULES ................................................................................................................................. 32 
7.5 
DOSAGE MODIFICATIONS ........................................................................................................................... 32 
7.6 
KNOWN DRUG REACTIONS AND INTERACTION WITH OTHER THERAPIES ................................................................ 33 
7.7 
CONCOMITANT MEDICATION ...................................................................................................................... 33 
7.8 
TRIAL RESTRICTIONS .................................................................................................................................. 33 
7.9 
ASSESSMENT OF ADHERENCE ...................................................................................................................... 33 
7.10 
PROVISION OF TREATMENT AFTER THE END OF THE TRIAL .................................................................................. 33 
8 
PHARMACOVIGILANCE .......................................................................................................................... 33 
8.1 
DEFINITIONS ........................................................................................................................................... 33 
8.2 
OPERATIONAL DEFINITIONS FOR (S)AES ....................................................................................................... 34 
8.2.1 
Assessment of intensity ................................................................................................................... 35 
8.2.2 
Assessment of causality .................................................................................................................. 35 
8.2.3 
Collection and Follow up of Adverse Events .................................................................................... 35 
8.3 
SERIOUS ADVERSE EVENTS (SAES) .............................................................................................................. 36 
8.3.1 
Recording and Reporting of SAEs and SUSARs ................................................................................ 36 
8.4 
RESPONSIBILITIES ..................................................................................................................................... 36 
8.4.1 
Principal Investigator (PI): ............................................................................................................... 36 
8.4.2 
Chief Investigator (CI) / delegate or independent clinical reviewer: ............................................... 37 
8.4.3 
Sponsor: .......................................................................................................................................... 37 
8.4.4 
Data Safety Monitoring Board (DSMB): .......................................................................................... 37 
8.4.5 
Trial Steering Committee (TSC): ...................................................................................................... 37 
8.5 
NOTIFICATION OF DEATHS .......................................................................................................................... 37 
8.6 
PREGNANCY REPORTING ............................................................................................................................ 38 
8.7 
OVERDOSE .............................................................................................................................................. 38 
8.8 
REPORTING URGENT SAFETY MEASURES ........................................................................................................ 38 
8.9 
DEVELOPMENT SAFETY UPDATE REPORTS ..................................................................................................... 38 
8.10 
SPECIAL REPORTING SITUATIONS ................................................................................................................. 38 
9 
STATISTICS AND DATA ANALYSIS ........................................................................................................... 39 
9.1 
SAMPLE SIZE CALCULATION ......................................................................................................................... 39 
9.2 
PLANNED RECRUITMENT RATE ..................................................................................................................... 39 
9.3 
STATISTICAL ANALYSIS PLAN ........................................................................................................................ 40 
9.3.1 
Summary of baseline data and flow of patients ............................................................................. 40 
9.3.2 
Primary outcome analysis ............................................................................................................... 40 
9.3.3 
Secondary outcome analysis ........................................................................................................... 40 
9.4 
SUBGROUP ANALYSES ................................................................................................................................ 41 
9.5 
INTERIM ANALYSIS AND CRITERIA FOR THE PREMATURE TERMINATION OF THE TRIAL ............................................... 41 
9.6 
SUBJECT POPULATION ............................................................................................................................... 42 
9.7 
PROCEDURE(S) TO ACCOUNT FOR MISSING OR SPURIOUS DATA .......................................................................... 42 
9.8 
OTHER STATISTICAL CONSIDERATIONS ........................................................................................................... 42 
10 
DATA HANDLING ................................................................................................................................... 42 
10.1 
DATA COLLECTION TOOLS AND SOURCE DOCUMENT IDENTIFICATION ................................................................... 42 
10.1.1 
Source Data ................................................................................................................................ 42 
10.1.2 
Source Documents ...................................................................................................................... 42 
10.1.3 
Case report forms ....................................................................................................................... 43 
10.2 
DATA HANDLING AND RECORD KEEPING ........................................................................................................ 43 
10.3 
ACCESS TO DATA ...................................................................................................................................... 43 
10.4 
ARCHIVING ............................................................................................................................................. 43 

 
 
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11 
MONITORING, AUDIT & INSPECTION ..................................................................................................... 44 
12 
ROLES AND RESPONSIBILITIES OF TRIAL OVERSIGHT COMMITEES/ GROUPS & INDIVIDUALS ................ 45 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................................................................... 45 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) REVIEW & REPORTS ......................... 45 
13.2 
PEER REVIEW ........................................................................................................................................... 46 
13.3 
REGULATORY COMPLIANCE ........................................................................................................................ 46 
13.4 
PROTOCOL COMPLIANCE ............................................................................................................................ 46 
13.5 
NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR THE PROTOCOL .............................................................. 46 
13.6 
DATA PROTECTION AND PATIENT CONFIDENTIALITY ......................................................................................... 47 
13.7 
FINANCIAL AND OTHER COMPETING INTERESTS FOR THE CI, PIS AT EACH SITE AND COMMITTEE MEMBERS FOR THE OVERALL 
TRIAL MANAGEMENT .............................................................................................................................................. 47 
13.8 
INDEMNITY ............................................................................................................................................. 47 
13.9 
AMENDMENTS ......................................................................................................................................... 47 
13.10 
POST TRIAL CARE.................................................................................................................................. 48 
13.11 
ACCESS TO THE FINAL TRIAL DATASET ....................................................................................................... 48 
14 
DISSEMINATION POLICY ........................................................................................................................ 48 
15 
REFERENCES .......................................................................................................................................... 48 
APPENDIX 1 - STUDY FLOWCHART ................................................................................................................. 51 
APPENDIX 2 – AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE ............................................................. 55 
APPENDIX 3 – AIDS-DEFINING CONDITIONS ................................................................................................... 55 
APPENDIX 4 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA ....................................................................... 56 
APPENDIX 5 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA ................................................................... 61 
APPENDIX 6 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA ........................ 69 
APPENDIX 7 – HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF CHILD BEARING 
POTENTIAL* ................................................................................................................................................... 80 
APPENDIX 8 – SAFETY REPORTING FLOW CHART ........................................................................................... 81 
APPENDIX 9 – AMENDMENT HISTORY ........................................................................................................... 82 
 
 

 
 
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KEY TRIAL CONTACTS 
Chief Investigator 
Prof. Georg Behrens 
Klinik für Immunologie und Rheumatologie, OE 6830 
Medizinische Hochschule Hannover 
Carl-Neuberg-Str. 1 
30625 Hannover 
Germany 
Sponsor 
 
NEAT ID Foundation 
PL709  
322 Rue Haute, 
1000 Brussels,  
Belgium  
Statistics 
Lambert Assoumou 
Epidémiologie clinique de l'infection à VIH: stratégies 
thérapeutiques et comorbidités  
Institut Pierre Louis d'Epidémiologie et de Santé Publique 
56 Bd Vincent Auriol, CS 81393 
75646 PARIS CEDEX 13 
France 
IMP Management 
PCI Pharma Services 
Biotec House, Central Park 
Western Avenue 
Bridgend 
CF31 3RT 
United Kingdom 
Central Laboratory 
(Resistance Testing) 
Monogram Biosciences 
345 Oyster Point Blvd 
San Francisco 
California 
94080-1913 
United States of America 
Central Laboratory  
(Storage and Logistics) 
ACM Global Laboratories, Ltd. 
23 Hospital Fields Road 
York 
YO10 4DZ 
United Kingdom 
Study Coordinating 
Organisation  
Research Organisation (KC) Ltd 
The Stanley Building 
7 Pancras Square 
London 
N1C 4AG 
United Kingdom 

 
 
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FUNDING AND SUPPORT  
FUNDERS/COLLABORATORS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City 
CA 94404 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
 

 
 
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STUDY SYNOPSIS 
Full Study Title 
An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor 
Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients with Advanced 
HIV-Disease  
Short Title/Acronym 
LAPTOP (The Late Presenter Treatment Optimisation Study) 
Clinical Phase  
IIIb 
Trial Design 
International, multi-centre, randomised, open-label, controlled study comparing two 
strategies for HIV-1 infected patients with advanced disease. Randomisation 1:1 into 
two arms, 48 weeks, stratified according to country and baseline CD4 cell count (<50 
cells/µL, 50-199 cells/µL, or ≥200 cells/µL). 
Name of Investigational 
Product 
Treatment Arm 1 
Bictegravir (50mg)/emtricitabine (200mg)/tenofovir alafenamide (25mg) [1 pill 
administered orally once daily for 48 weeks without regard to food] 
Treatment Arm 2 
Darunavir (800 mg)/cobicistat (150 mg)/emtricitabine (200 mg)/tenofovir 
alafenamide (10mg) [1 pill administered orally once daily for 48 weeks with food] 
Trial Participants 
Population 
HIV-1 infected patients ≥ 18 years and ART-naïve prior to enrolment. 
Planned Sample Size 
440 (220 subjects per treatment arm)  
Key Eligibility Criteria 
Subjects who meet the following eligibility criteria: 
1. 
Ability to understand and sign a written informed consent form (ICF) and must 
be willing to comply with all study requirements 
2. 
≥ 18 years  
3. 
HIV-1 infected AIDS except active tuberculosis (TB) or cryptococcal meningitis 
with any CD4 cell count, or; severe bacterial infection (BI) and must have a CD4 
cell count < 200/µL within 30 days prior to study entry, or; asymptomatic with 
CD4 cell count < 100/µL within 30 days prior to study entry and must have an 
entry HIV viral load > 1000 copies/mL, or; currently being treated for 
opportunistic infections (OI) 
4. 
ART-naïve prior to study enrolment 
5. 
Able to take oral medications 
6. 
Willing to use acceptable methods of contraception  
Treatment duration 
48 weeks 
Follow up duration 
30 days 
Formulation, Dose, 
Route of Administration 
Subjects will be randomised in a 1:1 ratio into one of two treatment arms: 
Group 1 
Integrase inhibitor containing regimen 
Bictegravir (50 mg)/emtricitabine (200 mg)/tenofovir alafenamide (25mg) [1 pill 
administered orally once daily without regard to food for 48 weeks] 
Group 2 
Boosted protease inhibitor regimen 

 
 
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Darunavir (800 mg)/cobicistat (150 mg)/emtricitabine (200 mg)/tenofovir 
alafenamide (10mg) [1 pill administered orally once daily with food for 48 weeks] 
Indication 
ART-naïve HIV-1 infected patients 
Methodology 
Eligible consented patients will be randomised in a 1:1 ratio 
Number of sites 
Up to 45 sites, in up to 8 countries 
Objectives 
Primary 
To demonstrate the non-inferiority of an 
INI containing regimen [bictegravir 
(B)/emtricitabine (F)/tenofovir 
alafenamide (TAF) QD] versus a boosted 
PI regimen [darunavir (D)/cobicistat 
(C)/emtricitabine (F)/tenofovir 
alafenamide (TAF) QD] in patients with 
advanced HIV infection. 
Secondary 
 To investigate the immunological and 
virological response, tolerability, 
resistance development, discontinuation 
of therapy due to tolerability, QOL and 
IRIS incidence. 
 
Outcome Measures 
Primary 
1. Time to failure, as the first 
occurrence of specified virological 
or clinical reasons.  
 
Secondary 
1. 
Proportion of patients with 
HIV-RNA viral load < 50 
copies/mL at week 24, 36, 48 
2. 
HIV-1 drug resistance at 
confirmed virological failure 
(genotype)  
3. 
Time to reach CD4 count > 
200/µL 
4. 
Proportion of patients with CD4 
cell count <200 and < 350µL at 
week 4, 8, 12, 24, 36, 48  
5. 
CD4/CD8 ratio at week 4, 8, 12, 
24, 36, 48 
6. 
Incidence of IRIS in the two 
arms through week 48 
7. 
Incidence and duration of 
hospitalisation, rate of relapse 
of specific OI/BI through week 
48 
8. 
Safety and tolerability, 
measured by Grade 2, 3 and 4 
signs and symptoms and 
laboratory toxicities through 
week 48 
9. 
ART and OI/BI treatment 
changes and dose 
modifications due to toxicities 
and DDI with ART, and IRIS 
through week 48 
10. Health care resource use, 
including total inpatient days 
and emergency room visits 
through week 48 
11.  QOL and functional status 
outcomes, including overall 
self-reported QOL and 
functional status compared in 
the two groups at week 48 
12. Discontinuation or modification 
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insufficient virological response, 
resistance 
mutations 
at 
baseline, or resistance mutation 
development before week 48 
 
 
LIST OF ABBREVIATIONS 
Acronym 
Description  
3TC 
Lamivudine 
ABC 
Abacavir 
ACTG 
AIDS Clinical Trial Group 
ADE 
Adverse Drug Event 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Transaminase 
ANRS 
Agence Nationale de Recherches sur le SIDA (National Agency 
for AIDS Research) 
AR 
Adverse Reaction 
ART 
Antiretroviral Therapy 
ARV 
Antiretroviral 
AST 
Aspartate Aminotransferase 
B/BIC 
Bictegravir 
BI 
Bacterial Infection 
BMD 
Bone Mineral Density 
C 
Cobicistat 
CA 
Competent Authority 
CDC 
Centres for Disease Control and Prevention 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Chief Investigator 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTA  
Clinical Trial Authorisation  
D/DRV 
Darunavir 
DDI 
Drug-Drug Interaction 
DIBD 
Developmental International Birth Date  
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
DTG 
Dolutegravir 
EACS 
European AIDS Clinical Society 

 
 
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ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELISPOT 
Enzyme-Linked ImmunoSpot 
ETV 
Early Termination Visit 
EU 
European Union 
EudraCT  
European Clinical Trials Database  
EVG 
Elvitegravir  
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FTC/F 
Emtricitabine 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation  
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HIV-1 
Human Immunodeficiency Virus Type-1 
IAS 
International AIDS Society 
IB 
Investigator’s Brochure 
IBI 
Invasive Bacterial Infection 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use 
IEC 
Independent Ethics Committee 
IGRA 
Interferon-Gamma Release Assays 
IMP  
Investigational Medicinal Product  
INI  
Integrase Inhibitor  
INSTI 
Integrase Strand Transfer Inhibitor 
IRB 
Institutional Review Board 
IRIS 
Immune Reconstitution Inflammatory Syndrome 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat  
LOCF 
Last Observation Carried Forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
NNRTI 
Non-Nucleoside Reverse-Transcriptase Inhibitor 
NRTI 
Nucleoside Reverse-Transcriptase Inhibitor 
OI 
Opportunistic Infection 
PBMC 
Peripheral Blood Mononuclear Cells 
PI 
Principal Investigator 

 
 
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PI 
Protease Inhibitor 
QD 
quaque die (once daily) 
QOL 
Quality of Life 
QP 
Qualified Person  
RAL 
Raltegravir 
RNA 
Ribonucleic Acid 
RSI 
Reference Safety Information 
RT 
Reverse Transcriptase 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TAF 
Tenofovir Alafenamide Fumarate 
TDF 
Tenofovir Disoproxil Fumarate 
TB 
Tuberculosis 
TFV 
Tenofovir 
TMG 
Trial Management Group 
TMF  
Trial Master File  
US 
United States 
USM 
Urgent Safety Measure 
 
 
 
 

 
 
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1. BACKGROUND AND RATIONALE 
Treatment responses to antiretroviral therapy (ART) have constantly improved. This is due to novel 
compounds and combinations with improved antiviral efficacy and side effect profiles resulting in less 
virologic failures and treatment discontinuation. On the other hand, most recent randomised 
controlled trials for first line treatment consider patients with less advanced disease (mean CD4 cell 
counts at baseline >350/µl, less than 15% of patients with CD4 cell counts <200/µl) and low baseline 
viral loads [DeJesus et al., Raffi et al., Walmsley et al., Sax et al, Gallant et al.]. This favours superior 
overall response rates, as these patients usually suffer from less co-morbidities, drug-drug interactions 
(DDI), and other risks for treatment failure. The rate of patients with Acquired Immune Deficiency 
Syndrome (AIDS)-defining events enrolled in these trials was low. 
Outside these trials, the number of patients considered as late presenters (CD4 cell count <350/µl) 
when diagnosed with Human Immunodeficiency Virus (HIV) remains high across Europe [Camoni et 
al., Montlahuc et al.]. According to a definition proposed in 2009, the term late presentation is used 
for persons presenting for care with a CD4 count <350 cells/mL or presenting with an AIDS-defining 
event, regardless of the CD4 cell count. Late presentation with advanced disease is restricted to 
persons presenting for care with a CD4 count <200 cells/mL or presenting with an AIDS-defining event, 
regardless of the CD4 cell count [Antinori et al.]. Patients with CD4 cell counts <200/µl and/or AIDS 
events at first diagnosis are frequent in clinical practice [Rafetti et al, Sobrino-Vegas et al, Late 
presenters working group in COHERE in EuroCoord et al.]. 
Strategic trials in this patient group thus far focused on time of treatment initiation to prevent immune 
reconstitution syndromes (IRIS) [Abdool Karim et al., Blanc et al.] or disease course of already 
diagnosed opportunistic infections (OIs) [Zolopa et al.; Manzardo C et al.]. The AIDS Clinical Trials 
Group (ACTG protocol 5164) reported that starting ART within the first 30 days after a diagnosis of 
non-tuberculosis (TB) OIs was associated with a lower rate of AIDS progression and death, compared 
to delaying initiation of ART, without an increase in adverse outcomes [Zolopa et al.]. 
Much less is known about which ART regimens perform best in late presenters in terms of viral 
efficacy, immune reconstitution, improvement of AIDS-related co-morbidities and adverse events 
(AEs). No specific combinations have been compared in sufficiently powered randomised clinical trials, 
and all regimens considered in international guidelines for first line therapies are judged as equal 
standard of care for these patients.  Initially, protease inhibitor (PI) containing regimens were 
frequently used in patients presenting late or with AIDS defining events [Mussini et al.]. 
However, specifically regimens containing integrase inhibitors (INI) are promising candidates for 
treatment combinations in patients with CD4 cell counts <200/µl due to their antiviral activity and 
rapid decline of viral load, beneficial side-effect profile and metabolism pathways compared to other 
regimens. Also, integrase inhibitors such as dolutegravir (DTG) and bictegravir (BIC/B) have high 
genetic barriers, thereby preventing resistance mutation development and ensuring sufficient 
antiviral activity in case of preexisting mutations against nucleosides [Demarest et al.]. Therefore, in 
cases when needs ART to be initiated before genotypic testing results are available, current European 
AIDS Clinical Society (EACS) Guidelines (EACS Treatment Guidelines 9.0) recommend to include a drug 
with a high genetic barrier to resistance in the first-line regimen (e.g. PI or DTG). Whilst some reports 
describe a higher risk for IRIS in patients receiving integrase inhibitors [Wijting et al., Dutertre et al., 
Psichogiou et al.], a meta-analysis did not [Hill et al.]. We therefore propose a strategic clinical trial to 
compare an INI containing regimen versus a boosted PI regimen in patients with advanced HIV-
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1.1 Funding and Collaborators 
Gilead Sciences, Inc. (Gilead) is the Funder for this Investigator-led study and will provide financial 
support, as well as supplying the study drug (Biktarvy®) for the INI containing treatment regimen. 
Janssen Pharmaceutica NV (Janssen) will also be providing support for the study by supplying the study 
drug (Symtuza®) for the boosted PI treatment regimen, as well as funds for the associated study drug 
management costs.   
1.2 Assessment and management of risk 
1.2.1 B/F/TAF 
Experience from Clinical Studies in Treatment-Naïve Patients 
Assessment of adverse reactions (ARs) is based on pooled data from two 48-week controlled clinical 
studies (GS-US-380-1489 (“Study 1489”) and GS-US-380-1490 (“Study 1490”)) in which 1274 
treatment-naïve patients received B/F/TAF (N=634), abacavir (ABC)/DTG/lamivudine (3TC) (N=315), 
or DTG+FTC/TAF (N=325). 
The ARs are listed below by system organ class and frequency.  Frequencies (based on all treatment-
emergent AEs, regardless of relationship to study drug) are defined as follows: very common (≥10%), 
common (≥1% and <10%) or uncommon (≥0.1% and <1%). 
NERVOUS SYSTEM DISORDERS 
Very common: headache 
GASTROINTESTINAL SYSTEM DISORDERS 
Very common: diarrhoea  
Common: nausea, vomiting, abdominal pain, dyspepsia, flatulence 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Common: rash 
GENERAL DISORDERS AND ADMINISTRATION SITE REACTIONS 
Common: fatigue 
Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of 
tubular secretion of creatinine without affecting renal glomerular function.  Increases in serum 
creatinine occurred by Week 4 of treatment and remained stable through Week 48.  In Studies 1489 
and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg/dL, 0.11 (0.03, 0.18) 
mg/dL, and 0.11 (0.04, 0.19) mg/dL from baseline to Week 48 in the B/F/TAF, ABC/DTG/3TC, and 
DTG+FTC/TAF groups, respectively.  There were no discontinuations due to renal adverse events 
through Week 48 in B/F/TAF clinical studies. 
Changes in Bilirubin: Total bilirubin increases were observed in 12% of patients administered B/F/TAF 
through Week 48.  Increases were primarily Grade 1 (9%) and Grade 2 (3%) and were not associated 
with hepatic ARs or other liver related laboratory abnormalities.  There were no discontinuations due 
to hepatic AEs through Week 48 in B/F/TAF clinical studies. 
Clinical Experience 
The efficacy and safety of B/F/TAF in HIV-1 infected, treatment-naïve adults are based on 48-week 
data from two randomised, double-blind, active-controlled studies, Study 1489 (N=629) and Study 
1490 (N=645). 
The efficacy and safety of B/F/TAF in virologically-suppressed HIV-1 infected adults are based on 48-
week data from a randomised, double-blind, active-controlled study, GS-US-380-1844 (“Study 1844”) 

 
 
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(N=563); and a randomised, open-label, active-controlled study, GS-US-380-1878 (“Study 1878”) 
(N=577). 
The efficacy and safety of FTC+TAF (components of B/F/TAF) in HIV-1 infected, virologically-
suppressed patients with mild to moderate renal impairment is based on 144-week data from an 
open-label study, GS-US-292-0112 (“Study 112”) (N=242). 
The efficacy and safety of FTC+TAF in adult patients coinfected with HIV-1 and chronic hepatitis B 
(HBV) are based on 48-week data from an open-label study, GS-US-292-1249 (“Study 1249”) (N=72). 
The efficacy and safety of B/F/TAF in adult patients coinfected with HIV-1 and chronic HBV are also 
supported by 48-week data in 8 HIV/HBV coinfected adults treated with B/F/TAF in Study 1490 and 8 
HIV/HBV coinfected adults treated with B/F/TAF in Study 1878. 
 
Treatment-Naïve Patients 
In Study 1489, patients were randomised in a 1:1 ratio to receive either B/F/TAF (N=314) or 
ABC/DTG/3TC (600/50/300 mg) (n=315) once daily.  In Study 1490, patients were randomised in a 1:1 
ratio to receive either B/F/TAF (N=320) or DTG+FTC/TAF (50+200/25 mg) (N=325) once daily. 
In Studies 1489 and 1490, the mean age was 35 years (range 18-77), 89% were male, 58% were White, 
33% were Black, and 3% were Asian. 24% of patients identified as Hispanic/Latino.  The mean baseline 
plasma HIV-1 RNA was 4.4 log10 copies/mL (range 1.3-6.6).  The mean baseline CD4+ cell count was 
460 cells/mm3 (range 0-1636) and 11% had CD4+ cell counts less than 200 cells/mm3.  18% of patients 
had baseline viral loads greater than 100,000 copies/mL.  In both studies, patients were stratified by 
baseline HIV-1 RNA (≤100,000 copies/mL, >100,000 copies/mL to ≤400,000 copies/mL, or >400,000 
copies/mL), by CD4 count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL), and by region (US or ex-
US). 
Treatment outcomes of Studies 1489 and 1490 through Week 48 are presented in Table 1-1. 
Table 1-1 Pooled Virologic Outcomes of Studies 1489 and 1490 at Week 48 in Treatment-Naïve 
Patientsa 
 
B/F/TAF  
(N=634)b 
ABC/DTG/3TC 
(N=315)c 
DTG+FTC/TAF 
(N=325)d 
HIV-1 RNA < 50 copies/mL 
91% 
93% 
93% 
Treatment 
Difference 
(95% 
CI) 
B/F/TAF vs Comparator 
- 
-2.1% 
(-5.9% to 1.6%) 
-1.9% 
(-5.6% to 1.8%) 
HIV-1 RNA ≥ 50 copies/mLe 
3% 
3% 
1% 
No Virologic Data at Week 48 Window 
6% 
4% 
6% 
Discontinued Study Drug Due to AE or 
Deathf 
<1% 
1% 
1% 
Discontinued Study Drug Due to Other 
Reasons and Last Available HIV-1 RNA 
< 50 copies/mLg 
4% 
3% 
4% 
Missing Data During Window but on 
Study Drug 
2% 
<1% 
1% 
a Week 48 window was between Day 295 and 378 (inclusive). 
b Pooled from Study 1489 (N=314) and Study 1490 (N=320). 
c Study 1489 
d Study 1490 
e Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of 
efficacy; patients who discontinued for reasons other than an AE, death or lack or loss of efficacy and at the time of 
discontinuation had a viral value of ≥ 50 copies/mL. 
f Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted 
in no virologic data on treatment during the specified window. 

 
 
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g Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, 
loss to follow-up, etc. 
 
B/F/TAF was non-inferior in achieving HIV-1 RNA < 50 copies/mL at Week 48 when compared to 
ABC/DTG/3TC and DTG+FTC/TAF, respectively.  Treatment outcomes were similar across subgroups 
by age, sex, race, baseline viral load, and baseline CD4+ cell count. 
In Studies 1489 and 1490, the mean increase from baseline in CD4+ count at Week 48 was 207, 229, 
and 201 cells/mm3 in the pooled B/F/TAF, ABC/DTG/3TC, and DTG+FTC/TAF groups, respectively. 
Bone Mineral Density: In Study 1489, bone mineral density (BMD) change from baseline to Week 48 
was assessed by dual-energy X-ray absorptiometry.  In patients who had both baseline and Week 48 
hip and lumbar spine BMD measurements (N=257 and 267 in the B/F/TAF group and N=270 and 274 
in the ABC/DTG/3TC group, for hip and lumbar spine, respectively), mean percentage changes in BMD 
were similar in the B/F/TAF group compared to the ABC/DTG/3TC group for hip (-0.8% vs -1.0%) and 
lumbar spine (-0.8% vs -0.6%). 
 
Pharmacology 
Mechanism of Action: 
BIC: BIC is an Integrase Strand Transfer Inhibitor (INSTI) that binds to the integrase active site and 
blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential 
for the HIV replication cycle.  
BIC has activity that is specific to HIV-1 and HIV-2. 
FTC: FTC is a nucleoside analogue of 2’-deoxycytidine.  FTC is phosphorylated by cellular enzymes to 
form FTC triphosphate.  FTC triphosphate inhibits HIV replication through incorporation into viral DNA 
by the HIV reverse transcriptase (RT), which results in DNA chain-termination.  
FTC has activity that is specific to HIV-1 and HIV-2 and HBV.   
FTC triphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA 
polymerase γ and there was no evidence of toxicity to mitochondria in vitro and in vivo. 
TAF: TAF is a phosphonamidate prodrug of TFV (2’-deoxyadenosine monophosphate analogue).  TAF 
is permeable into cells and due to increased plasma stability and intracellular activation through 
hydrolysis by cathepsin A, TAF is more efficient than TDF in loading TFV into peripheral blood 
mononuclear cells (PBMCs) (including lymphocytes and other HIV target cells) and macrophages.  
Intracellular TFV is subsequently phosphorylated to the pharmacologically active metabolite TFV 
diphosphate.  TFV diphosphate inhibits HIV replication through incorporation into viral DNA by the 
HIV RT, which results in DNA chain-termination.  
TFV has activity that is specific to HIV-1 and HIV-2 and HBV.  In vitro studies have shown that both FTC 
and TFV can be fully phosphorylated when combined in cells.  TFV diphosphate is a weak inhibitor of 
mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence 
of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses. 
 
Antiviral Activity: 
B/F/TAF: The triple combination of B, F and TAF demonstrated synergistic antiviral activity in cell 
culture. 
BIC: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes.  The 
EC50 values for BIC were in the range of < 0.05 to 6.6 nM.  The protein-adjusted EC95 of BIC was 361 
nM for wild type HIV-1 virus. 

 
 
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BIC displayed antiviral activity in cell culture against HIV-1 groups (M, N, O), including subtypes A, B, 
C, D, E, F, and G (EC50 values ranged from < 0.05 and 1.71 nM), and activity against HIV-2 (EC50 = 1.1 
nM). 
In a study of BIC with representatives from the major classes of approved anti-HIV agents (nucleoside 
reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), 
INSTIs, and PIs), additive to synergistic antiviral effects were observed.  No antagonism was observed 
for these combinations. 
FTC: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs.  The EC50 values for FTC were in the 
range of 0.0013 to 0.64 µM. 
FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values 
ranged from 0.007 to 0.075 µM) and showed activity against HIV-2 (EC50 values ranged from 0.007 to 
1.5 µM). 
In two-drug combination studies of FTC with NRTIs, NNRTIs, PIs, and INSTIs, additive to synergistic 
effects were observed.  No antagonism was observed for these combinations. 
TAF: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was 
assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4 T 
lymphocytes.  The EC50 values for TAF were in the range of 2.0 to 14.7 nM.   
TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, 
B, C, D, E, F, and G (EC50 values ranged from 0.10 and 12.0 nM), and activity against HIV-2 (EC50 values 
ranged from 0.91 to 2.63 nM). 
In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV 
agents (NRTIs, NNRTIs, INSTIs, and PIs), additive to synergistic antiviral effects were observed.  No 
antagonism was observed for these combinations. 
 
Pharmacokinetic Properties 
Absorption: 
BIC: BIC is absorbed following oral administration with peak plasma concentrations occurring at 2-4 
hours after administration of B/F/TAF.  Relative to fasting conditions, the administration of B/F/TAF 
with either a moderate fat (~600kcal, 27% fat) or high fat meal (~800kcal, 50% fat) resulted in an 
increase in BIC AUC (24%).  This modest change is not considered clinically meaningful and B/F/TAF 
can be administered with or without food. 
FTC: FTC is rapidly and extensively absorbed following oral administration with peak plasma 
concentrations occurring at 1.5-2 hours after administration of B/F/TAF. 
The mean absolute bioavailability of an FTC 200 mg capsule was 93%.  The mean absolute 
bioavailability of the FTC 10 mg/mL oral solution was 75%.   
FTC systemic exposure was unaffected when FTC was administered with food and B/F/TAF can be 
administered with or without food. 
TAF: TAF is rapidly absorbed following oral administration with peak plasma concentrations occurring 
at 0.5-2 hours after administration of B/F/TAF. 
Relative to fasting conditions, the administration of TAF with a moderate fat meal (~600kcal, 27% fat) 
and a high fat meal (~800kcal, 50% fat) resulted in an increase in AUClast of 48% and 63% respectively.  
These modest changes are not considered clinically meaningful and B/F/TAF can be administered with 
or without food. 
B/F/TAF: The multiple dose PK parameters of the components of B/F/TAF are provided in Table 1-2. 

 
 
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Table 1-2 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of B/F/TAF 
With or Without Food in HIV-Infected Adults. 
Parameter Mean (%CV) 
Bictegravira 
Emtricitabineb 
Tenofovir Alafenamidec 
Cmax  
(microgram per mL) 
6.15 (22.9) 
2.13 (34.7) 
0.121 (15.4) 
AUCtau  
(microgram·hour per mL) 
102 (26.9) 
12.3 (29.2) 
0.142 (17.3) 
Ctrough 
(microgram per mL) 
2.61 (35.2) 
0.096 (37.4) 
NA 
CV = Coefficient of Variation; NA = Not Applicable 
a From Population PK analysis in Studies 1489, 1490, 1844, and 1878; N = 1193 
b From Intensive PK analysis in Studies 1489, 1490, 1844, and 1878; N = 77 
c From Population PK analysis in Studies 1489 and 1490; N = 486 
 
Please refer to the Biktarvy® Summary of Product Characteristics (SmPC) for further information about 
clinical studies involving BIC. 
1.2.2 
Risk/Benefit Assessment for the Study 
All patients with HIV-1 infection should receive effective ART. Potential risks associated with all classes 
of ARVs include IRIS. The risk of class effects is considered to be low. Important identified risks 
appropriately managed by study inclusion/exclusion criteria as well as through close clinical and 
laboratory monitoring during the study, are as follows: hypersensitivity reaction, including liver injury, 
and allergy to any components of the regimens. Interim data will also be reviewed by an independent 
data monitoring committee. 
Potential benefits may include provision of a new ART that is not currently available, and which may 
have fewer side effects than alternative therapies. The benefits of participation for patients receiving 
B/F/TAF include provision of a therapy with less DDI due to the non-boosting regimen. Other potential 
benefits include provisions of fixed dose combination (FDC) therapy, and the knowledge that patient 
participation will contribute to the body of knowledge of HIV therapies. 
Following a chronic 39-week study in monkeys, animals administered the highest dose of BIC (1000 
mg/kg/day) had bile duct hyperplasia (increased cell growth) and hypertrophy (increased cell size), 
and some increased cell growth and inflammation in nearby liver cells. These effects were not seen in 
monkeys administered the mid-level dose (200 mg/kg/day), and these animals had plasma BIC 
exposures that were approximately 5-fold above human exposures when given the B/F/TAF FDC.  No 
adverse drug reactions associated with liver or bile duct problems have been identified in humans 
treated with BIC. 
Darunavir as a component of D/C/F/TAF fix-dose combination can cause transient and usually 
asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of 
clinically apparent, acute liver injury. No dose adjustment of D/C/F/TAF is required in patients with 
mild or moderate (Child-Pugh Class A/B) hepatic impairment or in patients with estimated glomerular 
filtration rate according to the Cockcroft-Gault formula (eGFRCG) ≥ 30 mL/min. The most frequent 
adverse reactions reported were diarrhea, nausea, fatigue, headache, and rash. Darunavir contains a 
sulphonamide moiety and should be used with caution in patients with a known sulphonamide allergy. 
Co-administration of D/C/F/TAF and medicinal products primarily metabolised by CYP3A may result in 
increased systemic exposure to such medicinal products, which could increase or prolong their 
therapeutic effect and adverse reactions. 
The overall benefit-risk assessment for B/F/TAF and D/C/F/TAF is favourable at this time. 
 

 
 
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1.2.3  Rationale for Dose Selection 
B/F/TAF 
The B/F/TAF FDC containing B (50 mg), F (200 mg), and TAF (25 mg), has been approved by the Food 
and Drugs Administration (FDA) for use once daily for the treatment of HIV-1 infection in adults. This 
regimen has been submitted to the European Medicines Agency for approval and was approved in 
June 2018. Phase 3 clinical trials with the B/F/TAF FDC in treatment-naïve patients have shown it to 
be safe and well tolerated and have demonstrated non-inferiority to ABC/DTG/3TC and DTG + F/TAF 
at Week 48 by snapshot algorithm (GS-US-380-1489 and GS-US-380-1490). B/F/TAF contains 25 mg of 
TAF, the approved and recommended dosage for the treatment of HBV infection with other 
antiretrovirals (ARVs) for treatment of HIV/HBV co-infection (Please refer to the Biktarvy® SmPC for 
further information).  
D/C/F/TAF 
The D/C/F/TAF FDC (Symtuza®) containing D (800 mg), C (150 mg), F (200 mg), and TAF (10 mg), has 
been approved in the European Union (EU) for use once daily for the treatment of HIV-1 infection in 
adults. 
2. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
2.1 Primary objective 
• 
To demonstrate the non-inferiority of an INI containing regimen [bictegravir (B)/emtricitabine 
(F)/tenofovir alafenamide (TAF) QD] versus a boosted PI regimen [darunavir (D)/cobicistat (C)/ 
emtricitabine (F)/tenofovir alafenamide (TAF) QD] in patients with advanced HIV infection.   
2.2 Secondary objectives 
• 
To investigate the immunological and virological response, tolerability, resistance 
development, discontinuation of therapy due to tolerability, quality of life (QoL) and IRIS 
incidence. 
2.3 Exploratory objectives 
• 
To assess whether virological response is better predicted by deep sequencing rather than 
standard population sequencing. 
2.4 Outcome measures/endpoints 
2.4.1 
Primary endpoint/outcome 
• 
Time to failure, as the first occurrence of any of the following components: 
 
1. Virological reasons 
a) Insufficient virological response, either:  
a. HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
b. Viral load > 50 HIV-1 RNA copies/mL at week 48  

 
 
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b) Viral rebound, which is subsequently confirmed at the following scheduled or 
unscheduled visit, defined as either: 
a. Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL  
b. Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients 
whose viral load has never been suppressed below 50 copies/mL 
 
2. Clinical reasons* 
a) Death related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS 
b) Any new or recurrent AIDS defining event on, or after 28 days of therapy 
c) Any new serious non-AIDS defining event documented by the endpoint review 
committee (including severe BI, end stage liver disease, renal failure, cardiovascular 
event, and non-AIDS related malignant disease)  
d) Clinically relevant AEs of any grade or IRIS which require treatment interruption 
(lasting > 5 days) of INI or boosted PI therapy within the first 48 weeks after 
randomisation 
Note: Discontinuation of BIC or boosted DRV followed by (within 5 days) continuation 
with another INI or PI, respectively, is not considered as a strategy failure or endpoint. 
2.4.2 
Secondary endpoints/outcomes 
• 
Proportion of patients with HIV-RNA viral load < 50 copies/mL at week 24, 36, 48 
• 
HIV-1 drug resistance at confirmed virological failure (genotype) 
• 
Time to reach CD4 count > 200/µL (first measurement) 
• 
Proportion of patients with CD4 cell count < 200 µL and < 350µL at week 4, 8, 12, 24, 36, 48 
• 
CD4/CD8 ratio at week 4, 8, 12, 24, 36, 48 
• 
Incidence of IRIS in the two arms through week 48 
• 
Incidence and duration of hospitalisation, rate of relapse of specific OI/BI through week 48 
• 
Safety and tolerability, measured by Grade 2, 3 and 4 signs and symptoms and laboratory 
toxicities through week 48 
• 
ART and OI/BI treatment changes and dose modifications due to toxicities and DDI with ART, 
and IRIS through week 48 
• 
Health care resource use, including total inpatient days and emergency room visits through 
week 48 
• 
QOL and functional status outcomes, including overall self-reported QOL and functional status 
compared in the two groups at week 48 
• 
Discontinuation or modification of study medication due to insufficient virological response, 
resistance mutations at baseline, or resistance mutation development before week 48 
 
2.4.3 
Exploratory endpoints/outcomes 
• 
Mutations detected by deep sequencing compared with those detected by population 
sequencing 
• 
Proportion of patients with HIV-RNA viral load < 50 copies/mL at week 4, 8, 12  
 
* Refer to Appendices 3 (AIDS-Defining Conditions), 4 (INSIGHT Serious Non-AIDS Events Criteria), 5 (INSIGHT Progression of 
HIV Disease Criteria) and 6 (Immune Reconstitution Inflammatory Syndrome Generic Criteria). 

 
 
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3 TRIAL DESIGN 
An open-label, randomised, two arm, multicentre trial over 48 weeks to compare two strategies for 
HIV-1 infected patients with advanced disease, stratified according to country and baseline CD4 cell 
count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL). 
Patients will be randomised to receive either an integrated inhibitor containing regimen (B (50mg)/F 
(200mg)/TAF (25mg) [1 pill administered orally once daily for 48 weeks]) or a boosted PI regimen (D 
(800mg)/C (150mg)/F(200mg)/TAF (10mg) [1 pill administered orally once daily for 48 weeks]).  
Study visits will take place at screening, baseline, weeks 4, 8, 12, 24, 36 and 48, as well as a follow-up 
visit 30 days following the week 48 visit.  
Routine investigations will include HIV-1 RNA, CD4, CD8, haematology (including haemoglobin, white 
cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, 
phosphorus, albumin, glucose, alanine transaminase (ALT), aspartate aminotransferase (AST), ALP, 
total and indirect bilirubin, total cholesterol, HDL, LDL, triglycerides), QoL questionnaire (EuroQoL EQ-
5D-3L), HIV Symptom Index (HIV-SI/SDM) urine sample (for haematuria, proteinuria, glycosuria, 
leukocytes, nitrites, pregnancy test in women of child-bearing potential (WOCBP)).   
For a full list of investigations please see the table of assessments in Appendix 1. 
3.1 Study Schema 
 
4 STUDY SETTING 
This study will be conducted within the NEAT ID network and include sites that have an excellent track 
record in clinical research and operate in up to eight countries. A full feasibility and qualification 
assessment plan will be undertaken for all potential sites. The sponsor will ensure that onsite visits 
are performed to assess GCP compliance, including (but not limited to); protocol adherence, informed 
consent documentation, data quality, drug accountability and overall site performance.  
Untreated HIV-patients with either; 
•
AIDS 
•
Severe BI and CD4 <200/μl 
•
CD4 <100/μl & VL>1,000 copies/ml 
•
Current OI treatment
INI Regimen QD 
B/F/TAF 
50mg/200mg/25mg 
PI Regimen QD  
Symtuza: D/C/F/TAF 
800mg/150mg/200mg/10mg 
N=220 
N=220 
Randomisation 
1:1 
Week 48 

 
 
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5 ELIGIBILITY CRITERIA 
5.1 Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation into this study. 
1. The ability to understand and sign a written informed consent form (ICF) and must be willing 
to comply with all study requirements. 
 
2. Male or non-pregnant, non-lactating females. 
 
3. Age ≥ 18 years. 
 
4. Has documented, untreated HIV-1 infection with either: 
 
a) AIDS with any CD4 cell count (AIDS-defining conditions are listed within Appendix 3). 
 
Or 
 
b) Severe bacterial infection (BI)† and must have a CD4 cell count < 200/µl within 30 days 
prior to study entry. 
 
Or 
 
c) Are asymptomatic with CD4 cell count < 100/µL within 30 days prior to study entry and 
must have an entry HIV viral load > 1000 copies/mL. 
 
Or 
 
d) Currently receiving treatment for OI‡.  
i. 
Subjects with other serious OIs, including other AIDS-defining and AIDS-related OIs 
for which appropriate therapy other than ART exists are eligible, but Investigator 
approval must be obtained. 
ii. 
Current OI treatment must have been started ≤ 14 days prior to study entry but can 
have been discontinued prior to study entry. 
 
5. Have the ability to take oral medications. 
 
6. Females of childbearing potential and heterosexually active males must be willing to use a 
highly effective method of contraception and be willing to continue practising these birth 
control methods during the trial and for at least 30 days after the last dose of study 
medication.  See Appendix 7 for further details.  
 
† A severe BI consists of any of bacterial pneumonia, IBI or any bacterial infectious disorder with grade 3 severity or requiring 
unscheduled hospital admission. An IBI is defined as the isolation of a bacterial organism from a normally sterile body site, 
or for bacterial nucleic acid to be detected at a normally sterile body site. Sterile body sites include blood, cerebrospinal 
fluid, pleural fluid, pericardial fluid, peritoneal fluid, joint fluid, bone aspirate, or a deep tissue abscess. 
‡  Including Pneumocystis jrovecii pneumonia [PCP]; disseminated histoplasmosis; cytomegalovirus [CMV] infection; 
toxoplasmic encephalitis; other atypical non-tuberculous, non-MAC mycobacterial infections; or other serious, invasive 
bacterial infections (IBI). 

 
 
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Such methods include: 
• 
True abstinence from penile-vaginal intercourse, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), and withdrawal are not 
acceptable methods of contraception). 
• 
Non-hormonal Intrauterine device or non-hormonal intrauterine system that 
meets the effectiveness criteria as stated in the product label. 
• 
Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject.  
• 
Combined (oestrogen and progesterone containing) hormonal contraception 
associated with the inhibition of ovulation*: 
• 
Oral 
• 
Intravaginal  
• 
Transdermal 
• 
Bilateral tubal occlusion 
 
• 
Note: Non-childbearing potential is defined as either post-menopausal (had amenorrhea for 
at least 12 months and have an FSH (follicle stimulating hormone) of greater than 40 IU/L or, 
if FSH testing is not available, they have had amenorrhea for 24 consecutive months) or 
physically incapable of becoming pregnant with documented  hysterectomy , bilateral 
salpingectomy or bilateral oophorectomy). 
*If a patient is randomised to Symtuza, an alternative highly effective method of 
contraception should be used  
5.2 Exclusion criteria 
1. Any ARV prior to study entry. 
 
2. Systemic cancer chemotherapy within 30 days prior to study entry, or current treatment for 
cancer (with the exception of Kaposi’s sarcoma) or lymphoma. 
 
3. Current or anticipated use of contraindicated medications (see Summary of Product 
Characteristics (SmPC) for Symtuza® and Biktarvy®) or anticipated systemic chemotherapy 
during study enrolment (administration of any contraindicated medication must be 
discontinued at least 30 days prior to the baseline visit and for the duration of the study). 
 
4. Known resistance to the components of study medications (see section 6.1.3 for more details). 
 
5. History or symptoms of advanced renal and/or hepatic impairment.  Such as, kidney failure 
requiring dialysis; eGFR <30 mL/min; hepatic transaminases (AST and ALT) > 5 x upper limit of 
normal (ULN); or, platelet count <50,000. 
 
6. Current drug or alcohol use that, in the opinion of the Investigator, would cause interference 
with the study. 
 
7. Cryptococcal meningitis or active TB or current or expected treatment requiring Rifampicin or 
Rifabutin (patients with expected latent TB will have a TB test (IGRAs e.g. ELISPOT, 
QuantiFERON etc.) at their screening visit). 

 
 
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8. History or presence of allergy to the study drugs or their components, or drugs of their class. 
 
9. Using any concomitant therapy disallowed as per the product labelling for the study drugs. 
 
10. Any investigational drug within 30 days prior to the study drug administration. 
 
11. Patients with severe (Child Pugh class C) hepatic impairment. 
 
12. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during 
the study. 
6 TRIAL PROCEDURES  
The schedule of assessments is summarised in Appendix 1. 
Please note that if additional tests/procedures are required in accordance with local practice, then these 
should still be performed (no usual tests/procedures should be withheld from the patients during the 
study). 
6.1 Recruitment 
Following full written informed consent, sites must keep a record of all screening and enrolled 
participants using screening and enrolment logs.  Diagnostic tests procedures may be used in 
determining eligibility however, written informed consent must be obtained prior to any study specific 
procedures.  All information collected for eligible participants will be pseudo-anonymised and 
recorded in the Investigator Site File (ISF). 
All eligible consented participants will be given a unique study identifier via an electronic study 
database. 
Anonymised information that will be collected: 
• 
age 
• 
gender 
• 
ethnicity  
• 
whether the patient is enrolled or not enrolled 
• 
if the patient is deemed ineligible, then the reason for this; or if they are eligible but choose 
not to participate, then their reason for declining (where available) 
6.1.1 
Patient identification 
Patients will be identified through clinic visits by their direct study medical care team and visits will be 
captured on a participant screening log.  Additionally, Investigators may use advertisements; however, 
these must be approved by the Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
prior to use. 
6.1.2 
Screening 
Written informed consent must be obtained from the subject prior to performing any study related 
evaluations or procedures. 

 
 
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Subjects will be provided with written information about the study in the form of a subject information 
sheet and will be allowed adequate time for questions and to consider the study before agreeing to 
participate.  It will be the responsibility of the Investigator or co-investigator to obtain written 
informed consent prior to undertaking any procedures detailed in the protocol. This responsibility may 
be delegated to other suitably trained personnel if allowed according to country-specific regulations 
and approved by the local IEC. 
The Investigator or designee must provide adequate explanation of the aims, methods, objectives and 
potential hazards of the study.  It must also be explained to the subject that they are free to refuse or 
withdraw from the study for any reason without detriment to their future care or treatment. 
See Appendix 1 for details of screening assessments required. 
6.1.3 
Resistance Testing and Results 
Resistance test results obtained at screening may influence randomisation.  
If resistance data of the RT, protease (Table 1 and 2), or integrase gene as described below become 
available after screening but before randomisation patients should not be randomised (and will be 
seen to be screen failures).  
If data becomes available after randomisation, patients may be considered to switch to the other 
treatment arm at the investigator’s discretion in the following scenarios: 
1. Patients randomised to the DRV arm may be considered to switch to the BIC arm only if they 
have any of the resistance mutation patterns as described in Table 1. In these patients, only 
TAF and FTC would have full ARV activity. The decision should be made by the investigator 
after consultations with the LAPTOP study team. 
Table 1:  Resistance mutation patterns leading to intermediate of high-level resistance against DRV. 
Resistance 
Mutation pattern21 
Darunavir 
V32I 
L33F 
K43T 
M46I 
I47V 
I54L/M 
G73T/S 
L76V 
V82A 
I84V 
L89V 
L90M 
Intermediate 
 
 
 
 
 
L 
 
 
 
 
 
+ 
Intermediate 
 
+ 
 
 
 
L 
T 
 
 
+ 
 
+ 
Intermediate 
 
 
 
+ 
 
 
 
+ 
 
+ 
 
 
High 
+ 
 
+ 
+ 
+ 
M 
 
 
+ 
 
 
+ 
High 
+ 
+ 
 
+ 
+ 
M 
 
 
+ 
 
 
+ 
High 
+ 
 
 
 
 
M 
S 
 
 
+ 
+ 
+ 
 
2. Patients randomised to the DRV or BIC arm may be considered to remain in their treatment 
arm or to switch to an alternative regime (e.g. PI + INI) only if they have any of the resistance 
mutation pattern as described in Table 2. Table 2 describes RT inhibitor associated resistance 
mutation pattern, in which intermediate or high-level resistance against FTC and TFV has to 
be expected. In these situations, only DRV or BIC would have full ARV activity. The decision to 
remain on therapy or to switch should be made by the investigator after consultations with 
the LAPTOP study team. 
 
Table 2:  
Resistance mutation patterns leading to intermediate of high-level resistance against FTC or tenofovir disoproxil 
fumarate (TDF). 
Resistance  
Mutation pattern 
FTC 
TDF 
M41L 
E44D 
K65R 
D67N 
T69D 
K70R 
M184V/I 
L210W 
T215Y 
K219N/Q 
High 
Interm 
+ 
 
 
 
 
 
V 
+ 
+ 
 
High 
Interm 
 
 
 
+ 
 
+ 
V 
 
+ 
Q 

 
 
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High 
Interm 
+ 
 
 
+ 
 
 
V 
+ 
+ 
 
High 
Interm 
 
 
+ 
 
 
 
V 
 
 
 
High 
Interm 
 
 
+ 
 
 
 
I 
 
 
 
High 
High 
+ 
+ 
 
+ 
 
 
 
+ 
+ 
 
High 
High 
+ 
+ 
 
+ 
+ 
 
V 
+ 
+ 
 
High 
High 
+ 
+ 
 
+ 
 
 
V 
+ 
+ 
N 
 
If any primary integrase strand transfer inhibitor resistance mutation (T66I/A/K, E92Q/G, T97A, F121Y, 
Y143R/H/C, S147G, Q148H/K/R, N155H/S, R263K) is identified please consult the LAPTOP study team.  
Resistance mutation patterns leading to possible resistance against BIC are Q148H/R/K plus 2 or more 
of the following mutations: (G140A/C/S, T97A, L74M, or E138A/K). 
 
6.1.4 
Consent  
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at 
their site and must ensure that any person delegated responsibility to participate in the informed 
consent process is duly authorised, trained and competent to perform their role according to the 
ethically approved protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki.  
Informed consent must be obtained prior to the participant undergoing procedures that are 
specifically for the purposes of the trial and are outside standard routine care at the participating site. 
The right of a participant to refuse participation without giving reasons must be respected.   
The participant must remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing his/her further treatment and must be provided with a contact point where 
he/she may obtain further information about the trial. Where a participant is required to re-consent 
or new information is required to be provided to a participant it is the responsibility of the PI to ensure 
this is done in a timely manner.  
The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate 
voluntarily in an environment free from coercion or undue influence. 
6.1.5 
The randomisation scheme 
Patients will be randomly allocated (1:1) to receive a BIC containing regimen or boosted PI containing 
regimen for 48 weeks. Randomisation will be computer-generated in permuted blocks and stratified 
by country and baseline CD4 cell count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL).  
Randomisation will be done at the baseline visit (date of the study treatment initiation). This study is 
open-label, therefore, all investigators, site pharmacists, study nurses and subjects will be unmasked 
and aware of the treatment allocation throughout the study. 
6.1.6 
Method of implementing the allocation sequence 
The method will be detailed in the randomisation plan. 
6.2 Baseline data 
See Appendix 1 for details of assessments required. 
6.3 Treatment Phase Assessments 
See Appendix 1 for details of assessments required. 

 
 
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6.4 Follow-Up/Early Termination Visit (ETV) 
In the case of early termination, every attempt will be made to ensure the subject has a termination visit.  
Patients will be encouraged to attend for remaining visits and complete study assessments to week 48 
even if they are no longer taking study medication. 
 
See Appendix 1 for details of assessments required. 
6.5 Withdrawal criteria  
A subject is free to withdraw from the study at any time.  In addition, the Investigator may decide, for 
reasons of medical prudence, to stop study medication (e.g. lack of efficacy).   
All patients who discontinue study medication will be followed up and encouraged to attend for 
study visits up until week 48. 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn from 
the study and the reason for withdrawal recorded in the Case Report Form (CRF). 
Study medication may also be discontinued in the following instances: 
1. If the subject withdraws their consent. 
2. If the investigator considers in the interest of the subject (i.e. intercurrent illness, 
unacceptable toxicity) that it is best for them to stop study medication. 
3. The subject fails to comply with the protocol requirements or fails to cooperate with 
investigator. 
4. Pregnancy during the study (for patients receiving B/F/TAF, the study medication must be 
discontinued). 
5. Discontinuation of the study at the request of the Sponsor, regulatory agency, or an IRB/IEC. 
The date and reasons for stopping medication will be clearly stated on the subject’s CRF and source 
document. Every attempt should be made to arrange follow up visits for subjects who are withdrawn 
from study medication. This visit should involve assessments as outlined in Appendix 1. 
Subjects withdrawing from the trial should be offered alternative treatment as per the local standard 
of care by the Investigator. 
Additional subjects may be recruited to account for any withdrawals should this be deemed necessary 
by the statistician or CI. 
6.6 Storage and analysis of samples 
All samples (with the exception of centrally analysed resistance samples) will be analysed at each site’s 
local laboratory. After analysis the samples will be destroyed in accordance with local laboratory 
requirements. Throughout the study a total of 234ml of blood will be collected from each patient, this 
equates to 26ml per visit. 
Collection, processing and storage instructions will be detailed in a separate laboratory manual.  
6.6.1 
Resistance testing 
Next generation sequencing (deep sequencing) may be performed centrally to evaluate the 
significance of the HIV-1 mutations detected by this method, which are identified during standard 
population sequencing of the HIV viral load response. 

 
 
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Blood samples for these tests will be taken at the baseline visit and treatment phase visits (Week 4, 8, 
12, 24, 36 and 48).  A sample will be taken at the ETV for patients with virological failure identified 
outside of a scheduled visit.   
Samples will be shipped on a periodic basis from the sites to ACM Global for central storage and 
shipped to Monogram Biosciences for analysis. 
At the end of the study, samples taken from patients that do not have virological failure will be 
destroyed, either locally, or at ACM Global. 
Collection, processing and storage instructions will be detailed in a separate laboratory manual. 
See Appendix 1 for details of assessments required. 
6.7 Virological Failure 
Virological failure is defined as: 
Insufficient virological response, either:  
o HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
o Viral load > 50 HIV-1 RNA copies/mL at week 48  
Or viral rebound, which is subsequently confirmed at the following scheduled or unscheduled visit, 
defined as either: 
o Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL  
o Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose viral 
load has never been suppressed below 50 copies/mL 
Local resistance testing should also be carried out in the event of viral failure from the first sample 
and patients should discontinue study medication and receive rescue medication at investigators 
discretion. 
6.8 End of trial 
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial in any 
country. 
The sponsor must notify the Competent Authority (CA) and main IRB/IEC of the end of a clinical trial 
within 90 days of its completion.  
7 TRIAL MEDICATION 
Name and description of investigational medicinal product(s) 
At baseline, participants will be enrolled into one of two treatment arms, either a BIC-based regimen 
or a DRV-based regimen: 
INI containing regimen (BIC-based regimen): One combined B 50mg/F 200mg/TAF 25mg tablet taken 
orally once daily for up to 48 weeks without regard to food. 
Boosted PI regimen (DRV-based regimen):  One combined D 800mg/C 150mg/F 200mg/TAF 10mg 
tablet taken orally once daily for up to 48 weeks with the addition of food. 
Participants will take the study medication from baseline, as randomised, to week 48. 

 
 
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Please refer to the study specific pharmacy manual for more information.  
7.1 Summary of Product Characteristics (SmPC), Investigator’s Brochure (IB) and Reference Safety 
Information (RSI) 
Information about Emtricitabine (Emtriva®, F/FTC) 
Emtricitabine (5-fluoro-1-[(2R, 5S)-2-(hydroxymethyl)-[1, 3]-oxathiolan-5-yl] cytosine, FTC) is a NRTI 
that has demonstrated potent and selective inhibition of the HIV. In HIV-infected adults, FTC is 
administered as a 200mg QD dose concurrently with other ARV drugs. The 200mg FTC capsule 
formulation was approved by the United States (US) FDA for marketing on 2 July 2003 and is available 
under the name Emtriva®. In the European Union (EU), marketing authorisation was granted for both 
the 200mg Emtriva® capsule formulation and a 10mg/mL Emtriva® oral solution formulation on 24 
October 2003, with indications for the treatment of HIV infection concurrently with other ARV drugs 
in both adult and pediatric patients. 
Further information is available in the current Prescribing Information for Emtriva®. 
Information about Tenofovir alafenamide (TAF, GS-7340) 
Tenofovir alafenamide (GS-7340, TAF) is a second-generation oral prodrug of tenofovir (TFV), a 
nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolised intracellularly to the 
active metabolite, tenofovir diphosphate, a competitive inhibitor of HIV-1 RT that terminates the 
elongation of the viral DNA chain. The intracellular metabolism of TAF and TFV are consistent with the 
600-fold enhancement in anti-HIV activity in cell culture of TAF over TFV. 
Further information about the co-formulated version of TAF/FTC is available in the current Prescribing 
Information for Descovy®. 
Information about Darunavir (Prezista ®, D/DRV) 
Prezista® is a PI which demonstrated potent inhibition of the HIV.  DRV received marketing 
authorisation valid throughout the EU 12/02/2007. Co-administered with low dose ritonavir is 
indicated in combination with other ARV medicinal products for the treatment of HIV-1 infection in 
adult and paediatric patients from the age of 3 years and at least 15 kg body weight. Co-administered 
with cobicistat (C) is indicated in combination with other ARV medicinal products for the treatment of 
HIV-1 infection in adult patients. In ART-naïve adult patients the recommended dose regimen is 800 
mg once daily with C 150 mg once daily or ritonavir 100 mg once daily taken with food. 
Further information about DRV is available in the current Prescribing Information for Prezista®. 
 
Information about Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide (D/C/F/TAF) fixed 
dose combination (Symtuza®) 
Symtuza® is a boosted PI indicated for the treatment of HIV-1 infection in adults and adolescents (aged 
12 years and older with body weight at least 40 kg). Symtuza® received marketing authorisation valid 
throughout the EU in September 2017.  The recommended dose regimen in adults and adolescents 
aged 12 years and older, weighing at least 40 kg, is one tablet taken once daily with food. Each film 
coated tablet contains 800 mg of D (as ethanolate), 150 mg of C, 200 mg of F, and 10 mg of TAF.  
Further information about the D/C/F/TAF FDC is available in the current Prescribing Information for 
Symtuza®. 
The Reference Safety Information for this regimen will be the Summary of Product Characteristics for 
Symtuza®. 
 

 
 
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Bictegravir (BIC) 
BIC is an inhibitor of HIV-1 integrase that is being evaluated for the treatment of HIV-1 infection. 
Antiviral testing has shown that BIC is active against a broad panel of HIV-1 viral lab strains and clinical 
isolates. BIC is fully active against a panel of mutant viruses with resistance to NRTIs, NNRTIs, and PIs. 
Integrase mutant viruses that are resistant to the INSTIs raltegravir (RAL) and elvitegravir (EVG) remain 
largely sensitive to BIC. Gilead Sciences (Gilead) has co-formulated BIC with the NRTI F and TAF into 
an FDC tablet that is suitable for once-daily use.  
Further information about the B/F/TAF fix-dose tablet is available in the current Prescribing 
Information for Biktarvy®. 
The Reference Safety Information for this regimen will be the Summary of Product Characteristics for 
Biktarvy®. 
7.2 Drug storage and supply  
Investigators are to ensure that the investigational medicinal product (IMP) is only used in accordance 
with the protocol. Drug supplies will be kept in a secure, limited access storage area under the 
recommended storage conditions, and accessible only to those authorised by the investigator to 
dispense to eligible subjects. 
The investigator will ensure that records are maintained showing the receipt and dispensation for all 
study supplies.  A drug accountability log will be kept with the investigational supplies for 
reconciliation purposes.  This should be used to record the identification of the subject to whom the 
IMP was dispensed, the date and quantity dispensed, and the quantity unused/returned by the 
subject. This will be verified by the study monitor. 
Partially used or empty containers may be destroyed by the pharmacy/designee at local site only after 
the study monitor has completed drug accountability. The pharmacy/designee are required to 
document destruction for verification by the sponsor.  
Further information can be found in the pharmacy manual. 
7.3 Preparation and labelling of Investigational Medicinal Product 
Both the INI containing regimen (B/F/TAF) and the boosted PI regimen (D/C/F/TAF) tablets will be 
labelled with Annex 13 compliant labels and QP certified by PCI Pharma Services; who will supply 
directly to each site on request of the sponsor. 
Further information can be found in the pharmacy manual. 
 
7.4 Dosage schedules 
Patients will be randomised into one of two treatment arms. 
INI containing regimen (BIC-based regimen): One combined B 50mg/F 200mg/TAF 25mg tablet taken 
orally once daily for up to 48 weeks without regard to food. 
Boosted PI regimen (DRV-based regimen):  One combined D 800mg/C 150mg/F 200mg/TAF 10mg 
tablet to be taken orally once daily for up to 48 weeks with the addition of food. 
7.5 Dosage modifications  
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Treatment modification will be captured as a secondary endpoint only and modifications will be based 
on the treating physician’s judgement. 
7.6 Known drug reactions and interaction with other therapies 
See section 8.2 and RSI. 
Drugs that affect the study medication and that are affected by the use of the study medication 
accordingly must be reviewed by the Investigator and/or avoided. 
7.7 Concomitant medication 
For a full list of contraindicated medications, please refer to the current SmPC for both Biktarvy® and  
Symtuza® (details can be found at https://www.medicines.org.uk/emc/). 
Prophylaxis for specific OI or TB shall be performed as per standard of care.  Reference can be made 
to the EACS guidelines. 
7.8 Trial restrictions  
Please refer to inclusion and exclusion criteria listed in sections 5.1 and 5.2. 
7.9 Assessment of adherence 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each 
visit.  The outcome of this questioning should be documented in the patient notes. Issues of adherence 
should be reported to the study monitor.  
All subjects should return unused medication and containers at weeks 12, 24, 36 and 48 for pharmacy 
accountability purposes (see section 7.2). 
7.10 Provision of treatment after the end of the trial 
No post trial medication will be provided to patients.  Following their last treatment visit at Week 48 
patients will receive treatment as per local standard of care. 
 
8 PHARMACOVIGILANCE 
8.1 Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal product 
has been administered, including occurrences which are not necessarily caused 
by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an investigational 
medicinal product which is related to any dose administered to that participant. 

 
 
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The phrase "response to an investigational medicinal product" means that a 
causal relationship between a trial medication and an AE is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as ARs. 
Serious Adverse Event 
(SAE) 
An SAE is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the 
above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which the participant was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Serious Adverse Reaction 
(SAR) 
An AE that is both serious and, in the opinion of the reporting Investigator, 
believed with reasonable probability to be due to one of the trial treatments, 
based on the information provided. 
Suspected 
Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A SAR, the nature and severity of which is not consistent with the information 
about the medicinal product in question set out: 
• in the case of a product with a marketing authorisation, in the SmPC  for 
that product 
• in the case of any other investigational medicinal product, in the IB 
relating to the trial in question 
 
“Severe” is often used to describe intensity of a specific event, which may be of relatively minor 
medical significance. “Seriousness” is the regulatory definition supplied above. 
8.2 Operational definitions for (S)AEs  
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with the study treatments. An AE can therefore 
be any unfavourable and/or unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to the IMP. 
AEs observed by the Investigator, or reported by the subject, and any remedial action taken, will be 
recorded in the subject’s CRF and should be verifiable in the subject’s notes throughout the study.  
The nature of each event, time of onset after drug administration, duration and severity will be 
documented together with the Investigator’s opinion of the causal relationship to the investigational 
product (unrelated, unlikely, possible, probable, and definite). 
All subjects experiencing AEs, whether considered associated with the use of the study medication or 
not, must be monitored until the symptoms subside and any clinically relevant changes in laboratory 
values have returned to baseline, or until there is a satisfactory explanation for the changes observed. 

 
 
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Procedures such as surgery should not be reported as AEs.  However, the medical condition for which 
the procedure was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted on the CRF. 
Planned procedures such as surgery scheduled prior to the subject’s enrolment into the study do not 
need to be reported as AEs if these are documented as planned at the screening visit. 
Clinically significant changes in physical examination and blood safety profiles should also be recorded 
as AEs. 
8.2.1 
Assessment of intensity 
Severity should be recorded and graded according to the ACTG Grading Scale (Appendix 2).  
Note: There is a distinction between the seriousness and the intensity of an AE. Severe is a measure 
of intensity; thus, a severe reaction is not necessarily an SAE. For example, a headache may be severe 
in intensity but would not be classified as serious unless it meets one of the seriousness criteria for 
serious events. 
All events deemed to be Grade 4 (potentially life threatening) according to the ACTG grading scale 
should be routinely reported as an SAE. However, there may be occasions where in the investigator’s 
clinical judgement they do not consider the event to be life threatening therefore they do not consider 
the event to meet the definition of an SAE. In these cases, the investigator must document clearly in 
the participants source documentation that the Grade 4 event has been assessed and why in their 
clinical judgement they do not consider the event to be life threatening.   
8.2.2 
Assessment of causality 
The relationship to study drug of each AE will be assessed by the PI (or a delegated clinician) using the 
following definitions: 
DEFINITE: 
distinct temporal relationship with drug treatment. Known reaction to agent or 
chemical group or predicted by known pharmacology. Event cannot be explained by 
subject’s clinical state or other factors. 
PROBABLE: 
reasonable temporal relationship with drug treatment. Likely to be known reaction to 
agent or chemical group or predicted by known pharmacology. Event cannot easily be 
explained by subject’s clinical state or other factors. 
POSSIBLE: 
reasonable temporal relationship with drug treatment. Event could be explained by 
subject’s clinical state or other factors. 
UNLIKELY: 
poor temporal relationship with drug treatment. Event easily explained by subject’s 
clinical state or other factors. 
UNRELATED: 
the event occurs prior to dosing. Event or intercurrent illness is due wholly to factors 
other than drug treatment. 
8.2.3 
Collection and Follow up of Adverse Events 
All AEs, however minor, will be documented in the CRF whether or not the Investigator considers the 
event to be treatment related. 
The AE reporting period will be from consent until the subject’s final study visit.  In addition, any 
untoward event that may occur subsequent to the reporting period that the Investigator assesses as 
possibly, probably or definitely related to the study drug medication should also be reported as an AE. 
AEs not already reported in the RSI for the study drugs will be considered unexpected.  

 
 
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AEs may be directly observed, reported spontaneously by the subject or by questioning the subject at 
each study visit. 
All AEs should be followed up until they are resolved or the subject’s participation in the study ends 
(i.e. until the final CRF is completed for that subject).  In addition, all serious and non-serious AEs 
assessed by the Investigator as possibly related to the investigational medication should continue to 
be followed up to last subject visit.  Such events should be followed until resolution, until no further 
change can reasonably be expected, or until 30 days following last subject visit.   
8.3 Serious Adverse Events (SAEs) 
Definition of an SAE can be found in section 8.1. 
The SAE should be reported to the sponsor using the study specific SAE form within 24 hours of a 
member of the study team becoming aware of the event via the fax number provided on the study 
pharmacovigilance plan. 
8.3.1 
Recording and Reporting of SAEs and SUSARs 
All SAEs/SUSARs occurring from the time of written informed consent until 30 days post cessation of 
trial treatment must be recorded on the study specific SAE Form and sent to the sponsor within 24 
hours of the research staff becoming aware of the event.  
For each SAE/SUSAR the following information will be collected: 
• 
full details in medical terms and case description 
• 
event duration (start and end dates, if applicable) 
• 
action taken 
• 
outcome 
• 
seriousness criteria 
• 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the Investigator 
• 
whether the event would be considered expected or unexpected 
Any change of condition or other follow-up information should be sent to the sponsor as soon as it is 
available or at least within 24 hours of the information becoming available. Events will be followed up 
until the event has resolved or a final outcome has been reached.   
All SAEs assigned by the PI or delegate (or following central review) as both suspected to be related 
to IMP-treatment and assessed by the CI as unexpected will be classified as SUSARs. The sponsor will 
inform the CA, the IRB/IEC and the funder as appropriate of SUSARs within the required expedited 
reporting timescales. 
8.4 Responsibilities 
8.4.1 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness and causality using the RSI approved 
for the trial. 
2. Ensuring that all SAEs and SARs (including SUSARs) are recorded and reported to the 
Sponsor within 24 hours of becoming aware of the event and provide further follow-
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3. Ensuring that SAEs and SARs (including SUSARs) are followed up with the Sponsor if a 
record of receipt is not received within 2 working days of initial reporting.  
4. Ensuring that AEs and ARs are recorded and reported to the Sponsor in line with the 
requirements of the protocol.  
8.4.2 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in reviewing seriousness and causality of SAEs reported.  
3. Using medical judgement in assignment of expectedness for all SARs reported using 
the approved RSI for the trial. 
4. Review of specific SAEs and SARs in accordance with the trial risk assessment, protocol 
and as detailed in the Trial Risk Based Monitoring Plan. 
5. Ensure immediate review of all SUSARs.  
6. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System 
coding to all SAEs and SARs as needed. 
7. Preparing the clinical sections and final sign off of the Development Safety Update 
Report (DSUR). 
8.4.3 
Sponsor: 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according 
to the trial protocol.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer for 
the ongoing assessment of the risk / benefit according to the Trial Risk Based 
Monitoring Plan. 
3. Reporting safety information to the independent oversight committees identified for 
the trial (Data Safety Monitoring Board (DSMB)/Trial Steering Committee (TSC)) 
according to the Trial Risk Based Monitoring Plan and committee charter documents. 
4. Expedited reporting of SUSARs to the CA and IRB/IEC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. Checking for (at least annually) and notifying PIs of updates to the RSI for the trial. 
7. Preparing standard tables and other relevant information for the DSUR in collaboration 
with the CI and ensuring timely submission to the CA and IRB/IEC. 
8.4.4 
Data Safety Monitoring Board (DSMB): 
In accordance with the DSMB Charter, periodically reviewing overall blinded safety data to determine 
patterns and trends of events, or to identify safety issues, which would not be apparent on an 
individual case basis.  
8.4.5 
Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing unblinded safety 
data and liaising with the DSMB regarding safety issues. 
8.5 Notification of deaths 
Any AE, AR or unexpected AR that results in death should be reported as an SAE.  See section 8.3 for 
SAE reporting format and timelines. 
Deaths occurring more than 30 days after the final dose, which are considered to be unrelated to the 
study medication, should not be reported as an SAE. 

 
 
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8.6 Pregnancy reporting  
Pregnancy information for all female participants who become pregnant while participating in the 
study will be collected on the study specific Pregnancy Reporting Form and should be reported to the 
Sponsor within 24 hours of becoming aware of the pregnancy or the pregnancy outcome.  The 
participant will also be followed up to determine the outcome of the pregnancy, which will also be 
reported to the sponsor.  
In the event of pregnancy, the participant may be withdrawn from the study (see Section 6.5). 
Pregnancies in female partners of male participants should be reported as a special reporting situation 
(see Section 8.10). 
8.7 Overdose  
All participants should be counselled about the importance of taking the medications as prescribed 
and they should understand the quantity of medicine they should be taking. Participants must be told 
to contact their clinic immediately if they take too much medication.  If the overdose fits the criteria 
of an SAE (see Section 8.1) it should be reported appropriately. 
8.8 Reporting urgent safety measures  
It is the responsibility of the investigator to apply the appropriate level of Urgent Safety Measure 
(USM) for the safety and protection of each participant in this study in order to prevent harm.  USMs 
may be applied immediately without prior approval from the sponsor, CA or IRB/IEC.  However, they 
must be reported to the sponsor immediately (within 24 hours) who will then inform the CA and 
IRB/IEC according to local regulation.   
8.9 Development Safety Update Reports  
The sponsor will provide (in addition to the expedited reporting above) DSURs once a year throughout 
the clinical trial, or on request, to the CA and IRB/IEC. 
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of 
the trial each year until the trial is declared ended. 
8.10 Special Reporting Situations 
Special reporting situations should be reported via email to the sponsor within 24 hours of the 
research staff becoming aware of the event (as for SAEs).   
The special situations include: 
• 
Pregnancy exposure (maternal and paternal), breastfeeding and AEs in infants following 
exposure from breastfeeding 
• 
Overdose (other than as defined in section 8.7), suspected abuse/misuse of the study product, 
and dependence 
• 
Medication error 
• 
DDI 
• 
Inadvertent or accidental exposure to the study product (including occupational exposure) 
• 
Any failure of expected of pharmacological or medical device action (i.e. lack of effect) of study 
product 
• 
Unexpected therapeutic or clinical benefit from use of the study product 

 
 
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• 
Suspected transmission of an infectious agent via the study product 
• 
Expired drug use and falsified medicine 
• 
Off-label use of study product 
Product Quality Complaint (PQC): Any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance 
of a study product after it is released for distribution. A complaint is any indication of the failure of 
the product to meet consumer or user expectations for quality or to meet performance specifications. 
It may allege an AR, injury, or malfunction associated with the use of the product. It may also involve 
the design, literature, packaging, advertising, availability, physical appearance, or promotion of a 
product. 
9 STATISTICS AND DATA ANALYSIS 
9.1 Sample size calculation 
In the ANRS 146 OPTIMAL trial [Levy et al.], of late presenters, the proportion of patients with severe 
morbidity (new adverse drug event (ADE), other HIV related diseases, serious non-AIDS events, IRIS 
and death) was estimated at 12.2% per year in the boosted PI arm. The virological failure was 
estimated at 20% at week 48 in the DRV/r group of the IMEA 040 DATA study (Slama L et al) that 
recruited a similar population. As a few subjects will meet more than one of these criteria, we assumed 
a cumulative probability of failure at 25% at 48 weeks in the PI regimen group. 
A total of 404 evaluable subjects, randomized in a 1:1 ratio to 2 treatment groups (202 subjects per 
treatment group), achieves at least 80% power to detect a non-inferiority margin of 1.606 in the 
hazard ratio, which corresponds to a 12% difference in the cumulative probability of failure rate 
between INI-based regimen group (37%) and PI-based regimen group (25%), with 97 events required. 
The sample size and power calculation assumes that the cumulative probability of failure is 25% for 
the PI regimen group and 23% for the INI-based regimen group (i.e. the expected hazard ratio is 0.909), 
using a non-inferiority margin of 1.606 in hazard ratio and a two-sided 95% confidence interval (CI). 
The sample size and power calculation were made using the statistical software package nQuery 
Advanced, non-inferiority testing of two survival curves using cox regression module (Version 8.1.2.0).  
With an estimated ~7.5% drop off rate/year, we plan to enroll 220 subjects per group to ensure we 
have sufficient power for this per-protocol analysis. 
Superiority of INI-based regimen group versus PI-based regimen group will be evaluated after the non-
inferiority is established. With an ITT analysis, 440 subjects and 78 events, a two-sided log-rank test 
at an alpha level of 0.05 will achieve at least 80% power to detect a 50% reduction in hazard rate in 
INI-based regimen (i.e. the hazard ratio is 0.5). A 50% reduction in hazard rate means that INI-based 
regimen could decrease the risk by 11.6% (25% for PI- vs 13.4% for INI- based regimen). 
9.2 Planned recruitment rate 
In the ANRS 146 OPTIMAL trial, in which similar patients were enrolled (late presenters with low CD4 
cell count or ADE), 10% of screened patients were not eligible. Based on this information, we 
estimated that about 489 patients should be screened. Centres of NEAT ID Network with infectious 
disease units for inpatient and outpatient care will be the prioritised study sites of the LAPTOP Trial. 
We expect that about 45 sites in total across eight European countries. Therefore, we estimated that 
about 7-15 patients should be screened per site. 

 
 
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9.3 Statistical analysis plan 
These analyses will assess the efficacy and safety of BIC containing regimen in comparison with the 
boosted PI containing regimen.  
All randomised patients who received at least 1 time any study treatment will be included in the 
intent-to-treat (ITT) analysis population. Of note patients lost-to follow-up or violating the protocol 
will not be excluded from the ITT population. Patients who switch treatment to another will be 
analysed as if they are remained in their initial randomisation group. All participants who are lost to 
follow-up or discontinued the study when they are endpoint free at time of leaving the study will be 
censored at the time of leaving the study. We will use time-to-event methods, including Kaplan–Meier 
survival curves and Cox proportional-hazards models to account for all participants in the analysis. The 
per-protocol population will include all patients from the ITT population except those who did not 
fulfil the inclusion/exclusion criteria, who withdrew their consent, gave up, lost to follow-up or 
discontinued early study medication for any reasons other than any component of the primary 
endpoint. 
9.3.1 
Summary of baseline data and flow of patients 
All continuous variables will be summarised using the following descriptive statistics: n (non-missing 
sample size), mean, standard deviation (SD), 1st quartile, median, 3rd quartile, maximum and 
minimum. The frequency and percentages (based on the non-missing sample size) of observed levels 
will be reported for all categorical variables.  
The number of patients and the flowchart of the study will be presented. The period of enrolment and 
the total number of patients screened to be included in the study will be presented. The number of 
ineligible patients and the total number of randomised patients will be presented. The number of 
patients who never take the study treatment will also be presented by group and those who remained 
on the study treatment up to week 48 will be presented. 
9.3.2 
Primary outcome analysis 
The primary outcome analysis will be performed with both ITT population and per-protocol 
population. The primary endpoint is the occurrence of a severe morbidity (virological failure; death 
related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS; new ADE; new serious 
non-AIDS events; and clinically relevant AEs of any grade leading to study treatment discontinuation). 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
adjustments for stratification factor (participating country and baseline CD4 cell counts). Separate 
analyses for each component of the primary endpoint will be done. Kaplan-Meier curves will be 
plotted for the primary endpoint and its component. 
9.3.3 
Secondary outcome analysis 
All secondary outcome analysis will be done with the ITT population. The p-values will be two-tailed, 
with a significant level of 0.05. 
The proportion of patients with HIV-ribonucleic acid (RNA) viral load <50 copies/mL at week 48 will be 
analysed using the snapshot approach. Fisher’s exact test will be used to compare the estimated 
proportion between the two groups.  
A genotypic resistance test will be performed in all patients with virological failure. Drugs resistance 
mutations will be identified from the International AIDS Society (IAS)-USA resistance testing panel (last 
version at the time of analysis) and for BIC we will use IAS, Agence Nationale de Recherches sur le 
SIDA (National Agency for AIDS Research) (ANRS) or Royal College of Physicians (RCP) lists to perform 
the analysis whenever they will be made available. Resistance to BIC will also be identified using 

 
 
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phenotypic resistance test. Fisher’s exact test will be used to compare the presence of at least one 
drug resistance mutation between the 2 groups.  
The median time to reach CD4 cell count >200/µl will be estimated using the Kaplan-Meier method, 
censoring at week 48 or last follow-up date if not seen at week 48. Time to reach CD4 cell count 
>200/µl will be defined as the time between the date of study treatment initiation (baseline, week 0) 
and the date of which patient reached CD4>200/µl. The log-rank test will be used to compare the two 
survival functions. The p-values will be two-tailed, with a significant level of 0.05. The proportion of 
patients with CD4 cell count <350/µl at week 48 will be done with the ITT population, with the last 
observation carried forward (LOCF) approach. Fisher’s exact test will be used to compare the 2 groups.  
The median change in CD4/CD8 ratio from baseline to week 48 will be analysed with the ITT 
population, with the LOCF approach. The non-parametric Mann Whitney test will be used to compare 
the change from baseline between the 2 groups.  
The incidence of IRIS will be analysed with the Kaplan-Meier method. The Log-rank test will be used 
to compare the two survival functions. The effect of study treatment on IRIS will be assessed using 
Cox regression model with treatment group and adjustments for stratification factors.    
The incidence of hospitalisation will be estimated by the Kaplan-Meier estimate. The Log-rank test will 
be used to compare the two survival functions. The duration of hospitalisation will be estimated by 
the cumulative days of hospitalisation during the course of study and will be compared between the 
2 groups by using the Mann-Whitney test. The rate of relapse/recurrence will be estimated by the 
number of patients with relapse/recurrence divided by the total number patients in ITT population. 
Fisher’s exact test will be used to compare the 2 groups.  
The frequency of each Grade 2, 3 or 4 AEs, laboratory toxicities, and ART and OI/BI treatment changes 
and dose modifications due to toxicities and IRIS will be described and compared by group. Fisher’s 
exact test will be used to compare the 2 groups.  
The proportion of patients with health care resource use, and emergency room visits will be compared 
in the two groups with Fisher’s exact test. The total inpatient days will be estimated by the cumulative 
inpatient days during the course of study and will be compared between the 2 groups by using the 
Mann-Whitney test. 
To assess the impact of study treatment on the evolution of QOL at week 48, we will use multiple 
imputation approach to replace missing values. We will compare the treatment effect on QOL on each 
of the 5 datasets generated, including the imputed values, and the results will be combined with 
Rubin’s rules. A generalized estimating equation (GEE) model will be used.  
9.4 Subgroup analyses 
Subgroup analyses for the primary endpoint will be done to explore whether estimated treatment 
effects vary significantly between subcategories of trial participants. The following variables will be 
assessed: age, gender, transmission group, ethnic group, baseline CD4 (<50, 50-199, ≥200), baseline 
viral load (<100,000, 100,000-500,000, >500,000), smoker, adherence (>/< 95%) and participating 
country. Heterogeneity of the treatment effect across subgroups will be assessed by including terms 
for interactions between treatment and subgroup variables in expanded Cox models. Age will be 
divided into three groups using tertiles/quartiles. 
9.5 Interim analysis and criteria for the premature termination of the trial 
No formal interim analysis will be done. However, a DSMB will be established and will review the data 
regularly during the course of the study (see Section 12 of the protocol for more details). 

 
 
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9.6 Subject population 
All randomised patients who received at least 1 time any study treatment will be included in the ITT 
analysis population. Of note patients lost-to follow-up or violating the protocol will not be excluded 
from the ITT population.  
The per-protocol population will include all patients from the ITT population except those who did not 
fulfil the inclusion/exclusion criteria, who withdrew their consent, gave up, lost to follow-up or 
discontinued study medication for any reasons other than study endpoint criteria. 
9.7 Procedure(s) to account for missing or spurious data  
To assess the impact of study treatment on the evolution of QOL at week 48, we will use multiple 
imputation approach to replace missing values. We will compare the treatment effect on QOL on each 
of the 5 datasets generated, including the imputed values, and the results will be combined with 
Rubin’s rules. A GEE model will be used. LOCF approach will be used to replace missing CD4 and CD8 
values. 
9.8 Other statistical considerations 
All deviations from the statistical analysis plan will be recorded during the conduct of the analysis. If 
there is a decision for major modifications to the statistical analysis while the clinical trial is in progress, 
this will be part of a protocol amendment. 
10 DATA HANDLING 
10.1 
Data collection tools and source document identification 
10.1.1 Source Data 
Source data will be all information in original records and certified copies of original records or clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in the source documents (original records or certified 
copies) maintained at site. 
10.1.2 Source Documents 
Original documents, data and records (e.g. hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects' diaries, evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial) will be maintained at site. 
The subject’s number and date of entry into the study, along with a study identifier, should be 
recorded in the subject’s study records.  The following should also be recorded in the study records; 
confirmation of written and verbal consent, the subject’s clinical status, date of every study visit, date 
study medication was started and stopped, concomitant medications, copies of all relevant reports 
and laboratory tests, comments on results and reference to any AEs. 

 
 
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Source documents include, but are not limited to, participant medical records, SAE and reportable 
event forms (see section 8), questionnaires, laboratory reports, participant progress notes, pharmacy 
records and any other reports or records of procedures performed in accordance with the protocol. 
10.1.3 Case report forms 
Subject data collected during the study will be recorded in a web-based electronic CRF (eCRF).  In 
order to maintain confidentiality, the subject information will be pseudo-anonymised.  
The design of CRFs will ensure that: 
• adequate collection of data has been performed 
• proper paper trails can be kept to demonstrate the validity of the trial (both during and 
after the trial) 
• only the data required by the protocol are captured in the CRF (using the CRF to capture 
secondary data not required for the study may be a criminal beach of the Data Protection 
Act, makes the CRF unnecessarily complicated, and can make it more difficult to extract 
the primary data for analysis) 
Data required for the study will be recorded in an eCRF collection tool by appropriately trained and 
authorised member(s) of the study team who must be identified and authorised in writing by the PI 
before they conduct any study related tasks.  A delegation of responsibility log identifying who can 
enter data and/or sign off a CRF will be maintained by the PI.   
The eCRF should be kept current by entering data ideally within 7 working days of collection to enable 
the study monitor to review the subject status throughout the course of the study. In the case of the 
eCRF being unavailable, a paper CRF can be made available to use at site. 
The data will be reviewed and approved by the Investigator following subject completion. 
10.2 
Data handling and record keeping 
The Study Monitor and Data Manager will review data on an on-going basis and raise any discrepancies 
with site staff as required.   
At the end of the study, the site will be provided with copies of their CRFs for filing in the ISF before 
the eCRF is decommissioned, ensuring site access to their data at all times. 
Data extracted from the eCRF will be kept on a secure network drive of the sponsor with access to 
authorised personnel of the Biometrics Team only. 
The data is pseudo-anonymised at all times and is transferred securely using an encrypted file share 
process.  All transfers are fully documented. 
10.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
10.4 
Archiving 
Following completion of the study, subject records, CRF and other study documentation will be 
retained by the Investigator in accordance with GCP and applicable regulatory requirements. 

 
 
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• 
Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations to 
be maintained elsewhere), in a safe and secure location. 
• 
The records must be maintained to allow easy and timely retrieval, when needed (e.g. for sponsor 
or regulatory inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff. 
• 
Where permitted by local laws/regulations or institutional policy, some or all of these records can 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution needs to be exercised before such action is taken. 
• 
The investigator must ensure that all reproductions are legible and are a true and accurate copy 
of the original and meet accessibility and retrieval standards, including re-generating a hard copy, 
if required. Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
• 
The ISFs must be retained for a minimum of 5 years from the date of the final CSR. Sponsor will 
inform the investigator of the retention period due date at the time when this CSR (or equivalent) 
is issued to the site. 
• 
The investigator must notify sponsor of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event 
the investigator is no longer associated with the site. 
Archiving will be authorised by the Sponsor following submission of the end of study report. 
The sponsor will be responsible for archiving the Trial Master File (TMF).  The Investigators at site(s) 
will be responsible for the retention/archiving of subject records, CRF, ISF and other study 
documentation (as applicable) in accordance with GCP and applicable regulatory requirements. 
Destruction of essential documents will require authorisation from the Sponsor in writing. 
The trial database will be maintained and stored in accordance with GCP. 
11 MONITORING, AUDIT & INSPECTION 
A risk-based monitoring plan will be followed for this study based on the trial risk assessment. The 
plan will detail monitoring frequency, requirements and processes. 
The purpose of monitoring is to verify the rights and wellbeing of human subjects are protected; that 
trial data is accurate, complete and verifiable with source data; that the trial is conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
A monitor will conduct regular site visits for the purpose of monitoring various aspects of the study.  
The Investigator must agree to allow the study monitor and authorised representatives of the 
Sponsor, to inspect all CRF and corresponding source documents, e.g. original medical records, subject 
records and laboratory raw data, access to the clinical supplies, dispensing and storage areas and 
agree to assist with their activities if requested.  The Investigator should provide adequate time and 
space for monitoring visits. 
The monitor will query any missing or spurious data with the Investigator, which should be resolved 
in a timely manner.  A monitoring log will be maintained recording each visit, the reason for the visit, 
the monitor’s signature and Investigator’s or designee’s confirmation signature. 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary for 
sponsor authorised Quality Assurance personnel and/or authorised personnel from an external 
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is to assess the quality of data with regard to accuracy, adequacy and consistency, and to assure that 
studies are in accordance with GCP, and Regulatory Agency guidelines.  Having the highest quality 
data from studies is an essential aspect of drug development. 
The Investigator will be given sufficient notice to prepare for such visits, which are planned to take 
usually between one and two days and may be conducted at any stage during the study.  The audit 
will involve the review of all study related documentation, which is required by GCP to be maintained 
by each site, review of drug storage, dispensing and return, review of all study related supplies and 
review of source documents against the CRF to assure the adequacy and accuracy of the information 
which has been recorded, including the verification of any AE which have occurred. 
12 ROLES AND RESPONSIBILITIES OF TRIAL OVERSIGHT COMMITEES/ GROUPS & 
INDIVIDUALS 
Three main trial management groups will be involved in the set up and management of the clinical 
trial. 
 
Trial Steering Committee (TSC) 
The TSC should meet to periodically review the safety data and will liaise with the DSMB regarding 
any safety issues.  The TSC must have a majority independent representation, including the Chair. 
Data Safety Monitoring Board (DSMB) 
The DSMB is the group that monitors the main safety and efficacy outcome measures and the overall 
conduct of the trial, with the aim of protecting the safety and interests of the trial participants. 
The DSMB will meet periodically to review blinded data.  The frequency of these meetings will be 
detailed in a separate document, the DSMB Charter, but are planned to take place on a quarterly basis 
as a minimum. 
Trial Management Group (TMG) 
The TMG should meet regularly to ensure all practical details of the trial are progressing well and 
working well and everyone within the trial understands them. 
 
The membership, frequency and the study aspects to be reviewed by the above groups, will be 
outlined in a separate document.  
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review & reports 
The study will comply with the following requirements 
• 
Before the start of the trial, approval will be sought from an IRB/IEC for the trial protocol, 
ICFs and other relevant documents e.g. advertisements and GP information letters 
• 
Substantial amendments that require review by IRB/IEC will not be implemented until the 
IRB/IEC grants a favourable opinion for the study (note that amendments may also need to 
be reviewed and accepted by the CAs before they can be implemented in practice at sites) 

 
 
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• 
All correspondence with the IRB/IEC will be retained in the TMF/ISF  
• 
An annual progress report (APR) will be submitted to the IRB/IEC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended 
• 
It is the CI’s responsibility to produce the annual reports as required 
• 
The CI will notify the IRB/IEC of the end of the study 
• 
If the study is ended prematurely, the CI will notify the IRB/IEC, including the reasons for 
the premature termination 
• 
Within one year after the end of the study, the CI will submit a final report with the results, 
including any publications/abstracts, to the IRB/IEC 
13.2 
Peer review 
The high-quality peer review process (initiated by study sponsor) for the trial protocol will meet the 
following review criteria:  
a) Independent: At least two individual experts will review the study. Reviewers are external to 
the investigators’ host institution and not involved in the study in any way.  
b) Expert: Reviewers will have knowledge of the relevant discipline to consider the clinical 
and/or service-based aspects of the protocol, and/or have the expertise to assess the 
methodological and statistical aspects of the study.  
c) Proportionate: Peer review commensurate with the size and complexity of the study.  
13.3 
Regulatory Compliance  
This study will comply with the following: 
• 
the trial will not commence until a Clinical Trial Authorisation (CTA) is obtained as required 
by local regulations 
• 
the protocol and trial conduct will comply with the EU directive and local regulations 
applicable to each country  
13.4 
Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed and must not be used e.g. 
it is not acceptable to enrol a subject if they do not meet the eligibility criteria or restrictions specified 
in the trial protocol 
Accidental protocol deviations can happen at any time. They must be adequately documented on the 
relevant forms and reported to the CI and Sponsor immediately.  
Deviations from the protocol which are found to frequently recur are not acceptable, will require 
immediate action and could potentially be classified as a serious breach. 
13.5 
Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
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Sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase. 
The sponsor will notify the licensing authority in writing of any serious breach of 
(a) the conditions and principles of GCP in connection with that trial; or  
(b) the protocol relating to that trial, as amended from time to time, within 7 days of 
becoming aware of that breach 
13.6 
Data protection and patient confidentiality  
All investigators and trial site staff will comply with the requirements of the current Data Protection 
Regulations with regards to the collection, storage, processing and disclosure of personal information 
and will uphold the Act’s core principles.  
Personal information is to be collected, kept secure, and maintained in line with the following 
requirements: 
• 
The creation of coded, depersonalised data where the participant’s identifying information 
is replaced by an unrelated sequence of characters. 
• 
Secure maintenance of the data and the linking code in separate locations using encrypted 
digital files within password protected folders and storage media. 
• 
Limiting access to the minimum number of individuals necessary for quality control, audit, 
and analysis. 
13.7 
Financial and other competing interests for the CI, PIs at each site and committee members 
for the overall trial management  
The sponsor will identify and collect the following disclosure information: 
• 
Ownership interests that may be related to products, services, or interventions considered 
for use in the trial or that may be significantly affected by the trial 
• 
Commercial ties requiring disclosure include, but are not restricted to, any pharmaceutical, 
behaviour modification, and/or technology company 
• 
Any non-commercial potential conflicts e.g. professional collaborations that may impact on 
academic promotion. 
13.8 
Indemnity 
The Sponsor will undertake indemnity and insurance cover for this trial. 
13.9 
Amendments  
The sponsor may make a non-substantial or substantial amendment at any time during a trial. If the 
sponsor wishes to make a substantial amendment to the CTA or the documents that supported the 
original application for the CTA, the sponsor will submit a valid notice of amendment to the 
appropriate IRB/IEC, trial registries, and regulatory agencies. It is the sponsor’s responsibility to decide 
whether an amendment is substantial or non-substantial. 

 
 
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13.10 Post trial care 
Post study medication will not be provided to participants.  Following study completion patients will 
receive treatment as per local standard of care. 
13.11 Access to the final trial dataset 
The investigators will be provided reasonable access to statistical tables, figures, and relevant reports.  
Sponsor will also provide the investigators with the full summary of the study results. The investigator 
is encouraged to share the summary results with the study subjects, as appropriate. 
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with sponsor policies. 
14 DISSEMINATION POLICY 
Whole or part of this study results will be communicated, orally presented, and/or published in 
appropriate scientific journals. Full anonymity of subject’s details will be maintained throughout. 
Subjects wanting to see the results of the trial can request a copy of the article from the investigators 
once it has been published. 
Preliminary data review and analysis may be conducted on the main study cohort or a sub study cohort 
throughout the study duration and may be presented in scientific presentations in both national and 
international conferences and publication. 
The data generated in the study will be submitted to a relevant medical journal according to criteria 
set out in The International Committee of Medical Journal Editors (www.icmje.org) who recommends 
that; 
i. 
Substantial contributions to the conception or design of the work; or the acquisition, analysis, 
or interpretation of data for the work; AND 
ii. 
Drafting the work or revising it critically for important intellectual content; AND 
iii. 
Final approval of the version to be published; AND 
iv. 
Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
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tuberculosis. N Engl J Med. 2011;365(16):1471-81 
 
14. Zolopa A et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with 
acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 
2009;4(5):e5575 
 
15. Mussini et al.. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. 
AIDs. 2008; 22(18):2461-2469 
 
16. Demarest et al. Dolutegravir-Based Regimens Are Active in Integrase Strand Transfer Inhibitor–
Naive Patients With Nucleoside Reverse Transcriptase Inhibitor Resistance. AIDS Research and 
Human Retroviruses. 2018 Feb 14(ja). 
 
17. Wijting I et al. Integrase Inhibitors are an Independent Risk Factor for IRIS: An ATHENA Cohort 
Study. Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, 
USA. Abstract 731. 

 
 
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18. Dutertre M et al. Initiation of ART Based on Integrase Inhibitors Increases the Risk of IRIS. 
Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, USA. 
Abstract 732. 
 
19. Psichogiou et al. Integrase Strand Transfer Inhibitors and the Emergence of Immune 
Reconstitution Inflammatory Syndrome (IRIS). Curr HIV Res. 2017;15(6):405-410 
 
20. Hill et al. Risks of cardiovascular or central nervous system adverse events and immune 
reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-
analysis of randomized trials. Curr Opin HIV AIDS. 2018 Mar;13(2):102-111 
 
21. Paredes R et al. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance 
test interpretation PLoS One. 2017; 12(7):e0181357 
 
22. Levy et al. ANRS 146 - GeSIDA 7211 OPTIMAL phase III trial: maraviroc plus cART in advanced HIV-
1-infected individuals. Journal Of The International Aids Society (Vol. 20, Pp. 6-7) 
 
23. Slama L et al. Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in 
combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART 
(cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, 
randomized, multicentre trial (IMEA 040 DATA trial). J Antimicrob Chemother 2016; 71: 2252–
2261 

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APPENDIX 1 - STUDY FLOWCHART  
 
Procedures 
Screening Visit 
Baseline Visit 
Treatment Phase 
Follow Up/Early Termination Visit 
 
Day -28 to Enrolment1 
 
Week 4 
(± 7 days) 
Week 8 
(± 7 days) 
Week 12 
(± 7 days) 
Week 24 
(± 7 days) 
Week 36 
(± 7 days) 
Week 48 
(± 7 days) 
30 days following Week 48 visit 
(± 7 days) 
Informed consent 
• 
 
 
 
 
 
 
 
 
Eligibility assessment2 
• 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
Medical and social history3 
• 
 
 
 
 
 
 
 
 
ECG4 
• 
 
 
 
 
 
 
 
 
HBV and HCV testing5 
• 
 
 
 
 
 
 
 
 
TB test6 
• 
 
 
 
 
 
 
 
 
Local Resistance testing 7 
• 
 
 
 
 
 
 
 
• 
Physical examination (including height & weight)18 
• 
 
 
 
 
• 
 
• 
 
Randomisation  
 
• 
 
 
 
 
 
 
 
Symptom-directed physical examination 
 
• 
• 
• 
• 
• 
• 
• 
• 
Vital signs8 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Urinalysis9 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Haematology (including CD4 & CD8 testing)10 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Clinical chemistry11 (including urinary chemistry) 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Viral load testing12 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Sample collection for central resistance testing (deep sequencing)13 
 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant medications 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse event assessments  
 
• 
• 
• 
• 
• 
• 
• 
• 
Quality of Life questionnaire (EuroQoL EQ-5D-3L) 
 
• 
• 
• 
• 
• 
• 
• 
• 
HIV Symptom Index questionnaire (HIV-SI/SDM) 
 
• 
• 
• 
• 
• 
• 
• 
• 
Dispensing of trial drugs14 
 
• 
 
 
• 
• 
• 
 
 
Adherence15 
 
 
 
 
• 
• 
• 
• 
 
Serum pregnancy test16 
• 
 
 
 
 
 
 
 
 
Urine pregnancy test17 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
 

 
 
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Assessment sub notes 
Parameters/Notes 
1 
Screening visit 
The maximum screening window is 28 days; however, participants should be invited for their baseline visit as soon as reasonably possible in 
order to start their treatment. 
The baseline resistance result is not required for eligibility or prior to randomisation.  
2 
Eligibility 
According to the inclusion/exclusion criteria. 
3 
Medical & social 
history 
Including: 
• 
Recreational drug use 
• 
Smoking history 
• 
Alcohol intake 
• 
Concomitant diseases 
• 
Past & present medical history, including HIV- associated conditions 
• 
Review of any medication taken within the last 30 days 
4 
ECG 
12-Lead ECG performed supine  
5 
HBV & HCV testing  
HBV antigen test and hepatitis C (HCV) antibodies test (if patient tests positive for HCV antibodies, test for HCV RNA, if positive and chronic for 
either HBV or HCV, add HBV DNA test at baseline visit). 
HBV test to be repeated in event of positive result.  Participants with active HBV infection at study entry will be monitored throughout the study 
and additional HBV DNA tests performed at the Week 24 and 48 visits.  
6 
TB Testing 
A TB test (IGRAs e.g. ELISPOT, QuantiFERON) will be performed in patients with expected latent TB at the screening visit. 
A TB test can be performed at subsequent visits on the basis of clinical suspicion.   
7 
Resistance testing 
(performed locally) 
A local resistance test will be performed at the screening visit.  This result is not required for eligibility or prior to randomisation.  
An additional resistance test will be performed at the ETV for patients with virological failure or insufficient virological response. 
8 
Vital Signs  
(10 mins resting) 
Including: 
• 
Pulse 
• 
Blood pressure 

 
 
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Assessment sub notes 
Parameters/Notes 
9 
 Urinalysis 
Including: 
• 
Urinary creatinine*  
• 
Urinary glucose* 
• 
Urinary proteins* 
• 
Albumin* 
• 
Nitrites* 
• 
Albumin: Creatinine Ratio (ACR) and Protein: Creatinine Ratio (PCR) 
• 
Urinary phosphate 
• 
Beta-2 microglobulin 
• 
Leukocytes§ 
 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for the study. 
§ Baseline only 
10 
Haematology 
 
(non-fasting) 
Including: 
• 
Platelet count* 
• 
RBC Count (indices MCV & MCH)* 
• 
WBC count (absolute)* 
• 
CD4 Count and %* 
• 
CD8 Count and %* 
• 
Haemoglobin* 
• 
Haematocrit* 
RBC Count indices: 
• 
MCV*   
• 
MCH* 
Automated WBC differentials:  
• 
Neutrophils* 
• 
Lymphocytes* 
• 
Monocytes* 
• 
Eosinophils* 
• 
Basophils* 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for 
the study. 

 
 
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Assessment sub notes 
Parameters/Notes 
11 
Clinical chemistry 
 
(non-fasting) 
• 
Urea*  
• 
Chloride*  
• 
Alkaline phosphatase*  
• 
Creatine phosphokinase* 
• 
Creatinine*  
• 
Calcium*  
• 
Phosphate*  
• 
Creatinine clearance, eGFR* 
(Calculations: Cockcroft-Gault (requires weight), MDRD, CX-Epi) 
• 
Glucose*   
• 
Total* and indirect bilirubin 
• 
Potassium*  
• 
Total protein* 
• 
Sodium*  
• 
ALT* 
• 
AST*  
• 
Albumin* 
• 
Cholesterol* 
• 
HDL* 
• 
LDL* 
• 
Triglycerides* 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for the study. 
12 
Viral load testing 
HIV RNA viral load 
13 
Resistance testing for deep 
sequencing 
 
(sent to central laboratory) 
In addition to the resistance test performed locally, a resistance testing sample will be taken at the Baseline visit, each visit in the treatment 
phase (Week 4, 8, 12, 24, 36 and 48) and at the ETV (for patients with virological failure identified outside of a scheduled visit.   
All resistance testing samples for patients with virological failure will be sent to a central laboratory for next generation sequencing to look for 
low-level pre-existing resistance in cases of suspected resistance development. 
14 
Drug dispensing 
There will be four dispensations of the study medication to the patient (Baseline visit, Week 12, 24 and 36). 
15 
Adherence 
Also performed at the ETV if required. 
16 
Serum pregnancy test 
For women of child bearing potential only (see Appendix 7 for definition).  
17 
Urine pregnancy test  
Dipstick and urine pregnancy test (WOCBP only - see Appendix 7 for definition). This is a mandatory assessment.  
18 
Physical examination  
For weeks 24 and 48, only a weight measurement is required 

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APPENDIX 2 – AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE  
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
 
Attached as a separate document and available online at: 
https://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf?sfvrsn=6  
APPENDIX 3 – AIDS-DEFINING CONDITIONS 
From CDC, available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm  
• 
Bacterial infections, multiple or recurrent* 
• 
Candidiasis of bronchi, trachea, or lungs 
• 
Candidiasis of esophagus† 
• 
Cervical cancer, invasive§ 
• 
Coccidioidomycosis, disseminated or extrapulmonary 
• 
Cryptococcosis, extrapulmonary 
• 
Cryptosporidiosis, chronic intestinal (>1 month's duration) 
• 
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
• 
Cytomegalovirus retinitis (with loss of vision) † 
• 
Encephalopathy, HIV related 
• 
Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis (onset 
at age >1 month) 
• 
Histoplasmosis, disseminated or extrapulmonary 
• 
Isosporiasis, chronic intestinal (>1 month's duration) 
• 
Kaposi sarcoma† 
• 
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*† 
• 
Lymphoma, Burkitt (or equivalent term) 
• 
Lymphoma, immunoblastic (or equivalent term) 
• 
Lymphoma, primary, of brain 
• 
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary† 
• 
Mycobacterium tuberculosis of any site, pulmonary, †§ disseminated, † or extrapulmonary† 
• 
Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary† 
• 
Pneumocystis jirovecii pneumonia† 
• 
Pneumonia, recurrent†§ 
• 
Progressive multifocal leukoencephalopathy 
• 
Salmonella septicemia, recurrent 
• 
Toxoplasmosis of brain, onset at age >1 month† 
• 
Wasting syndrome attributed to HIV 
* Only among children aged <13 years. (CDC. 1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age. MMWR 1994;43[No. RR-12].) 
† Condition that might be diagnosed presumptively. 
§ Only among adults and adolescents aged >13 years. (CDC. 1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41[No. RR-17].) 

 
 
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APPENDIX 4 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA 
Version 4, August 2012 
ACUTE MYOCARDIAL INFARCTION 
A. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above 99th 
percentile of upper reference limit (URL) 
 
B. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent 
with myocardial ischemia 
 
C. ECG changes indicative of new ischemia (new ST-changes or new left bundle branch block [LBBB]), 
or development of pathological Q waves on the ECG 
 
D. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
 
E. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or before 
a time when biomarkers appear, along with (1) new ST-changes or new LBB, or (2) evidence of fresh 
thrombus on coronary angiography or at autopsy 
 
F. In patients with percutaneous coronary interventions and normal baseline troponin, increases in 
troponin of three times the 99th percentile of URL 
 
G. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL PLUS at least one of the following: (1) new pathological Q-
waves or new LBBB, (2) angiographically documented new graft or native artery occlusion, or (3) 
imaging evidence of new loss of viable myocardium 
 
H. Pathologic findings of acute myocardial infarction (including acute MI demonstrated as the cause 
of death on autopsy) 
 
I. Development of 1) evolving new Q waves, or 2) evolving ST elevation, preferably based on at least 
2 ECGs taken during the same hospital admission 
 
J. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL 
 
Confirmed: One of the following 5 criteria (adapted from 2007 Universal Definition of Myocardial 
Infarction): 
1. A + (B or C or D) 
2. E 
3. F 
4. G 
5. H 
Probable: B+I or J 
 
CONGESTIVE HEART FAILURE 
 
A. Clinical signs and symptoms compatible with left or right sided heart failure (e.g., paroxysmal 
nocturnal dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative 
explanation 

 
 
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B. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac 
catheterization, or multiple gated acquisition scan showing a decreased ejection fraction of < 45% 
 
C. Echocardiogram, cardiac catheterization or other studies showing evidence of increased left atrial 
pressure or right heart failure 
 
D. Elevated levels of Brain Natriuretic Peptide (BNP) or NT-proBNP 
 
E. Chest x-ray or other imaging study showing evidence of congestive heart failure, including cardiac 
enlargement 
 
F. Documentation of treatment for congestive heart failure 
 
Confirmed: (A+B) or (A+C) or (A+D) 
Probable: A+E+F 
 
CORONARY ARTERY DISEASE REQUIRING DRUG TREATMENT 
 
A written report in the medical record documenting: 
 
A. Evidence of myocardial ischemia based on either diagnostic imaging (such as a stress 
echocardiogram or thallium scan) or diagnostic changes on an electrocardiogram (such as during 
stress testing or an episode of chest pain) 
 
B. Evidence of coronary artery disease based on coronary angiography or other diagnostic imaging 
 
C. Other evidence of myocardial ischemia and/or coronary artery disease (including that based 
primarily upon symptoms and clinical presentation, such as chest pain with exertion) 
 
D. Use of medication given to treat or prevent angina (e.g., nitrates, beta blockers, calcium channel 
blockers) 
 
Confirmed: (A or B) + D 
Probable: C+D 
 
CORONARY REVASCULARIZATION 
 
Confirmed: A procedure report, hospital discharge summary, or other medical record from the 
hospitalization during which the procedure was performed for treatment of coronary artery disease 
(including coronary artery bypass graft, coronary artery stent implant, coronary atherectomy, and 
percutaneous transluminal angioplasty), or a consultation note from the participant’s cardiologist 
documenting the occurrence of the procedure 
 
Probable: Not applicable 
 
DECOMPENSATED LIVER DISEASE 
 
A. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by one of the 
following: 
1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy 

 
 
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2. MRI or CT consistent with cirrhosis 
3. A positive result on transient elastography (FibroScan) or other ultrasound imaging consistent 
with cirrhosis 
 
B. Clinical evidence of decompensation, as documented by one of the following, and without an 
alternative explanation: 
1. Ascites 
2. Hepatic encephalopathy 
3. Bleeding from gastric or esophageal varices 
4. Spontaneous bacterial peritonitis 
 
Confirmed: A+B 
Probable: B 
 
DEEP VEIN THROMBOSIS 
 
A. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed tomography, 
MRI, or ultrasonography other comparable imaging techniques 
 
B. An elevated D-dimer test OR abnormal plethysmography 
 
C. A score on the Wells Clinical Prediction Rule for DVT of ≥ 3 points 
 
D. Absence of alternative diagnosis as likely or greater than that of deep venous thrombosis 
 
Wells Clinical Prediction Rule for DVT 
One point for each of the following: 
• Active cancer (treatment ongoing or within previous 6 months, or palliative) 
• Paralysis, paresis, or plaster immobilization of lower extremities 
• Recently bedridden for more than 3 days, or major surgery, within 4 weeks 
• Localized tenderness along distribution of the deep venous system 
• Entire leg swollen 
• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm 
below tibial tuberosity) 
• Pitting edema (greater in the symptomatic leg) 
• Collateral superficial veins (non-varicose) 
(Adapted from: Wells PS et al. Lancet 1997;350:1796) 
 
Confirmed: A 
Probable: B+C+D 
 
DIABETES MELLITUS 
 
A. Classic symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose 
concentration >=200 mg/dl (11.1 mmol/l). (Classic symptoms include polyuria and polydipsia; Random 
is defined as any time of day without regard to last meal) 
 
B. 2-hour plasma glucose >=200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (The test 
should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose 
dissolved in water). 
 

 
 
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C. Repeated abnormal fasting plasma glucose (FPG) and/or abnormal Haemoglobin A1C level (HA1C) 
results using the following criteria: 
1. FPG >=126 mg/dl (7.0 mmol/l) on at least two different dates (Fasting is defined as no caloric 
intake for at least 8 hours). 
2. HA1C >=6.5% on at least two different dates 
3. An FPG >=126 mg/dl (7.0 mmol/l) PLUS a HA1C >=6.5%, with these tests performed on two 
different dates 
 
D. Documentation of taking an approved anti-diabetic medication to lower glucose levels in the blood, 
such as insulin or oral hypoglycaemic agents. 
 
E. A single abnormal FBS OR a single abnormal HA1C 
 
Confirmed: A or B or C 
Probable: D 
Possible: E 
 
END-STAGE RENAL DISEASE 
 
A. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least three 
months 
 
B. A kidney transplant documented in a clinical note 
 
C. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least one month 
and up to the time of death in a patient who dies within three months after dialysis begins 
 
Confirmed: A or B 
Probable: C 
 
NON-AIDS-DEFINING CANCER 
 
A. Diagnosis of cancer other than lymphoma, Kaposi's sarcoma (KS), or invasive cervical cancer in an 
autopsy report 
 
B. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report that 
established the diagnosis 
 
C. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge 
summary or consultation note from the hospitalization or clinic visit during which the diagnosis was 
established 
 
Confirmed: A or B 
Probable: C 
 
PERIPHERAL ARTERIAL DISEASE 
 
A. Compatible clinical signs and symptoms (e.g., intermittent claudication, femoral bruit, decreased 
peripheral pulses, change in colour or temperature of limb suggesting peripheral arterial disease) 
 

 
 
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B. Positive results on diagnostic imaging studies (e.g., Doppler ultrasound, contrast arteriography, MRI 
arteriography) 
 
C. Ankle Brachial Pressure Index < 0.90 in non-diabetics 
 
D. A procedure report, hospital discharge summary, or other medical record from the hospitalization 
during which the procedure was performed documenting an invasive procedure for treatment of 
peripheral arterial disease (e.g., percutaneous transluminal angioplasty, endovascular procedures, or 
vascular surgery), or a consultation note documenting the occurrence of the procedure 
 
Confirmed: (A+B) or (A+C) or D 
Probable: A 
 
PULMONARY EMBOLISM 
 
A. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or 
haemoptysis 
 
B. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical CT, 
ventilation-perfusion scan or other comparable imaging studies 
 
C. A diagnosis of pulmonary embolism on autopsy 
D. Results consistent with a diagnosis of deep venous thrombosis on venography, ultrasound, or other 
comparable imaging studies 
 
E. A chest x-ray which, if performed, does not suggest an alternative aetiology for the symptoms 
described in criteria A 
 
Confirmed: (A+B) or C 
Probable: 
A+D+E  
 
STROKE 
 
A. Acute onset with a clinically compatible course, including unequivocal objective findings of a 
localizing neurologic deficit 
 
B. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms 
 
C. Stroke diagnosed as cause of death at autopsy 
 
D. Positive lumbar puncture compatible with subarachnoid haemorrhage 
 
E. Death certificate or death note from medical record listing stroke as cause of death 
 
Confirmed: (A+B) or C 
Probable: (A+D) or (A+E) 
 
 

 
 
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APPENDIX 5 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA 
Version 2.0, September 2010 
CONFIRMED 
PROBABLE 
CONSTITUTIONAL DISEASE 
HIV wasting syndrome 
None 
A plus B plus C: (A) unexplained, 
involuntary weight loss >10% from 
baseline, (B) persistent diarrhea 
with > 2 liquid stools/d for > 1 
month or weakness for 
> 1 month or fever for > 1 month, 
(C) tests for alternate causes of 
weight loss, such as cancer, TB, 
MAC, cryptosporidiosis or other 
specific causes of weight loss, if 
obtained, should be negative 
INFECTIONS 
Aspergillosis, invasive pulmonary 
A plus B plus C: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy, 
(C) positive culture from lung biopsy or 
sputum collected by any method 
A plus B: (A) CXR abnormality 
compatible with aspergillosis, 
(B) invasive mycelia consistent with 
Aspergillus on lung biopsy or 
positive culture of lung tissue or 
positive culture of sputum collected 
by any method 
Aspergillosis, other invasive 
A plus B plus C: (A) compatible clinical 
course, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
clinical evidence of infection, (C) 
positive culture from the affected tissue 
A plus B: (A) clinical evidence of 
invasive infection, (B) invasive 
mycelia consistent with Aspergillus 
on tissue biopsy or positive culture 
at a normally sterile site (e.g., 
blood) apart from the involved 
tissue 
Bartonellosis 
A plus B: (A) Clinical or histologic 
evidence of bacillary angiomatosis or 
bacillary peliosis, (B) a positive culture 
or PCR for B. quintana or B. henselae 
A plus B: (A) Clinical evidence of 
bacillary angiomatosis or bacillary 
peliosis, (B) positive silver stain for 
bacilli from a skin lesion or an 
affected organ 
Candidiasis of bronchi, trachea, or lungs 
Macroscopic appearance at 
bronchoscopy or autopsy plus 
microscopic evidence of yeasts or 
pseudo hyphae 
None 
Candidiasis, esophageal 
A plus B: (A) Macroscopic 
appearance at esophagoscopy or 
autopsy, 
(B) microscopic evidence of yeasts or 
pseudo hyphae 
A plus B plus C: (A) Recent onset 
of retrosternal pain or difficulty 
on swallowing, (B) a clinical 
diagnosis of oral candidiasis, 
endoscopic visualization of 
candidiasis and/or microscopic 
evidence of yeasts or pseudo 
hyphae from oropharyngeal 
mucosa, 
(C) clinical response to 
treatment 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Chagas disease (American 
trypanosomiasis) of the CNS 
Histologic evidence obtained by brain 
tissue biopsy or autopsy 
A plus B plus C plus D: (A) Focal, 
typically hemispheral neurological 
dysfunction with onset over several 
days or weeks; (B) enhancing focal 
lesion(s) with mass effect, and 
surrounding edema and contrast 
enhancement, typically located in 
grey matter; 
(C) serum antibodies to T. cruzi, (D) 
response to standard therapy with 
documented clinical or radiographic 
improvement (if radiography was 
done, it must be improved), or 
peripheral blood smear or CSF 
smear positive for T. cruzi 
Coccidioidomycosis, 
disseminated or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C: (A) Microscopic 
demonstration of spherules, (B) 
positive culture, (C) antigen detection 
None 
Cryptococcosis, meningitis or 
extrapulmonary 
From tissue other than lung or hilum, A 
or B or C or D: (A) microscopic 
demonstration of narrow based 
budding yeast, 
(B) for meningitis, if done, a 
positive CSF India ink test, 
(C) positive culture, (D) 
antigen detention 
None 
Cryptosporidiosis 
Diarrhea for > 1 month and positive 
microscopy 
None 
CMV retinitis 
Autopsy demonstration 
Typical appearance on fundoscopy 
of discrete patches of retinal 
whitening, spreading along blood 
vessels, associated with vasculitis, 
hemorrhage and necrosis, 
confirmed by ophthalmologist 
CMV radiculomyelitis 
Autopsy demonstration 
A plus B plus C plus D plus E plus F: 
(A) Loss of sensation, leg 
weakness, or decreased reflexes, 
(B) presentation over 3 days to 3 
weeks, (C) CT, MRI or myelogram 
must be done and all imaging 
studies must not show a mass 
lesion, 
(D) CSF shows > 10 WBC with 
> 50% polymorphs, (E) CSF shows 
no other pathogen, (F) persistence 
of symptoms in the absence of CMV 
treatment, or elevated quantitative 
CMV in the CSF by PCR 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
CMV meningoencephalitis 
Autopsy or brain biopsy 
demonstration 
A plus B: (A) Rapid < 4 weeks 
syndrome with progressive 
delirium, cognitive impairment and 
fever, (B) CT/MRI demonstration of 
periventricular abnormalities or 
elevated quantitative CMV DNA in 
the CSF by PCR 
CMV, other disease 
A plus B plus C plus D: (A) compatible 
illness, (B) histologic demonstration of 
inclusion bodies from affected tissue, 
(C) if done, detectible CMV antibodies, 
(D) if done, detectible CMV DNA or 
CMV antigen in blood 
A plus B plus C plus D: (A) 
Compatible illness, (B) moderate to 
markedly high CMV antigen or CMV 
DNA in blood, (C) response to 
therapy, (D) if done, detectible 
CMV antibodies 
HSV mucocutaneous 
ulceration 
A plus B: (A) Ulceration for > 1 month, 
(B) histology, culture, PCR, or detection 
of antigen from affected tissue 
A plus B: (A) Typical HSV ulceration 
for > 1 month, (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
HSV, bronchitis, pneumonitis, 
esophagitis, or other visceral disease 
A plus B: (A) Compatible symptoms, 
(B) histology, culture, PCR, or 
detection of antigen from affected 
tissue 
None 
HZV, disseminated 
A plus B: (A) multiple ulcerated lesions 
affecting at least 2 non-contiguous 
dermatomes, or with generalized 
cutaneous dissemination; or HZV 
involvement of the lung, liver, brain, 
or other internal organs 
(B) positive culture, PCR, or antigen 
assay from affected tissue 
A plus B: (A) multiple typical 
ulcerated lesions affecting at least 2 
non-contiguous dermatomes, or 
with generalized cutaneous 
dissemination (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
Histoplasmosis, disseminated or 
extrapulmonary 
A plus B: (A) Compatible symptoms, 
(B) histology or culture or elevated 
blood or urine antigen levels 
None 
Isosporiasis 
Diarrhea for > 1 month, plus 
microscopic identification of 
Isospora belli 
None 
Leishmaniasis, visceral 
Compatible symptoms, plus 
microscopic identification of 
Leishmania 
Compatible symptoms, plus a 
positive PCR test for Leishmania 
Microsporidiosis 
Diarrhea for > 1 month plus 
Microscopic identification of 
Microsporidia 
None 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
MAC and other mycobacterial 
disseminated disease 
A plus B: (A) Fever, fatigue, anemia or 
diarrhea, (B) positive culture from 
blood, body fluids or tissue other than 
pulmonary, hilar or stool 
A plus B plus C: (A) Fever, 
fatigue, anemia or diarrhea, 
(B) AFB or positive direct MAC PCR 
in blood, body fluids or tissue other 
than pulmonary, hilar or stool (C) 
no concurrent non-pulmonary TB 
M. tuberculosis disease, pulmonary 
A plus B: (A) Compatible symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, 
(B) culture or PCR from sputum or 
bronchial lavage or lung tissue 
A plus B plus C plus D: (A) 
Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, 
(B) abnormal chest X-ray, (C) AFBs 
seen in sputum or lavage or lung 
tissue but not grown in culture, (D) 
responds to treatment 
POSSIBLE (pulmonary TB only) 
A plus B plus C plus D: 
(A) Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, (B) 
abnormal chest X-ray compatible 
with pulmonary TB (such as upper 
lobe cavitation, pleural exudate), 
(C) No other etiology for pulmonary 
symptoms and signs identified, (D) 
Responds to anti-tuberculosis 
treatment 
M. tuberculosis disease, 
extrapulmonary 
A plus B: (A) Compatible symptoms, 
(B) culture or PCR from blood or 
affected tissue 
A plus B plus C: (A) Compatible 
symptoms, (B) AFBs seen from 
affected tissue or blood (C) 
concurrent diagnosis of pulmonary 
TB or responds to treatment 
Nocardiosis 
Clinical evidence of invasive infection 
plus a positive culture from the 
affected tissue or blood 
Clinical evidence of invasive 
infection plus microscopic 
evidence of bronchial weakly 
acid-fast organisms from the 
affected tissue 
Penicillium marneffei, 
disseminated 
Culture from a non-pulmonary site 
Known presence in a P. marneffei 
endemic area plus characteristic 
skin lesions plus response to 
antifungal therapy for penicillosis 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
PcP 
A plus B: (A) compatible clinical 
syndrome, (B) microscopic or 
histological demonstration of P. 
jirovecii cysts in a pulmonary specimen 
A plus B plus C plus D plus E: 
(A) dyspnea or cough, or fever 
progressive over > 1 week, (B) 
diffuse chest x-ray abnormality or, if 
on inhalational pentamidine, diffuse 
upper lung field abnormality, (C) 
evidence of hypoxia, (D) not 
suggestive of bacterial pneumonia 
(i.e., not purulent sputum or 
hemoptysis, no bacterial pathogen 
identified in blood or bronchial 
wash), (E) response to PcP 
treatment 
Pneumocystis jirovecii, 
extrapulmonary 
Compatible symptoms, plus 
microscopy 
None 
Pneumonia, recurrent bacterial, excludes: 
(a) post- obstructive pneumonias, 
including in those with 
intrapulmonary/bronchial lesions, (b) 
aspiration pneumonia, including in those 
with decreased consciousness levels, (c) 
nosocomial ventilator-associated 
pneumonias 
Both pneumonia episodes must occur 
after enrollment and satisfy criteria (A) 
plus (B) plus (C). The recurrent 
pneumonia must also satisfy criteria (D) 
plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) identification 
of a bacterial pathogen by positive 
blood culture, positive bronchoscopic 
sputum culture, detection of Legionella 
or pneumococcal antigen in urine or 
blood or diagnostic serologic findings, 
(D) the second pneumonia had onset of 
symptoms < 365 days after the first 
episode, (E) there is strong evidence 
that the first episode was cured such as 
an intervening clear CXR or absence of 
symptoms after > 1 month off 
antibacterials effective against 
pathogens commonly producing 
pneumonia 
Both pneumonia episodes must 
occur after enrollment and satisfy 
criteria (A) plus (B). The recurrent 
pneumonia must also satisfy criteria 
(C) plus (D): (A) Signs and symptoms 
suggestive of bacterial pneumonia, 
(B) focal CXR abnormality 
compatible with bacterial 
pneumonia, (C) the second 
pneumonia had onset of symptoms 
< 365 days after the first episode, 
(D) there is strong evidence that the 
first episode was cured such as an 
intervening clear CXR or absence of 
symptoms after 
> 1 month off antibacterials 
effective against pathogens 
commonly producing 
pneumonia 
PML (progressive multifocal 
leukoencephalopathy) 
A or B: (A) positive histology, 
(B) compatible clinical and radiologic 
course and positive CSF PCR for JK 
virus 
A plus B plus C: (A) Consistent 
symptoms, (B) brain image 
consistent with PML, (C) no 
response to toxo treatment or 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Rhodococcus equi disease 
Clinical evidence of invasive infection 
plus microbiologic identification of 
the organism in the affected tissue or 
blood 
None 
Salmonella septicemia, recurrent 
Both episodes must occur after 
enrollment and met criterion (A). The 
second episode must meet criteria (B) 
and C: (A) Positive blood or tissue 
culture, (B) the second septicemia had 
onset of symptoms < 365 days after 
the first episode, (C) the second 
septicemia must be due to a different 
Salmonella serotype or there must be 
strong evidence that the first episode 
was cured such as a negative blood 
culture off effective antibacterials for > 
1 week or absence of symptoms off 
antibacterials for > 1 month 
None 
Toxoplasmosis of brain 
Microscopy 
A plus B plus C: (A) Symptoms of 
focal intracranial abnormality or 
decreased consciousness, 
(B) brain image consistent with 
lesion(s) enhanced by contrast, 
(C) positive toxoplasma serology 
or responds to treatment 
clinically or by scan 
NEOPLASMS 
Cervical carcinoma, invasive 
Histology (NOT carcinoma-in- situ) 
None 
Kaposi sarcoma, (mucocutaneous or 
visceral) 
Histology 
Highly typical appearance and 
persistence for > 1 month 
Lymphoma, primary, of brain 
Histology 
Symptoms consistent with 
lymphoma plus at least one CNS 
lesion with mass effect plus lack of 
clinical and radiographic response 
to at least 2 weeks of treatment 
for toxoplasmosis 
Lymphoma, Hodgkin's 
Histology 
None 
Lymphoma, non-Hodgkin's, all cell 
types 
Histology 
None 
 
 
 
 

 
 
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CONFIRMED 
PROBABLE 
NEUROLOGICAL 
HIV-related encephalopathy 
(including AIDS Dementia Complex) 
None 
Cognitive or motor dysfunction 
interfering with usual activity, 
progressive over weeks or months 
plus no other condition to explain 
the findings plus brain image 
obtained and suggests no other 
causes plus grade 2 or worse 
impairment in at least 2 domains 
by NARS (see below) excluding 
abnormal domains at trial entry. 
(For persons with abnormal 
domains at entry worsening by at 
least two grades meets criteria.) 
 
 
 

 
 
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Abbreviated NARS (Neuropsychiatric AIDS Rating Scale) Grading for HIV Encephalopathy  
Adapted from: Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988; 158 (5): 1079- 83, 
and Hughes CP, Berg L, Danziger WL. A new clinical scale for the staging of dementia. Brit J Psych 
1982; 140: 566-92. 
NARS
stage 
Cognitive-Behavioral Domains 
Orientation 
Memory 
Motor 
Behavior 
Problem 
solving 
Activities 
of 
daily living 
0.5 
fully oriented 
complains of 
memory 
problems 
fully 
ambulatory 
slightly 
slowed 
movements 
normal 
has slight 
mental 
slowing 
slight 
impairment in 
business 
dealings 
1 
fully oriented, 
may have brief 
periods of 
“spaciness" 
mild memory 
problems 
balance, co- 
ordination 
and 
handwriting 
difficulties 
more irritable, 
labile or 
apathetic, 
withdrawn 
difficulty 
planning and 
completing 
work 
can do simple 
daily tasks, may 
need prompting 
2 
some 
disorientation 
memory 
moderately 
impaired, 
new learning 
impaired 
ambulatory 
but may 
require 
walking aid 
some 
impulsivity or 
agitated 
behavior 
severe 
impairment, 
poor social 
judgement, 
gets lost easily 
needs 
assistance 
with ADLs 
3 
frequent 
disorientation 
severe 
memory loss, 
only 
fragments of 
memory 
remain 
ambulatory 
with 
assistance 
may have 
organic 
psychosis 
judgement 
very poor 
cannot live 
independently 
4 
confused and 
disoriented 
virtually no 
memory 
bedridden 
mute and 
unresponsive 
no problem-
solving ability 
nearly 
vegetative 
 
 
 

 
 
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APPENDIX 6 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA  
 (Revised 01/10/09) 
From ACTG, available under https://actgnetwork.org/IRIS_Case_Definitions  
   
1. Initiation, reintroduction or change in antiretroviral therapy/regimen or therapy for 
opportunistic infections (OI).   
 
AND 
 
2. 
1Evidence of:   
 
a. an increase in CD4+ cell count as defined by ≥50 cells/mm3 or a ≥2- fold rise in CD4+ cell 
count, and/or    
 
b. decrease in the HIV-1 viral load of >0.5 log10 and/or    
 
c. weight gain or other investigator-defined signs of clinical improvement in response to 
initiation, reintroduction or change of either antiretroviral therapy/regimen or OI therapy.     
 
     AND   
3. Symptoms and/or signs that are consistent with an infectious or inflammatory condition.     
 
     AND  
4. These symptoms and/or signs cannot be explained by a newly acquired infection, the expected 
clinical course of a previously recognized infectious agent, or the side effects of medications. 
AND 
   
5. For purposes of data collection, the infectious/inflammatory condition must be attributable to 
a specific pathogen or condition. A Clinical Events form should be completed 16 weeks (+ 4 
weeks) after initial report if diagnosis confirmed or changed from initial report 
 
1 If the study participant is being evaluated for an inflammatory condition at a time that is <4 weeks 
after initiation, reintroduction or change in antiretroviral therapy/regimen or OI therapy, items 2a 
through 2c are not required.     
 
Refer to the “Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes 
(IRIS)” document for specific Opportunistic Infection (OI) and non-pathogen condition diagnosis 
criteria.

 
 
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Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes (IRIS) 
IRIS Focus Group 
Given the paucity of data for a clearly-defined immune reconstitution inflammatory syndrome for each 
opportunistic pathogen, the IRIS Working Group concentrated on developing specific definitions for the 
most well-characterized IRIS in the literature. IRIS events may occur as paradoxical worsening or as an 
unmasking. Paradoxical responses are described as an initial clinical worsening when patients are started 
on pathogen-specific therapy and/or ART simultaneously. Unmasking refers to aberrant clinical 
presentations of previously common OIs such as localized Mycobacterium avium complex (MAC) 
lymphadenitis and Cytomegalovirus (CMV) vitritis occurring within the first weeks of starting ART 
suggesting that patients have sub-clinical disease prior to the initiation of ART. There are specific 
definitions including confirmed and probable for the following specific pathogen IRIS:  Mycobacterium 
avium complex (MAC), Progressive Multifocal Leukoencephalopathy (PML), Cytomegalovirus (CMV), 
Mycobacterium tuberculosis (TB) and Cryptococcus neoformans. All other clinical syndromes attributed 
to immune reconstitution will be treated as probable IRIS events without specific definitions and will 
include Pneumocystis jirovecii pneumonia (PCP), Varicella Zoster (VZV), Herpes Simplex (HSV), Hepatitis B, 
Hepatitis C, Toxoplasmosis, Kaposi’s Sarcoma, Graves’ disease, Sarcoidosis, and other autoimmune 
disorders. For these less well-defined IRIS, key data will be captured on a generic form that includes clinical 
signs/symptoms, CD4, HIV RNA data, and clinical outcomes.  
 
Specific IRIS Case Definitions  
 
1. Cytomegalovirus (CMV): {Ophthalmologic only} IRIS associated with CMV is fairly common; 
syndromes include uveitis, vitritis, extension or new development of retinal opacification, 
proliferative vitreoretinopathy (leading to retinal detachment), neovascularization, macular or 
optic nerve edema and subcapsular cataracts (leading to visual impairment) [1, 2]. The 
inflammatory component is marked, with significant anterior and/or posterior chamber 
inflammation. Vitritis and extension or new development of retinal opacification usually occurs 
within 3-12 weeks of beginning antiretroviral therapy/regimen and/or CMV antiviral therapy; 
uveitis may occur months to years after beginning antiretroviral therapy. Antiretroviral 
therapy/regimen is usually continued; some patients are also treated with anti-CMV drugs, 
especially those with sight-threatening disease. IRIS associated with gastrointestinal or neurologic 
(non-ocular) CMV disease have not be adequately characterized 
 
Confirmed CMV IRIS in patients with a prior history of CMV retinitis:  previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by an experienced ophthalmologist.  
 
Confirmed CMV IRIS in patients without a prior history of CMV retinitis:  the development of 
significant ocular inflammation in the uveovitreal tract, lens or retina attributed to CMV in the 
absence of ophthalmologic findings typical for acute CMV retinitis, with or without visual changes, 
as documented by an experienced ophthalmologist. 
 
Probable CMV IRIS in patients with a prior history of CMV retinitis previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by a non-ophthalmologist clinician 
 

 
 
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2. Cryptococcus neoformans. The best described cases of Cryptococcus neoformans IRIS involve 
inflammatory changes developing in patients with recently diagnosed cryptococcal meningitis, 
cryptococcemia or pneumonia who have responded to appropriate antifungal therapy [1, 3,4].  
Most have presented as meningitis, associated with CSF abnormalities (significantly elevated 
protein, lymphocytes, hypoglycorrhachia and cryptococcal antigen titers) with negative cultures. 
CNS imaging may demonstrate new meningeal inflammation. Significant elevations of intracranial 
pressure may occur. Non-CNS presentations are also common and have included the development 
of mediastinal or cervical adenopathy, necrotizing pneumonia, cavitation of previously 
documented pulmonary lesions, focal lymphadenitis and cutaneous abscesses. Biopsies may 
demonstrate granulomatous changes and cryptococci but typically cultures are negative. These 
presentations have occurred anywhere from two weeks to 11 months after initiation of 
antiretroviral therapy/regimen, with most cases occurring within three months. Less well 
described are cases of cryptococcal meningitis presenting only after initiation and response to 
antiretroviral therapy/regimen, also associated with elevated CSF cryptococcal antigen (CRAG) 
titers, negative CSF cultures and significant meningeal enhancement on scan. 
 
Confirmed cryptococcal IRIS in patients with a prior history of cryptococcosis: Cryptococcal 
meningitis or other diagnosis of systemic cryptococcal infection (fungemia, pneumonia) by ACTG 
criteria and improvement of signs/symptoms with antifungal therapy, with the subsequent 
development of new or worsening pulmonary infiltrates, new meningeal enhancement on scan or 
abnormal CSF findings (low glucose, elevated WBC, CSF CRAG with negative fungal culture), 
mediastinal or cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal 
lesions at other sites;  histopathology from non-meningeal site demonstrating inflammatory 
changes and organisms in the absence of a positive culture or positive culture.   
 
Confirmed cryptococcal IRIS in patients without a prior history of cryptococcosis:  the 
development of meningitis with meningeal enhancement on scan with abnormal CSF findings (low 
glucose, elevated WBC, positive CSF CRAG with negative or positive fungal culture), mediastinal 
or cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal lesions at 
other sites;  histopathology from non-meningeal site demonstrating inflammatory changes and 
organisms in the absence of a positive culture or positive culture.   
 
Probable cryptococcal IRIS in patients with a prior diagnosis of cryptococcosis:  previous 
cryptococcosis diagnosis by ACTG criteria and improvement of signs/symptoms with anti-cryptococcal 
therapy, and the subsequent development of focal inflammatory site(s); histopathology from involved 
site or sterile body fluid analysis  demonstrating inflammatory changes (e.g., granulomas, 
lymphocytes) in the absence of positive stains or cultures for any other pathogen or any non-infectious 
histopathologic diagnosis; and negative blood cultures for Cryptococcosis; and negative CSF CRAG if 
obtained or development of new onset CNS signs or symptoms with meningeal enhancement or other 
atypical radiographic changes with no evidence of other neurologic disease to explain the findings. 
 
Probable cryptococcal IRIS in patients without a prior diagnosis of cryptococcosis: the subsequent 
development of focal inflammatory site(s); histopathology from involved site or sterile body fluid 
analysis demonstrating inflammatory changes (e.g., granulomas, lymphocytes) accompanied by 
evidence consistent with cryptococcosis in the absence of positive cultures for any other pathogen. 
   
3. Mycobacterium avium complex (MAC). This is one of the best described IRIS. The most common 
presentation is focal lymphadenitis (especially cervical) with high fever, elevated WBC counts and 
negative blood cultures; fistula formation may occur. There is a significant inflammatory 
component on biopsy with necrotizing granulomas, caseation and AFB. The syndrome usually 

 
 
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occurs within 3-12 weeks of initiating antiretroviral therapy/regimen and/or anti-mycobacterial 
therapy, although rare cases have been described beyond 6 months with deep tissue foci, e.g. 
psoas abscess. MAC IRIS has presented as diffuse adenopathy, and as focal disease in diverse sites 
(paraspinous, mediastinal, abdominal, vertebral, pulmonary and CNS). [1,5,6]  
 
Confirmed MAC IRIS in patients with a prior history of disseminated MAC (dMAC): previous 
disseminated MAC diagnosis by ACTG criteria and improvement of signs/symptoms with anti-MAC 
therapy, with the subsequent development of focal inflammatory site(s). 
 
Confirmed MAC IRIS in patients without a prior history of dMAC: the development of focal 
inflammatory site(s); histopathology from the involved site demonstrating inflammatory changes 
(e.g., granulomas) accompanied by histologic or culture evidence of AFB consistent with MAC in 
the absence of positive cultures for any other AFB; and may have positive blood cultures for MAC.   
 
Probable MAC IRIS in patients with a prior history of dMAC: previous dMAC diagnosis by ACTG 
criteria and improvement of signs/symptoms with anti-MAC therapy, and the subsequent 
development of focal inflammatory site(s); histopathology from involved site demonstrating 
inflammatory changes (e.g., granulomas) in the absence of positive stains or cultures for any other 
pathogen or any non-infectious histopathologic diagnosis; and negative blood cultures for MAC. 
 
Probable MAC IRIS in patients without a prior diagnosis of MAC: the subsequent development 
of focal inflammatory site(s); histopathology from involved site demonstrating inflammatory 
changes (e.g., granulomas, lymphocytic infiltrates) and without evidence of any other specific 
pathogen (stains may be positive for AFB); and negative blood cultures for MAC. 
 
4. Mycobacterium tuberculosis (TB). Tuberculosis-associated IRIS can present as one of two main 
syndromes: (1) a paradoxical reaction after the start of ART in patients receiving tuberculosis 
treatment (“paradoxical” tuberculosis-associated IRIS), or (2) a new presentation of tuberculosis 
that is “unmasked” in the weeks following initiation of ART with an exaggerated inflammatory 
clinical presentation or complicated by a paradoxical response (“unmasking” tuberculosis 
associated IRIS). A “paradoxical” response to anti-tuberculous therapy was described as far back 
as 1955 in patients initiating therapy. In the HAART era, IRIS associated with TB is common and 
occurs in approximately 8-43% and typically consists of new and persistent fever after starting 
antiretroviral therapy/regimen; worsening or emergence of intrathoracic adenopathy, pulmonary 
infiltrates or pleural effusions, or worsening or emergence of cervical nodes on serial exam or of 
other tuberculous lesions, such as skin and CNS. It usually occurs within the first 4 weeks of 
beginning antimycobacterial therapy with or without antiretroviral therapy/regimen but has been 
described as late as 9 months when the patient is smear-negative. Antiretroviral therapy/regimen 
can usually be continued, often with anti-inflammatory support; corticosteroids have been used 
in those with CNS lesions or who are critically ill [7-12]. 
 
Confirmed TB IRIS in patients with a prior history of TB (paradoxical TB-associated IRIS): There 
are three components to this case-definition (adopted from Lancet Infect Dis 2008, reference 12): 
 
A) Antecedent requirements 
i) Diagnosis of tuberculosis: previous pulmonary (smear positive or smear-negative) or 
extrapulmonary TB diagnosis by ACTG criteria  

 
 
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AND 
ii) Initial response with anti-TB therapy (i.e. stabilization or improvement of signs/symptoms with 
appropriate anti-TB therapy prior to initiation of ART)*. For example, there has been cessation or 
improvement of fevers, cough, night sweats).  
* (Note: this does not apply to patients starting ART within 2 weeks of starting tuberculosis 
treatment since insufficient time may have elapsed for a clinical response to be reported) 
 
(B) Clinical criteria 
The onset of tuberculosis-associated IRIS manifestations should be within 3 months of ART 
initiation, re-initiation, or regimen change because of HIV treatment failure. 
 
Of the following, at least one major criterion or two minor clinical criteria are required: 
 
Major criteria 
• New or enlarging lymph nodes, cold abscesses, or other focal tissue involvement—e.g. 
tuberculous arthritis 
• New or worsening radiological features of tuberculosis (found by chest radiography, abdominal 
ultrasonography, CT, or MRI) 
• New or worsening CNS tuberculosis (meningitis or focal neurological deficit; e.g. caused by 
tuberculoma) 
• New or worsening serositis (pleural effusion, ascites, or pericardial effusion) 
 
Minor criteria 
• New or worsening constitutional symptoms such as fever, night sweats, or weight loss 
• New or worsening respiratory symptoms such as cough, dyspnea, or stridor 
• New or worsening abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or 
abdominal adenopathy 
 
 
(C) Alternative explanations for clinical deterioration must be excluded 
• Failure of tuberculosis treatment because of tuberculosis drug resistance 
• Poor adherence to tuberculosis treatment 
• Another opportunistic infection or neoplasm (it is particularly important to exclude an 
alternative diagnosis in patients with smear-negative pulmonary tuberculosis and extrapulmonary 
tuberculosis where the initial tuberculosis diagnosis has not been microbiologically confirmed) 
• Drug toxicity or reaction 
 
Confirmed TB IRIS in patients without a prior history of TB (ART “unmasking” TB-associated 
IRIS): Patient is not receiving treatment for TB when ART is initiated. Active TB is diagnosed after 
initiation of ART and the diagnosis of TB fulfils ACTG criteria for smear-positive pulmonary TB, 
smear-negative pulmonary TB or extrapulmonary TB. Active TB develops within 3 months of 
starting ART and one of the following criteria is met: heightened intensity of clinical 
manifestations, particularly if there is evidence of a marked inflammatory component. For 

 
 
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example, presentations may include TB lymphadenitis or TB abscesses with prominent acute 
inflammatory features; the development of pulmonary* or extrapulmonary TB with no evidence 
of miliary disease accompanied by marked focal inflammation; or histopathology from involved 
site demonstrating inflammatory changes (e.g., granulomas, caseation) accompanied by histologic 
or culture evidence of AFB consistent with TB in the absence of positive cultures for any other 
AFB. 
 
Probable TB IRIS in patients with a prior history of TB: “Probable” status should be assigned for 
cases where criteria A and B are met (see confirmed TB IRIS with a prior history of TB definition) 
but an alternative diagnosis or explanation for clinical deterioration cannot be fully excluded.  
 
Probable TB IRIS in patients without a prior diagnosis of TB: Patient is not receiving treatment 
for TB when ART is initiated. Active TB is diagnosed after initiation of ART and the diagnosis of TB 
fulfils ACTG criteria for smear-positive pulmonary TB, smear-negative pulmonary TB or 
extrapulmonary TB. There is heightened intensity of clinical manifestations but there is not clear 
evidence of a marked inflammatory component to the presentation or the subsequent 
development of focal inflammatory site(s) is beyond 3 months of ART initiation.  
 
5. Progressive Multifocal Leukoencephalopathy (PML). Inflammatory responses to PML usually 
occur within 3 months of beginning antiretroviral therapy. Based on available data, the 
simultaneous diagnosis of PML and IRIS post-HAART initiation is more commonly observed (i.e. 
unmasking IRIS). Furthermore, it appears that paradoxical worsening PML IRIS is identified sooner 
(within 4 weeks) than unmasking PML IRIS. MRI with gadolinium shows contrast enhancement 
suggesting an inflammatory response, and biopsy reveals significant inflammation with gliosis, 
marked intraparenchymal and perivascular infiltration by macrophages and lymphocytic 
infiltrates (especially CD8 T cells), giant cells, with or without demyelination. Intense JC-specific 
PCR signals (or other immunoreactivity to papovavirus antigens) are detected in brain tissue even 
in the absence of positive JC CSF PCR. The clinical responses are mixed:  some improve, and some 
have significant worsening with progression to death. A variable response to steroids has been 
described [1,13,14].  
 
Confirmed PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG 
criteria (consistent CT or MRI scan with positive biopsy or positive CSF JC PCR and the absence of 
any alternative diagnosis), with the subsequent development of new or worsening CT or MRI 
findings with contrast enhancement; brain biopsy shows focal inflammatory changes 
accompanied by histologic or PCR evidence of PML in the absence of another diagnosis.   
 
Confirmed PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in patient with no previously recognized CNS infection or malignancy, 
accompanied by CT or MRI changes showing contrast enhancement; brain biopsy shows focal 
inflammatory changes accompanied by histologic or PCR evidence of PML in the absence of 
another diagnosis. 
 
Probable PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG 
criteria (consistent CT or MRI scan with positive biopsy or CSF JC PCR and the absence of any 
alternative diagnosis), with the subsequent development of new or worsening CT or MRI findings 
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Probable PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in a patient with no previously recognized CNS infection or malignancy 
accompanied by CT or MRI changes showing contrast enhancement consistent with PML with no 
brain biopsy obtained. CSF findings cannot be attributable to another pathogen or disease 
process. 
 
IRIS Diagnoses without Specific Case Definitions 
 
Pathogen-Directed: 
 
1.  Kaposi’s Sarcoma (KS). Rapid KS progression [15] and local swelling with adjacent 
lymphadenopathy [20] have both been reported as a manifestation of immune reconstitution 
after antiretroviral therapy/regimen initiation. Whereas the latter syndrome may truly represent 
an IRIS syndrome, if there is no clear evidence of any characteristic inflammatory component [1, 
16], then the progression could be due to a failure to reconstitute KSHV-specific immune 
responses. KS-IRIS is defined as a sudden or more dramatic progression of disease than expected 
as part of natural history that occurs within 12 weeks of initiation of ART. ART alone should be 
continued for 4-6 weeks to monitor for clinical response. If the lesions stabilize, have a regression 
of inflammation or lesion number or size diminishes, this will be defined as IRIS. Should disease 
progression continue, then this is unlikely to be IRIS and should be defined as progression of 
disease and managed with appropriate KSHV specific therapies. The presence of inflammation on 
biopsy may assist in distinguishing progression of disease vs. IRIS. 
 
 
2. Hepatitis B and C. Significant increase in ALT over baseline (flares) have been documented after 
beginning antiretroviral therapy/regimen with HBV co-infection as well as after interruption of 
antiretroviral therapy/regimen (especially in patients with HBV on a 3TC- or tenofovir-containing 
regimen). After immune recovery HBV "flares" may occur if HBV is not being concomitantly treated, 
although there are other potential reasons to consider. These include: 
 
a) spontaneous HBeAg seroconversion; 
b) treatment induced exacerbation of the underlying disease; 
c) hepatotoxic effects of treatment; 
d) withdrawal of active HBV drug; 
e) development of resistance and return of replication, and/or  
f) superimposed and unrelated acute liver disease (e.g. hepatitis A) 
 
Liver biopsy may be helpful in determining evidence of drug related (eosinophilic infiltrate) vs. 
acute viral hepatitis (hepatocyte swelling with lobular inflammation). 
 
Biopsy may also grade and stage chronic viral hepatitis. IRIS is less well-defined in HCV co-
infection, and increases in liver enzymes on antiretroviral therapy/regimen may be multifactorial 
as well.  
 
3. Herpes simplex virus (HSV). The development of unusual presentations of HSV following the initiation 
of antiretroviral therapy/regimen attributed to immune reconstitution have been rarely described. 

 
 
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Localized HSV vesicles may occur within 8 weeks of initiating ART among persons with no prior history 
and no new source contact to attribute it to. Symptoms and signs are frequently consistent with a 
primary infection. Chronic erosive or ulcerative lesions of the genitals have been described in 
individuals who had prior histories of genital HSV. The appearance and clinical course of the lesions 
attributed to immune reconstitution appeared inconsistent with these patients’ previous HSV 
presentations. Proctitis has also been reported [1,18,19].  Routine viral cultures may or may not yield 
HSV though histochemistry studies may show evidence of HSV antigens in the absence of a positive 
viral culture. Histopathology in some cases may demonstrate an inflammatory infiltrate with unusual 
prominence of plasma cells and eosinophils. Response to antivirals appears to be variable.  
 
4. Pneumocystis jirovecii pneumonia (PCP). Despite being the most common OI with a relatively 
high CD4 threshold for development, few clear cases of Pneumocystis pneumonia IRIS have been 
documented so far (likely because steroids have been established for the use of severe PCP). Cases 
have been described as worsening of pneumonia and even respiratory failure, although the 
patients reported received suboptimal courses of steroids [20]. To entertain a diagnosis of PCP 
IRIS, bronchoscopy should rule out an intercurrent pulmonary process. 
 
5. Syphilis. New reactive RPR within 12 weeks of starting ART in setting of known previously treated 
syphilis and documented nonreactive within past 2 years without new attributable source. May also 
present serologically as less than or equal to 4-fold change in titer in someone with previous history 
of treated syphilis and no new attributable source. May present with systemic symptoms including 
arthralgia. May improve with anti-inflammatories. 
 
6. Toxoplasmosis. There is also a very small database for possible toxoplasmosis IRIS. No specific 
clinical pattern has been seen, and there is no clear evidence of an inflammatory component. 
 
7. Varicella Zoster (VZV). The development of herpes zoster after initiation of antiretroviral 
therapy/regimen has been attributed to immune reconstitution. The incidence of zoster appears 
to be 2- to 5-fold greater in those receiving antiretroviral therapy/regimen compared to those not 
receiving antiretroviral therapy/regimen. Most cases occur in the first 16 weeks following 
initiation of antiretroviral therapy/regimen. Those with higher percentage of CD8+ lymphocytes 
at the time of initiation of HAART and at one month following antiretroviral therapy/regimen 
appeared to be at higher risk for zoster [21].  Most cases present as cutaneous dermatomal 
disease or mucocutaneous disease, are mild, occur without systemic symptoms and respond to 
antiviral therapy. Iritis and keratitis have been described rarely [1,22]. It is not clear that cutaneous 
zoster following initiation of antiretroviral therapy/regimen has a significant inflammatory 
component that differentiates this from routine VZV.  
 
8. Other viral dermatoses. Eruptive onset of new common warts, flat warts, or epidermodysplasia 
verruciformis-type warts, or inflammation/rapid growth of previously stable cutaneous or genital 
warts, have been noted during immune restoration [23-24]. In addition, eruptive onset of new 
molluscum contagiosum or inflammation/enlargement of pre-existing mollusca during immune 
restoration has been described [25]. 
 
Non-Pathogen or Unknown Pathogen Directed 
   
1. Autoimmune disorders. Systemic lupus erythematosus, polymyositis, rheumatoid arthritis, 
relapsing polychondritis and Guillain-Barre have also been attributed to immune reconstitution 
following administration of antiretroviral therapy/regimen [1,26]. 

 
 
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2. Follicular inflammatory eruptions. Sudden onset of follicular papulopustular inflammatory 
eruptions resembling acne vulgaris or acne rosacea have been reported within first 4 months of 
immune reconstitution [27]. Eosinophilic folliculitis, distinguished from acneiform eruptions by 
intense pruritus, an urticarial appearance to the papules, and histopathology showing follicular 
inflammation containing eosinophils, has been documented. An increased incidence of 
eosinophilic folliculitis has been noted in the first 6 months of HAART therapy [28]. 
 
3. Graves’ Disease. New onset of clinically significant Graves’ disease (hyperthyroidism) has been 
reported following the initiation of antiretroviral therapy/regimen. The development of anti-
thyrotropin receptor antibodies in individuals following antiretroviral therapy/regimen, not 
present before antiretroviral therapy/regimen initiation has been described [1, 26]. 
 
4. Sarcoidosis. Worsening of previously diagnosed sarcoidosis or newly diagnosed sarcoidosis following 
antiretroviral therapy/regimen has been reported. Pulmonary involvement as well as extrapulmonary 
involvement (erythema nodosum) has been described [1, 26].  

 
 
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Selected References 
1. Shelburne SA, 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: 
emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213-27. 
2. Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus 
retinitis patients following institution of successful highly active antiretroviral therapy. Journal of Infectious 
Diseases 1999;179:697-700. 
3. Shelburne SA 3rd, Darcourt J, White AC Jr, et al. The role of immune reconstitution inflammatory syndrome 
in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect 
Dis. 2005;40(7):1049-52. 
4. Manosuthi W, Thongyen S, Chimsuntorn S, Sungkanuparph S. Immune Reconstitution Syndrome in HIV-
infected Patients with Cryptococcal Meningitis: A Prospective Study. The joint meeting of the 48th Interscience 
Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and the 46th Annual Meeting of the Infectious 
Disease Society of America (IDSA), Washington DC 2008; Abstract H-1162.  
5. Phillips P, Kwiatkowski MB, Copland M, Craib K and Montaner J. Mycobacterial lymphadenitis associated with 
the initiation of combination antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes & 
Human Retrovirology 1999;20:122-8. 
6. Aberg JA, Chin-Hong PV, McCutchan A, Koletar SL, Currier JS and the ACTG 362 and 393 Study Teams. Localized 
Osteomyelitis due to Mycobacterium avium Complex in Patients with Human Immunodeficiency Virus Receiving 
Highly Active Antiretroviral Therapy. Clin Infect Dis 2002;35:e8-13.  
7. Narita M, Ashkin D, Hollender ES and Pitchenik AE. Paradoxical worsening of tuberculosis following 
antiretroviral therapy in patients with AIDS. American Journal of Respiratory & Critical Care Medicine 
1998;158:157-61. 
8. John M, French MA. Exacerbation of the inflammatory response to Mycobacterium tuberculosis after 
antiretroviral therapy. Medical Journal of Australia 1998;169:473-4. 
9. Fishman JE, Saraf-Lavi E, Narita M, Hollender ES, Ramsinghani R and Ashkin D. Pulmonary tuberculosis in AIDS 
patients: transient chest radiographic worsening after initiation of antiretroviral therapy. AJR. American Journal 
of Roentgenology 2000;174:43-9. 
10. Furrer H, Malinverni R. Systemic inflammatory reaction after starting highly active antiretroviral therapy in 
AIDS patients treated for extrapulmonary tuberculosis.[see comment]. American Journal of Medicine 
1999;106:371-2. 
11. Orlovic D, Smego RA, Jr. Paradoxical tuberculous reactions in HIV-infected patients. International Journal of 
Tuberculosis & Lung Disease 2001;5:370-5 
12. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: 
case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8(8):516-23. 
13. Safdar A, Rubocki RJ, Horvath JA, Narayan KK and Waldron RL. Fatal immune restoration disease in human 
immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of 
antiretroviral therapy-associated immune reconstitution. Clinical Infectious Diseases 2002;35:1250-7. 
14. Gray F, Bazille C, Adle-Biassette H, et al. Central nervous system immune reconstitution disease in acquired 
immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol. 2005;11 
Suppl 3:16-22. 
15. Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Mandalia S, Dhillon T, Holmes P, Gazzard BG, 
Stebbing J. Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma. J Clin Oncol. 2005 
Aug 1;23(22):5224-8.  
16. Connick E, Kane MA, White IE, Ryder J, Campbell TB. Immune reconstitution inflammatory syndrome 
associated with Kaposi sarcoma during potent antiretroviral therapy. Clin Infect Dis. 2004 Dec 15;39(12):1852-
5. 

 
 
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17. Bihl F, Mosam A, Henry LN, et al. Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution 
and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma. 
AIDS. 2007;21(10):1245-52.  
18. Couppie P, Sarazin F, Clyti E, et al. Increased incidence of genital herpes after HAART initiation: a frequent 
presentation of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients. AIDS Patient Care 
and STDs. March 1, 2006, 20(3): 143-145. 
19. Fox PA, Barton SE, Francis N, et al. Chronic erosive herpes simplex virus infection of the penis, a possible 
immune reconstitution disease. HIV Medicine 1999;1:10-8. 
20. Zolopa A. Session 313. Complex Medical Management of HIV: Initiating ART in advanced AIDS at The joint 
meeting of the 48th Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and the 46th 
Annual Meeting of the Infectious Disease Society of America (IDSA), Washington DC 2008. 
21. Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation 
of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J 
Med. 2001 Jun 1;110(8):605-9.  
22. Feller L, Wood NH, Lemmer J. Herpes zoster infection as an immune reconstitution inflammatory syndrome 
in HIV-seropositive subjects: a review. 
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Oct;104(4):455-60. 
23. Kerob D, Dupuy A, Vignon-Pennamen MD, Bournerias I, Dohin E, Lebbe C. A case of efflorescence of 
cutaneous warts as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected 
patient. Clin Infect Dis 2007; 45(3):405-6. 
24. Mermet I, Guerrini JS, Cairey-Remonnay S, Drobacheff C, Faivre B et al. Cervical intraepithelial neoplasia 
associated with epidermodysplasia verruciformis HPV in an HIV-infected patient: a manifestation of immune 
restoration syndrome. Eur J Dermatol 2007; 17(2):149-52. 
25.  Pereira B, Fernandes C, Nachiambo E, Catarino MC, Rodrigues A, Cardoso J. Exuberant molluscum 
contagiosum as a manifestation of the immune reconstitution inflammatory syndrome. Dermatol Online J 
2007;13(2):6 
26.French MA, Price P and Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 
2004;18:1615-27. 
27. Scott C, Staughton, R, Hawkins D, Asboe D. Acne vulgaris and acne rosacea immune reconstitution disease 
following highly active antiretroviral therapy (HAART) for HIV infection: a case series. HIV Medicine 2007;44 (8): 
142. 
28. Rajendran PM, Dolev JC, Heaphy MR Jr,  Maurer T. Eosinophilic folliculitis: before and after the introduction 
of antiretroviral therapy. Arch Dermatol 2005;141(10):1227-31. 
 
 

 
 
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APPENDIX 7 – HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF CHILD BEARING 
POTENTIAL*  
 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy (i.e., have 
a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in 
accordance with the product label). 
The list does not apply to females of child bearing potential (FCBP) with same sex partners, when this 
is their preferred and usual lifestyle. 
• 
True abstinence from penile-vaginal intercourse, when this is in line with the preferred and 
usual lifestyle of the subject [Hatcher, 2007a] (Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of 
contraception]. 
• 
Non-hormonal Intrauterine device or non-hormonal intrauterine system that meets the 
effectiveness criteria as stated in the product label [Hatcher, 2007a] 
• 
Male partner sterilization prior to the female subject's entry into the study, and this male is 
the sole partner for that subject [Hatcher, 2007a]. The information on the male sterility can 
come from the site personnel’s: review of subject’s medical records; medical examination 
of the subject and/or semen analysis; or interview with the subject on his medical history. 
• 
Combined (oestrogen and progesterone containing) hormonal contraception associated 
with the inhibition of ovulation***: 
• 
Oral 
• 
Intravaginal  
• 
Transdermal 
• 
Bilateral tubal occlusion 
 
a Nonoxynol-9 is the critical component in most spermicides and is regarded as an acceptable 
spermicidal agent. Concern has been raised that nonoxynol-9 damages the epithelial lining of the 
vagina, and exposure may facilitate transmission of viruses, particularly HIV. The World Health 
Organization conducted a technical consultation in October 2001 and concluded that the increased 
risk for such transmission was low to minimal [WHO/CONRAD, 2003]. 
 
* A Woman of childbearing potential (WOCBP) is defined as any female who has: 
• 
Experienced menarche  
• 
Not undergone surgical sterilization (hysterectomy , bilateral salpingectomy or bilateral 
oophorectomy)  
• 
Not experienced menopause. Women are considered menopausal if they have not had a 
menses for at least 12 months and have an FSH (follicle stimulating hormone) of greater than 
40 IU/L or, if FSH testing is not available, they have had amenorrhea for 24 consecutive 
months**. 
**Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level.  
 
***If a patient is randomised to Symtuza, an alternative highly effective method of contraception 
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APPENDIX 8 – SAFETY REPORTING FLOW CHART  
 
Safety Data 
Reporting Format 
Timelines 
All SAEs arising during the Clinical Trial, 
regardless 
of 
Investigator/designee 
causality assessments against IMP(s)   
SAE form 
 
 
 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Pregnancy information for all female 
Clinical Trial Subjects who become 
pregnant while participating in the 
Clinical Trial and following exposure to 
an IMP.  
The subject will also be followed to 
determine 
the 
outcome 
of 
the 
pregnancy (including information on 
the status of the mother and child), 
which will also be reported to sponsor. 
Copies of the original 
Pregnancy CRF pages 
Site to send to sponsor within 24 
hours of first becoming aware of the 
pregnancy 
or 
the 
pregnancy 
outcome. 
Sponsor to report to Funder within 
24 hours of awareness. 
Deaths 
Any AE, AR or unexpected 
AR that results in death 
should be reported as an 
SAE on an SAE form. 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Overdose 
If the overdose fits the 
criteria of an SAE (see 
Section 8) it should be 
reported appropriately on 
an SAE form, else report as 
a 
Special 
Reporting 
Situation. 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Special Reporting Situations: 
(See section 8.10) 
Email 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Product Quality Complaints 
Email 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
 
 

 
 
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APPENDIX 9 – AMENDMENT HISTORY  
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
 
 
 
 
 
 
 

 
 
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An Open-Label, Multi-Centre, Randomised Study to Investigate 
Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral 
Therapy for Patients with Advanced HIV Disease 
-The Late Presenter Treatment Optimisation Study (LAPTOP)- 
Version 5.0 dated 11 MAR 2024 
 
SPONSOR: NEAT ID Foundation 
 
Sponsor code: NEAT44 
EudraCT: 2018-003481-13 
EUCT: 2023-505167-36-00 
 
 
 
PLEASE RETAIN ONE COPY FOR THE SITE FILE 
 
 
 
 
 
 
 
Private & Confidential 
 
 
 
GCP Compliance Statement: 
This trial will be conducted in compliance with the protocol, the principles that have their origin in the Declaration of 
Helsinki and all applicable regulatory requirements 

 
 
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SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to 
the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 
2004/1031), amended regulations (SI 2006/1928) , Clinical Trial Regulation (EU) No 536/2014  and any 
subsequent amendments of the clinical trial regulations, GCP guidelines, the Sponsor’s SOPs, and 
other regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
For and on behalf of the trial sponsor 
 
Signature:  
 
 
 
 
 
 
 
Chief Investigator 
 
 
Signature: 
 

 
 
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STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Statistician or Study Analyst agrees to conduct the trial in compliance with the approved protocol, 
Statistical Principles for Clinical Trials, ICH E10 and will adhere to the principles outlined in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 
2006/1928), Clinical Trial Regulation (EU) No 536/2014  and any subsequent amendments of the 
clinical trial regulations, GCP guidelines, the Sponsor’s SOPs and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
 
Statistician or Study Analyst 
 
 
Signature: 
 

 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the trial in accordance with ICH-GCP and the applicable regulatory requirements 
and with the approved protocol. 
I agree to comply with the procedures for data recording/reporting 
I agree to permit monitoring, auditing and inspection at this site and to retain all trial related essential 
documentation for the duration of the study as required according to ICH-GCP. 
 
 
Principal Investigator: 
Signature:  
Date: ____ / _____ / ________ 
Name (print): 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE ..................................................................................2 
STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE ......................................................................................3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................................................................4 
TABLE OF CONTENTS ........................................................................................................................................5 
KEY TRIAL CONTACTS .......................................................................................................................................8 
FUNDING AND SUPPORT .................................................................................................................................9 
STUDY SYNOPSIS ........................................................................................................................................... 10 
LIST OF ABBREVIATIONS ................................................................................................................................ 12 
1. 
BACKGROUND AND RATIONALE ............................................................................................................ 15 
1.1 
FUNDING AND COLLABORATORS.................................................................................................................. 16 
1.2 
ASSESSMENT AND MANAGEMENT OF RISK ..................................................................................................... 16 
1.2.1 
B/F/TAF ........................................................................................................................................... 16 
1.2.2 
Risk/Benefit Assessment for the Study............................................................................................ 20 
1.2.3  Rationale for Dose Selection ........................................................................................................... 21 
2. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ........................................................................... 21 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................. 21 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................ 21 
2.3 
EXPLORATORY OBJECTIVES ......................................................................................................................... 21 
2.4 
OUTCOME MEASURES/ENDPOINTS .............................................................................................................. 21 
2.4.1 
Primary endpoint/outcome ............................................................................................................. 21 
2.4.2 
Secondary endpoints/outcomes...................................................................................................... 22 
2.4.3 
Exploratory endpoints/outcomes .................................................................................................... 22 
3 
TRIAL DESIGN ........................................................................................................................................ 23 
3.1 
STUDY SCHEMA ....................................................................................................................................... 23 
4 
STUDY SETTING ..................................................................................................................................... 23 
5 
ELIGIBILITY CRITERIA ............................................................................................................................. 24 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 24 
5.2 
EXCLUSION CRITERIA ................................................................................................................................. 25 
6 
TRIAL PROCEDURES ............................................................................................................................... 26 
6.1 
RECRUITMENT ......................................................................................................................................... 26 
6.1.1 
Patient identification ...................................................................................................................... 27 
6.1.2 
Screening......................................................................................................................................... 27 
6.1.3 
Resistance Testing and Results ....................................................................................................... 27 
6.1.4 
Consent ........................................................................................................................................... 28 
6.1.5 
The randomisation scheme ............................................................................................................. 28 
6.1.6 
Method of implementing the allocation sequence ......................................................................... 29 
6.2 
BASELINE DATA ........................................................................................................................................ 29 
6.3 
TREATMENT PHASE ASSESSMENTS ............................................................................................................... 29 
6.4 
FOLLOW-UP/EARLY TERMINATION VISIT (ETV) ............................................................................................. 29 
6.5 
WITHDRAWAL CRITERIA ............................................................................................................................. 29 
6.6 
STORAGE AND ANALYSIS OF SAMPLES ........................................................................................................... 30 
6.6.1 
Resistance testing ........................................................................................................................... 30 
6.7 VIROLOGICAL FAILURE ...................................................................................................................................... 30 
6.8 END OF TRIAL .................................................................................................................................................. 30 

 
 
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7 
TRIAL MEDICATION ............................................................................................................................... 31 
7.1 
SUMMARY OF PRODUCT CHARACTERISTICS (SMPC), AND REFERENCE SAFETY INFORMATION (RSI) ......................... 31 
7.2 
DRUG STORAGE AND SUPPLY ...................................................................................................................... 32 
7.3 
PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT .......................................................... 32 
7.4 
DOSAGE SCHEDULES ................................................................................................................................. 33 
7.5 
DOSAGE MODIFICATIONS ........................................................................................................................... 33 
7.6 
KNOWN DRUG REACTIONS AND INTERACTION WITH OTHER THERAPIES ................................................................ 33 
7.7 
CONCOMITANT MEDICATION ...................................................................................................................... 33 
7.8 
TRIAL RESTRICTIONS .................................................................................................................................. 33 
7.9 
ASSESSMENT OF ADHERENCE ...................................................................................................................... 33 
7.10 
PROVISION OF TREATMENT AFTER THE END OF THE TRIAL .................................................................................. 33 
8 
PHARMACOVIGILANCE .......................................................................................................................... 34 
8.1 
DEFINITIONS ........................................................................................................................................... 34 
8.2 
OPERATIONAL DEFINITIONS FOR (S)AES ....................................................................................................... 34 
8.2.1 
Assessment of intensity ................................................................................................................... 35 
8.2.2 
Assessment of causality .................................................................................................................. 35 
8.2.3 
Collection and Follow up of Adverse Events .................................................................................... 35 
8.2.4 
Recording and Reporting of SAEs and SUSARs ................................................................................ 36 
8.3 
RESPONSIBILITIES ..................................................................................................................................... 36 
8.3.1 
Principal Investigator (PI): ............................................................................................................... 36 
8.3.2 
Chief Investigator (CI) / delegate or independent clinical reviewer: ............................................... 37 
8.3.3 
Sponsor: .......................................................................................................................................... 37 
8.3.4 
Data Safety Monitoring Board (DSMB): .......................................................................................... 37 
8.3.5 
Trial Steering Committee (TSC): ...................................................................................................... 37 
8.3.6 
Endpoint Review Committee ........................................................................................................... 38 
8.4 
NOTIFICATION OF DEATHS .......................................................................................................................... 38 
8.5 
PREGNANCY REPORTING ............................................................................................................................ 38 
8.6 
OVERDOSE .............................................................................................................................................. 38 
8.7 
REPORTING URGENT SAFETY MEASURES ........................................................................................................ 38 
8.8 
DEVELOPMENT SAFETY UPDATE REPORTS ..................................................................................................... 38 
8.9 
SPECIAL REPORTING SITUATIONS ................................................................................................................. 39 
9 
STATISTICS AND DATA ANALYSIS ........................................................................................................... 39 
9.1 
SAMPLE SIZE CALCULATION ......................................................................................................................... 39 
9.2 
PLANNED RECRUITMENT RATE ..................................................................................................................... 40 
9.3 
STATISTICAL ANALYSIS PLAN ........................................................................................................................ 40 
9.3.1 
Summary of baseline data and flow of patients ............................................................................. 40 
9.3.2 
Primary outcome analysis ............................................................................................................... 40 
9.3.3 
Secondary outcome analysis ........................................................................................................... 41 
9.4 
SUBGROUP ANALYSES ................................................................................................................................ 42 
9.5 
INTERIM ANALYSIS AND CRITERIA FOR THE PREMATURE TERMINATION OF THE TRIAL ............................................... 42 
9.6 
SUBJECT POPULATION ............................................................................................................................... 42 
9.7 
PROCEDURE(S) TO ACCOUNT FOR MISSING OR SPURIOUS DATA .......................................................................... 42 
9.8 
OTHER STATISTICAL CONSIDERATIONS ........................................................................................................... 42 
10 
DATA HANDLING ................................................................................................................................... 42 
10.1 
DATA COLLECTION TOOLS AND SOURCE DOCUMENT IDENTIFICATION ................................................................... 42 
10.1.1 Source Data ..................................................................................................................................... 42 
10.1.2 Source Documents .......................................................................................................................... 43 
10.1.3 Case report forms ........................................................................................................................... 43 
10.2 
DATA HANDLING AND RECORD KEEPING ........................................................................................................ 43 
10.3 
ACCESS TO DATA ...................................................................................................................................... 44 
10.4 
ARCHIVING ............................................................................................................................................. 44 
11 
MONITORING, AUDIT & INSPECTION ..................................................................................................... 44 

 
 
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12 
ROLES AND RESPONSIBILITIES OF TRIAL OVERSIGHT COMMITEES/ GROUPS & INDIVIDUALS ................ 45 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................................................................... 46 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) REVIEW & REPORTS ......................... 46 
13.2 
PEER REVIEW ........................................................................................................................................... 46 
13.3 
REGULATORY COMPLIANCE ........................................................................................................................ 46 
13.4 
PROTOCOL COMPLIANCE ............................................................................................................................ 47 
13.5 
NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR THE PROTOCOL .............................................................. 47 
13.6 
DATA PROTECTION AND PATIENT CONFIDENTIALITY ......................................................................................... 47 
13.7 
INDEMNITY ............................................................................................................................................. 48 
13.8 
AMENDMENTS ......................................................................................................................................... 48 
13.9 
POST TRIAL CARE ...................................................................................................................................... 49 
13.10 
ACCESS TO THE FINAL TRIAL DATASET ....................................................................................................... 49 
14 
DISSEMINATION POLICY ........................................................................................................................ 49 
15 
REFERENCES .......................................................................................................................................... 49 
APPENDIX 1 - STUDY FLOWCHART ................................................................................................................. 52 
APPENDIX 2 – AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE ............................................................. 57 
APPENDIX 3 – AIDS-DEFINING CONDITIONS ................................................................................................... 57 
APPENDIX 4 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA ....................................................................... 58 
APPENDIX 5 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA ................................................................... 63 
APPENDIX 6 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA ........................ 71 
APPENDIX 7 – HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF CHILD BEARING 
POTENTIAL* ................................................................................................................................................... 82 
APPENDIX 8 – SAFETY REPORTING FLOW CHART ........................................................................................... 83 
APPENDIX 9 – AMENDMENT HISTORY ........................................................................................................... 84 
 
 

 
 
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KEY TRIAL CONTACTS 
Chief Investigator 
Prof. Georg Behrens 
Klinik für Immunologie und Rheumatologie, OE 6830 
Medizinische Hochschule Hannover 
Carl-Neuberg-Str. 1 
30625 Hannover 
Germany 
Sponsor 
 
NEAT ID Foundation 
PL709  
322 Rue Haute, 
1000 Brussels,  
Belgium  
Statistics 
Lambert Assoumou 
Epidémiologie clinique de l'infection à VIH: stratégies 
thérapeutiques et comorbidités  
Institut Pierre Louis d'Epidémiologie et de Santé Publique 
56 Bd Vincent Auriol, CS 81393 
75646 PARIS CEDEX 13 
France 
IMP Management 
PCI Pharma Services 
Biotec House, Central Park 
Western Avenue 
Bridgend 
CF31 3RT 
United Kingdom 
Central Laboratory 
(Resistance Testing) 
Monogram Biosciences 
345 Oyster Point Blvd 
San Francisco 
California 
94080-1913 
United States of America 
Central Laboratory  
(Storage and Logistics) 
ACM Global Laboratories, Ltd. 
23 Hospital Fields Road 
York 
YO10 4DZ 
United Kingdom 
Study Coordinating 
Organisation  
Research Organisation (KC) Ltd 
The Stanley Building 
7 Pancras Square 
London 
N1C 4AG 
United Kingdom 
 

 
 
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FUNDING AND SUPPORT  
FUNDERS/COLLABORATORS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City 
CA 94404 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
 
 

 
 
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STUDY SYNOPSIS 
Full Study Title 
An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor 
Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients with Advanced 
HIV-Disease  
Short Title/Acronym 
LAPTOP (The Late Presenter Treatment Optimisation Study) 
Clinical Phase  
IIIb 
Trial Design 
International, multi-centre, randomised, open-label, controlled study comparing two 
strategies for HIV-1 infected patients with advanced disease. Randomisation 1:1 into 
two arms, 48 weeks, stratified according to country and baseline CD4 cell count (<50 
cells/µL, 50-199 cells/µL, or ≥200 cells/µL). 
Name of Investigational 
Product 
Treatment Arm 1 
Bictegravir (50mg)/emtricitabine (200mg)/tenofovir alafenamide (25mg) [1 pill 
administered orally once daily for 48 weeks without regard to food] 
Treatment Arm 2 (Comparator Arm) 
Darunavir (800 mg)/cobicistat (150 mg)/emtricitabine (200 mg)/tenofovir 
alafenamide (10mg) [1 pill administered orally once daily for 48 weeks with food] 
Trial Participants 
Population 
HIV-1 infected patients ≥ 18 years and ART-naïve prior to enrolment. 
Planned Sample Size 
440 (220 subjects per treatment arm)  
Key Eligibility Criteria 
Subjects who meet the following eligibility criteria: 
1. 
Ability to understand and sign a written informed consent form (ICF) and must 
be willing to comply with all study requirements 
2. 
≥ 18 years  
3. 
HIV-1 infected AIDS except active tuberculosis (TB) or cryptococcal meningitis 
with any CD4 cell count, or; severe bacterial infection (BI) and must have a CD4 
cell count < 200/µL within 28 days prior to study entry, or; any symptoms or no 
symptoms with CD4 cell count < 100/µL within 28 days prior to study entry and 
must have an entry HIV viral load > 1000 copies/mL, or; currently being treated 
for opportunistic infections (OI) 
4. 
Have an entry HIV viral load > 1000 copies/mL 
5. 
Able to take oral medications 
6. 
ART-naïve prior to study enrolment 
7. 
Willing to use acceptable methods of contraception  
Treatment duration 
48 weeks 
Follow up duration 
30 days 
Formulation, Dose, 
Route of Administration 
Subjects will be randomised in a 1:1 ratio into one of two treatment arms: 
Group 1 
Integrase inhibitor containing regimen 
Bictegravir (50 mg)/emtricitabine (200 mg)/tenofovir alafenamide (25mg) [1 pill 
administered orally once daily without regard to food for 48 weeks] 
Group 2 

 
 
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Boosted protease inhibitor regimen 
Darunavir (800 mg)/cobicistat (150 mg)/emtricitabine (200 mg)/tenofovir 
alafenamide (10mg) [1 pill administered orally once daily with food for 48 weeks] 
Indication 
ART-naïve HIV-1 infected patients 
Methodology 
Eligible consented patients will be randomised in a 1:1 ratio 
Number of sites 
Up to 61 sites, in up to 11 countries 
Objectives 
Primary 
To demonstrate the non-inferiority of an 
INI containing regimen [bictegravir 
(B)/emtricitabine (F)/tenofovir 
alafenamide (TAF) QD] versus a boosted 
PI regimen [darunavir (D)/cobicistat 
(C)/emtricitabine (F)/tenofovir 
alafenamide (TAF) QD] in patients with 
advanced HIV infection. 
Secondary 
 To investigate the immunological and 
virological response, tolerability, 
resistance development, discontinuation 
of therapy due to tolerability, QOL and 
IRIS incidence. 
 
Outcome Measures 
Primary 
1. Time to failure, as the first 
occurrence of specified virological 
or clinical reasons.  
 
Secondary 
1. 
Proportion of patients with 
HIV-RNA viral load < 50 
copies/mL at week 24, 36, 48 
2. 
HIV-1 drug resistance at 
confirmed virological failure 
(genotype)  
3. 
Time to reach CD4 count > 
200/µL 
4. 
Proportion of patients with CD4 
cell count <200 and < 350µL at 
week 4, 8, 12, 24, 36, 48  
5. 
CD4/CD8 ratio at week 4, 8, 12, 
24, 36, 48 
6. 
Incidence of IRIS in the two 
arms through week 48 
7. 
Incidence and duration of 
hospitalisation, rate of relapse 
of specific OI/BI through week 
48 
8. 
Safety and tolerability, 
measured by Grade 2, 3 and 4 
signs and symptoms and 
laboratory toxicities through 
week 48 
9. 
ART and OI/BI treatment 
changes and dose 
modifications due to toxicities 
and DDI with ART, and IRIS 
through week 48 
10. Health care resource use, 
including total inpatient days 
and emergency room visits 
through week 48 
11.  QOL and functional status 
outcomes, including overall 
self-reported QOL and 
functional status compared in 
the two groups at week 48 

 
 
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12. Discontinuation or modification 
of study medication due to 
insufficient virological response, 
resistance 
mutations 
at 
baseline, or resistance mutation 
development before week 48 
 
 
LIST OF ABBREVIATIONS 
Acronym 
Description  
3TC 
Lamivudine 
ABC 
Abacavir 
ACTG 
AIDS Clinical Trial Group 
ADE 
Adverse Drug Event 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Transaminase 
ANRS 
Agence Nationale de Recherches sur le SIDA (National Agency 
for AIDS Research) 
AR 
Adverse Reaction 
ART 
Antiretroviral Therapy 
ARV 
Antiretroviral 
AST 
Aspartate Aminotransferase 
B/BIC 
Bictegravir 
BI 
Bacterial Infection 
BMD 
Bone Mineral Density 
C 
Cobicistat 
CA 
Competent Authority 
CDC 
Centres for Disease Control and Prevention 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Chief Investigator 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTA  
Clinical Trial Authorisation  
D/DRV 
Darunavir 
DDI 
Drug-Drug Interaction 
DIBD 
Developmental International Birth Date  
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
DTG 
Dolutegravir 

 
 
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EACS 
European AIDS Clinical Society 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELISPOT 
Enzyme-Linked ImmunoSpot 
ETV 
Early Termination Visit 
EU 
European Union 
EudraCT  
European Clinical Trials Database  
EVG 
Elvitegravir  
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FTC/F 
Emtricitabine 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation  
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HIV-1 
Human Immunodeficiency Virus Type-1 
IAS 
International AIDS Society 
IB 
Investigator’s Brochure 
IBI 
Invasive Bacterial Infection 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use 
IEC 
Independent Ethics Committee 
IGRA 
Interferon-Gamma Release Assays 
IMP  
Investigational Medicinal Product  
INI  
Integrase Inhibitor  
INSTI 
Integrase Strand Transfer Inhibitor 
IRB 
Institutional Review Board 
IRIS 
Immune Reconstitution Inflammatory Syndrome 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat  
LOCF 
Last Observation Carried Forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
NNRTI 
Non-Nucleoside Reverse-Transcriptase Inhibitor 
NRTI 
Nucleoside Reverse-Transcriptase Inhibitor 
OI 
Opportunistic Infection 
PBMC 
Peripheral Blood Mononuclear Cells 

 
 
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PI 
Principal Investigator 
PI 
Protease Inhibitor 
QD 
quaque die (once daily) 
QOL 
Quality of Life 
QP 
Qualified Person  
RAL 
Raltegravir 
RNA 
Ribonucleic Acid 
RSI 
Reference Safety Information 
RT 
Reverse Transcriptase 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TAF 
Tenofovir Alafenamide Fumarate 
TDF 
Tenofovir Disoproxil Fumarate 
TB 
Tuberculosis 
TFV 
Tenofovir 
TMG 
Trial Management Group 
TMF  
Trial Master File  
US 
United States 
USM 
Urgent Safety Measure 
 
 
 
 

 
 
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1. BACKGROUND AND RATIONALE 
Treatment responses to antiretroviral therapy (ART) have constantly improved. This is due to novel 
compounds and combinations with improved antiviral efficacy and side effect profiles resulting in less 
virologic failures and treatment discontinuation. On the other hand, most recent randomised 
controlled trials for first line treatment consider patients with less advanced disease (mean CD4 cell 
counts at baseline >350/µl, less than 15% of patients with CD4 cell counts <200/µl) and low baseline 
viral loads [DeJesus et al., Raffi et al., Walmsley et al., Sax et al, Gallant et al.]. This favours superior 
overall response rates, as these patients usually suffer from less co-morbidities, drug-drug interactions 
(DDI), and other risks for treatment failure. The rate of patients with Acquired Immune Deficiency 
Syndrome (AIDS)-defining events enrolled in these trials was low. 
Outside these trials, the number of patients considered as late presenters (CD4 cell count <350/µl) 
when diagnosed with Human Immunodeficiency Virus (HIV) remains high across Europe [Camoni et 
al., Montlahuc et al.]. According to a definition proposed in 2009, the term late presentation is used 
for persons presenting for care with a CD4 count <350 cells/mL or presenting with an AIDS-defining 
event, regardless of the CD4 cell count. Late presentation with advanced disease is restricted to 
persons presenting for care with a CD4 count <200 cells/mL or presenting with an AIDS-defining event, 
regardless of the CD4 cell count [Antinori et al.]. Patients with CD4 cell counts <200/µl and/or AIDS 
events at first diagnosis are frequent in clinical practice [Rafetti et al, Sobrino-Vegas et al, Late 
presenters working group in COHERE in EuroCoord et al.]. 
Strategic trials in this patient group thus far focused on time of treatment initiation to prevent immune 
reconstitution syndromes (IRIS) [Abdool Karim et al., Blanc et al.] or disease course of already 
diagnosed opportunistic infections (OIs) [Zolopa et al.; Manzardo C et al.]. The AIDS Clinical Trials 
Group (ACTG protocol 5164) reported that starting ART within the first 30 days after a diagnosis of 
non-tuberculosis (TB) OIs was associated with a lower rate of AIDS progression and death, compared 
to delaying initiation of ART, without an increase in adverse outcomes [Zolopa et al.]. 
Much less is known about which ART regimens perform best in late presenters in terms of viral 
efficacy, immune reconstitution, improvement of AIDS-related co-morbidities and adverse events 
(AEs). No specific combinations have been compared in sufficiently powered randomised clinical trials, 
and all regimens considered in international guidelines for first line therapies are judged as equal 
standard of care for these patients.  Initially, protease inhibitor (PI) containing regimens were 
frequently used in patients presenting late or with AIDS defining events [Mussini et al.]. 
However, specifically regimens containing integrase inhibitors (INI) are promising candidates for 
treatment combinations in patients with CD4 cell counts <200/µl due to their antiviral activity and 
rapid decline of viral load, beneficial side-effect profile and metabolism pathways compared to other 
regimens. Also, integrase inhibitors such as dolutegravir (DTG) and bictegravir (BIC/B) have high 
genetic barriers, thereby preventing resistance mutation development and ensuring sufficient 
antiviral activity in case of preexisting mutations against nucleosides [Demarest et al.]. Therefore, in 
cases when ART needs to be initiated before genotypic testing results are available, current European 
AIDS Clinical Society (EACS) Guidelines (EACS Treatment Guidelines 9.0) recommend to include a drug 
with a high genetic barrier to resistance in the first-line regimen (e.g. PI or DTG). Whilst some reports 
describe a higher risk for IRIS in patients receiving integrase inhibitors [Wijting et al., Dutertre et al., 
Psichogiou et al.], a meta-analysis did not [Hill et al.]. We therefore propose a strategic clinical trial to 
compare an INI containing regimen versus a boosted PI regimen in patients with advanced HIV-
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1.1 Funding and Collaborators 
Gilead Sciences, Inc. (Gilead) is the Funder for this Investigator-led study and will provide financial 
support, as well as supplying the study drug (Biktarvy®) for the INI containing treatment regimen. 
Janssen Pharmaceutica NV (Janssen) will also be providing support for the study by supplying the study 
drug (Symtuza®) for the boosted PI treatment regimen, as well as funds for the associated study drug 
management costs.   
1.2 Assessment and management of risk 
1.2.1 B/F/TAF 
Experience from Clinical Studies in Treatment-Naïve Patients 
Assessment of adverse reactions (ARs) is based on pooled data from two 48-week controlled clinical 
studies (GS-US-380-1489 (“Study 1489”) and GS-US-380-1490 (“Study 1490”)) in which 1274 
treatment-naïve patients received B/F/TAF (N=634), abacavir (ABC)/DTG/lamivudine (3TC) (N=315), 
or DTG+FTC/TAF (N=325). 
The ARs are listed below by system organ class and frequency.  Frequencies (based on all treatment-
emergent AEs, regardless of relationship to study drug) are defined as follows: very common (≥10%), 
common (≥1% and <10%) or uncommon (≥0.1% and <1%). 
NERVOUS SYSTEM DISORDERS 
Very common: headache 
GASTROINTESTINAL SYSTEM DISORDERS 
Very common: diarrhoea  
Common: nausea, vomiting, abdominal pain, dyspepsia, flatulence 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Common: rash 
Uncommon: Urticaria 
GENERAL DISORDERS AND ADMINISTRATION SITE REACTIONS 
Common: fatigue 
Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of 
tubular secretion of creatinine without affecting renal glomerular function.  Increases in serum 
creatinine occurred by Week 4 of treatment and remained stable through Week 96.  In Studies 1489 
and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg/dL, 0.11 (0.03, 0.18) 
mg/dL, and 0.11 (0.04, 0.19) mg/dL from baseline to Week 96 in the B/F/TAF, ABC/DTG/3TC, and 
DTG+FTC/TAF groups, respectively.  There were no discontinuations due to renal adverse events 
through Week 96 in B/F/TAF clinical studies. 
Changes in Bilirubin: Total bilirubin increases were observed in 12% of patients administered B/F/TAF 
through Week 96.  Increases were primarily Grade 1 (9%) and Grade 2 (3%) and were not associated 
with hepatic ARs or other liver related laboratory abnormalities.  There were no discontinuations due 
to hepatic AEs through Week 96 in B/F/TAF clinical studies. 
Clinical Experience 
The efficacy and safety of B/F/TAF in HIV-1 infected, treatment-naïve adults are based on 48-week 
data from two randomised, double-blind, active-controlled studies, Study 1489 (N=629) and Study 
1490 (N=645). 

 
 
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The efficacy and safety of B/F/TAF in virologically-suppressed HIV-1 infected adults are based on 48-
week data from a randomised, double-blind, active-controlled study, GS-US-380-1844 (“Study 1844”) 
(N=563); and a randomised, open-label, active-controlled study, GS-US-380-1878 (“Study 1878”) 
(N=577). 
The efficacy and safety of FTC+TAF (components of B/F/TAF) in HIV-1 infected, virologically-
suppressed patients with mild to moderate renal impairment is based on 144-week data from an 
open-label study, GS-US-292-0112 (“Study 112”) (N=242). 
The efficacy and safety of FTC+TAF in adult patients coinfected with HIV-1 and chronic hepatitis B 
(HBV) are based on 48-week data from an open-label study, GS-US-292-1249 (“Study 1249”) (N=72). 
The efficacy and safety of B/F/TAF in adult patients coinfected with HIV-1 and chronic HBV are also 
supported by 48-week data in 8 HIV/HBV coinfected adults treated with B/F/TAF in Study 1490 and 8 
HIV/HBV coinfected adults treated with B/F/TAF in Study 1878. 
 
Treatment-Naïve Patients 
In Study 1489, patients were randomised in a 1:1 ratio to receive either B/F/TAF (N=314) or 
ABC/DTG/3TC (600/50/300 mg) (n=315) once daily.  In Study 1490, patients were randomised in a 1:1 
ratio to receive either B/F/TAF (N=320) or DTG+FTC/TAF (50+200/25 mg) (N=325) once daily. 
In Studies 1489 and 1490, the mean age was 35 years (range 18-77), 89% were male, 58% were White, 
33% were Black, and 3% were Asian. 24% of patients identified as Hispanic/Latino.  The mean baseline 
plasma HIV-1 RNA was 4.4 log10 copies/mL (range 1.3-6.6).  The mean baseline CD4+ cell count was 
460 cells/mm3 (range 0-1636) and 11% had CD4+ cell counts less than 200 cells/mm3.  18% of patients 
had baseline viral loads greater than 100,000 copies/mL.  In both studies, patients were stratified by 
baseline HIV-1 RNA (≤100,000 copies/mL, >100,000 copies/mL to ≤400,000 copies/mL, or >400,000 
copies/mL), by CD4 count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL), and by region (US or ex-
US). 
Treatment outcomes of Studies 1489 and 1490 through Week 48 are presented in Table 1-1. 
Table 1-1 Pooled Virologic Outcomes of Studies 1489 and 1490 at Week 48 in Treatment-Naïve 
Patientsa 
 
B/F/TAF  
(N=634)b 
ABC/DTG/3TC 
(N=315)c 
DTG+FTC/TAF 
(N=325)d 
HIV-1 RNA < 50 copies/mL 
91% 
93% 
93% 
Treatment 
Difference 
(95% 
CI) 
B/F/TAF vs Comparator 
- 
-2.1% 
(-5.9% to 1.6%) 
-1.9% 
(-5.6% to 1.8%) 
HIV-1 RNA ≥ 50 copies/mLe 
3% 
3% 
1% 
No Virologic Data at Week 48 Window 
6% 
4% 
6% 
Discontinued Study Drug Due to AE or 
Deathf 
<1% 
1% 
1% 
Discontinued Study Drug Due to Other 
Reasons and Last Available HIV-1 RNA 
< 50 copies/mLg 
4% 
3% 
4% 
Missing Data During Window but on 
Study Drug 
2% 
<1% 
1% 
a Week 48 window was between Day 295 and 378 (inclusive). 
b Pooled from Study 1489 (N=314) and Study 1490 (N=320). 
c Study 1489 
d Study 1490 
e Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of 
efficacy; patients who discontinued for reasons other than an AE, death or lack or loss of efficacy and at the time of 
discontinuation had a viral value of ≥ 50 copies/mL. 

 
 
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f Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted 
in no virologic data on treatment during the specified window. 
g Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, 
loss to follow-up, etc. 
 
B/F/TAF was non-inferior in achieving HIV-1 RNA < 50 copies/mL at Week 48 when compared to 
ABC/DTG/3TC and DTG+FTC/TAF, respectively.  Treatment outcomes were similar across subgroups 
by age, sex, race, baseline viral load, and baseline CD4+ cell count. 
In Studies 1489 and 1490, the mean increase from baseline in CD4+ count at Week 48 was 207, 229, 
and 201 cells/mm3 in the pooled B/F/TAF, ABC/DTG/3TC, and DTG+FTC/TAF groups, respectively. 
Bone Mineral Density: In Study 1489, bone mineral density (BMD) change from baseline to Week 48 
was assessed by dual-energy X-ray absorptiometry.  In patients who had both baseline and Week 48 
hip and lumbar spine BMD measurements (N=257 and 267 in the B/F/TAF group and N=270 and 274 
in the ABC/DTG/3TC group, for hip and lumbar spine, respectively), mean percentage changes in BMD 
were similar in the B/F/TAF group compared to the ABC/DTG/3TC group for hip (-0.8% vs -1.0%) and 
lumbar spine (-0.8% vs -0.6%). 
 
Pharmacology 
Mechanism of Action: 
BIC: BIC is an Integrase Strand Transfer Inhibitor (INSTI) that binds to the integrase active site and 
blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential 
for the HIV replication cycle.  
BIC has activity that is specific to HIV-1 and HIV-2. 
FTC: FTC is a nucleoside analogue of 2’-deoxycytidine.  FTC is phosphorylated by cellular enzymes to 
form FTC triphosphate.  FTC triphosphate inhibits HIV replication through incorporation into viral DNA 
by the HIV reverse transcriptase (RT), which results in DNA chain-termination.  
FTC has activity that is specific to HIV-1 and HIV-2 and HBV.   
FTC triphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA 
polymerase γ and there was no evidence of toxicity to mitochondria in vitro and in vivo. 
TAF: TAF is a phosphonamidate prodrug of TFV (2’-deoxyadenosine monophosphate analogue).  TAF 
is permeable into cells and due to increased plasma stability and intracellular activation through 
hydrolysis by cathepsin A, TAF is more efficient than TDF in loading TFV into peripheral blood 
mononuclear cells (PBMCs) (including lymphocytes and other HIV target cells) and macrophages.  
Intracellular TFV is subsequently phosphorylated to the pharmacologically active metabolite TFV 
diphosphate.  TFV diphosphate inhibits HIV replication through incorporation into viral DNA by the 
HIV RT, which results in DNA chain-termination.  
TFV has activity that is specific to HIV-1 and HIV-2 and HBV.  In vitro studies have shown that both FTC 
and TFV can be fully phosphorylated when combined in cells.  TFV diphosphate is a weak inhibitor of 
mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence 
of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses. 
 
Antiviral Activity: 
B/F/TAF: The triple combination of B, F and TAF demonstrated synergistic antiviral activity in cell 
culture. 
BIC: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes.  The 

 
 
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EC50 values for BIC were in the range of < 0.05 to 6.6 nM.  The protein-adjusted EC95 of BIC was 361 
nM for wild type HIV-1 virus. 
BIC displayed antiviral activity in cell culture against HIV-1 groups (M, N, O), including subtypes A, B, 
C, D, E, F, and G (EC50 values ranged from < 0.05 and 1.71 nM), and activity against HIV-2 (EC50 = 1.1 
nM). 
In a study of BIC with representatives from the major classes of approved anti-HIV agents (nucleoside 
reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), 
INSTIs, and PIs), additive to synergistic antiviral effects were observed.  No antagonism was observed 
for these combinations. 
FTC: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs.  The EC50 values for FTC were in the 
range of 0.0013 to 0.64 µM. 
FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values 
ranged from 0.007 to 0.075 µM) and showed activity against HIV-2 (EC50 values ranged from 0.007 to 
1.5 µM). 
In two-drug combination studies of FTC with NRTIs, NNRTIs, PIs, and INSTIs, additive to synergistic 
effects were observed.  No antagonism was observed for these combinations. 
TAF: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was 
assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4 T 
lymphocytes.  The EC50 values for TAF were in the range of 2.0 to 14.7 nM.   
TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, 
B, C, D, E, F, and G (EC50 values ranged from 0.10 and 12.0 nM), and activity against HIV-2 (EC50 values 
ranged from 0.91 to 2.63 nM). 
In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV 
agents (NRTIs, NNRTIs, INSTIs, and PIs), additive to synergistic antiviral effects were observed.  No 
antagonism was observed for these combinations. 
 
Pharmacokinetic Properties 
Absorption: 
BIC: BIC is absorbed following oral administration with peak plasma concentrations occurring at 2-4 
hours after administration of B/F/TAF.  Relative to fasting conditions, the administration of B/F/TAF 
with either a moderate fat (~600kcal, 27% fat) or high fat meal (~800kcal, 50% fat) resulted in an 
increase in BIC AUC (24%).  This modest change is not considered clinically meaningful and B/F/TAF 
can be administered with or without food. 
FTC: FTC is rapidly and extensively absorbed following oral administration with peak plasma 
concentrations occurring at 1.5-2 hours after administration of B/F/TAF. 
The mean absolute bioavailability of an FTC 200 mg capsule was 93%.  The mean absolute 
bioavailability of the FTC 10 mg/mL oral solution was 75%.   
FTC systemic exposure was unaffected when FTC was administered with food and B/F/TAF can be 
administered with or without food. 
TAF: TAF is rapidly absorbed following oral administration with peak plasma concentrations occurring 
at 0.5-2 hours after administration of B/F/TAF. 
Relative to fasting conditions, the administration of TAF with a moderate fat meal (~600kcal, 27% fat) 
and a high fat meal (~800kcal, 50% fat) resulted in an increase in AUClast of 48% and 63% respectively.  

 
 
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These modest changes are not considered clinically meaningful and B/F/TAF can be administered with 
or without food. 
B/F/TAF: The multiple dose PK parameters of the components of B/F/TAF are provided in Table 1-2. 
Table 1-2 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of B/F/TAF 
With or Without Food in HIV-Infected Adults. 
Parameter Mean (%CV) 
Bictegravira 
Emtricitabineb 
Tenofovir Alafenamidec 
Cmax  
(microgram per mL) 
6.15 (22.9) 
2.13 (34.7) 
0.121 (15.4) 
AUCtau  
(microgram·hour per mL) 
102 (26.9) 
12.3 (29.2) 
0.142 (17.3) 
Ctrough 
(microgram per mL) 
2.61 (35.2) 
0.096 (37.4) 
NA 
CV = Coefficient of Variation; NA = Not Applicable 
a From Population PK analysis in Studies 1489, 1490, 1844, and 1878; N = 1193 
b From Intensive PK analysis in Studies 1489, 1490, 1844, and 1878; N = 77 
c From Population PK analysis in Studies 1489 and 1490; N = 486 
 
Please refer to the latest prescribing information for further information about clinical studies involving 
BIC. 
1.2.2 
Risk/Benefit Assessment for the Study 
All patients with HIV-1 infection should receive effective ART. Potential risks associated with all classes 
of ARVs include IRIS. The risk of class effects is considered to be low. Important identified risks 
appropriately managed by study inclusion/exclusion criteria as well as through close clinical and 
laboratory monitoring during the study, are as follows: hypersensitivity reaction, including liver injury, 
and allergy to any components of the regimens. Interim data will also be reviewed by an independent 
data monitoring committee. 
Potential benefits may include provision of a new ART that is not currently available, and which may 
have fewer side effects than alternative therapies. The benefits of participation for patients receiving 
B/F/TAF include provision of a therapy with less DDI due to the non-boosting regimen. Other potential 
benefits include provisions of fixed dose combination (FDC) therapy, and the knowledge that patient 
participation will contribute to the body of knowledge of HIV therapies. 
Following a chronic 39-week study in monkeys, animals administered the highest dose of BIC (1000 
mg/kg/day) had bile duct hyperplasia (increased cell growth) and hypertrophy (increased cell size), 
and some increased cell growth and inflammation in nearby liver cells. These effects were not seen in 
monkeys administered the mid-level dose (200 mg/kg/day), and these animals had plasma BIC 
exposures that were approximately 5-fold above human exposures when given the B/F/TAF FDC.  No 
adverse drug reactions associated with liver or bile duct problems have been identified in humans 
treated with BIC. 
Darunavir as a component of D/C/F/TAF fix-dose combination can cause transient and usually 
asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of 
clinically apparent, acute liver injury. No dose adjustment of D/C/F/TAF is required in patients with 
mild or moderate (Child-Pugh Class A/B) hepatic impairment or in patients with estimated glomerular 
filtration rate according to the Cockcroft-Gault formula (eGFRCG) ≥ 30 mL/min. The most frequent 
adverse reactions reported were diarrhea, nausea, fatigue, headache, and rash. Darunavir contains a 
sulphonamide moiety and should be used with caution in patients with a known sulphonamide allergy. 
Co-administration of D/C/F/TAF and medicinal products primarily metabolised by CYP3A may result in 
increased systemic exposure to such medicinal products, which could increase or prolong their 
therapeutic effect and adverse reactions. 

 
 
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The overall benefit-risk assessment for B/F/TAF and D/C/F/TAF is favourable at this time. 
 
1.2.3  Rationale for Dose Selection 
B/F/TAF 
The B/F/TAF FDC containing B (50 mg), F (200 mg), and TAF (25 mg), has been approved by the Food 
and Drugs Administration (FDA) for use once daily for the treatment of HIV-1 infection in adults. This 
regimen has been submitted to the European Medicines Agency for approval and was approved in 
June 2018. Phase 3 clinical trials with the B/F/TAF FDC in treatment-naïve patients have shown it to 
be safe and well tolerated and have demonstrated non-inferiority to ABC/DTG/3TC and DTG + F/TAF 
at Week 48 by snapshot algorithm (GS-US-380-1489 and GS-US-380-1490). B/F/TAF contains 25 mg of 
TAF, the approved and recommended dosage for the treatment of HBV infection with other 
antiretrovirals (ARVs) for treatment of HIV/HBV co-infection (Please refer to the Biktarvy® SmPC for 
further information).  
D/C/F/TAF 
The D/C/F/TAF FDC (Symtuza®) containing D (800 mg), C (150 mg), F (200 mg), and TAF (10 mg), has 
been approved in the European Union (EU) for use once daily for the treatment of HIV-1 infection in 
adults. 
2. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
2.1 Primary objective 
• 
To demonstrate the non-inferiority of an INI containing regimen [bictegravir (B)/emtricitabine 
(F)/tenofovir alafenamide (TAF) QD] versus a boosted PI regimen [darunavir (D)/cobicistat (C)/ 
emtricitabine (F)/tenofovir alafenamide (TAF) QD] in patients with advanced HIV infection.   
2.2 Secondary objectives 
• 
To investigate the immunological and virological response, tolerability, resistance 
development, discontinuation of therapy due to tolerability, quality of life (QoL) and IRIS 
incidence. 
2.3 Exploratory objectives 
• 
To assess whether virological response is better predicted by deep sequencing rather than 
standard population sequencing. 
2.4 Outcome measures/endpoints 
2.4.1 
Primary endpoint/outcome 
• 
Time to failure, as the first occurrence of any of the following components: 
 
1. Virological reasons 

 
 
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a) Insufficient virological response, either:  
a. HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
b. Viral load > 50 HIV-1 RNA copies/mL at week 48  
b) Viral rebound, which is subsequently confirmed at the following scheduled or 
unscheduled visit, defined as either: 
a. Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL  
b. Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients 
whose viral load has never been suppressed below 50 copies/mL 
 
2. Clinical reasons* 
a) Death related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS 
b) Any new or recurrent AIDS defining event on, or after 28 days of therapy 
c) Any new serious non-AIDS defining event documented by the endpoint review 
committee (including severe BI, end stage liver disease, renal failure, cardiovascular 
event, and non-AIDS related malignant disease)  
d) Clinically relevant AEs of any grade or IRIS which require treatment interruption 
(lasting > 5 days) of INI or boosted PI therapy within the first 48 weeks after 
randomisation 
Note: Discontinuation of BIC or boosted DRV followed by (within 5 days) continuation 
with another INI or PI, respectively, is not considered as a strategy failure or endpoint. 
2.4.2 
Secondary endpoints/outcomes 
• 
Proportion of patients with HIV-RNA viral load < 50 copies/mL at week 24, 36, 48 
• 
HIV-1 drug resistance at confirmed virological failure (genotype) 
• 
Time to reach CD4 count > 200/µL (first measurement) 
• 
Proportion of patients with CD4 cell count < 200 µL and < 350µL at week 4, 8, 12, 24, 36, 48 
• 
CD4/CD8 ratio at week 4, 8, 12, 24, 36, 48 
• 
Incidence of IRIS in the two arms through week 48 
• 
Incidence and duration of hospitalisation, rate of relapse of specific OI/BI through week 48 
• 
Safety and tolerability, measured by Grade 2, 3 and 4 signs and symptoms and laboratory 
toxicities through week 48 
• 
ART and OI/BI treatment changes and dose modifications due to toxicities and DDI with ART, 
and IRIS through week 48 
• 
Health care resource use, including total inpatient days and emergency room visits through 
week 48 
• 
QOL and functional status outcomes, including overall self-reported QOL and functional status 
compared in the two groups at week 48 
• 
Discontinuation or modification of study medication due to insufficient virological response, 
resistance mutations at baseline, or resistance mutation development before week 48 
 
2.4.3 
Exploratory endpoints/outcomes 
• 
Mutations detected by deep sequencing compared with those detected by population 
sequencing 
• 
Proportion of patients with HIV-RNA viral load < 50 copies/mL at week 4, 8, 12  
 
* Refer to Appendices 3 (AIDS-Defining Conditions), 4 (INSIGHT Serious Non-AIDS Events Criteria), 5 (INSIGHT Progression of 
HIV Disease Criteria) and 6 (Immune Reconstitution Inflammatory Syndrome Generic Criteria). 

 
 
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3 TRIAL DESIGN 
An open-label, randomised, two arm, multicentre trial over 48 weeks to compare two strategies for 
HIV-1 infected patients with advanced disease, stratified according to country and baseline CD4 cell 
count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL). 
Patients will be randomised to receive either an integrated inhibitor containing regimen (B (50mg)/F 
(200mg)/TAF (25mg) [1 pill administered orally once daily for 48 weeks]) or a boosted PI regimen (D 
(800mg)/C (150mg)/F(200mg)/TAF (10mg) [1 pill administered orally once daily for 48 weeks]).  
Study visits will take place at screening, baseline, weeks 4, 8, 12, 24, 36 and 48, as well as a follow-up 
visit 30 days following the week 48 visit.  
Routine investigations will include HIV-1 RNA, CD4, CD8, haematology (including haemoglobin, white 
cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, 
phosphorus, albumin, glucose, alanine transaminase (ALT), aspartate aminotransferase (AST), ALP, 
total and indirect bilirubin, total cholesterol, HDL, LDL, triglycerides), QoL questionnaire (EuroQoL EQ-
5D-3L), HIV Symptom Index (HIV-SI/SDM) urine sample (for haematuria, proteinuria, glycosuria, 
leukocytes, nitrites, pregnancy test in women of child-bearing potential (WOCBP)).   
For a full list of investigations please see the table of assessments in Appendix 1. 
3.1 Study Schema 
 
4 STUDY SETTING 
This study will be conducted within the NEAT ID network and include sites that have an excellent track 
record in clinical research and operate in up to eight countries. A full feasibility and qualification 
assessment plan will be undertaken for all potential sites. The sponsor will ensure that onsite visits 
are performed to assess GCP compliance, including (but not limited to); protocol adherence, informed 
consent documentation, data quality, drug accountability and overall site performance.  
Untreated HIV-patients with either; 
•
AIDS 
•
Severe BI and CD4 <200/μl 
•
CD4 <100/μl & VL>1,000 copies/ml 
•
Current OI treatment
INI Regimen QD 
B/F/TAF 
50mg/200mg/25mg 
PI Regimen QD  
Symtuza: D/C/F/TAF 
800mg/150mg/200mg/10mg 
N=220 
N=220 
Randomisation 
1:1 
Week 48 

 
 
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5 ELIGIBILITY CRITERIA 
5.1 Inclusion criteria 
Patients must meet all the following inclusion criteria to be eligible for participation into this study. 
1. The ability to understand and sign a written informed consent form (ICF) and must be willing 
to comply with all study requirements. 
 
2. Male or non-pregnant, non-lactating females†. 
 
3. Age ≥ 18 years. 
 
4. Have documented, untreated HIV-1 infection with either: 
 
a) AIDS with any CD4 cell count (AIDS-defining conditions are listed within Appendix 3). 
 
Or 
 
b) Severe bacterial infection (BI)‡ and must have a CD4 cell count < 200/µl within 28 days 
prior to study entry§. 
 
Or 
 
c) Any symptoms or no symptoms and must have a CD4 cell count < 100/µL within 28 days 
prior to study entry and must have an entry HIV viral load > 1000 copies/mL. 
 
Or 
 
d) Currently receiving treatment for OI**.  
i. 
Subjects with other serious OIs, including other AIDS-defining and AIDS-related OIs 
for which appropriate therapy other than ART exists are eligible, but Investigator 
approval must be obtained. 
ii. 
Current OI treatment can  have  been  discontinued  prior  to  start  of  ART. 
 
5. Have an entry HIV viral load > 1000 copies/mL 
6. Have the ability to take oral medications. 
 
 
†Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade haemoglobin based on the gender with which they identify (i.e. a 
transgender female should be graded using the female sex at birth haemoglobin laboratory values) 
‡ A severe BI consists of any of bacterial pneumonia, IBI or any bacterial infectious disorder with grade 3 severity (severe or 
medically significant but not immediately life-threatening, see Appendix 2) or requiring unscheduled hospital admission. An 
IBI is defined as the isolation of a bacterial organism from a normally sterile body site, or for bacterial nucleic acid to be 
detected at a normally sterile body site. Sterile body sites include blood, cerebrospinal fluid, pleural fluid, pericardial fluid, 
peritoneal fluid, joint fluid, bone aspirate, or a deep tissue abscess. 
§Study entry is defined as the start of the screening process 
**  Including Pneumocystis jrovecii pneumonia [PCP]; disseminated histoplasmosis; cytomegalovirus [CMV] infection; 
toxoplasmic encephalitis; other atypical non-tuberculous, non-MAC mycobacterial infections; or other serious, invasive 
bacterial infections (IBI). 

 
 
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7. Females of childbearing potential and heterosexually active males must be willing to use a 
highly effective method of contraception and be willing to continue practising these birth 
control methods during the trial and for at least 30 days after the last dose of study 
medication.  See Appendix 7 for further details.  
Such methods include: 
• 
True abstinence from penile-vaginal intercourse, when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), and withdrawal are not 
acceptable methods of contraception). 
• 
Non-hormonal Intrauterine device or non-hormonal intrauterine system that 
meets the effectiveness criteria as stated in the product label. 
• 
Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject.  
• 
Combined (oestrogen and progesterone containing) hormonal contraception 
associated with the inhibition of ovulation*: 
• 
Oral 
• 
Intravaginal  
• 
Transdermal 
• 
Bilateral tubal occlusion 
 
• 
Note: Non-childbearing potential is defined as either post-menopausal (had amenorrhea for 
at least 12 months and have an FSH (follicle stimulating hormone) of greater than 40 IU/L or, 
if FSH testing is not available, they have had amenorrhea for 24 consecutive months) or 
physically incapable of becoming pregnant with documented hysterectomy, bilateral 
salpingectomy or bilateral oophorectomy). 
*If a patient is randomised to Symtuza, an alternative highly effective method of 
contraception should be used  
5.2 Exclusion criteria 
1. Any therapeutic ARV which commenced less than 2 weeks prior to screening and which was 
taken for more than 48 hours. 
 
2. Systemic cancer chemotherapy within 30 days prior to study entry, or current treatment for 
cancer (with the exception of Kaposi’s sarcoma) or lymphoma. 
 
3. Current or anticipated use of contraindicated medications (see current Summary of Product 
Characteristics (SmPC) for Symtuza® and Biktarvy®) or anticipated systemic chemotherapy 
during study enrolment (administration of any contraindicated medication must be 
discontinued prior to the baseline visit and for the duration of the study). 
 
4. Known resistance to the components of study medications (see section 6.1.3 for more details). 
 
5. History or symptoms of advanced renal and/or hepatic impairment.  Such as, kidney failure 
requiring dialysis; eGFR <30 mL/min; hepatic transaminases (AST and ALT) > 5 x upper limit of 
normal (ULN); or, platelet count <50,000. 
 

 
 
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6. Current drug or alcohol use that, in the opinion of the Investigator, would cause interference 
with the study. 
 
7. Cryptococcal meningitis or active TB or current or expected treatment requiring Rifampicin or 
Rifabutin (patients with expected latent TB may have a TB test (IGRAs e.g. ELISPOT, 
QuantiFERON etc.) at their screening visit). 
 
8. History or presence of allergy to the study drugs or their components, or drugs of their class. 
 
9. Using any concomitant therapy disallowed as per the product labelling for the study drugs. 
 
10. Any investigational drug within 30 days prior to the study drug administration. 
 
11. Patients with severe (Child Pugh class C) hepatic impairment. 
 
12. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during 
the study. 
6 TRIAL PROCEDURES  
The schedule of assessments is summarised in Appendix 1. 
Please note that if additional tests/procedures are required in accordance with local practice, then these 
should still be performed (no usual tests/procedures should be withheld from the patients during the 
study). 
6.1 Recruitment 
Following full written informed consent, sites must keep a record of all screening and enrolled 
participants using screening and enrolment logs.  Diagnostic tests procedures may be used in 
determining eligibility however, written informed consent must be obtained prior to any study specific 
procedures.  All information collected for eligible participants will be pseudo-anonymised and 
recorded in the Investigator Site File (ISF). 
All eligible consented participants will be given a unique study identifier via an electronic study 
database. 
Anonymised information that will be collected: 
• 
age 
• 
gender 
• 
ethnicity  
• 
whether the patient is enrolled or not enrolled 
• 
if the patient is deemed ineligible, then the reason for this; or if they are eligible but choose 
not to participate, then their reason for declining (where available) 

 
 
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6.1.1 
Patient identification 
Patients will be identified through clinic visits by their direct study medical care team and visits will be 
captured on a participant screening log.  Additionally, Investigators may use advertisements; however, 
these must be approved by the Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
prior to use. 
6.1.2 
Screening 
Written informed consent must be obtained from the subject prior to performing any study related 
evaluations or procedures. 
Subjects will be provided with written information about the study in the form of a subject information 
sheet and will be allowed adequate time for questions and to consider the study before agreeing to 
participate.  It will be the responsibility of the Investigator or co-investigator to obtain written 
informed consent prior to undertaking any procedures detailed in the protocol. This responsibility may 
be delegated to other suitably trained personnel if allowed according to country-specific regulations 
and approved by the local IEC. 
The Investigator or designee must provide adequate explanation of the aims, methods, objectives and 
potential hazards of the study.  It must also be explained to the subject that they are free to refuse or 
withdraw from the study for any reason without detriment to their future care or treatment. 
See Appendix 1 for details of screening assessments required. 
6.1.3 
Resistance Testing and Results 
Resistance test results obtained at screening may influence randomisation.  
If resistance data of the RT, protease (Table 1 and 2), or integrase gene as described below become 
available after screening but before randomisation patients should not be randomised (and will be 
seen to be screen failures).  
If data becomes available after randomisation, patients may be considered to switch to the other 
treatment arm at the investigator’s discretion in the following scenarios: 
1. Patients randomised to the DRV arm may be considered to switch to the BIC arm only if they 
have any of the resistance mutation patterns as described in Table 1. In these patients, only 
TAF and FTC would have full ARV activity. The decision should be made by the investigator 
after consultations with the LAPTOP study team. 
Table 1:  Resistance mutation patterns leading to intermediate of high-level resistance against DRV. 
Resistance 
Mutation pattern21 
Darunavir 
V32I 
L33F 
K43T 
M46I 
I47V 
I54L/M 
G73T/S 
L76V 
V82A 
I84V 
L89V 
L90M 
Intermediate 
 
 
 
 
 
L 
 
 
 
 
 
+ 
Intermediate 
 
+ 
 
 
 
L 
T 
 
 
+ 
 
+ 
Intermediate 
 
 
 
+ 
 
 
 
+ 
 
+ 
 
 
High 
+ 
 
+ 
+ 
+ 
M 
 
 
+ 
 
 
+ 
High 
+ 
+ 
 
+ 
+ 
M 
 
 
+ 
 
 
+ 
High 
+ 
 
 
 
 
M 
S 
 
 
+ 
+ 
+ 
 
2. Patients randomised to the DRV or BIC arm may be considered to remain in their treatment 
arm or to switch to an alternative regime (e.g. PI + INI) only if they have any of the resistance 
mutation pattern as described in Table 2. Table 2 describes RT inhibitor associated resistance 
mutation pattern, in which intermediate or high-level resistance against FTC and TFV has to 
be expected. In these situations, only DRV or BIC would have full ARV activity. The decision to 

 
 
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remain on therapy or to switch should be made by the investigator after consultations with 
the LAPTOP study team. 
 
Table 2:  
Resistance mutation patterns leading to intermediate of high-level resistance against FTC or tenofovir disoproxil 
fumarate (TDF). 
Resistance  
Mutation pattern 
FTC 
TDF 
M41L 
E44D 
K65R 
D67N 
T69D 
K70R 
M184V/I 
L210W 
T215Y 
K219N/Q 
High 
Interm 
+ 
 
 
 
 
 
V 
+ 
+ 
 
High 
Interm 
 
 
 
+ 
 
+ 
V 
 
+ 
Q 
High 
Interm 
+ 
 
 
+ 
 
 
V 
+ 
+ 
 
High 
Interm 
 
 
+ 
 
 
 
V 
 
 
 
High 
Interm 
 
 
+ 
 
 
 
I 
 
 
 
High 
High 
+ 
+ 
 
+ 
 
 
 
+ 
+ 
 
High 
High 
+ 
+ 
 
+ 
+ 
 
V 
+ 
+ 
 
High 
High 
+ 
+ 
 
+ 
 
 
V 
+ 
+ 
N 
 
If any primary integrase strand transfer inhibitor resistance mutation (T66I/A/K, E92Q/G, T97A, F121Y, 
Y143R/H/C, S147G, Q148H/K/R, N155H/S, R263K) is identified please consult the LAPTOP study team.  
Resistance mutation patterns leading to possible resistance against BIC are Q148H/R/K plus 2 or more 
of the following mutations: (G140A/C/S, T97A, L74M, or E138A/K). 
 
6.1.4 
Consent  
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at 
their site and must ensure that any person delegated responsibility to participate in the informed 
consent process is duly authorised, trained and competent to perform their role according to the 
ethically approved protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki.  
Informed consent must be obtained prior to the participant undergoing procedures that are 
specifically for the purposes of the trial and are outside standard routine care at the participating site. 
The right of a participant to refuse participation without giving reasons must be respected.   
The participant must remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing his/her further treatment and must be provided with a contact point where 
he/she may obtain further information about the trial. Where a participant is required to re-consent 
or new information is required to be provided to a participant it is the responsibility of the PI to ensure 
this is done in a timely manner.  
The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate 
voluntarily in an environment free from coercion or undue influence. 
6.1.5 
The randomisation scheme 
Patients will be randomly allocated (1:1) to receive a BIC containing regimen or boosted PI containing 
regimen for 48 weeks. Randomisation will be computer-generated in permuted blocks and stratified 
by country and baseline CD4 cell count (<50 cells/µL, 50-199 cells/µL, or ≥200 cells/µL).  
Randomisation will be done at the baseline visit (date of the study treatment initiation). This study is 
open-label, therefore, all investigators, site pharmacists, study nurses and subjects will be unmasked 
and aware of the treatment allocation throughout the study. 

 
 
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6.1.6 
Method of implementing the allocation sequence 
The method will be detailed in the randomisation plan. 
6.2 Baseline data 
See Appendix 1 for details of assessments required. 
6.3 Treatment Phase Assessments 
See Appendix 1 for details of assessments required. 
6.4 Follow-Up/Early Termination Visit (ETV) 
In the case of early termination, every attempt will be made to ensure the subject has a termination visit.  
Patients will be encouraged to attend for remaining visits and complete study assessments to week 48 
even if they are no longer taking study medication. 
 
See Appendix 1 for details of assessments required. 
6.5 Withdrawal criteria  
A subject is free to withdraw from the study at any time.  In addition, the Investigator may decide, for 
reasons of medical prudence, to stop study medication (e.g. lack of efficacy).   
All patients who discontinue study medication will be followed up and encouraged to attend for 
study visits up until week 48. 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn from 
the study and the reason for withdrawal recorded in the Case Report Form (CRF). 
Study medication may also be discontinued in the following instances: 
1. If the subject withdraws their consent. 
2. If the investigator considers in the interest of the subject (i.e. intercurrent illness, 
unacceptable toxicity) that it is best for them to stop study medication. 
3. The subject fails to comply with the protocol requirements or fails to cooperate with 
investigator. 
4. Pregnancy during the study (for patients receiving B/F/TAF, the study medication must be 
discontinued). 
5. Discontinuation of the study at the request of the Sponsor, regulatory agency, or an IRB/IEC. 
The date and reasons for stopping medication will be clearly stated on the subject’s CRF and source 
document. Every attempt should be made to arrange follow up visits for subjects who are withdrawn 
from study medication. This visit should involve assessments as outlined in Appendix 1. 
Subjects withdrawing from the trial should be offered alternative treatment as per the local standard 
of care by the Investigator. 
Additional subjects may be recruited to account for any withdrawals should this be deemed necessary 
by the statistician or CI. 

 
 
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6.6 Storage and analysis of samples 
All samples (with the exception of centrally analysed resistance samples) will be analysed at each site’s 
local laboratory. After analysis the samples will be destroyed in accordance with local laboratory 
requirements. Throughout the study a total of 234ml of blood will be collected from each patient, this 
equates to 26ml per visit. 
Collection, processing and storage instructions will be detailed in a separate laboratory manual.  
6.6.1 
Resistance testing 
Next generation sequencing (deep sequencing) may be performed centrally to evaluate the 
significance of the HIV-1 mutations detected by this method, which are identified during standard 
population sequencing of the HIV viral load response. 
Blood samples for these tests will be taken at the baseline visit and treatment phase visits (Week 4, 8, 
12, 24, 36 and 48).  A sample will be taken at the ETV for patients with virological failure identified 
outside of a scheduled visit.   
Samples will be shipped on a periodic basis from the sites to ACM Global for central storage and 
shipped to Monogram Biosciences for analysis. 
At the end of the study, samples taken from patients that do not have virological failure will be 
destroyed, either locally, or at ACM Global. 
Collection, processing and storage instructions will be detailed in a separate laboratory manual. 
See Appendix 1 for details of assessments required. 
6.7 Virological Failure 
Virological failure is defined as: 
Insufficient virological response, either:  
o HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
o Viral load > 50 HIV-1 RNA copies/mL at week 48  
Or viral rebound, which is subsequently confirmed at the following scheduled or unscheduled visit, 
defined as either: 
o Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL  
o Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose viral 
load has never been suppressed below 50 copies/mL 
Local resistance testing should also be carried out in the event of viral failure from the first sample 
and patients should discontinue study medication and receive rescue medication at investigators 
discretion. 
6.8 End of trial 
The end of the trial is defined as the date of the last visit of the last subject undergoing the trial in any 
country. 
The sponsor must notify the Competent Authority (CA) and main IRB/IEC of the end of a clinical trial 
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7 TRIAL MEDICATION 
Name and description of investigational medicinal product(s) 
At baseline, participants will be enrolled into one of two treatment arms, either a BIC-based regimen 
or a DRV-based regimen: 
INI containing regimen (BIC-based regimen): One combined B 50mg/F 200mg/TAF 25mg tablet taken 
orally once daily for up to 48 weeks without regard to food. 
Boosted PI regimen (DRV-based regimen):  One combined D 800mg/C 150mg/F 200mg/TAF 10mg 
tablet taken orally once daily for up to 48 weeks with the addition of food. 
Participants will take the study medication from baseline, as randomised, to week 48. 
Please refer to the study specific pharmacy manual for more information.  
7.1 Summary of Product Characteristics (SmPC), and Reference Safety Information (RSI) 
Information about Emtricitabine (Emtriva®, F/FTC) 
Emtricitabine (5-fluoro-1-[(2R, 5S)-2-(hydroxymethyl)-[1, 3]-oxathiolan-5-yl] cytosine, FTC) is a NRTI 
that has demonstrated potent and selective inhibition of the HIV. In HIV-infected adults, FTC is 
administered as a 200mg QD dose concurrently with other ARV drugs. The 200mg FTC capsule 
formulation was approved by the United States (US) FDA for marketing on 2 July 2003 and is available 
under the name Emtriva®. In the European Union (EU), marketing authorisation was granted for both 
the 200mg Emtriva® capsule formulation and a 10mg/mL Emtriva® oral solution formulation on 24 
October 2003, with indications for the treatment of HIV infection concurrently with other ARV drugs 
in both adult and pediatric patients. 
Further information is available in the current Prescribing Information for Emtriva®. 
Information about Tenofovir alafenamide (TAF, GS-7340) 
Tenofovir alafenamide (GS-7340, TAF) is a second-generation oral prodrug of tenofovir (TFV), a 
nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolised intracellularly to the 
active metabolite, tenofovir diphosphate, a competitive inhibitor of HIV-1 RT that terminates the 
elongation of the viral DNA chain. The intracellular metabolism of TAF and TFV are consistent with the 
600-fold enhancement in anti-HIV activity in cell culture of TAF over TFV. 
Further information about the co-formulated version of TAF/FTC is available in the current Prescribing 
Information for Descovy®. 
Information about Darunavir (Prezista ®, D/DRV) 
Prezista® is a PI which demonstrated potent inhibition of the HIV.  DRV received marketing 
authorisation valid throughout the EU 12/02/2007. Co-administered with low dose ritonavir is 
indicated in combination with other ARV medicinal products for the treatment of HIV-1 infection in 
adult and paediatric patients from the age of 3 years and at least 15 kg body weight. Co-administered 
with cobicistat (C) is indicated in combination with other ARV medicinal products for the treatment of 
HIV-1 infection in adult patients. In ART-naïve adult patients the recommended dose regimen is 800 
mg once daily with C 150 mg once daily or ritonavir 100 mg once daily taken with food. 
Further information about DRV is available in the current Prescribing Information for Prezista®. 
 
Information about Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide (D/C/F/TAF) fixed 
dose combination (Symtuza®) 

 
 
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Symtuza® is a boosted PI indicated for the treatment of HIV-1 infection in adults and adolescents (aged 
12 years and older with body weight at least 40 kg). Symtuza® received marketing authorisation valid 
throughout the EU in September 2017.  The recommended dose regimen in adults and adolescents 
aged 12 years and older, weighing at least 40 kg, is one tablet taken once daily with food. Each film 
coated tablet contains 800 mg of D (as ethanolate), 150 mg of C, 200 mg of F, and 10 mg of TAF.  
Further information about the D/C/F/TAF FDC is available in the current Prescribing Information for 
Symtuza®. 
The Reference Safety Information for this regimen will be the formally approved and implemented 
version of the Summary of Product Characteristics for Symtuza® provided to investigators by the 
sponsor. 
. 
Bictegravir (BIC) 
BIC is an inhibitor of HIV-1 integrase that is being evaluated for the treatment of HIV-1 infection. 
Antiviral testing has shown that BIC is active against a broad panel of HIV-1 viral lab strains and clinical 
isolates. BIC is fully active against a panel of mutant viruses with resistance to NRTIs, NNRTIs, and PIs. 
Integrase mutant viruses that are resistant to the INSTIs raltegravir (RAL) and elvitegravir (EVG) remain 
largely sensitive to BIC. Gilead Sciences (Gilead) has co-formulated BIC with the NRTI F and TAF into 
an FDC tablet that is suitable for once-daily use.  
Further information about the B/F/TAF fix-dose tablet is available in the current Prescribing 
Information for Biktarvy®. 
The Reference Safety Information for this regimen will be the formally approved and implemented 
version of the Summary of Product Characteristics for Biktarvy provided to investigators by the 
sponsor. 
7.2 Drug storage and supply  
Investigators are to ensure that the investigational medicinal product (IMP) is only used in accordance 
with the protocol. Drug supplies will be kept in a secure, limited access storage area under the 
recommended storage conditions, and accessible only to those authorised by the investigator to 
dispense to eligible subjects. 
The investigator will ensure that records are maintained showing the receipt and dispensation for all 
study supplies.  A drug accountability log will be kept with the investigational supplies for 
reconciliation purposes.  This should be used to record the identification of the subject to whom the 
IMP was dispensed, the date and quantity dispensed, and the quantity unused/returned by the 
subject. This will be verified by the study monitor. 
Partially used or empty containers may be destroyed by the pharmacy/designee at local site only after 
the study monitor has completed drug accountability. The pharmacy/designee are required to 
document destruction for verification by the sponsor.  
Further information can be found in the pharmacy manual. 
7.3 Preparation and labelling of Investigational Medicinal Product 
Both the INI containing regimen (B/F/TAF) and the boosted PI regimen (D/C/F/TAF) tablets will be 
labelled with Annex 13 compliant labels and QP certified by PCI Pharma Services; who will supply 
directly to each site on request of the sponsor. 

 
 
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Further information can be found in the pharmacy manual. 
7.4 Dosage schedules 
Patients will be randomised into one of two treatment arms. 
INI containing regimen (BIC-based regimen): One combined B 50mg/F 200mg/TAF 25mg tablet taken 
orally once daily for up to 48 weeks without regard to food. 
Boosted PI regimen (DRV-based regimen):  One combined D 800mg/C 150mg/F 200mg/TAF 10mg 
tablet to be taken orally once daily for up to 48 weeks with the addition of food. 
7.5 Dosage modifications  
Please refer to section 6.5 for withdrawal and stopping rules. 
Treatment modification will be captured as a secondary endpoint only and modifications will be based 
on the treating physician’s judgement. 
7.6 Known drug reactions and interaction with other therapies 
See section 8.2 and RSI. 
Drugs that affect the study medication and that are affected by the use of the study medication 
accordingly must be reviewed by the Investigator and/or avoided. 
7.7 Concomitant medication 
For a full list of contraindicated medications, please refer to the current the current Prescribing 
Information for for both Biktarvy® and  Symtuza®  
Prophylaxis for specific OI or TB shall be performed as per standard of care.  Reference can be made 
to the EACS guidelines. 
7.8 Trial restrictions  
Please refer to inclusion and exclusion criteria listed in sections 5.1 and 5.2. 
7.9 Assessment of adherence 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each 
visit.  The outcome of this questioning should be documented in the patient notes. Issues of adherence 
should be reported to the study monitor.  
All subjects should return unused medication and containers at weeks 12, 24, 36 and 48 for pharmacy 
accountability purposes (see section 7.2). 
7.10 Provision of treatment after the end of the trial 
No post trial medication will be provided to patients.  Following their last treatment visit at Week 48 
patients will receive treatment as per local standard of care. 
 

 
 
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8 PHARMACOVIGILANCE 
8.1 Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal product 
has been administered, including occurrences which are not necessarily caused 
by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an investigational 
medicinal product which is related to any dose administered to that participant. 
The phrase "response to an investigational medicinal product" means that a 
causal relationship between a trial medication and an AE is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as ARs. 
Serious Adverse Event 
(SAE) 
An SAE is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the 
above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which the participant was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Serious Adverse Reaction 
(SAR) 
An AE that is both serious and, in the opinion of the reporting Investigator, 
believed with reasonable probability to be due to one of the trial treatments, 
based on the information provided. 
Suspected 
Unexpected 
Serious Adverse Reaction 
(SUSAR) 
• A SAR, the nature and severity of which is not consistent with the 
information about the medicinal product  set out in section 4.8 
“Undesirable Effect” of the SmPC 
 
“Severe” is often used to describe intensity of a specific event, which may be of relatively minor 
medical significance. “Seriousness” is the regulatory definition supplied above. 
8.2 Operational definitions for (S)AEs  
AEs observed by the Investigator, or reported by the subject, and any remedial action taken, will be 
recorded in the subject’s CRF and should be verifiable in the subject’s notes throughout the study.  
The nature of each event, time of onset after drug administration, duration and severity will be 
documented together with the Investigator’s opinion of the causal relationship to the investigational 
product (unrelated, unlikely, possible, probable, and definite). 

 
 
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All subjects experiencing AEs, whether considered associated with the use of the study medication or 
not, must be monitored until the symptoms subside and any clinically relevant changes in laboratory 
values have returned to baseline, or until there is a satisfactory explanation for the changes observed. 
Procedures such as surgery should not be reported as AEs.  However, the medical condition for which 
the procedure was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted on the CRF. 
Planned procedures such as surgery scheduled prior to the subject’s enrolment into the study do not 
need to be reported as AEs if these are documented as planned at the screening visit. 
Clinically significant changes in physical examination and blood safety profiles should also be recorded 
as AEs. 
8.2.1 
Assessment of intensity 
Severity should be recorded and graded according to the ACTG Grading Scale (Appendix 2).  
Note: There is a distinction between the seriousness and the intensity of an AE. Severe is a measure 
of intensity; thus, a severe reaction is not necessarily an SAE. For example, a headache may be severe 
in intensity but would not be classified as serious unless it meets one of the seriousness criteria for 
serious events. 
All events deemed to be Grade 4 (potentially life threatening) according to the ACTG grading scale 
should be routinely reported as an SAE. However, there may be occasions where in the investigator’s 
clinical judgement they do not consider the event to be life threatening therefore they do not consider 
the event to meet the definition of an SAE. In these cases, the investigator must document clearly in 
the participants source documentation that the Grade 4 event has been assessed and why in their 
clinical judgement they do not consider the event to be life threatening.   
8.2.2 
Assessment of causality 
The relationship to study drug of each AE will be assessed by the PI (or a delegated clinician) using the 
following definitions: 
DEFINITE: 
distinct temporal relationship with drug treatment. Known reaction to agent or 
chemical group or predicted by known pharmacology. Event cannot be explained by 
subject’s clinical state or other factors. 
PROBABLE: 
reasonable temporal relationship with drug treatment. Likely to be known reaction to 
agent or chemical group or predicted by known pharmacology. Event cannot easily be 
explained by subject’s clinical state or other factors. 
POSSIBLE: 
reasonable temporal relationship with drug treatment. Event could be explained by 
subject’s clinical state or other factors. 
UNLIKELY: 
poor temporal relationship with drug treatment. Event easily explained by subject’s 
clinical state or other factors. 
UNRELATED: 
the event occurs prior to dosing. Event or intercurrent illness is due wholly to factors 
other than drug treatment. 
8.2.3 
Collection and Follow up of Adverse Events 
All AEs, however minor, will be documented in the CRF whether or not the Investigator considers the 
event to be treatment related. 
The AE reporting period will be from consent until the subject’s final study visit.  In addition, any 
untoward event that may occur subsequent to the reporting period that the Investigator assesses as 
possibly, probably or definitely related to the study drug medication should also be reported as an AE. 

 
 
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AEs may be directly observed, reported spontaneously by the subject or by questioning the subject at 
each study visit. 
All AEs should be followed up until they are resolved or the subject’s participation in the study ends 
(i.e. until the final CRF is completed for that subject).  In addition, all serious and non-serious AEs 
assessed by the Investigator as possibly related to the investigational medication should continue to 
be followed up to last subject visit.  Such events should be followed until resolution, until no further 
change can reasonably be expected, or until 30 days following last subject visit.   
8.2.4 
Recording and Reporting of SAEs and SUSARs 
Definition of an SAE can be found in section 8.1. 
The SAE should be reported to the sponsor using the study specific Safety Event Reporting Form 
(SERF),  within 24 hours of a member of the study team becoming aware of the event via e-mail to 
Safety@rokcservices.com or via the fax number provided on the SERF. 
 
All SAEs occurring from the time of written informed consent until 30 days post cessation of trial 
treatment must be recorded on the study specific SAE Form and sent to the sponsor within 24 hours 
of the research staff becoming aware of the event.  
For each SAE the following information will be collected in the SERF: 
• 
full details in medical terms and case description 
• 
event duration (start and end dates, if applicable) 
• 
action taken 
• 
outcome 
• 
seriousness criteria 
• 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the Investigator 
• 
details of the reporter(s) 
Any change of condition or other follow-up information should be sent to the sponsor in a follow up 
SERF as soon as it is available or at least within 24 hours of the information becoming available. Events 
will be followed up until the event has resolved or a final outcome has been reached. 
The Sponsor representative (CI) will assess whether events suspected to be related to IMP-treatment 
would be considered expected or unexpected (using the formally approved and implemented version 
of the reference safety information (RSI) for either Symtuza® or Biktarvy®). 
 
All SAEs assigned by the PI or delegate (or following central review) as both suspected to be related 
to IMP-treatment and assessed by the CI as unexpected will be classified as SUSARs. The sponsor will 
inform the CA, the IRB/IEC and the funder as appropriate of SUSARs within the required expedited 
reporting timescales. The sponsor will update the Eudravigilance database, as required.  
8.3 Responsibilities 
8.3.1 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness, and assessing causality (using the 
formally approved and implemented version of the reference safety information (RSI) 
for either Symtuza® or Biktarvy® provided to investigators by the sponsor). 

 
 
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2. Ensuring that all SAEs and SARs (including SUSARs) are recorded and reported to the 
Sponsor within 24 hours of becoming aware of the event and provide further follow-
up information as soon as available.  
3. Ensuring that SAEs and SARs (including SUSARs) are followed up with the Sponsor if a 
record of receipt is not received within 2 working days of initial reporting.  
4. Ensuring that AEs and ARs are recorded and reported to the Sponsor in line with the 
requirements of the protocol.  
8.3.2 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in reviewing seriousness and causality of SAEs reported, 
when required.  
3. Using medical judgement in assignment of expectedness for all SARs reported (using 
the formally approved and implemented version of the reference safety information 
(RSI) for either Symtuza® or Biktarvy®) 
4. Review of specific SAEs and SARs in accordance with the trial risk assessment, protocol 
and as detailed in the Trial Risk Based Monitoring Plan, and pharmacovigilance 
management plan (PVMP). 
5. Ensure immediate review of all SUSARs.  
6. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System 
coding to all SAEs and SARs as needed. 
7. Preparing the clinical sections and final sign off of the Development Safety Update 
Report (DSUR). 
8.3.3 
Sponsor: 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according 
to the trial protocol.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer for 
the ongoing assessment of the risk / benefit according to the Trial Risk Based 
Monitoring Plan, and pharmacovigilance management plan (PVMP). 
3. Reporting safety information to the independent oversight committees identified for 
the trial (Data Safety Monitoring Board (DSMB)/Trial Steering Committee (TSC)) 
according to the Trial Risk Based Monitoring Plan and committee charter documents. 
4. Expedited reporting of SUSARs to the CA and IRB/IEC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. Checking for (at least annually) and notifying PIs of updates to the RSI for the trial. 
7. Preparing standard tables and other relevant information for the DSUR in collaboration 
with the CI and ensuring timely submission to the CA and IRB/IEC. 
8.3.4 
Data Safety Monitoring Board (DSMB): 
In accordance with the DSMB Charter, periodically reviewing overall unblinded safety data to 
determine patterns and trends of events, or to identify safety issues, which would not be apparent on 
an individual case basis.  
8.3.5 
Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing safety data and 
liaising with the DSMB regarding safety issues. 

 
 
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8.3.6 
Endpoint Review Committee 
The endpoint review committee will convene to review unblinded endpoint data, as and when 
required by the DSMB or TSC. 
8.4 Notification of deaths 
Any SAE, SAR or unexpected SAR that results in death should be immediately reported to the sponsor, 
refer to section 8.3 for SAE reporting format and timelines. 
Deaths occurring more than 30 days after the final dose, which are considered to be unrelated to the 
study medication, should not be reported as an SAE. 
8.5 Pregnancy reporting  
Pregnancy information for all female participants who become pregnant while participating in the 
study will be collected on the study specific Pregnancy Reporting Form and should be reported to the 
Sponsor via e-mail to Safety@rokcservices.com or via the fax number provided on the SERF within 24 
hours of becoming aware of the pregnancy or the pregnancy outcome.  The participant will also be 
followed up to determine the outcome of the pregnancy, which will also be reported to the sponsor.  
In the event of pregnancy, the participant may be withdrawn from the study (see Section 6.5). 
Pregnancies in female partners of male participants should be reported as a special reporting situation 
(see Section 8.9). 
8.6 Overdose  
All participants should be counselled about the importance of taking the medications as prescribed 
and they should understand the quantity of medicine they should be taking. Participants must be told 
to contact their clinic immediately if they take too much medication.  If the overdose fits the criteria 
of an SAE (see Section 8.1) it should be reported appropriately. 
8.7 Reporting urgent safety measures  
It is the responsibility of the investigator to apply the appropriate level of Urgent Safety Measure 
(USM) for the safety and protection of each participant in this study in order to prevent harm.  USMs 
may be applied immediately without prior approval from the sponsor, CA or IRB/IEC.  However, they 
must be reported to the sponsor and to the CI immediately (within 24 hours) who will then inform the 
CA and IRB/IEC according to local regulation.   
8.8 Development Safety Update Reports  
The sponsor will provide (in addition to the expedited reporting above) DSURs once a year throughout 
the clinical trial, or on request, to the CA and IRB/IEC. The sponsor intends to submit a single safety 
report on all investigational medicinal products used in the clinical trial in accordance with Article 
43(2) of the Clinical Trial Regulation (EU) No 536/2014. 
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of 
the trial each year until the trial is declared ended. 

 
 
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8.9 
Special Reporting Situations 
Special reporting situations should be reported to the sponsor via email  to Safety@rokcservices.com 
within 24 hours of the research staff becoming aware of the event (as for SAEs).   
The special situations include: 
• 
Pregnancy exposure (maternal and paternal), breastfeeding and AEs in infants following 
exposure from breastfeeding 
• 
Overdose (other than as defined in section 8.7), suspected abuse/misuse of the study product, 
and dependence 
• 
Medication error 
• 
DDI 
• 
Inadvertent or accidental exposure to the study product (including occupational exposure) 
• 
Any failure of expected of pharmacological or medical device action (i.e. lack of effect) of study 
product 
• 
Unexpected therapeutic or clinical benefit from use of the study product 
• 
Suspected transmission of an infectious agent via the study product 
• 
Expired drug use and falsified medicine 
• 
Off-label use of study product 
Product Quality Complaint (PQC): Any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance 
of a study product after it is released for distribution. A complaint is any indication of the failure of 
the product to meet consumer or user expectations for quality or to meet performance specifications. 
It may allege an AR, injury, or malfunction associated with the use of the product. It may also involve 
the design, literature, packaging, advertising, availability, physical appearance, or promotion of a 
product. 
9 STATISTICS AND DATA ANALYSIS 
9.1 Sample size calculation 
In the ANRS 146 OPTIMAL trial [Levy et al.], of late presenters, the proportion of patients with severe 
morbidity (new adverse drug event (ADE), other HIV related diseases, serious non-AIDS events, IRIS 
and death) was estimated at 12.2% per year in the boosted PI arm. The virological failure was 
estimated at 20% at week 48 in the DRV/r group of the IMEA 040 DATA study (Slama L et al) that 
recruited a similar population. As a few subjects will meet more than one of these criteria, we assumed 
a cumulative probability of failure at 25% at 48 weeks in the PI regimen group. 
A total of 404 evaluable subjects, randomized in a 1:1 ratio to 2 treatment groups (202 subjects per 
treatment group), achieves at least 80% power to detect a non-inferiority margin of 1.606 in the 
hazard ratio, which corresponds to a 12% difference in the cumulative probability of failure rate 
between INI-based regimen group (37%) and PI-based regimen group (25%), with 97 events required. 
The sample size and power calculation assumes that the cumulative probability of failure is 25% for 
the PI regimen group and 23% for the INI-based regimen group (i.e. the expected hazard ratio is 0.909), 
using a non-inferiority margin of 1.606 in hazard ratio and a two-sided 95% confidence interval (CI). 
The sample size and power calculation were made using the statistical software package nQuery 
Advanced, non-inferiority testing of two survival curves using cox regression module (Version 8.1.2.0).  
With an estimated ~7.5% drop off rate/year, we plan to enroll 220 subjects per group to ensure we 
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Superiority of INI-based regimen group versus PI-based regimen group will be evaluated after the non-
inferiority is established. With an ITT analysis, 440 subjects and 78 events, a two-sided log-rank test 
at an alpha level of 0.05 will achieve at least 80% power to detect a 50% reduction in hazard rate in 
INI-based regimen (i.e. the hazard ratio is 0.5). A 50% reduction in hazard rate means that INI-based 
regimen could decrease the risk by 11.6% (25% for PI- vs 13.4% for INI- based regimen). 
9.2 Planned recruitment rate 
In the ANRS 146 OPTIMAL trial, in which similar patients were enrolled (late presenters with low CD4 
cell count or ADE), 10% of screened patients were not eligible. Based on this information, we 
estimated that about 489 patients should be screened. Centres of NEAT ID Network with infectious 
disease units for inpatient and outpatient care will be the prioritised study sites of the LAPTOP Trial. 
We expect that about 45 sites in total across eight European countries. Therefore, we estimated that 
about 7-15 patients should be screened per site. 
9.3 Statistical analysis plan 
These analyses will assess the efficacy and safety of BIC containing regimen in comparison with the 
boosted PI containing regimen.  
All randomised patients who received at least 1 time any study treatment will be included in the 
intent-to-treat (ITT) analysis population. Of note patients lost-to follow-up or violating the protocol 
will not be excluded from the ITT population. Patients who switch treatment to another will be 
analysed as if they are remained in their initial randomisation group. All participants who are lost to 
follow-up or discontinued the study when they are endpoint free at time of leaving the study will be 
censored at the time of leaving the study. We will use time-to-event methods, including Kaplan–Meier 
survival curves and Cox proportional-hazards models to account for all participants in the analysis. The 
per-protocol population will include all patients from the ITT population except those who did not 
fulfil the inclusion/exclusion criteria, who withdrew their consent, gave up, lost to follow-up or 
discontinued early study medication for any reasons other than any component of the primary 
endpoint. 
9.3.1 
Summary of baseline data and flow of patients 
All continuous variables will be summarised using the following descriptive statistics: n (non-missing 
sample size), mean, standard deviation (SD), 1st quartile, median, 3rd quartile, maximum and 
minimum. The frequency and percentages (based on the non-missing sample size) of observed levels 
will be reported for all categorical variables.  
The number of patients and the flowchart of the study will be presented. The period of enrolment and 
the total number of patients screened to be included in the study will be presented. The number of 
ineligible patients and the total number of randomised patients will be presented. The number of 
patients who never take the study treatment will also be presented by group and those who remained 
on the study treatment up to week 48 will be presented. 
9.3.2 
Primary outcome analysis 
The primary outcome analysis will be performed with both ITT population and per-protocol 
population. The primary endpoint is the occurrence of a severe morbidity (virological failure; death 
related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS; new ADE; new serious 
non-AIDS events; and clinically relevant AEs of any grade leading to study treatment discontinuation). 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
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analyses for each component of the primary endpoint will be done. Kaplan-Meier curves will be 
plotted for the primary endpoint and its component. 
9.3.3 
Secondary outcome analysis 
All secondary outcome analysis will be done with the ITT population. The p-values will be two-tailed, 
with a significant level of 0.05. 
The proportion of patients with HIV-ribonucleic acid (RNA) viral load <50 copies/mL at week 48 will be 
analysed using the snapshot approach. Fisher’s exact test will be used to compare the estimated 
proportion between the two groups.  
A genotypic resistance test will be performed in all patients with virological failure. Drugs resistance 
mutations will be identified from the International AIDS Society (IAS)-USA resistance testing panel (last 
version at the time of analysis) and for BIC we will use IAS, Agence Nationale de Recherches sur le 
SIDA (National Agency for AIDS Research) (ANRS) or Royal College of Physicians (RCP) lists to perform 
the analysis whenever they will be made available. Resistance to BIC will also be identified using 
phenotypic resistance test. Fisher’s exact test will be used to compare the presence of at least one 
drug resistance mutation between the 2 groups.  
The median time to reach CD4 cell count >200/µl will be estimated using the Kaplan-Meier method, 
censoring at week 48 or last follow-up date if not seen at week 48. Time to reach CD4 cell count 
>200/µl will be defined as the time between the date of study treatment initiation (baseline, week 0) 
and the date of which patient reached CD4>200/µl. The log-rank test will be used to compare the two 
survival functions. The p-values will be two-tailed, with a significant level of 0.05. The proportion of 
patients with CD4 cell count <350/µl at week 48 will be done with the ITT population, with the last 
observation carried forward (LOCF) approach. Fisher’s exact test will be used to compare the 2 groups.  
The median change in CD4/CD8 ratio from baseline to week 48 will be analysed with the ITT 
population, with the LOCF approach. The non-parametric Mann Whitney test will be used to compare 
the change from baseline between the 2 groups.  
The incidence of IRIS will be analysed with the Kaplan-Meier method. The Log-rank test will be used 
to compare the two survival functions. The effect of study treatment on IRIS will be assessed using 
Cox regression model with treatment group and adjustments for stratification factors.    
The incidence of hospitalisation will be estimated by the Kaplan-Meier estimate. The Log-rank test will 
be used to compare the two survival functions. The duration of hospitalisation will be estimated by 
the cumulative days of hospitalisation during the course of study and will be compared between the 
2 groups by using the Mann-Whitney test. The rate of relapse/recurrence will be estimated by the 
number of patients with relapse/recurrence divided by the total number patients in ITT population. 
Fisher’s exact test will be used to compare the 2 groups.  
The frequency of each Grade 2, 3 or 4 AEs, laboratory toxicities, and ART and OI/BI treatment changes 
and dose modifications due to toxicities and IRIS will be described and compared by group. Fisher’s 
exact test will be used to compare the 2 groups.  
The proportion of patients with health care resource use, and emergency room visits will be compared 
in the two groups with Fisher’s exact test. The total inpatient days will be estimated by the cumulative 
inpatient days during the course of study and will be compared between the 2 groups by using the 
Mann-Whitney test. 
To assess the impact of study treatment on the evolution of QOL at week 48, we will use multiple 
imputation approach to replace missing values. We will compare the treatment effect on QOL on each 
of the 5 datasets generated, including the imputed values, and the results will be combined with 
Rubin’s rules. A generalized estimating equation (GEE) model will be used.  

 
 
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9.4 Subgroup analyses 
Subgroup analyses for the primary endpoint will be done to explore whether estimated treatment 
effects vary significantly between subcategories of trial participants. The following variables will be 
assessed: age, gender, transmission group, ethnic group, baseline CD4 (<50, 50-199, ≥200), baseline 
viral load (<100,000, 100,000-500,000, >500,000), smoker, adherence (>/< 95%) and participating 
country. Heterogeneity of the treatment effect across subgroups will be assessed by including terms 
for interactions between treatment and subgroup variables in expanded Cox models. Age will be 
divided into three groups using tertiles/quartiles. 
9.5 Interim analysis and criteria for the premature termination of the trial 
No formal interim analysis will be done. However, a DSMB will be established and will review the data 
regularly during the course of the study (see Section 12 of the protocol for more details). 
There is no trial-specific stopping criterion as the trial involves licensed products used within the 
marketing authorisation dosing instruction.  
9.6 Subject population 
All randomised patients who received at least 1 time any study treatment will be included in the ITT 
analysis population. Of note patients lost-to follow-up or violating the protocol will not be excluded 
from the ITT population.  
The per-protocol population will include all patients from the ITT population except those who did not 
fulfil the inclusion/exclusion criteria, who withdrew their consent, gave up, lost to follow-up or 
discontinued study medication for any reasons other than study endpoint criteria. 
9.7 Procedure(s) to account for missing or spurious data  
To assess the impact of study treatment on the evolution of QOL at week 48, we will use multiple 
imputation approach to replace missing values. We will compare the treatment effect on QOL on each 
of the 5 datasets generated, including the imputed values, and the results will be combined with 
Rubin’s rules. A GEE model will be used. LOCF approach will be used to replace missing CD4 and CD8 
values. 
9.8 Other statistical considerations 
All deviations from the statistical analysis plan will be recorded during the conduct of the analysis. If 
there is a decision for major modifications to the statistical analysis while the clinical trial is in progress, 
this will be part of a protocol amendment. 
10 DATA HANDLING 
10.1 
Data collection tools and source document identification 
10.1.1 Source Data 
Source data will be all information in original records and certified copies of original records or clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 

 
 
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evaluation of the trial. Source data are contained in the source documents (original records or certified 
copies) maintained at site. 
10.1.2 Source Documents 
Original documents, data and records (e.g. hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects' diaries, evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial) will be maintained at site. 
The subject’s number and date of entry into the study, along with a study identifier, should be 
recorded in the subject’s study records.  The following should also be recorded in the study records; 
confirmation of written and verbal consent, the subject’s clinical status, date of every study visit, date 
study medication was started and stopped, concomitant medications, copies of all relevant reports 
and laboratory tests, comments on results and reference to any AEs. 
Source documents include, but are not limited to, participant medical records, SAE and reportable 
event forms (see section 8), questionnaires, laboratory reports, participant progress notes, pharmacy 
records and any other reports or records of procedures performed in accordance with the protocol. 
10.1.3 Case report forms 
Subject data collected during the study will be recorded in a web-based electronic CRF (eCRF).  In 
order to maintain confidentiality, the subject information will be pseudo-anonymised.  
The design of CRFs will ensure that: 
• adequate collection of data has been performed 
• proper paper trails can be kept to demonstrate the validity of the trial (both during and 
after the trial) 
• only the data required by the protocol are captured in the CRF (using the CRF to capture 
secondary data not required for the study may be a criminal beach of the Data Protection 
Act, makes the CRF unnecessarily complicated, and can make it more difficult to extract 
the primary data for analysis) 
Data required for the study will be recorded in an eCRF collection tool by appropriately trained and 
authorised member(s) of the study team who must be identified and authorised in writing by the PI 
before they conduct any study related tasks.  A delegation of responsibility log identifying who can 
enter data and/or sign off a CRF will be maintained by the PI.   
The eCRF should be kept current by entering data ideally within 7 working days of collection to enable 
the study monitor to review the subject status throughout the course of the study. In the case of the 
eCRF being unavailable, a paper CRF can be made available to use at site. 
The data will be reviewed and approved by the Investigator following subject completion. 
10.2 
Data handling and record keeping 
The Study Monitor and Data Manager will review data on an on-going basis and raise any discrepancies 
with site staff as required.   
At the end of the study, the site will be provided with copies of their CRFs for filing in the ISF before 
the eCRF is decommissioned, ensuring site access to their data at all times. 

 
 
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Data extracted from the eCRF will be kept on a secure network drive of the sponsor with access to 
authorised personnel of the Biometrics Team only. 
The data is pseudo-anonymised at all times and is transferred securely using an encrypted file share 
process.  All transfers are fully documented. 
10.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
10.4 
Archiving 
Following completion of the study, subject records, CRF and other study documentation will be 
retained by the Investigator in accordance with GCP and applicable regulatory requirements. 
• 
Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations to 
be maintained elsewhere), in a safe and secure location. 
• 
The records must be maintained to allow easy and timely retrieval, when needed (e.g. for sponsor 
or regulatory inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff. 
• 
Where permitted by local laws/regulations or institutional policy, some or all of these records can 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution needs to be exercised before such action is taken. 
• 
The investigator must ensure that all reproductions are legible and are a true and accurate copy 
of the original and meet accessibility and retrieval standards, including re-generating a hard copy, 
if required. Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
• 
The ISFs must be retained for a minimum of 5 years from the date of the final CSR. Sponsor will 
inform the investigator of the retention period due date at the time when this CSR (or equivalent) 
is issued to the site. 
• 
The investigator must notify sponsor of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event 
the investigator is no longer associated with the site. 
Archiving will be authorised by the Sponsor following submission of the end of study report. 
The sponsor will be responsible for archiving the Trial Master File (TMF).  The Investigators at site(s) 
will be responsible for the retention/archiving of subject records, CRF, ISF and other study 
documentation (as applicable) in accordance with GCP and applicable regulatory requirements. 
Destruction of essential documents will require authorisation from the Sponsor in writing. 
The trial database will be maintained and stored in accordance with GCP. 
11 MONITORING, AUDIT & INSPECTION 
A risk-based monitoring plan will be followed for this study based on the trial risk assessment. The 
plan will detail monitoring frequency, requirements and processes. 

 
 
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The purpose of monitoring is to verify the rights and wellbeing of human subjects are protected; that 
trial data is accurate, complete and verifiable with source data; that the trial is conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
A monitor will conduct regular site visits for the purpose of monitoring various aspects of the study.  
The Investigator must agree to allow the study monitor and authorised representatives of the 
Sponsor, to inspect all CRF and corresponding source documents, e.g. original medical records, subject 
records and laboratory raw data, access to the clinical supplies, dispensing and storage areas and 
agree to assist with their activities if requested.  The Investigator should provide adequate time and 
space for monitoring visits. 
The monitor will query any missing or spurious data with the Investigator, which should be resolved 
in a timely manner.  A monitoring log will be maintained recording each visit, the reason for the visit, 
the monitor’s signature and Investigator’s or designee’s confirmation signature. 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary for 
sponsor authorised Quality Assurance personnel and/or authorised personnel from an external 
regulatory agency to conduct an audit/inspection of an Investigational site.  The purpose of an audit 
is to assess the quality of data with regard to accuracy, adequacy and consistency, and to assure that 
studies are in accordance with GCP, and Regulatory Agency guidelines.  Having the highest quality 
data from studies is an essential aspect of drug development. 
The Investigator will be given sufficient notice to prepare for such visits, which are planned to take 
usually between one and two days and may be conducted at any stage during the study.  The audit 
will involve the review of all study related documentation, which is required by GCP to be maintained 
by each site, review of drug storage, dispensing and return, review of all study related supplies and 
review of source documents against the CRF to assure the adequacy and accuracy of the information 
which has been recorded, including the verification of any AE which have occurred. 
12 ROLES AND RESPONSIBILITIES OF TRIAL OVERSIGHT COMMITEES/ GROUPS & 
INDIVIDUALS 
Three main trial management groups will be involved in the set up and management of the clinical 
trial. 
 
Trial Steering Committee (TSC) 
The TSC members should meet to periodically review the safety data and will liaise with the DSMB 
regarding any safety issues.  The TSC must have a majority independent representation, including the 
Chair. 
Data Safety Monitoring Board (DSMB) 
The DSMB is the group that monitors the main safety and efficacy outcome measures and the overall 
conduct of the trial, with the aim of protecting the safety and interests of the trial participants. 
The DSMB will meet periodically to review unblinded data.  The frequency of these meetings will be 
detailed in a separate document, the DSMB Charter, but are planned to take place on a quarterly basis 
as a minimum. 
Endpoint Committee 
The DSMB or TSC may request the endpoint review committee meet to review the trial endpoints to 
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Trial Management Group (TMG) 
The TMG should meet regularly to ensure all practical details of the trial are progressing well and 
working well and everyone within the trial understands them. 
 
The membership, frequency and the study aspects to be reviewed by the above groups, will be 
outlined in a separate document.  
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review & reports 
The study will comply with the following requirements 
• 
Before the start of the trial, approval will be sought from an IRB/IEC for the trial protocol, 
ICFs and other relevant documents e.g. advertisements and GP information letters 
• 
Substantial amendments that require review by IRB/IEC will not be implemented until the 
IRB/IEC grants a favourable opinion for the study (note that amendments may also need to 
be reviewed and accepted by the CAs before they can be implemented in practice at sites) 
• 
All correspondence with the IRB/IEC will be retained in the TMF/ISF  
• 
An annual progress report (APR) will be submitted to the IRB/IEC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended 
• 
It is the CI’s responsibility to produce the annual reports as required 
• 
The CI will notify the IRB/IEC of the end of the study 
• 
If the study is ended prematurely, the CI will notify the IRB/IEC, including the reasons for 
the premature termination 
• 
Within one year after the end of the study, the CI will submit a final report with the results, 
including any publications/abstracts, to the IRB/IEC 
13.2 
Peer review 
The high-quality peer review process (initiated by study sponsor) for the trial protocol will meet the 
following review criteria:  
a) Independent: At least two individual experts will review the study. Reviewers are external to 
the investigators’ host institution and not involved in the study in any way.  
b) Expert: Reviewers will have knowledge of the relevant discipline to consider the clinical 
and/or service-based aspects of the protocol, and/or have the expertise to assess the 
methodological and statistical aspects of the study.  
c) Proportionate: Peer review commensurate with the size and complexity of the study.  
13.3 
Regulatory Compliance  
This study will comply with the following: 

 
 
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• 
the trial will not commence until a Clinical Trial Authorisation (CTA) is obtained as required 
by local regulations 
• 
the protocol and trial conduct will comply with the Clinical Trial Regulation (EU) No 
536/2014  and local regulations applicable to each country  
13.4 
Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed and must not be used e.g. 
it is not acceptable to enrol a subject if they do not meet the eligibility criteria or restrictions specified 
in the trial protocol 
Accidental protocol deviations can happen at any time. They must be adequately documented on the 
relevant forms and reported to the CI and Sponsor immediately.  
Deviations from the protocol which are found to frequently recur are not acceptable, will require 
immediate action and could potentially be classified as a serious breach. 
13.5 
Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity or rights of the subjects of the trial; or 
(b) the scientific value of the trial and the reliability and robustness of the data generated 
in the trial 
Sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase. 
The sponsor will notify the licensing authority in writing of any serious breach of 
(a) the conditions and principles of GCP in connection with that trial; or  
(b) Clinical Trial Regulation; or 
(c) the protocol relating to that trial, as amended from time to time, within 7 calendar 
days of becoming aware of that breach 
13.6 
Data protection and patient confidentiality  
All data collected during the trial will be processed in agreement with the requirements set forth in 
applicable national data protection laws and in compliance with the General Data Protection 
Regulation (Regulation EU 2016/679) (GDPR), the UK Data Protection Act 2018 (DPA 2018), and the 
UK GDPR. All investigators and investigator site staff will comply with the data protection 
requirements applicable to the country in which they are conducting trial activities.  
  
The security of personal data collected in the trial will be upheld using the following technical and 
organisational measures: 
• 
Participant data will be pseudo-anonymised by replacing the information that identifies the 
participant with a unique identifier (pseudonym) at the point of enrolment. Datasets sent to 
data processors and third parties authorised by the Sponsor to process personal data will no 
longer be attributable to a specific participant without the use of additional information.  
• 
The link between the unique identifier and the participant’s identity will be securely 
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made available to regulatory agencies for the purposes of audits or inspections, or to study 
monitors authorised by the Sponsor to monitor the trial.  
• 
It is the responsibility of the investigator to protect the identity of the participant, and the 
security of personal data held at site should be maintained per local technical and 
organisational measures.  
• 
Trial data will be stored in a secure electronic data capture system (EDC) overseen by the CRO. 
The EDC system is protected by high levels of physical and cyber security. The EDC meets the 
requirements for the storage of personal data. The data will be stored on a secure / backed 
up network accessed by authorised personnel only. A log of authorised personnel with access 
permissions is maintained centrally.  
• 
Only sufficiently trained and delegated personnel will have access to the EDC.  
• 
Pseudonymised data will be used for statistical analysis. The statistical analysis will produce 
an aggregated output rendering the data anonymous. Only the anonymous statistical analysis 
output will be used for the trial results reporting. 
• 
At the end of the trial, the EDC will be decommissioned and the pseudonymised data will be 
securely maintained in the archived TMF for the remainder of the retention period. The TMF 
retention period is 25 years from the end of the trial in line with the Clinical Trials Regulation 
(Regulation EU No 536/2014). 
• 
At the end of the trial, each clinical trial site will receive a copy of the case report forms of the 
participants recruited at that site only, for archiving purposes in line with their own standard 
operating procedures. The protection of these data remains the responsibility of the 
investigator.  
• 
Data collection will be kept to the minimum required to answer the objectives of the trial.  
• 
The privacy and confidentiality of personal data on stored samples will be protected by the 
same standards applicable to all other clinical trial data.  
  
In the event of a data security breach, the investigator or site staff will report the incident to the Data 
Protection Officer of the sponsor (dpo@neat-id.org). The severity of the risk will be assessed to 
determine reporting requirements per relevant data protection legislation. It remains the 
responsibility of the Sponsor to report applicable data breaches to the relevant Data Protection 
Authority(ies). Depending on the result of this assessment, the participant(s) to whom the breach 
relates may be informed. A Corrective and Preventative Action review may also be performed to 
reduce the risk of future data security breaches.  
13.7 
Indemnity 
The Sponsor will undertake indemnity and insurance cover for this trial. 
13.8 
Amendments  
The sponsor may make a non-substantial or substantial amendment at any time during a trial. If the 
sponsor wishes to make a substantial amendment to the CTA or the documents that supported the 
original application for the CTA, the sponsor will submit a valid notice of amendment to the 
appropriate IRB/IEC, trial registries, and regulatory agencies. It is the sponsor’s responsibility to decide 
whether an amendment is substantial or non-substantial. 

 
 
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13.9 
Post trial care 
Post study medication will not be provided to participants.  Following study completion patients will 
receive treatment as per local standard of care. 
13.10 Access to the final trial dataset 
The investigators will be provided reasonable access to statistical tables, figures, and relevant reports.  
Sponsor will also provide the investigators with the full summary of the study results. The investigator 
is encouraged to share the summary results with the study subjects, as appropriate. 
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with sponsor policies. 
14 DISSEMINATION POLICY 
Whole or part of this study results will be communicated, orally presented, and/or published in 
appropriate scientific journals. Full anonymity of subject’s details will be maintained throughout. 
Subjects wanting to see the results of the trial can request a copy of the article from the investigators 
once it has been published. 
Preliminary data review and analysis may be conducted on the main study cohort or a sub study cohort 
throughout the study duration and may be presented in scientific presentations in both national and 
international conferences and publication. 
The data generated in the study will be submitted to a relevant medical journal according to criteria 
set out in The International Committee of Medical Journal Editors (www.icmje.org) who recommends 
that; 
i. 
Substantial contributions to the conception or design of the work; or the acquisition, analysis, 
or interpretation of data for the work; AND 
ii. 
Drafting the work or revising it critically for important intellectual content; AND 
iii. 
Final approval of the version to be published; AND 
iv. 
Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
15 REFERENCES 
1. DeJesus et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil 
fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir 
disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 
3, non-inferiority trial. Lancet. 2012;379(9835):2429-38 
 
2. Raffi F et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-
1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 
study. Lancet. 2013;381(9868):735-43 
 
3. Walsmley S et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. 
N Engl J Med. 2013;369(19):1807-18 
 

 
 
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4. Sax et al. Phase 3 Randomized, Controlled, Clinical Trial of Bictegravir Coformulated With FTC/TAF 
in a Fixed-Dose Combination vs Dolutegravir + FTC/TAF in Treatment-Naïve HIV-1-Positive Adults: 
Week 48 Results. 9th IAS Conference on HIV Science; Paris, France; July 23–26, 2017. 
TUPDB0201LB. 
 
5. Gallant et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose 
combination, B/F/TAF, vs ABC/DTG/3TC in treatment-naïve adults at week 48. 9th IAS 
Conference on HIV Science; Paris, France; July 23–26, 2017. MOAB0105LB. 
 
6. Camoni L et al. Late presenters among persons with a new HIV diagnosis in Italy, 2010-2011. BMC 
Public Health. 2013; 13:281  
 
7. Montlahuc C et al. Impact of late presentation on the risk of death among HIV-infected people in 
France (2003-2009). J Acquir Immune Defic Syndr. 2013;64(2):197-203 
 
8. Antorini A et al. Late presentation of HIV infection: a consensus definition. HIV Med. 2011;12:61-
64 
 
9. Raffetti E et al. The risk of late or advanced presentation of HIV infected patients is still high, 
associated factors evolve but impact on overall mortality is vanishing over calendar years: results 
from the Italian MASTER Cohort. BMC Public Health. 2016;16(1):878. 
 
10. Sobrino-Vegas  P et al.  Educational gradient in HIV diagnosis delay, mortality, antiretroviral 
treatment initiation and response in a country with universal health care. Antivir Ther. 
2012;17(1):1–8 
 
11. Mocroft A et al. Late presenters working group in COHERE in EuroCoord. Late presentation for 
HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological 
Research Europe (COHERE) Study, 2010 to 2013. Euro Surveill 2015; 20. doi:10.2807/1560-
7917.ES.2015.20.47.30070 
 
12. Abdool Karim SS et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl 
J Med. 2011;365(16):1492-501  
 
13. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with 
tuberculosis. N Engl J Med. 2011;365(16):1471-81 
 
14. Zolopa A et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with 
acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 
2009;4(5):e5575 
 
15. Mussini et al.. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. 
AIDs. 2008; 22(18):2461-2469 
 
16. Demarest et al. Dolutegravir-Based Regimens Are Active in Integrase Strand Transfer Inhibitor–
Naive Patients With Nucleoside Reverse Transcriptase Inhibitor Resistance. AIDS Research and 
Human Retroviruses. 2018 Feb 14(ja). 
 
17. Wijting I et al. Integrase Inhibitors are an Independent Risk Factor for IRIS: An ATHENA Cohort 
Study. Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, 
USA. Abstract 731. 

 
 
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18. Dutertre M et al. Initiation of ART Based on Integrase Inhibitors Increases the Risk of IRIS. 
Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, USA. 
Abstract 732. 
 
19. Psichogiou et al. Integrase Strand Transfer Inhibitors and the Emergence of Immune 
Reconstitution Inflammatory Syndrome (IRIS). Curr HIV Res. 2017;15(6):405-410 
 
20. Hill et al. Risks of cardiovascular or central nervous system adverse events and immune 
reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-
analysis of randomized trials. Curr Opin HIV AIDS. 2018 Mar;13(2):102-111 
 
21. Paredes R et al. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance 
test interpretation PLoS One. 2017; 12(7):e0181357 
 
22. Levy et al. ANRS 146 - GeSIDA 7211 OPTIMAL phase III trial: maraviroc plus cART in advanced HIV-
1-infected individuals. Journal Of The International Aids Society (Vol. 20, Pp. 6-7) 
 
23. Slama L et al. Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in 
combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART 
(cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, 
randomized, multicentre trial (IMEA 040 DATA trial). J Antimicrob Chemother 2016; 71: 2252–
2261 

 
 
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APPENDIX 1 - STUDY FLOWCHART  
 
Procedures 
Screening Visit 
Baseline Visit 
Treatment Phase 
Follow Up/Early Termination Visit 
 
Day -28 to Enrolment1 
 
Week 4 
(± 7 days) 
Week 8 
(± 7 days) 
Week 12 
(± 7 days) 
Week 24 
(± 7 days) 
Week 36 
(± 7 days) 
Week 48 
(± 7 days) 
30 days following Week 48 visit 
(± 7 days) 
Informed consent 
• 
 
 
 
 
 
 
 
 
Eligibility assessment3 
• 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
Medical and social history4 
• 
 
 
 
 
 
 
 
 
ECG5 
• 
 
 
 
 
 
 
 
 
HBV and HCV testing6 
• 
 
 
 
 
 
 
 
 
Latent TB test7 
• 
 
 
 
 
 
 
 
 
Local Resistance testing 8 
• 
 
 
 
 
 
 
 
• 
Randomisation  
 
• 
 
 
 
 
 
 
 
Symptom-directed physical examination 
 
• 
• 
• 
• 
• 
• 
• 
• 
Vital signs9 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Urinalysis10 
 
• 
 
 
• 
• 
• 
• 
• 
Haematology (including CD4 & CD8 testing)11 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Clinical chemistry12  
• 
• 
• 
• 
• 
• 
• 
• 
• 
Viral load testing13 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Sample collection for central resistance testing (deep sequencing)14 
 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant medications 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse event assessments  
 
• 
• 
• 
• 
• 
• 
• 
• 
Quality of Life questionnaire (EuroQoL EQ-5D-3L) 
 
• 
• 
• 
• 
• 
• 
• 
• 
HIV Symptom Index questionnaire (HIV-SI/SDM) 
 
• 
• 
• 
• 
• 
• 
• 
• 
Dispensing of trial drugs15 
 
• 
 
 
• 
• 
• 
 
 
Adherence16 
 
 
 
 
• 
• 
• 
• 
 
Serum pregnancy test17 
• 
 
 
 
 
 
 
 
 
Urine pregnancy test18 
 
• 
• 
• 
• 
• 
• 
• 
• 
Physical examination (including height & weight)19 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 

 
 
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Assessment sub notes 
Parameters/Notes 
1 
Screening visit 
The maximum time between screening visit and baseline visitis 28 days; however, participants should be invited for their baseline visit as soon 
as reasonably possible in order to start their treatment. 
. 
Only the following laboratory assessments are required for screening and historic (up to 28 days old) tests results may be used for screening: 
• 
HBV and HCV testing 
• 
TB test 
• 
CD4 & CD8 testing 
• 
Platelet count testing 
• 
Clinical chemistry (only creatinine, creatinine clearance, eGFR, potassium, sodium, ALT, AST is required) 
• 
Viral load testing 
• 
Resistance testing (the last resistance test carried out can be used) 
 
A serum pregnancy test is mandatory at the screening visit for women of child bearing potential 
  
2 
Baseline Visit 
For baseline results, all screening tests carried out within 10 days before baseline can be used. This includes historic screening results, as long as 
they fall within the 10 day window before baseline. Screening data obtained more than 10 days from baseline, must be repeated at baseline. 
3 
Eligibility 
According to the inclusion/exclusion criteria. 
4 
Medical & social 
history 
Including: 
• 
Recreational drug use 
• 
Smoking history 
• 
Alcohol intake 
• 
Concomitant diseases 
• 
Past & present medical history, including HIV- associated conditions 
• 
Review of any medication taken within the last 30 days 
5 
ECG 
12-Lead ECG performed supine. If an ECG is not performed at screening, it must be performed by the time of the baseline visit.  
6 
HBV & HCV testing  
HBV antigen test and hepatitis C (HCV) antibodies test (if patient tests positive for HCV antibodies, test for HCV RNA, if positive and chronic for 
either HBV or HCV, add HBV DNA test at baseline visit). 
HBV test to be repeated in event of positive result.  Participants with active HBV infection at study entry will be monitored throughout the study 
and additional HBV DNA tests performed at the Week 24 and 48 visits.  
For screening, test results 28 days prior to the screening visit can be used 
7 
Latent TB Testing 
A Latent TB test (IGRAs e.g. ELISPOT, QuantiFERON) may be performed in patients with expected latent TB at the screening visit. For screening, 
test results 28 days prior to the screening visit can be used.  
Patients can be randomised into the study without having the latent TB screening results available at randomisation 
A TB test can be performed at subsequent visits because of clinical suspicion.   

 
 
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Assessment sub notes 
Parameters/Notes 
8 
Resistance testing 
(performed locally) 
A local resistance test will be performed at the screening visit.  This result is not required for eligibility or prior to randomisation. If a HIV resistance 
test was done previously and results are available, the last resistance test carried out shall be considered. 
An additional resistance test will be performed at the ETV for patients with virological failure or insufficient virological response. 
9 
Vital Signs  
(10 mins resting) 
Including: 
• 
Pulse 
• 
Blood pressure 
1
0 
 Urinalysis 
Including: 
• 
Urinary creatinine* (not mandatory if ACR and PCR are available) 
• 
Albumin: Creatinine Ratio (ACR)* and Protein: Creatinine Ratio (PCR)* – mandatory if urinary creatinine not available 
• 
Urinary glucose (dipstick test sufficient)* 
• 
Urinary proteins* 
• 
Albumin (can be obtained from ‘spot’ urine test)* 
• 
Nitrites (dipstick test sufficient)  
• 
Urinary phosphate 
• 
Beta-2 microglobulin 
• 
Leukocytes (dipstick test sufficient) 
 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for the study at 
the visits required in the table. 
 

 
 
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Assessment sub notes 
Parameters/Notes 
11 
Haematology 
 
(non-fasting) 
Including: 
• 
Platelet count* 
• 
RBC Count (indices MCV & MCH)* 
• 
WBC count (absolute)* 
• 
CD4 Count and %* (CD4 count can be calculated from % and total lymphocytes) 
• 
CD8 Count and %* (CD8 count can be calculated from % and total lymphocytes) 
• 
Haemoglobin* 
• 
Haematocrit* 
RBC Count indices: 
• 
MCV  
• 
MCH 
Automated WBC differentials:  
• 
Neutrophils* 
• 
Lymphocytes* 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for 
the study. 
Assessments that have been underlined are required at screening (results up to 28 days old can be used). 

 
 
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Assessment sub notes 
Parameters/Notes 
12 
Clinical chemistry 
 
(non-fasting) 
• 
Urea*  
• 
Chloride*  
• 
Alkaline phosphatase*  
• 
Creatine phosphokinase* 
• 
Creatinine*  
• 
Calcium*  
• 
Phosphate*  
• 
Creatinine clearance, eGFR* 
(Calculations: Cockcroft-Gault (requires weight), MDRD, CX-Epi) 
• 
Glucose*   
• 
Total* and indirect bilirubin 
• 
Potassium*  
• 
Total protein* 
• 
Sodium*  
• 
ALT* 
• 
AST*  
• 
Albumin* 
• 
Cholesterol* 
• 
HDL* 
• 
LDL* 
• 
Triglycerides* 
* Assessments should be performed as per local site procedure; however, assessments marked with an asterisk are mandatory for the study at 
and after baseline. 
Assessments that have been underlined are required at screening (results up to 28 days old can be used). 
13 
Viral load testing 
HIV RNA viral load results obtained 28 days prior to screening can be used. 
14 
Resistance testing for deep 
sequencing 
 
(sent to central laboratory) 
In addition to the resistance test performed locally, a resistance testing sample will be taken at the Baseline visit, each visit in the treatment 
phase (Week 4, 8, 12, 24, 36 and 48) and at the ETV (for patients with virological failure identified outside of a scheduled visit.   
All resistance testing samples for patients with virological failure will be sent to a central laboratory for next generation sequencing to look for 
low-level pre-existing resistance in cases of suspected resistance development. 
15 
Drug dispensing 
There will be four dispensations of the study medication to the patient (Baseline visit, Week 12, 24 and 36). 
16 
Adherence 
Also performed at the ETV if required. 
17 
Serum pregnancy test 
For women of child bearing potential only (see Appendix 7 for definition).  
18 
Urine pregnancy test  
Dipstick and urine pregnancy test (WOCBP only - see Appendix 7 for definition). This is a mandatory assessment. If a urine pregnancy test is not 
possible, a serum pregnancy test can replace this. 
19 
Physical examination  
 Weight is required at all visits, as detailed in the appendix 1, however height is only required at baseline. 

 
 
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APPENDIX 2 – AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE  
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
 
Attached as a separate document and available online at: 
https://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf?sfvrsn=6  
APPENDIX 3 – AIDS-DEFINING CONDITIONS 
From CDC, available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm  
• 
Bacterial infections, multiple or recurrent* 
• 
Candidiasis of bronchi, trachea, or lungs 
• 
Candidiasis of esophagus† 
• 
Cervical cancer, invasive§ 
• 
Coccidioidomycosis, disseminated or extrapulmonary 
• 
Cryptococcosis, extrapulmonary 
• 
Cryptosporidiosis, chronic intestinal (>1 month's duration) 
• 
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
• 
Cytomegalovirus retinitis (with loss of vision) † 
• 
Encephalopathy, HIV related 
• 
Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis (onset 
at age >1 month) 
• 
Histoplasmosis, disseminated or extrapulmonary 
• 
Isosporiasis, chronic intestinal (>1 month's duration) 
• 
Kaposi sarcoma† 
• 
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*† 
• 
Lymphoma, Burkitt (or equivalent term) 
• 
Lymphoma, immunoblastic (or equivalent term) 
• 
Lymphoma, primary, of brain 
• 
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary† 
• 
Mycobacterium tuberculosis of any site, pulmonary, †§ disseminated, † or extrapulmonary† 
• 
Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary† 
• 
Pneumocystis jirovecii pneumonia† 
• 
Pneumonia, recurrent†§ 
• 
Progressive multifocal leukoencephalopathy 
• 
Salmonella septicemia, recurrent 
• 
Toxoplasmosis of brain, onset at age >1 month† 
• 
Wasting syndrome attributed to HIV 
* Only among children aged <13 years. (CDC. 1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age. MMWR 1994;43[No. RR-12].) 
† Condition that might be diagnosed presumptively. 
§ Only among adults and adolescents aged >13 years. (CDC. 1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41[No. RR-17].) 

 
 
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APPENDIX 4 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA 
Version 4, August 2012 
ACUTE MYOCARDIAL INFARCTION 
A. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above 99th 
percentile of upper reference limit (URL) 
 
B. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent 
with myocardial ischemia 
 
C. ECG changes indicative of new ischemia (new ST-changes or new left bundle branch block [LBBB]), 
or development of pathological Q waves on the ECG 
 
D. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
 
E. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or before 
a time when biomarkers appear, along with (1) new ST-changes or new LBB, or (2) evidence of fresh 
thrombus on coronary angiography or at autopsy 
 
F. In patients with percutaneous coronary interventions and normal baseline troponin, increases in 
troponin of three times the 99th percentile of URL 
 
G. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL PLUS at least one of the following: (1) new pathological Q-
waves or new LBBB, (2) angiographically documented new graft or native artery occlusion, or (3) 
imaging evidence of new loss of viable myocardium 
 
H. Pathologic findings of acute myocardial infarction (including acute MI demonstrated as the cause 
of death on autopsy) 
 
I. Development of 1) evolving new Q waves, or 2) evolving ST elevation, preferably based on at least 
2 ECGs taken during the same hospital admission 
 
J. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL 
 
Confirmed: One of the following 5 criteria (adapted from 2007 Universal Definition of Myocardial 
Infarction): 
1. A + (B or C or D) 
2. E 
3. F 
4. G 
5. H 
Probable: B+I or J 
 
CONGESTIVE HEART FAILURE 
 
A. Clinical signs and symptoms compatible with left or right sided heart failure (e.g., paroxysmal 
nocturnal dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative 
explanation 

 
 
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B. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac 
catheterization, or multiple gated acquisition scan showing a decreased ejection fraction of < 45% 
 
C. Echocardiogram, cardiac catheterization or other studies showing evidence of increased left atrial 
pressure or right heart failure 
 
D. Elevated levels of Brain Natriuretic Peptide (BNP) or NT-proBNP 
 
E. Chest x-ray or other imaging study showing evidence of congestive heart failure, including cardiac 
enlargement 
 
F. Documentation of treatment for congestive heart failure 
 
Confirmed: (A+B) or (A+C) or (A+D) 
Probable: A+E+F 
 
CORONARY ARTERY DISEASE REQUIRING DRUG TREATMENT 
 
A written report in the medical record documenting: 
 
A. Evidence of myocardial ischemia based on either diagnostic imaging (such as a stress 
echocardiogram or thallium scan) or diagnostic changes on an electrocardiogram (such as during 
stress testing or an episode of chest pain) 
 
B. Evidence of coronary artery disease based on coronary angiography or other diagnostic imaging 
 
C. Other evidence of myocardial ischemia and/or coronary artery disease (including that based 
primarily upon symptoms and clinical presentation, such as chest pain with exertion) 
 
D. Use of medication given to treat or prevent angina (e.g., nitrates, beta blockers, calcium channel 
blockers) 
 
Confirmed: (A or B) + D 
Probable: C+D 
 
CORONARY REVASCULARIZATION 
 
Confirmed: A procedure report, hospital discharge summary, or other medical record from the 
hospitalization during which the procedure was performed for treatment of coronary artery disease 
(including coronary artery bypass graft, coronary artery stent implant, coronary atherectomy, and 
percutaneous transluminal angioplasty), or a consultation note from the participant’s cardiologist 
documenting the occurrence of the procedure 
 
Probable: Not applicable 
 
DECOMPENSATED LIVER DISEASE 
 
A. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by one of the 
following: 
1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy 

 
 
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2. MRI or CT consistent with cirrhosis 
3. A positive result on transient elastography (FibroScan) or other ultrasound imaging consistent 
with cirrhosis 
 
B. Clinical evidence of decompensation, as documented by one of the following, and without an 
alternative explanation: 
1. Ascites 
2. Hepatic encephalopathy 
3. Bleeding from gastric or esophageal varices 
4. Spontaneous bacterial peritonitis 
 
Confirmed: A+B 
Probable: B 
 
DEEP VEIN THROMBOSIS 
 
A. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed tomography, 
MRI, or ultrasonography other comparable imaging techniques 
 
B. An elevated D-dimer test OR abnormal plethysmography 
 
C. A score on the Wells Clinical Prediction Rule for DVT of ≥ 3 points 
 
D. Absence of alternative diagnosis as likely or greater than that of deep venous thrombosis 
 
Wells Clinical Prediction Rule for DVT 
One point for each of the following: 
• Active cancer (treatment ongoing or within previous 6 months, or palliative) 
• Paralysis, paresis, or plaster immobilization of lower extremities 
• Recently bedridden for more than 3 days, or major surgery, within 4 weeks 
• Localized tenderness along distribution of the deep venous system 
• Entire leg swollen 
• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm 
below tibial tuberosity) 
• Pitting edema (greater in the symptomatic leg) 
• Collateral superficial veins (non-varicose) 
(Adapted from: Wells PS et al. Lancet 1997;350:1796) 
 
Confirmed: A 
Probable: B+C+D 
 
DIABETES MELLITUS 
 
A. Classic symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose 
concentration >=200 mg/dl (11.1 mmol/l). (Classic symptoms include polyuria and polydipsia; Random 
is defined as any time of day without regard to last meal) 
 
B. 2-hour plasma glucose >=200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (The test 
should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose 
dissolved in water). 
 

 
 
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C. Repeated abnormal fasting plasma glucose (FPG) and/or abnormal Haemoglobin A1C level (HA1C) 
results using the following criteria: 
1. FPG >=126 mg/dl (7.0 mmol/l) on at least two different dates (Fasting is defined as no caloric 
intake for at least 8 hours). 
2. HA1C >=6.5% on at least two different dates 
3. An FPG >=126 mg/dl (7.0 mmol/l) PLUS a HA1C >=6.5%, with these tests performed on two 
different dates 
 
D. Documentation of taking an approved anti-diabetic medication to lower glucose levels in the blood, 
such as insulin or oral hypoglycaemic agents. 
 
E. A single abnormal FBS OR a single abnormal HA1C 
 
Confirmed: A or B or C 
Probable: D 
Possible: E 
 
END-STAGE RENAL DISEASE 
 
A. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least three 
months 
 
B. A kidney transplant documented in a clinical note 
 
C. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least one month 
and up to the time of death in a patient who dies within three months after dialysis begins 
 
Confirmed: A or B 
Probable: C 
 
NON-AIDS-DEFINING CANCER 
 
A. Diagnosis of cancer other than lymphoma, Kaposi's sarcoma (KS), or invasive cervical cancer in an 
autopsy report 
 
B. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report that 
established the diagnosis 
 
C. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge 
summary or consultation note from the hospitalization or clinic visit during which the diagnosis was 
established 
 
Confirmed: A or B 
Probable: C 
 
PERIPHERAL ARTERIAL DISEASE 
 
A. Compatible clinical signs and symptoms (e.g., intermittent claudication, femoral bruit, decreased 
peripheral pulses, change in colour or temperature of limb suggesting peripheral arterial disease) 
 

 
 
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B. Positive results on diagnostic imaging studies (e.g., Doppler ultrasound, contrast arteriography, MRI 
arteriography) 
 
C. Ankle Brachial Pressure Index < 0.90 in non-diabetics 
 
D. A procedure report, hospital discharge summary, or other medical record from the hospitalization 
during which the procedure was performed documenting an invasive procedure for treatment of 
peripheral arterial disease (e.g., percutaneous transluminal angioplasty, endovascular procedures, or 
vascular surgery), or a consultation note documenting the occurrence of the procedure 
 
Confirmed: (A+B) or (A+C) or D 
Probable: A 
 
PULMONARY EMBOLISM 
 
A. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or 
haemoptysis 
 
B. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical CT, 
ventilation-perfusion scan or other comparable imaging studies 
 
C. A diagnosis of pulmonary embolism on autopsy 
D. Results consistent with a diagnosis of deep venous thrombosis on venography, ultrasound, or other 
comparable imaging studies 
 
E. A chest x-ray which, if performed, does not suggest an alternative aetiology for the symptoms 
described in criteria A 
 
Confirmed: (A+B) or C 
Probable: A+D+E  
 
STROKE 
 
A. Acute onset with a clinically compatible course, including unequivocal objective findings of a 
localizing neurologic deficit 
 
B. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms 
 
C. Stroke diagnosed as cause of death at autopsy 
 
D. Positive lumbar puncture compatible with subarachnoid haemorrhage 
 
E. Death certificate or death note from medical record listing stroke as cause of death 
 
Confirmed: (A+B) or C 
Probable: (A+D) or (A+E) 
 
 

 
 
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APPENDIX 5 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA 
Version 2.0, September 2010 
CONFIRMED 
PROBABLE 
CONSTITUTIONAL DISEASE 
HIV wasting syndrome 
None 
A plus B plus C: (A) unexplained, 
involuntary weight loss >10% from 
baseline, (B) persistent diarrhea 
with > 2 liquid stools/d for > 1 
month or weakness for 
> 1 month or fever for > 1 month, 
(C) tests for alternate causes of 
weight loss, such as cancer, TB, 
MAC, cryptosporidiosis or other 
specific causes of weight loss, if 
obtained, should be negative 
INFECTIONS 
Aspergillosis, invasive pulmonary 
A plus B plus C: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy, 
(C) positive culture from lung biopsy or 
sputum collected by any method 
A plus B: (A) CXR abnormality 
compatible with aspergillosis, 
(B) invasive mycelia consistent with 
Aspergillus on lung biopsy or 
positive culture of lung tissue or 
positive culture of sputum collected 
by any method 
Aspergillosis, other invasive 
A plus B plus C: (A) compatible clinical 
course, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
clinical evidence of infection, (C) 
positive culture from the affected tissue 
A plus B: (A) clinical evidence of 
invasive infection, (B) invasive 
mycelia consistent with Aspergillus 
on tissue biopsy or positive culture 
at a normally sterile site (e.g., 
blood) apart from the involved 
tissue 
Bartonellosis 
A plus B: (A) Clinical or histologic 
evidence of bacillary angiomatosis or 
bacillary peliosis, (B) a positive culture 
or PCR for B. quintana or B. henselae 
A plus B: (A) Clinical evidence of 
bacillary angiomatosis or bacillary 
peliosis, (B) positive silver stain for 
bacilli from a skin lesion or an 
affected organ 
Candidiasis of bronchi, trachea, or lungs 
Macroscopic appearance at 
bronchoscopy or autopsy plus 
microscopic evidence of yeasts or 
pseudo hyphae 
None 
Candidiasis, esophageal 
A plus B: (A) Macroscopic 
appearance at esophagoscopy or 
autopsy, 
(B) microscopic evidence of yeasts or 
pseudo hyphae 
A plus B plus C: (A) Recent onset 
of retrosternal pain or difficulty 
on swallowing, (B) a clinical 
diagnosis of oral candidiasis, 
endoscopic visualization of 
candidiasis and/or microscopic 
evidence of yeasts or pseudo 
hyphae from oropharyngeal 
mucosa, 
(C) clinical response to 
treatment 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Chagas disease (American 
trypanosomiasis) of the CNS 
Histologic evidence obtained by brain 
tissue biopsy or autopsy 
A plus B plus C plus D: (A) Focal, 
typically hemispheral neurological 
dysfunction with onset over several 
days or weeks; (B) enhancing focal 
lesion(s) with mass effect, and 
surrounding edema and contrast 
enhancement, typically located in 
grey matter; 
(C) serum antibodies to T. cruzi, (D) 
response to standard therapy with 
documented clinical or radiographic 
improvement (if radiography was 
done, it must be improved), or 
peripheral blood smear or CSF 
smear positive for T. cruzi 
Coccidioidomycosis, 
disseminated or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C: (A) Microscopic 
demonstration of spherules, (B) 
positive culture, (C) antigen detection 
None 
Cryptococcosis, meningitis or 
extrapulmonary 
From tissue other than lung or hilum, A 
or B or C or D: (A) microscopic 
demonstration of narrow based 
budding yeast, 
(B) for meningitis, if done, a 
positive CSF India ink test, 
(C) positive culture, (D) 
antigen detention 
None 
Cryptosporidiosis 
Diarrhea for > 1 month and positive 
microscopy 
None 
CMV retinitis 
Autopsy demonstration 
Typical appearance on fundoscopy 
of discrete patches of retinal 
whitening, spreading along blood 
vessels, associated with vasculitis, 
hemorrhage and necrosis, 
confirmed by ophthalmologist 
CMV radiculomyelitis 
Autopsy demonstration 
A plus B plus C plus D plus E plus F: 
(A) Loss of sensation, leg 
weakness, or decreased reflexes, 
(B) presentation over 3 days to 3 
weeks, (C) CT, MRI or myelogram 
must be done and all imaging 
studies must not show a mass 
lesion, 
(D) CSF shows > 10 WBC with 
> 50% polymorphs, (E) CSF shows 
no other pathogen, (F) persistence 
of symptoms in the absence of CMV 
treatment, or elevated quantitative 
CMV in the CSF by PCR 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
CMV meningoencephalitis 
Autopsy or brain biopsy 
demonstration 
A plus B: (A) Rapid < 4 weeks 
syndrome with progressive 
delirium, cognitive impairment and 
fever, (B) CT/MRI demonstration of 
periventricular abnormalities or 
elevated quantitative CMV DNA in 
the CSF by PCR 
CMV, other disease 
A plus B plus C plus D: (A) compatible 
illness, (B) histologic demonstration of 
inclusion bodies from affected tissue, 
(C) if done, detectible CMV antibodies, 
(D) if done, detectible CMV DNA or 
CMV antigen in blood 
A plus B plus C plus D: (A) 
Compatible illness, (B) moderate to 
markedly high CMV antigen or CMV 
DNA in blood, (C) response to 
therapy, (D) if done, detectible 
CMV antibodies 
HSV mucocutaneous 
ulceration 
A plus B: (A) Ulceration for > 1 month, 
(B) histology, culture, PCR, or detection 
of antigen from affected tissue 
A plus B: (A) Typical HSV ulceration 
for > 1 month, (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
HSV, bronchitis, pneumonitis, 
esophagitis, or other visceral disease 
A plus B: (A) Compatible symptoms, 
(B) histology, culture, PCR, or 
detection of antigen from affected 
tissue 
None 
HZV, disseminated 
A plus B: (A) multiple ulcerated lesions 
affecting at least 2 non-contiguous 
dermatomes, or with generalized 
cutaneous dissemination; or HZV 
involvement of the lung, liver, brain, 
or other internal organs 
(B) positive culture, PCR, or antigen 
assay from affected tissue 
A plus B: (A) multiple typical 
ulcerated lesions affecting at least 2 
non-contiguous dermatomes, or 
with generalized cutaneous 
dissemination (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
Histoplasmosis, disseminated or 
extrapulmonary 
A plus B: (A) Compatible symptoms, 
(B) histology or culture or elevated 
blood or urine antigen levels 
None 
Isosporiasis 
Diarrhea for > 1 month, plus 
microscopic identification of 
Isospora belli 
None 
Leishmaniasis, visceral 
Compatible symptoms, plus 
microscopic identification of 
Leishmania 
Compatible symptoms, plus a 
positive PCR test for Leishmania 
Microsporidiosis 
Diarrhea for > 1 month plus 
Microscopic identification of 
Microsporidia 
None 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
MAC and other mycobacterial 
disseminated disease 
A plus B: (A) Fever, fatigue, anemia or 
diarrhea, (B) positive culture from 
blood, body fluids or tissue other than 
pulmonary, hilar or stool 
A plus B plus C: (A) Fever, 
fatigue, anemia or diarrhea, 
(B) AFB or positive direct MAC PCR 
in blood, body fluids or tissue other 
than pulmonary, hilar or stool (C) 
no concurrent non-pulmonary TB 
M. tuberculosis disease, pulmonary 
A plus B: (A) Compatible symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, 
(B) culture or PCR from sputum or 
bronchial lavage or lung tissue 
A plus B plus C plus D: (A) 
Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, 
(B) abnormal chest X-ray, (C) AFBs 
seen in sputum or lavage or lung 
tissue but not grown in culture, (D) 
responds to treatment 
POSSIBLE (pulmonary TB only) 
A plus B plus C plus D: 
(A) Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, (B) 
abnormal chest X-ray compatible 
with pulmonary TB (such as upper 
lobe cavitation, pleural exudate), 
(C) No other etiology for pulmonary 
symptoms and signs identified, (D) 
Responds to anti-tuberculosis 
treatment 
M. tuberculosis disease, 
extrapulmonary 
A plus B: (A) Compatible symptoms, 
(B) culture or PCR from blood or 
affected tissue 
A plus B plus C: (A) Compatible 
symptoms, (B) AFBs seen from 
affected tissue or blood (C) 
concurrent diagnosis of pulmonary 
TB or responds to treatment 
Nocardiosis 
Clinical evidence of invasive infection 
plus a positive culture from the 
affected tissue or blood 
Clinical evidence of invasive 
infection plus microscopic 
evidence of bronchial weakly 
acid-fast organisms from the 
affected tissue 
Penicillium marneffei, 
disseminated 
Culture from a non-pulmonary site 
Known presence in a P. marneffei 
endemic area plus characteristic 
skin lesions plus response to 
antifungal therapy for penicillosis 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
PcP 
A plus B: (A) compatible clinical 
syndrome, (B) microscopic or 
histological demonstration of P. 
jirovecii cysts in a pulmonary specimen 
A plus B plus C plus D plus E: 
(A) dyspnea or cough, or fever 
progressive over > 1 week, (B) 
diffuse chest x-ray abnormality or, if 
on inhalational pentamidine, diffuse 
upper lung field abnormality, (C) 
evidence of hypoxia, (D) not 
suggestive of bacterial pneumonia 
(i.e., not purulent sputum or 
hemoptysis, no bacterial pathogen 
identified in blood or bronchial 
wash), (E) response to PcP 
treatment 
Pneumocystis jirovecii, 
extrapulmonary 
Compatible symptoms, plus 
microscopy 
None 
Pneumonia, recurrent bacterial, excludes: 
(a) post- obstructive pneumonias, 
including in those with 
intrapulmonary/bronchial lesions, (b) 
aspiration pneumonia, including in those 
with decreased consciousness levels, (c) 
nosocomial ventilator-associated 
pneumonias 
Both pneumonia episodes must occur 
after enrollment and satisfy criteria (A) 
plus (B) plus (C). The recurrent 
pneumonia must also satisfy criteria (D) 
plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) identification 
of a bacterial pathogen by positive 
blood culture, positive bronchoscopic 
sputum culture, detection of Legionella 
or pneumococcal antigen in urine or 
blood or diagnostic serologic findings, 
(D) the second pneumonia had onset of 
symptoms < 365 days after the first 
episode, (E) there is strong evidence 
that the first episode was cured such as 
an intervening clear CXR or absence of 
symptoms after > 1 month off 
antibacterials effective against 
pathogens commonly producing 
pneumonia 
Both pneumonia episodes must 
occur after enrollment and satisfy 
criteria (A) plus (B). The recurrent 
pneumonia must also satisfy criteria 
(C) plus (D): (A) Signs and symptoms 
suggestive of bacterial pneumonia, 
(B) focal CXR abnormality 
compatible with bacterial 
pneumonia, (C) the second 
pneumonia had onset of symptoms 
< 365 days after the first episode, 
(D) there is strong evidence that the 
first episode was cured such as an 
intervening clear CXR or absence of 
symptoms after 
> 1 month off antibacterials 
effective against pathogens 
commonly producing 
pneumonia 
PML (progressive multifocal 
leukoencephalopathy) 
A or B: (A) positive histology, 
(B) compatible clinical and radiologic 
course and positive CSF PCR for JK 
virus 
A plus B plus C: (A) Consistent 
symptoms, (B) brain image 
consistent with PML, (C) no 
response to toxo treatment or 
toxoplasma seronegative 

 
 
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CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Rhodococcus equi disease 
Clinical evidence of invasive infection 
plus microbiologic identification of 
the organism in the affected tissue or 
blood 
None 
Salmonella septicemia, recurrent 
Both episodes must occur after 
enrollment and met criterion (A). The 
second episode must meet criteria (B) 
and C: (A) Positive blood or tissue 
culture, (B) the second septicemia had 
onset of symptoms < 365 days after 
the first episode, (C) the second 
septicemia must be due to a different 
Salmonella serotype or there must be 
strong evidence that the first episode 
was cured such as a negative blood 
culture off effective antibacterials for > 
1 week or absence of symptoms off 
antibacterials for > 1 month 
None 
Toxoplasmosis of brain 
Microscopy 
A plus B plus C: (A) Symptoms of 
focal intracranial abnormality or 
decreased consciousness, 
(B) brain image consistent with 
lesion(s) enhanced by contrast, 
(C) positive toxoplasma serology 
or responds to treatment 
clinically or by scan 
NEOPLASMS 
Cervical carcinoma, invasive 
Histology (NOT carcinoma-in- situ) 
None 
Kaposi sarcoma, (mucocutaneous or 
visceral) 
Histology 
Highly typical appearance and 
persistence for > 1 month 
Lymphoma, primary, of brain 
Histology 
Symptoms consistent with 
lymphoma plus at least one CNS 
lesion with mass effect plus lack of 
clinical and radiographic response 
to at least 2 weeks of treatment 
for toxoplasmosis 
Lymphoma, Hodgkin's 
Histology 
None 
Lymphoma, non-Hodgkin's, all cell 
types 
Histology 
None 
 
 
 
 

 
 
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CONFIRMED 
PROBABLE 
NEUROLOGICAL 
HIV-related encephalopathy 
(including AIDS Dementia Complex) 
None 
Cognitive or motor dysfunction 
interfering with usual activity, 
progressive over weeks or months 
plus no other condition to explain 
the findings plus brain image 
obtained and suggests no other 
causes plus grade 2 or worse 
impairment in at least 2 domains 
by NARS (see below) excluding 
abnormal domains at trial entry. 
(For persons with abnormal 
domains at entry worsening by at 
least two grades meets criteria.) 
 
 
 

 
 
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Abbreviated NARS (Neuropsychiatric AIDS Rating Scale) Grading for HIV Encephalopathy  
Adapted from: Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988; 158 (5): 1079- 83, 
and Hughes CP, Berg L, Danziger WL. A new clinical scale for the staging of dementia. Brit J Psych 
1982; 140: 566-92. 
NARS
stage 
Cognitive-Behavioral Domains 
Orientation 
Memory 
Motor 
Behavior 
Problem 
solving 
Activities 
of 
daily living 
0.5 
fully oriented 
complains of 
memory 
problems 
fully 
ambulatory 
slightly 
slowed 
movements 
normal 
has slight 
mental 
slowing 
slight 
impairment in 
business 
dealings 
1 
fully oriented, 
may have brief 
periods of 
“spaciness" 
mild memory 
problems 
balance, co- 
ordination 
and 
handwriting 
difficulties 
more irritable, 
labile or 
apathetic, 
withdrawn 
difficulty 
planning and 
completing 
work 
can do simple 
daily tasks, may 
need prompting 
2 
some 
disorientation 
memory 
moderately 
impaired, 
new learning 
impaired 
ambulatory 
but may 
require 
walking aid 
some 
impulsivity or 
agitated 
behavior 
severe 
impairment, 
poor social 
judgement, 
gets lost easily 
needs 
assistance 
with ADLs 
3 
frequent 
disorientation 
severe 
memory loss, 
only 
fragments of 
memory 
remain 
ambulatory 
with 
assistance 
may have 
organic 
psychosis 
judgement 
very poor 
cannot live 
independently 
4 
confused and 
disoriented 
virtually no 
memory 
bedridden 
mute and 
unresponsive 
no problem-
solving ability 
nearly 
vegetative 
 
 
 

 
 
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APPENDIX 6 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA  
 (Revised 01/10/09) 
From ACTG, available under https://actgnetwork.org/IRIS_Case_Definitions  
   
1. Initiation, reintroduction or change in antiretroviral therapy/regimen or therapy for 
opportunistic infections (OI).   
 
AND 
 
2. 
1Evidence of:   
 
a. an increase in CD4+ cell count as defined by ≥50 cells/mm3 or a ≥2- fold rise in CD4+ cell 
count, and/or    
 
b. decrease in the HIV-1 viral load of >0.5 log10 and/or    
 
c. weight gain or other investigator-defined signs of clinical improvement in response to 
initiation, reintroduction or change of either antiretroviral therapy/regimen or OI therapy.     
 
     AND   
3. Symptoms and/or signs that are consistent with an infectious or inflammatory condition.     
 
     AND  
4. These symptoms and/or signs cannot be explained by a newly acquired infection, the expected 
clinical course of a previously recognized infectious agent, or the side effects of medications. 
AND 
   
5. For purposes of data collection, the infectious/inflammatory condition must be attributable to 
a specific pathogen or condition. A Clinical Events form should be completed 16 weeks (+ 4 
weeks) after initial report if diagnosis confirmed or changed from initial report 
 
1 If the study participant is being evaluated for an inflammatory condition at a time that is <4 weeks 
after initiation, reintroduction or change in antiretroviral therapy/regimen or OI therapy, items 2a 
through 2c are not required.     
 
Refer to the “Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes 
(IRIS)” document for specific Opportunistic Infection (OI) and non-pathogen condition diagnosis 
criteria.

 
 
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Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes (IRIS) 
IRIS Focus Group 
Given the paucity of data for a clearly-defined immune reconstitution inflammatory syndrome for each 
opportunistic pathogen, the IRIS Working Group concentrated on developing specific definitions for the 
most well-characterized IRIS in the literature. IRIS events may occur as paradoxical worsening or as an 
unmasking. Paradoxical responses are described as an initial clinical worsening when patients are started 
on pathogen-specific therapy and/or ART simultaneously. Unmasking refers to aberrant clinical 
presentations of previously common OIs such as localized Mycobacterium avium complex (MAC) 
lymphadenitis and Cytomegalovirus (CMV) vitritis occurring within the first weeks of starting ART 
suggesting that patients have sub-clinical disease prior to the initiation of ART. There are specific 
definitions including confirmed and probable for the following specific pathogen IRIS:  Mycobacterium 
avium complex (MAC), Progressive Multifocal Leukoencephalopathy (PML), Cytomegalovirus (CMV), 
Mycobacterium tuberculosis (TB) and Cryptococcus neoformans. All other clinical syndromes attributed 
to immune reconstitution will be treated as probable IRIS events without specific definitions and will 
include Pneumocystis jirovecii pneumonia (PCP), Varicella Zoster (VZV), Herpes Simplex (HSV), Hepatitis B, 
Hepatitis C, Toxoplasmosis, Kaposi’s Sarcoma, Graves’ disease, Sarcoidosis, and other autoimmune 
disorders. For these less well-defined IRIS, key data will be captured on a generic form that includes clinical 
signs/symptoms, CD4, HIV RNA data, and clinical outcomes.  
 
Specific IRIS Case Definitions  
 
1. Cytomegalovirus (CMV): {Ophthalmologic only} IRIS associated with CMV is fairly common; 
syndromes include uveitis, vitritis, extension or new development of retinal opacification, 
proliferative vitreoretinopathy (leading to retinal detachment), neovascularization, macular or 
optic nerve edema and subcapsular cataracts (leading to visual impairment) [1, 2]. The 
inflammatory component is marked, with significant anterior and/or posterior chamber 
inflammation. Vitritis and extension or new development of retinal opacification usually occurs 
within 3-12 weeks of beginning antiretroviral therapy/regimen and/or CMV antiviral therapy; 
uveitis may occur months to years after beginning antiretroviral therapy. Antiretroviral 
therapy/regimen is usually continued; some patients are also treated with anti-CMV drugs, 
especially those with sight-threatening disease. IRIS associated with gastrointestinal or neurologic 
(non-ocular) CMV disease have not be adequately characterized 
 
Confirmed CMV IRIS in patients with a prior history of CMV retinitis:  previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by an experienced ophthalmologist.  
 
Confirmed CMV IRIS in patients without a prior history of CMV retinitis:  the development of 
significant ocular inflammation in the uveovitreal tract, lens or retina attributed to CMV in the 
absence of ophthalmologic findings typical for acute CMV retinitis, with or without visual changes, 
as documented by an experienced ophthalmologist. 
 
Probable CMV IRIS in patients with a prior history of CMV retinitis previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by a non-ophthalmologist clinician 
 

 
 
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2. Cryptococcus neoformans. The best described cases of Cryptococcus neoformans IRIS involve 
inflammatory changes developing in patients with recently diagnosed cryptococcal meningitis, 
cryptococcemia or pneumonia who have responded to appropriate antifungal therapy [1, 3,4].  
Most have presented as meningitis, associated with CSF abnormalities (significantly elevated 
protein, lymphocytes, hypoglycorrhachia and cryptococcal antigen titers) with negative cultures. 
CNS imaging may demonstrate new meningeal inflammation. Significant elevations of intracranial 
pressure may occur. Non-CNS presentations are also common and have included the development 
of mediastinal or cervical adenopathy, necrotizing pneumonia, cavitation of previously 
documented pulmonary lesions, focal lymphadenitis and cutaneous abscesses. Biopsies may 
demonstrate granulomatous changes and cryptococci but typically cultures are negative. These 
presentations have occurred anywhere from two weeks to 11 months after initiation of 
antiretroviral therapy/regimen, with most cases occurring within three months. Less well 
described are cases of cryptococcal meningitis presenting only after initiation and response to 
antiretroviral therapy/regimen, also associated with elevated CSF cryptococcal antigen (CRAG) 
titers, negative CSF cultures and significant meningeal enhancement on scan. 
 
Confirmed cryptococcal IRIS in patients with a prior history of cryptococcosis: Cryptococcal 
meningitis or other diagnosis of systemic cryptococcal infection (fungemia, pneumonia) by ACTG 
criteria and improvement of signs/symptoms with antifungal therapy, with the subsequent 
development of new or worsening pulmonary infiltrates, new meningeal enhancement on scan or 
abnormal CSF findings (low glucose, elevated WBC, CSF CRAG with negative fungal culture), 
mediastinal or cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal 
lesions at other sites;  histopathology from non-meningeal site demonstrating inflammatory 
changes and organisms in the absence of a positive culture or positive culture.   
 
Confirmed cryptococcal IRIS in patients without a prior history of cryptococcosis:  the 
development of meningitis with meningeal enhancement on scan with abnormal CSF findings (low 
glucose, elevated WBC, positive CSF CRAG with negative or positive fungal culture), mediastinal 
or cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal lesions at 
other sites;  histopathology from non-meningeal site demonstrating inflammatory changes and 
organisms in the absence of a positive culture or positive culture.   
 
Probable cryptococcal IRIS in patients with a prior diagnosis of cryptococcosis:  previous 
cryptococcosis diagnosis by ACTG criteria and improvement of signs/symptoms with anti-cryptococcal 
therapy, and the subsequent development of focal inflammatory site(s); histopathology from involved 
site or sterile body fluid analysis  demonstrating inflammatory changes (e.g., granulomas, 
lymphocytes) in the absence of positive stains or cultures for any other pathogen or any non-infectious 
histopathologic diagnosis; and negative blood cultures for Cryptococcosis; and negative CSF CRAG if 
obtained or development of new onset CNS signs or symptoms with meningeal enhancement or other 
atypical radiographic changes with no evidence of other neurologic disease to explain the findings. 
 
Probable cryptococcal IRIS in patients without a prior diagnosis of cryptococcosis: the subsequent 
development of focal inflammatory site(s); histopathology from involved site or sterile body fluid 
analysis demonstrating inflammatory changes (e.g., granulomas, lymphocytes) accompanied by 
evidence consistent with cryptococcosis in the absence of positive cultures for any other pathogen. 
   
3. Mycobacterium avium complex (MAC). This is one of the best described IRIS. The most common 
presentation is focal lymphadenitis (especially cervical) with high fever, elevated WBC counts and 
negative blood cultures; fistula formation may occur. There is a significant inflammatory 
component on biopsy with necrotizing granulomas, caseation and AFB. The syndrome usually 

 
 
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occurs within 3-12 weeks of initiating antiretroviral therapy/regimen and/or anti-mycobacterial 
therapy, although rare cases have been described beyond 6 months with deep tissue foci, e.g. 
psoas abscess. MAC IRIS has presented as diffuse adenopathy, and as focal disease in diverse sites 
(paraspinous, mediastinal, abdominal, vertebral, pulmonary and CNS). [1,5,6]  
 
Confirmed MAC IRIS in patients with a prior history of disseminated MAC (dMAC): previous 
disseminated MAC diagnosis by ACTG criteria and improvement of signs/symptoms with anti-MAC 
therapy, with the subsequent development of focal inflammatory site(s). 
 
Confirmed MAC IRIS in patients without a prior history of dMAC: the development of focal 
inflammatory site(s); histopathology from the involved site demonstrating inflammatory changes 
(e.g., granulomas) accompanied by histologic or culture evidence of AFB consistent with MAC in 
the absence of positive cultures for any other AFB; and may have positive blood cultures for MAC.   
 
Probable MAC IRIS in patients with a prior history of dMAC: previous dMAC diagnosis by ACTG 
criteria and improvement of signs/symptoms with anti-MAC therapy, and the subsequent 
development of focal inflammatory site(s); histopathology from involved site demonstrating 
inflammatory changes (e.g., granulomas) in the absence of positive stains or cultures for any other 
pathogen or any non-infectious histopathologic diagnosis; and negative blood cultures for MAC. 
 
Probable MAC IRIS in patients without a prior diagnosis of MAC: the subsequent development 
of focal inflammatory site(s); histopathology from involved site demonstrating inflammatory 
changes (e.g., granulomas, lymphocytic infiltrates) and without evidence of any other specific 
pathogen (stains may be positive for AFB); and negative blood cultures for MAC. 
 
4. Mycobacterium tuberculosis (TB). Tuberculosis-associated IRIS can present as one of two main 
syndromes: (1) a paradoxical reaction after the start of ART in patients receiving tuberculosis 
treatment (“paradoxical” tuberculosis-associated IRIS), or (2) a new presentation of tuberculosis 
that is “unmasked” in the weeks following initiation of ART with an exaggerated inflammatory 
clinical presentation or complicated by a paradoxical response (“unmasking” tuberculosis 
associated IRIS). A “paradoxical” response to anti-tuberculous therapy was described as far back 
as 1955 in patients initiating therapy. In the HAART era, IRIS associated with TB is common and 
occurs in approximately 8-43% and typically consists of new and persistent fever after starting 
antiretroviral therapy/regimen; worsening or emergence of intrathoracic adenopathy, pulmonary 
infiltrates or pleural effusions, or worsening or emergence of cervical nodes on serial exam or of 
other tuberculous lesions, such as skin and CNS. It usually occurs within the first 4 weeks of 
beginning antimycobacterial therapy with or without antiretroviral therapy/regimen but has been 
described as late as 9 months when the patient is smear-negative. Antiretroviral therapy/regimen 
can usually be continued, often with anti-inflammatory support; corticosteroids have been used 
in those with CNS lesions or who are critically ill [7-12]. 
 
Confirmed TB IRIS in patients with a prior history of TB (paradoxical TB-associated IRIS): There 
are three components to this case-definition (adopted from Lancet Infect Dis 2008, reference 12): 
 
A) Antecedent requirements 
i) Diagnosis of tuberculosis: previous pulmonary (smear positive or smear-negative) or 
extrapulmonary TB diagnosis by ACTG criteria  

 
 
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AND 
ii) Initial response with anti-TB therapy (i.e. stabilization or improvement of signs/symptoms with 
appropriate anti-TB therapy prior to initiation of ART)*. For example, there has been cessation or 
improvement of fevers, cough, night sweats).  
* (Note: this does not apply to patients starting ART within 2 weeks of starting tuberculosis 
treatment since insufficient time may have elapsed for a clinical response to be reported) 
 
(B) Clinical criteria 
The onset of tuberculosis-associated IRIS manifestations should be within 3 months of ART 
initiation, re-initiation, or regimen change because of HIV treatment failure. 
 
Of the following, at least one major criterion or two minor clinical criteria are required: 
 
Major criteria 
• New or enlarging lymph nodes, cold abscesses, or other focal tissue involvement—e.g. 
tuberculous arthritis 
• New or worsening radiological features of tuberculosis (found by chest radiography, abdominal 
ultrasonography, CT, or MRI) 
• New or worsening CNS tuberculosis (meningitis or focal neurological deficit; e.g. caused by 
tuberculoma) 
• New or worsening serositis (pleural effusion, ascites, or pericardial effusion) 
 
Minor criteria 
• New or worsening constitutional symptoms such as fever, night sweats, or weight loss 
• New or worsening respiratory symptoms such as cough, dyspnea, or stridor 
• New or worsening abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or 
abdominal adenopathy 
 
 
(C) Alternative explanations for clinical deterioration must be excluded 
• Failure of tuberculosis treatment because of tuberculosis drug resistance 
• Poor adherence to tuberculosis treatment 
• Another opportunistic infection or neoplasm (it is particularly important to exclude an 
alternative diagnosis in patients with smear-negative pulmonary tuberculosis and extrapulmonary 
tuberculosis where the initial tuberculosis diagnosis has not been microbiologically confirmed) 
• Drug toxicity or reaction 
 
Confirmed TB IRIS in patients without a prior history of TB (ART “unmasking” TB-associated 
IRIS): Patient is not receiving treatment for TB when ART is initiated. Active TB is diagnosed after 
initiation of ART and the diagnosis of TB fulfils ACTG criteria for smear-positive pulmonary TB, 
smear-negative pulmonary TB or extrapulmonary TB. Active TB develops within 3 months of 
starting ART and one of the following criteria is met: heightened intensity of clinical 
manifestations, particularly if there is evidence of a marked inflammatory component. For 

 
 
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example, presentations may include TB lymphadenitis or TB abscesses with prominent acute 
inflammatory features; the development of pulmonary* or extrapulmonary TB with no evidence 
of miliary disease accompanied by marked focal inflammation; or histopathology from involved 
site demonstrating inflammatory changes (e.g., granulomas, caseation) accompanied by histologic 
or culture evidence of AFB consistent with TB in the absence of positive cultures for any other 
AFB. 
 
Probable TB IRIS in patients with a prior history of TB: “Probable” status should be assigned for 
cases where criteria A and B are met (see confirmed TB IRIS with a prior history of TB definition) 
but an alternative diagnosis or explanation for clinical deterioration cannot be fully excluded.  
 
Probable TB IRIS in patients without a prior diagnosis of TB: Patient is not receiving treatment 
for TB when ART is initiated. Active TB is diagnosed after initiation of ART and the diagnosis of TB 
fulfils ACTG criteria for smear-positive pulmonary TB, smear-negative pulmonary TB or 
extrapulmonary TB. There is heightened intensity of clinical manifestations but there is not clear 
evidence of a marked inflammatory component to the presentation or the subsequent 
development of focal inflammatory site(s) is beyond 3 months of ART initiation.  
 
5. Progressive Multifocal Leukoencephalopathy (PML). Inflammatory responses to PML usually 
occur within 3 months of beginning antiretroviral therapy. Based on available data, the 
simultaneous diagnosis of PML and IRIS post-HAART initiation is more commonly observed (i.e. 
unmasking IRIS). Furthermore, it appears that paradoxical worsening PML IRIS is identified sooner 
(within 4 weeks) than unmasking PML IRIS. MRI with gadolinium shows contrast enhancement 
suggesting an inflammatory response, and biopsy reveals significant inflammation with gliosis, 
marked intraparenchymal and perivascular infiltration by macrophages and lymphocytic 
infiltrates (especially CD8 T cells), giant cells, with or without demyelination. Intense JC-specific 
PCR signals (or other immunoreactivity to papovavirus antigens) are detected in brain tissue even 
in the absence of positive JC CSF PCR. The clinical responses are mixed:  some improve, and some 
have significant worsening with progression to death. A variable response to steroids has been 
described [1,13,14].  
 
Confirmed PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG 
criteria (consistent CT or MRI scan with positive biopsy or positive CSF JC PCR and the absence of 
any alternative diagnosis), with the subsequent development of new or worsening CT or MRI 
findings with contrast enhancement; brain biopsy shows focal inflammatory changes 
accompanied by histologic or PCR evidence of PML in the absence of another diagnosis.   
 
Confirmed PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in patient with no previously recognized CNS infection or malignancy, 
accompanied by CT or MRI changes showing contrast enhancement; brain biopsy shows focal 
inflammatory changes accompanied by histologic or PCR evidence of PML in the absence of 
another diagnosis. 
 
Probable PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG 
criteria (consistent CT or MRI scan with positive biopsy or CSF JC PCR and the absence of any 
alternative diagnosis), with the subsequent development of new or worsening CT or MRI findings 
with contrast in the absence of another diagnosis.   
 

 
 
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Probable PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in a patient with no previously recognized CNS infection or malignancy 
accompanied by CT or MRI changes showing contrast enhancement consistent with PML with no 
brain biopsy obtained. CSF findings cannot be attributable to another pathogen or disease 
process. 
 
IRIS Diagnoses without Specific Case Definitions 
 
Pathogen-Directed: 
 
1.  Kaposi’s Sarcoma (KS). Rapid KS progression [15] and local swelling with adjacent 
lymphadenopathy [20] have both been reported as a manifestation of immune reconstitution 
after antiretroviral therapy/regimen initiation. Whereas the latter syndrome may truly represent 
an IRIS syndrome, if there is no clear evidence of any characteristic inflammatory component [1, 
16], then the progression could be due to a failure to reconstitute KSHV-specific immune 
responses. KS-IRIS is defined as a sudden or more dramatic progression of disease than expected 
as part of natural history that occurs within 12 weeks of initiation of ART. ART alone should be 
continued for 4-6 weeks to monitor for clinical response. If the lesions stabilize, have a regression 
of inflammation or lesion number or size diminishes, this will be defined as IRIS. Should disease 
progression continue, then this is unlikely to be IRIS and should be defined as progression of 
disease and managed with appropriate KSHV specific therapies. The presence of inflammation on 
biopsy may assist in distinguishing progression of disease vs. IRIS. 
 
 
2. Hepatitis B and C. Significant increase in ALT over baseline (flares) have been documented after 
beginning antiretroviral therapy/regimen with HBV co-infection as well as after interruption of 
antiretroviral therapy/regimen (especially in patients with HBV on a 3TC- or tenofovir-containing 
regimen). After immune recovery HBV "flares" may occur if HBV is not being concomitantly treated, 
although there are other potential reasons to consider. These include: 
 
a) spontaneous HBeAg seroconversion; 
b) treatment induced exacerbation of the underlying disease; 
c) hepatotoxic effects of treatment; 
d) withdrawal of active HBV drug; 
e) development of resistance and return of replication, and/or  
f) superimposed and unrelated acute liver disease (e.g. hepatitis A) 
 
Liver biopsy may be helpful in determining evidence of drug related (eosinophilic infiltrate) vs. 
acute viral hepatitis (hepatocyte swelling with lobular inflammation). 
 
Biopsy may also grade and stage chronic viral hepatitis. IRIS is less well-defined in HCV co-
infection, and increases in liver enzymes on antiretroviral therapy/regimen may be multifactorial 
as well.  
 
3. Herpes simplex virus (HSV). The development of unusual presentations of HSV following the initiation 
of antiretroviral therapy/regimen attributed to immune reconstitution have been rarely described. 

 
 
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Localized HSV vesicles may occur within 8 weeks of initiating ART among persons with no prior history 
and no new source contact to attribute it to. Symptoms and signs are frequently consistent with a 
primary infection. Chronic erosive or ulcerative lesions of the genitals have been described in 
individuals who had prior histories of genital HSV. The appearance and clinical course of the lesions 
attributed to immune reconstitution appeared inconsistent with these patients’ previous HSV 
presentations. Proctitis has also been reported [1,18,19].  Routine viral cultures may or may not yield 
HSV though histochemistry studies may show evidence of HSV antigens in the absence of a positive 
viral culture. Histopathology in some cases may demonstrate an inflammatory infiltrate with unusual 
prominence of plasma cells and eosinophils. Response to antivirals appears to be variable.  
 
4. Pneumocystis jirovecii pneumonia (PCP). Despite being the most common OI with a relatively 
high CD4 threshold for development, few clear cases of Pneumocystis pneumonia IRIS have been 
documented so far (likely because steroids have been established for the use of severe PCP). Cases 
have been described as worsening of pneumonia and even respiratory failure, although the 
patients reported received suboptimal courses of steroids [20]. To entertain a diagnosis of PCP 
IRIS, bronchoscopy should rule out an intercurrent pulmonary process. 
 
5. Syphilis. New reactive RPR within 12 weeks of starting ART in setting of known previously treated 
syphilis and documented nonreactive within past 2 years without new attributable source. May also 
present serologically as less than or equal to 4-fold change in titer in someone with previous history 
of treated syphilis and no new attributable source. May present with systemic symptoms including 
arthralgia. May improve with anti-inflammatories. 
 
6. Toxoplasmosis. There is also a very small database for possible toxoplasmosis IRIS. No specific 
clinical pattern has been seen, and there is no clear evidence of an inflammatory component. 
 
7. Varicella Zoster (VZV). The development of herpes zoster after initiation of antiretroviral 
therapy/regimen has been attributed to immune reconstitution. The incidence of zoster appears 
to be 2- to 5-fold greater in those receiving antiretroviral therapy/regimen compared to those not 
receiving antiretroviral therapy/regimen. Most cases occur in the first 16 weeks following 
initiation of antiretroviral therapy/regimen. Those with higher percentage of CD8+ lymphocytes 
at the time of initiation of HAART and at one month following antiretroviral therapy/regimen 
appeared to be at higher risk for zoster [21].  Most cases present as cutaneous dermatomal 
disease or mucocutaneous disease, are mild, occur without systemic symptoms and respond to 
antiviral therapy. Iritis and keratitis have been described rarely [1,22]. It is not clear that cutaneous 
zoster following initiation of antiretroviral therapy/regimen has a significant inflammatory 
component that differentiates this from routine VZV.  
 
8. Other viral dermatoses. Eruptive onset of new common warts, flat warts, or epidermodysplasia 
verruciformis-type warts, or inflammation/rapid growth of previously stable cutaneous or genital 
warts, have been noted during immune restoration [23-24]. In addition, eruptive onset of new 
molluscum contagiosum or inflammation/enlargement of pre-existing mollusca during immune 
restoration has been described [25]. 
 
Non-Pathogen or Unknown Pathogen Directed 
   
1. Autoimmune disorders. Systemic lupus erythematosus, polymyositis, rheumatoid arthritis, 
relapsing polychondritis and Guillain-Barre have also been attributed to immune reconstitution 
following administration of antiretroviral therapy/regimen [1,26]. 

 
 
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2. Follicular inflammatory eruptions. Sudden onset of follicular papulopustular inflammatory 
eruptions resembling acne vulgaris or acne rosacea have been reported within first 4 months of 
immune reconstitution [27]. Eosinophilic folliculitis, distinguished from acneiform eruptions by 
intense pruritus, an urticarial appearance to the papules, and histopathology showing follicular 
inflammation containing eosinophils, has been documented. An increased incidence of 
eosinophilic folliculitis has been noted in the first 6 months of HAART therapy [28]. 
 
3. Graves’ Disease. New onset of clinically significant Graves’ disease (hyperthyroidism) has been 
reported following the initiation of antiretroviral therapy/regimen. The development of anti-
thyrotropin receptor antibodies in individuals following antiretroviral therapy/regimen, not 
present before antiretroviral therapy/regimen initiation has been described [1, 26]. 
 
4. Sarcoidosis. Worsening of previously diagnosed sarcoidosis or newly diagnosed sarcoidosis following 
antiretroviral therapy/regimen has been reported. Pulmonary involvement as well as extrapulmonary 
involvement (erythema nodosum) has been described [1, 26].  

 
 
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Selected References 
1. Shelburne SA, 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: 
emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213-27. 
2. Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus 
retinitis patients following institution of successful highly active antiretroviral therapy. Journal of Infectious 
Diseases 1999;179:697-700. 
3. Shelburne SA 3rd, Darcourt J, White AC Jr, et al. The role of immune reconstitution inflammatory syndrome 
in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect 
Dis. 2005;40(7):1049-52. 
4. Manosuthi W, Thongyen S, Chimsuntorn S, Sungkanuparph S. Immune Reconstitution Syndrome in HIV-
infected Patients with Cryptococcal Meningitis: A Prospective Study. The joint meeting of the 48th Interscience 
Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and the 46th Annual Meeting of the Infectious 
Disease Society of America (IDSA), Washington DC 2008; Abstract H-1162.  
5. Phillips P, Kwiatkowski MB, Copland M, Craib K and Montaner J. Mycobacterial lymphadenitis associated with 
the initiation of combination antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes & 
Human Retrovirology 1999;20:122-8. 
6. Aberg JA, Chin-Hong PV, McCutchan A, Koletar SL, Currier JS and the ACTG 362 and 393 Study Teams. Localized 
Osteomyelitis due to Mycobacterium avium Complex in Patients with Human Immunodeficiency Virus Receiving 
Highly Active Antiretroviral Therapy. Clin Infect Dis 2002;35:e8-13.  
7. Narita M, Ashkin D, Hollender ES and Pitchenik AE. Paradoxical worsening of tuberculosis following 
antiretroviral therapy in patients with AIDS. American Journal of Respiratory & Critical Care Medicine 
1998;158:157-61. 
8. John M, French MA. Exacerbation of the inflammatory response to Mycobacterium tuberculosis after 
antiretroviral therapy. Medical Journal of Australia 1998;169:473-4. 
9. Fishman JE, Saraf-Lavi E, Narita M, Hollender ES, Ramsinghani R and Ashkin D. Pulmonary tuberculosis in AIDS 
patients: transient chest radiographic worsening after initiation of antiretroviral therapy. AJR. American Journal 
of Roentgenology 2000;174:43-9. 
10. Furrer H, Malinverni R. Systemic inflammatory reaction after starting highly active antiretroviral therapy in 
AIDS patients treated for extrapulmonary tuberculosis.[see comment]. American Journal of Medicine 
1999;106:371-2. 
11. Orlovic D, Smego RA, Jr. Paradoxical tuberculous reactions in HIV-infected patients. International Journal of 
Tuberculosis & Lung Disease 2001;5:370-5 
12. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: 
case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8(8):516-23. 
13. Safdar A, Rubocki RJ, Horvath JA, Narayan KK and Waldron RL. Fatal immune restoration disease in human 
immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of 
antiretroviral therapy-associated immune reconstitution. Clinical Infectious Diseases 2002;35:1250-7. 
14. Gray F, Bazille C, Adle-Biassette H, et al. Central nervous system immune reconstitution disease in acquired 
immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol. 2005;11 
Suppl 3:16-22. 
15. Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Mandalia S, Dhillon T, Holmes P, Gazzard BG, 
Stebbing J. Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma. J Clin Oncol. 2005 
Aug 1;23(22):5224-8.  
16. Connick E, Kane MA, White IE, Ryder J, Campbell TB. Immune reconstitution inflammatory syndrome 
associated with Kaposi sarcoma during potent antiretroviral therapy. Clin Infect Dis. 2004 Dec 15;39(12):1852-
5. 

 
 
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17. Bihl F, Mosam A, Henry LN, et al. Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution 
and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma. 
AIDS. 2007;21(10):1245-52.  
18. Couppie P, Sarazin F, Clyti E, et al. Increased incidence of genital herpes after HAART initiation: a frequent 
presentation of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients. AIDS Patient Care 
and STDs. March 1, 2006, 20(3): 143-145. 
19. Fox PA, Barton SE, Francis N, et al. Chronic erosive herpes simplex virus infection of the penis, a possible 
immune reconstitution disease. HIV Medicine 1999;1:10-8. 
20. Zolopa A. Session 313. Complex Medical Management of HIV: Initiating ART in advanced AIDS at The joint 
meeting of the 48th Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and the 46th 
Annual Meeting of the Infectious Disease Society of America (IDSA), Washington DC 2008. 
21. Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation 
of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection. Am J 
Med. 2001 Jun 1;110(8):605-9.  
22. Feller L, Wood NH, Lemmer J. Herpes zoster infection as an immune reconstitution inflammatory syndrome 
in HIV-seropositive subjects: a review. 
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Oct;104(4):455-60. 
23. Kerob D, Dupuy A, Vignon-Pennamen MD, Bournerias I, Dohin E, Lebbe C. A case of efflorescence of 
cutaneous warts as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected 
patient. Clin Infect Dis 2007; 45(3):405-6. 
24. Mermet I, Guerrini JS, Cairey-Remonnay S, Drobacheff C, Faivre B et al. Cervical intraepithelial neoplasia 
associated with epidermodysplasia verruciformis HPV in an HIV-infected patient: a manifestation of immune 
restoration syndrome. Eur J Dermatol 2007; 17(2):149-52. 
25.  Pereira B, Fernandes C, Nachiambo E, Catarino MC, Rodrigues A, Cardoso J. Exuberant molluscum 
contagiosum as a manifestation of the immune reconstitution inflammatory syndrome. Dermatol Online J 
2007;13(2):6 
26.French MA, Price P and Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 
2004;18:1615-27. 
27. Scott C, Staughton, R, Hawkins D, Asboe D. Acne vulgaris and acne rosacea immune reconstitution disease 
following highly active antiretroviral therapy (HAART) for HIV infection: a case series. HIV Medicine 2007;44 (8): 
142. 
28. Rajendran PM, Dolev JC, Heaphy MR Jr,  Maurer T. Eosinophilic folliculitis: before and after the introduction 
of antiretroviral therapy. Arch Dermatol 2005;141(10):1227-31. 
 
 

 
 
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APPENDIX 7 – HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF CHILD BEARING 
POTENTIAL*  
 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy (i.e., have 
a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in 
accordance with the product label). 
The list does not apply to females of childbearing potential (FCBP) with same sex partners, when this 
is their preferred and usual lifestyle. 
• 
True abstinence from penile-vaginal intercourse, when this is in line with the preferred and 
usual lifestyle of the subject [Hatcher, 2007a] (Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of 
contraception]. 
• 
Non-hormonal Intrauterine device or non-hormonal intrauterine system that meets the 
effectiveness criteria as stated in the product label [Hatcher, 2007a] 
• 
Male partner sterilization prior to the female subject's entry into the study, and this male is 
the sole partner for that subject [Hatcher, 2007a]. The information on the male sterility can 
come from the site personnel’s: review of subject’s medical records; medical examination 
of the subject and/or semen analysis; or interview with the subject on his medical history. 
• 
Combined (oestrogen and progesterone containing) hormonal contraception associated 
with the inhibition of ovulation***: 
• 
Oral 
• 
Intravaginal  
• 
Transdermal 
• 
Bilateral tubal occlusion 
 
 
* A Woman of childbearing potential (WOCBP) is defined as any female who has: 
• 
Experienced menarche  
• 
Not undergone surgical sterilization (hysterectomy , bilateral salpingectomy or bilateral 
oophorectomy)  
• 
Not experienced menopause. Women are considered menopausal if they have not had a 
menses for at least 12 months and have an FSH (follicle stimulating hormone) of greater than 
40 IU/L or, if FSH testing is not available, they have had amenorrhea for 24 consecutive 
months**. 
**Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level.  
 
***If a patient is randomised to Symtuza, an alternative highly effective method of contraception 
should be used  
 
 

 
 
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APPENDIX 8 – SAFETY REPORTING FLOW CHART  
 
Safety Data 
Reporting Format 
Timelines 
All SAEs arising during the Clinical Trial, 
regardless 
of 
Investigator/designee 
causality assessments against IMP(s)   
SAE form 
 
 
 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Pregnancy information for all female 
Clinical Trial Subjects who become 
pregnant while participating in the 
Clinical Trial and following exposure to 
an IMP.  
The subject will also be followed to 
determine 
the 
outcome 
of 
the 
pregnancy (including information on 
the status of the mother and child), 
which will also be reported to sponsor. 
Copies of the original 
Pregnancy CRF pages 
Site to send to sponsor within 24 
hours of first becoming aware of the 
pregnancy 
or 
the 
pregnancy 
outcome. 
Sponsor to report to Funder within 
24 hours of awareness. 
Deaths 
Any AE, AR or unexpected 
AR that results in death 
should be reported as an 
SAE on an SAE form. 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Overdose 
If the overdose fits the 
criteria of an SAE (see 
Section 8) it should be 
reported appropriately on 
an SAE form, else report as 
a 
Special 
Reporting 
Situation. 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Special Reporting Situations: 
(See section 8.10) 
Email 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
Product Quality Complaints 
Email 
Site to report to sponsor within 24 
hours of first becoming aware of the 
event. 
Sponsor to report to Funder within 
24 hours of awareness. 
 
 

 
 
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APPENDIX 9 – AMENDMENT HISTORY  
Comparative table with Description of Change and Rationale for change to the Protocol from 
Version 2.0 to Version 4.0. 
Please note version 3.0 was never fully approved in any territory as it did not include changes 
approved between versions 1.5 and version 2.0. V4.0 re-incorporates all approved changes made 
previously and also includes the following:  
Change No. 
Description of Change 
Rationale for Change 
1.  
Changes made to reference the 
compliance with Clinical Trial Regulation 
(EU) No 536/2014 in the statements the CI, 
Sponsor, statistician, and PIs sign. 
Addition of EUCT number to title page. 
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
2.  
Protocol summary: 
Number of sites and countries changed 
from 45 to 61, and 7 to 11, respectively. 
Expansion of trial sites and territories 
is ongoing. 
3.  
Section 1.2.1: Therefore, in cases when 
needs ART needs to be initiated before 
genotypic testing results are available 
Typographical error on in the 
background and rationale section 
 
4.  
Section 1.2.1, Section 7.1 and Section 7.7: 
Change to the language regarding the 
referenced RSI provided by the sponsor in  
Changed to emphasize that the study 
team should refer to the particular 
SmPC provided and authorised as the 
RSI in the study, even if this is not the 
local country version or most current.  
 
5.  
Section 5.2: Exclusion Criteria: 
Removal of the requirement that 
forbidden concomitant medications should 
have been stopped at least 30 days ahead 
of baseline. 
30 days was added initially at the start 
of the trial when there was less safety 
data available for Biktarvy, in 
particular, as it was not yet authorised 
when the protocol was written. 
Therefore, it was thought to exclude 
all contraindicated medication for 30 
days as a safety precaution. However, 
it is now thought this is unnecessary 
and the sites should follow any 
recommendations in the SmPC. 
6.  
Section 5.2 and Appendix 1: 
A latent TB test may be performed. 
Previously a TB test will be performed 
To clarify that the test is to confirm if 
latent TB is present. 
Additionally, TB testing has always 
been intended to be done in those 
patients in who it may be suspected. 
This wording has been changed to 
clarify that.  
7.  
Removal of “Investigator Brochure” from 
the title of section 7.1 
There is no Investigator Brochure used 
for the trial.  
8.  
Section 8.2.4 and Section 8.3.3.: 
Addition in line with change to 
Sponsor’s safety event reporting form 

 
 
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Change No. 
Description of Change 
Rationale for Change 
1. 
Additional text to state that details 
of reporter included on the Safety 
Event Report Form 
2. 
Addition of text to mention the 
pharmacovigilance management 
plan (PVMP) will be used by the CI 
and sponsor in assessment of 
safety reporting 
to include the pharmacovigilance 
management plan (PVMP). 
9.  
Section 8.2.4 Recording and Reporting of 
SAEs and SUSARs 
Statement made that the Sponsor will 
update the Eudrvigilance database.  
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
10.  
Section 8.3.6 and Section 12 
Addition of details regarding Endpoint 
committee review  
An endpoint committee may be 
requested ahead of any data analysis 
required by the DSMB or the TSC. 
11.  
8.8 Development Safety Update Reports 
Statement of intent for the sponsor to 
submit a single safety report for both IMP 
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
12.  
9.5 
Interim analysis and criteria for the 
premature termination of the trial 
Statement that there are no specific trial 
stopping criteria  
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
13.  
13.3 Regulatory Compliance 
Change to reflect the trial will be conduct 
in compliance with Clinical Trial Regulation 
(EU) No 536/2014  
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
14.  
13.6 Data protection and patient 
confidentiality 
Updated to comply with the Clinical Trial 
Regulation (EU) No 536/2014 
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
15.  
Section 13.5: 
Change to the definition of serious breach 
and reporting timelines  
The previously included strictly MHRA 
definition has hence been modified to 
include the Clinical Trial Regulation 
wording. 
16.  
Appendix 1: Study Flowchart 
Removal of “including urinary chemistry” 
after “Clinical Chemistry” in the 
description of this assessment 
The words are superfluous as the 
actual tests required are described in 
the footnote 12 – removing them for 
clarity for the sites.  
17.  
Appendix 1:  
Change to the footnote 10 wording after 
the asterisk: regarding when assessments 
should be taken. Changing from “after 
baseline” to “at all visits required” 
Changing this for clarity as it is 
ambiguous about whether urinalysis 
assessments should be done at all 
visits.  
18.  
Appendix 1: 
Additional wording to state that either 
urinary creatinine or ACR and PCR are 
mandatory, not both 
As it is the ACR and PCR which are 
required, and these are calculated 
from the urinary creatinine, if the ACR 
and PCR are provided by the site 
directly and the site do not routinely 

 
 
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Change No. 
Description of Change 
Rationale for Change 
also provide the urinary creatinine in 
lab reports, this is acceptable. 
19.  
Appendix 1: 
Change to clarify that, as CD4 and CD8 can 
be calculated from total lymphocytes and 
CD4% and CD8%, CD4 and CD8 count are 
not mandatory 
CD4% and CD8% and lymphocytes are 
already mandatory.  
20.  
Appendix 1: 
Urinary nitrites are no longer mandatory 
It is considered that urinary nitrites are 
not a necessary safety test that is 
needed.  
 
Comparative table with Description of Change and Rationale for change to the Protocol from 
Version 4.0 to Version 5.0. 
Change No. 
Description of Change 
Rationale for Change 
1. 
Section 13.6: 
Additional wording to clarify how data is 
stored and processed at the end of the 
study, and in what format 
Compliance with Clinical Trial 
Regulation (EU) No 536/2014 
 
 

 
 
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STATISTICAL ANALYSIS PLAN 
 
TRIAL FULL TITLE 
An Open-Label, Multi-Centre, Randomized Study to Investigate 
Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral 
Therapy for Patients with Advanced HIV Disease 
Short 
Title/Acronym 
LAPTOP -The Late Presenter Treatment Optimization Study - 
Clinical Phase 
3 
EUDRACT 
NUMBER 
2018-003481-13 
Clinitrials.gov 
identifier 
NCT03696160 
SAP VERSION 
0.3 
SAP VERSION 
DATE 
22.11.2023 
SAP AUTHOR 
Lambert ASSOUMOU 
 
 
 
SIGNATURES 
Responsibility 
Name 
Signature 
Date 
Trial statistician 
Lambert ASSOUMOU 
 
 
Chief Investigator 
Georg BEHRENS 
 
 
Sponsor 
Anton POZNIAK 
 
 
 
 

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DOCUMENT HISTORY 
Document 
version number Section change Summary of changes 
Reason for change 
 
 
 

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TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................................... 1 
DOCUMENT HISTORY ....................................................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................................................ 3 
ABBREVIATIONS AND DEFINITIONS ................................................................................................................. 6 
1. 
INTRODUCTION ....................................................................................................................................... 8 
1.1 
PREFACE ................................................................................................................................................... 8 
1.2 
PURPOSE OF THE ANALYSES ......................................................................................................................... 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................................... 9 
2.1 
STUDY OBJECTIVES ..................................................................................................................................... 9 
2.1.1 
Primary objective .............................................................................................................................. 9 
2.1.2 
Secondary objectives ......................................................................................................................... 9 
2.1.3 
Exploratory objectives ....................................................................................................................... 9 
2.2 
ENDPOINTS ............................................................................................................................................. 10 
2.2.1 
Primary endpoint/outcome ............................................................................................................. 10 
2.2.2 
Secondary endpoints/outcomes...................................................................................................... 10 
2.2.3 
Exploratory endpoints/outcomes .................................................................................................... 11 
3. 
STUDY METHODS .................................................................................................................................. 11 
3.1 
GENERAL STUDY DESIGN AND PLAN ............................................................................................................. 11 
3.2 
RANDOMISATION SCHEME AND BLINDING ..................................................................................................... 12 
3.3 
STUDY SCHEDULE ..................................................................................................................................... 13 
4. 
SAMPLE SIZE CALCULATION ................................................................................................................... 17 
5. 
GENERAL CONSIDERATIONS .................................................................................................................. 17 
5.1 
TIMING OF ANALYSES ................................................................................................................................ 18 
5.2 
ANALYSIS POPULATIONS ............................................................................................................................ 18 
5.2.1 
Full Analysis Population .................................................................................................................. 18 
5.2.2 
Per Protocol Population .................................................................................................................. 18 
5.2.3 
Safety Population ............................................................................................................................ 18 
5.3 
HANDLING OF MISSING DATA ...................................................................................................................... 19 
5.4 
INTERIM ANALYSIS .................................................................................................................................... 19 
5.5 
MULTIPLE TESTING ................................................................................................................................... 20 
6. 
SUMMARY OF STUDY DATA .................................................................................................................. 20 
6.1 
SUBJECT DISPOSITION ............................................................................................................................... 20 
6.2 
PROTOCOL DEVIATIONS ............................................................................................................................. 21 
6.3 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................................................................. 21 
6.3.1 
Descriptive statistics ....................................................................................................................... 21 
6.3.2 
Baseline data .................................................................................................................................. 21 
6.4 
STUDY TREATMENT COMPLIANCE ................................................................................................................ 23 
6.5 
STRATIFICATION FACTOR ........................................................................................................................... 23 
7. 
EFFICACY ANALYSES .............................................................................................................................. 23 
7.1 
PRIMARY EFFICACY ANALYSIS ..................................................................................................................... 24 
7.2 
SECONDARY EFFICACY ANALYSES ................................................................................................................. 25 
7.2.1 
Cumulative incidence of the composite primary endpoint.............................................................. 25 
7.2.2 
HIV-RNA viral load <50 copies/mL at week 24, 36 and 48 .............................................................. 26 
7.2.3 
Genotypic resistance test among patients with virological failure ................................................. 27 
7.2.4 
Time to reach CD4 cell count >200/µl ............................................................................................. 27 
7.2.5 
CD4 cell count <200/µl and <350 at week 4, 8, 12, 24, 36 and 48 .................................................. 28 
7.2.6 
Change in CD4/CD8 ratio from baseline to week 48 ....................................................................... 28 

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7.2.7 
Incidence of IRIS .............................................................................................................................. 29 
7.2.8 
Incidence of hospitalisation ............................................................................................................ 29 
7.2.9 
Duration of hospitalisation ............................................................................................................. 30 
7.2.10 
Rate of relapse recurrence of specific opportunistic infection or bacterial infection through 
week 48 
30 
8. 
SAFETY ANALYSES ................................................................................................................................. 31 
9. 
SUBGROUP ANALYSES ........................................................................................................................... 32 
10. 
OTHER ANALYSES .............................................................................................................................. 32 
10.1 
OTHER SECONDARY ENDPOINTS .................................................................................................................. 33 
10.1.1 
ART and/or opportunistic infection/bacterial infection treatment changes and/or dose 
modifications due to toxicities and/or DDI with ART, and/or IRIS through week 48 ................................... 33 
10.1.2 
Health care resource use, through week 48 ............................................................................... 33 
10.1.3 
Quality of life (EQ-5D-3L questionnaire) and HIV Symptoms index ............................................ 34 
10.1.4 
discontinuation or modification of study medication due to insufficient virological response or 
resistance mutation development before week 48 ...................................................................................... 35 
10.1.5 
Adherence to study medication over time .................................................................................. 36 
10.1.6 
Change from baseline in plasma and urine laboratory parameters ........................................... 36 
10.2 
EXPLANATORY ENDPOINTS ......................................................................................................................... 37 
10.2.1 
Mutations detected by deep sequencing compared with those detected by population 
sequencing ................................................................................................................................................... 37 
10.2.2 
Proportion of patients with HIV RNA viral load <50 copies/mL at week 4, 8, and 12 ................ 37 
10.2.3 
Evolution of HIV RNA in individuals with viral load >50 copies/mL at week 48 .......................... 38 
1. 
REPORTING CONVENTIONS ................................................................................................................... 38 
2. 
STATISTICAL SOFTWARE ........................................................................................................................ 39 
3. 
REFERENCES .......................................................................................................................................... 40 
4. 
LISTING OF TABLES AND FIGURES .......................................................................................................... 41 
TABLE 1. BASELINE CHARACTERISTICS ........................................................................................................................ 41 
TABLE 1B: BASELINE RESISTANCE MUTATIONS ............................................................................................................. 43 
TABLE 2. PRIMARY COMPOSITE ENDPOINT AND ITS COMPONENT .................................................................................... 44 
TABLE 2B. CUMULATIVE INCIDENCE OF THE PRIMARY COMPOSITE ENDPOINT .................................................................... 44 
TABLE 3. HIV-RNA VIRAL LOAD <50 COPIES/ML AT WEEK 24, 36 AND 48 ..................................................................... 45 
TABLE 4. OTHER SECONDARY EFFICACY ENDPOINTS ...................................................................................................... 46 
TABLE 5: EVOLUTION OF CD4 CELL COUNT <200/µL AND <350 AT WEEK 4, 8, 12, 24, 36 AND 48 ..................................... 46 
TABLE 6: EVOLUTION OF CD4/CD8 RATIO AT WEEK 4, 8, 12, 24, 36 AND 48 ................................................................. 46 
TABLE 7: SAFETY ................................................................................................................................................... 47 
TABLE 8. OTHER SECONDARY ENDPOINTS ................................................................................................................... 47 
TABLE 9: EVOLUTION OF QUALITY OF LIFE (HEALTH STATUS SCORE) AND HIV SYMPTOMS INDEX ............................................ 48 
TABLE 10: QUALITY OF LIFE DIMENSIONS: MOBILITY AND SELF- CARE .............................................................................. 49 
TABLE 11: QUALITY OF LIFE DIMENSIONS: USUAL ACTIVITIES AND PAIN/DISCOMFORT ........................................................ 50 
TABLE 12: QUALITY OF LIFE DIMENSIONS: ANXIETY/DEPRESSION .................................................................................... 51 
TABLE 13. HIV-RNA VIRAL LOAD <50 COPIES/ML AT WEEK 4, 8 AND 12 ....................................................................... 52 
TABLE 14: ADHERENCE TO STUDY MEDICATION OVER TIME ........................................................................................... 53 
TABLE 15: CHANGE FROM BASELINE IN LABORATORY RESULTS ........................................................................................ 54 
TABLE 16: CHANGE FROM BASELINE IN URINE PARAMETERS .......................................................................................... 64 
5. 
APPENDICES .......................................................................................................................................... 67 
APPENDIX 1 – AIDS-DEFINING CONDITIONS ................................................................................................... 67 
APPENDIX 2 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA ....................................................................... 67 
APPENDIX 3 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA ................................................................... 73 
APPENDIX 4 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA ........................ 79 

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ABBREVIATIONS AND DEFINITIONS 
 
Acronym 
Description  
3TC 
Lamivudine 
ABC 
Abacavir 
ACTG 
AIDS Clinical Trial Group 
ADE 
Adverse Drug Event 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Transaminase 
ANRS 
Agence Nationale de Recherches sur le SIDA (National Agency for AIDS Research) 
AST 
Aspartate Aminotransferase 
B/BIC 
Bictegravir 
BI 
Bacterial Infection 
C 
Cobicistat 
CDC 
Centres for Disease Control and Prevention 
CI 
Chief Investigator 
CI 
Confidence Interval 
CRF 
Case Report Form 
SAP 
Statistical Analysis Plan 
D/DRV 
Darunavir 
DDI 
Drug-Drug Interaction 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DTG 
Dolutegravir 
EACS 
European AIDS Clinical Society 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELISPOT 
Enzyme-Linked ImmunoSpot 
ETV 
Early Termination Visit 
EU 
European Union 
EudraCT  
European Clinical Trials Database  
EVG 
Elvitegravir  
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FTC/F 
Emtricitabine 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation  
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HIV-1 
Human Immunodeficiency Virus Type-1 
IAS 
International AIDS Society 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IGRA 
Interferon-Gamma Release Assays 
IMP  
Investigational Medicinal Product  
INI  
Integrase Inhibitor  

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INSTI 
Integrase Strand Transfer Inhibitor 
IRIS 
Immune Reconstitution Inflammatory Syndrome 
ITT 
Intent-to-Treat  
LOCF 
Last Observation Carried Forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
NNRTI 
Non-Nucleoside Reverse-Transcriptase Inhibitor 
NRTI 
Nucleoside Reverse-Transcriptase Inhibitor 
OI 
Opportunistic Infection 
PI 
Protease Inhibitor 
QD 
quaque die (once daily) 
QOL 
Quality of Life 
RAL 
Raltegravir 
RNA 
Ribonucleic Acid 
RT 
Reverse Transcriptase 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TAF 
Tenofovir Alafenamide Fumarate 
TDF 
Tenofovir Disoproxil Fumarate 
TB 
Tuberculosis 
TFV 
Tenofovir 
US 
United States 
 
 

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1. INTRODUCTION 
1.1 
PREFACE  
The effectiveness of HIV antiretroviral therapy (ART) has consistently improved over the years. This is 
due to novel compounds and combinations with improved antiviral efficacy and side effect profiles 
resulting in less virologic failures and treatment discontinuation. On the other hand, most recent 
randomised controlled trials for first line treatment consider patients with less advanced disease 
(mean CD4 cell counts at baseline >350/µl, less than 15% of patients with CD4 cell counts <200/µl) 
and low baseline viral loads (DeJesus et al., 2012) (Raffi et al., 2013) (Walmsley et al., 2013) (P.E. Sax 
et al., 2017) (Gallant et al., 2017). This favours superior overall response rates, as these patients 
usually suffer from less co-morbidity, drug-drug interactions (DDI), and other risks for treatment 
failure. The rate of patients with acquired immunodeficiency syndrome (AIDS) recruited into these 
trials was low, while a third of HIV-positive patients are diagnosed late in the course of the disease 
(CD4 T-cell count <200 cells/L or presence of AIDS) (Raffetti et al., 2016) (Sobrino-Vegas et al., 2012). 
Much less is known about which ART regimens perform best in late presenters in terms of viral 
efficacy, immune reconstitution, improvement of AIDS-related co-morbidities and adverse events 
(AEs). No specific combinations have been compared in sufficiently powered randomised clinical trials, 
and all regimens considered in international guidelines for first line therapies are judged as equal 
standard of care for these patients. Initially, protease inhibitor (PI) containing regimens were 
frequently used in patients presenting late or with AIDS defining events (Mussini et al., 2008). 
However, specifically regimens containing integrase inhibitors (INI) are promising candidates for 
treatment combinations in patients with CD4 cell counts <200/µl due to their antiviral activity and 
rapid decline of viral load, beneficial side-effect profile and metabolism pathways compared to other 
regimens. Also, integrase inhibitors such as dolutegravir (DTG) and bictegravir (BIC/B) have high 
genetic barriers, thereby preventing resistance mutation development and ensuring sufficient 
antiviral activity in case of pre-existing mutations against nucleosides (Demarest et al., 2018). 
Therefore, in cases when needs ART to be initiated before genotypic testing results are available, 
current European AIDS Clinical Society (EACS) Guidelines (EACS Treatment Guidelines 9.0) recommend 
to include a drug with a high genetic barrier to resistance in the first-line regimen (e.g. PI or DTG).  
We therefore propose a strategic clinical trial to compare an INI containing regimen versus a boosted 
PI regimen in patients with advanced HIV-infection. We aimed to demonstrate the non-inferiority of 
an INI containing regimen [bictegravir (B) /emtricitabine (F) /tenofovir alafenamide (TAF) QD] versus 
a boosted PI regimen [darunavir (D) /cobicistat(C) /emtricitabine (F) /tenofovir alafenamide (TAF) QD] 
in patients with advanced HIV infection. The superiority of the INI-based treatment group over the PI-
based treatment group will be assessed in the event that non-inferiority is established. 

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This Statistical Analysis Plan (SAP) details the different populations of analysis and the statistical 
methodology that will be used to analyse the data. It describes the efficacy and safety variables and 
anticipated data transformations and manipulations, and other details of the analyses not provided in 
the study protocol. The analyses described are based upon the clinical study protocol Version 2.0 
dated 16 June 2020. This SAP will be validated and signed before the primary endpoint analysis is 
performed. 
1.2 
PURPOSE OF THE ANALYSES 
The main purpose of this analysis is to compare two different types of HIV treatments, in terms of 
effectiveness and improvement of side effects, for patients who are diagnosed with a more advanced 
HIV infection. Patients with advanced HIV infections are otherwise known as 'late presenters'. These 
analyses will assess the efficacy and safety of BIC containing regimen in comparison with the boosted 
PI containing regimen. Advanced HIV infection is defined by an AIDS-Defining-Events (ADE) and/or an 
absolute number of T CD4+ lymphocytes ≤ 200/mm3. 
The statistical analyses of the primary and secondary endpoints will be performed after the database 
locked and cleaned. The analysis will include all randomised patients enrolled who received at least 
one dose of the study drugs. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
2.1.1 Primary objective 
The primary objective of this study is to demonstrate the non-inferiority of an INI containing regimen 
[bictegravir (B)/emtricitabine(F)/tenofovir alafenamide (TAF) QD] versus a boosted PI regimen 
[darunavir (D)/cobicistat (C)/emtricitabine (F)/tenofovir alafenamide (TAF) QD] in patients with 
advanced HIV infection, in terms of reducing the occurrence of a composite outcome including 
virological and clinical reasons.  
2.1.2 Secondary objectives 
The secondary objective of this study is to investigate the immunological and virologic response, 
tolerability, resistance development, discontinuation of therapy due to tolerability, quality of life (QoL) 
and IRIS incidence. 
2.1.3 Exploratory objectives 

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The exploratory objective of this study is to assess whether virologic response is better predicted by 
deep sequencing rather than standard population sequencing. 
2.2 
ENDPOINTS 
2.2.1 Primary endpoint/outcome 
The primary endpoint is time to failure. Failure is defined as the first occurrence of any of the 
following components: 
1. Virologic reasons 
a) Insufficient virologic response, either: 
a. HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
b. Viral load > 50 HIV-1 RNA copies/mL at week 48 
b) Viral rebound, which is subsequently confirmed at the following scheduled or unscheduled 
visit, defined as either: 
a. Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL 
b. Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose 
viral load has never been suppressed below 50 copies/mL 
2. Clinical reasons 
a) Death related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS 
b) Any new or recurrent AIDS defining event on, or after 28 days of therapy 
c) Any new serious non-AIDS defining event documented by the endpoint review committee 
(including severe BI, end stage liver disease, renal failure, cardiovascular event, and non-
AIDS related malignant disease) 
d) Clinically relevant AEs of any grade or IRIS which require treatment interruption (lasting > 5 
days) of INI or boosted PI therapy within the first 48 weeks after randomisation 
Note: Discontinuation of BIC or boosted DRV followed by (within 5 days) continuation with 
another INI or PI, respectively, is not considered as a strategy failure or endpoint. 
All clinical events will be validated as endpoints by the Clinical Endpoint Committee. 
Clinical events are referenced in the appendices : Appendices 1 (AIDS-Defining Conditions), 2 (INSIGHT 
Serious Non-AIDS Events Criteria), 3 (INSIGHT Progression of HIV Disease Criteria) and 4 (Immune 
Reconstitution Inflammatory Syndrome Generic Criteria). 
2.2.2 Secondary endpoints/outcomes 

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Secondary endpoints/outcomes included: 
 
Cumulative incidence of the composite primary endpoint at week 48 
 
Proportion of patients with HIV-RNA viral load <50 copies/mL at week 24, 36, 48 
 
HIV-1 drug resistance at confirmed virological failure [ Time Frame: Through study completion, 
an average of 1 year] 
 
Time to reach CD4 count >200/µL (first measurement) 
 
Proportion of patients with CD4 cell count < 200 μL and < 350μL at week 4, 8, 12, 24, 36, 48 
 
CD4/CD8 ratio at week 4, 8, 12, 24, 36, 48  
 
Incidence of IRIS in the two arms through week 48  
 
Incidence and duration of hospitalisation or rate of relapse of specific opportunistic infection 
(OI) or bacterial infection (BI) through week 48 
 
Number and proportion of participants with Grade 2, 3 and 4 adverse events (AEs), treatment-
related AEs, AEs leading to the study drug discontinuation, and death through week 48 
 
ART and OI/BI treatment changes and dose modifications due to toxicities and DDI with ART, 
and IRIS through week 48 
 
Healthcare resource use, including total inpatient days and emergency room visits through 
week 48 
 
QOL and functional status outcomes, including overall self-reported QOL and functional status 
compared in the two groups at week 48 
 
Discontinuation or modification of study medication due to insufficient virological response, 
resistance mutations at baseline, or resistance mutation development before week 48 
2.2.3 Exploratory endpoints/outcomes 
 
Mutations detected by deep sequencing compared with those detected by population 
sequencing 
 
Proportion of patients with HIV-RNA viral load < 50 copies/mL at week 4, 8, 12  
3. STUDY METHODS 
3.1 
GENERAL STUDY DESIGN AND PLAN 
LAPTOP study is an international, open-label, randomised, two arm, multicentre trial over 48 weeks 
to compare two strategies for HIV-1 infected patients with advanced disease. 
Eligible patients will be randomised to receive either an integrated inhibitor containing regimen (B 
(50mg)/F (200mg)/TAF (25mg) [1 pill administered orally once daily for 48 weeks]) or a boosted PI 
regimen (D (800mg)/C (150mg)/F(200mg)/TAF (10mg) [1 pill administered orally once daily for 48 
weeks]). Randomisation is stratified by country and baseline CD4 cell count (<50 cells/µL, 50-199 
cells/µL, or ≥200 cells/µL). 
 

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Figure 1: Study design 
Study participants will be ART-naïve, HIV-1-infected individuals aged 18 or older who have at entry 
HIV viral load > 1000 copies/ml and at least one of the following: i) have AIDS with any CD4 cell count; 
ii) have severe bacterial infection (BI) and must have a CD4 cell count < 200/μl within 30 days prior to 
study entry; iii) are asymptomatic with CD4 cell count < 100/μL within 30 days prior to study entry; iv) 
are currently receiving treatment for OI. Women who were pregnant or breastfeeding or who declined 
a contraceptive method at screening were not eligible. 
After the screening visit, participants will be seen at baseline, when they initiated c-ART and weeks 4, 
8, 12, 24, 36 and 48, as well as a follow-up visit 30 days following the week 48 visit. 
At each visit, participants will have routine safety monitoring as well as measurement of plasma HIV-
1 RNA viral load, CD4, CD8 cells counts and a deep sequence resistance test. In the event of 
virological failure, local resistance tests should be performed on the first sample, and participants 
should discontinue study treatment and receive rescue therapy at the investigators' discretion. 
Quality of life (QoL) questionnaire (EuroQoL EQ-5D-3L) and HIV Symptom Index (HIV-SI/SDM) 
questionnaire will be administrated at each visit from baseline. 
3.2 
RANDOMISATION SCHEME AND BLINDING 
The randomization list will be generated by an independent statistician not part of the study team. 
The list will be generated by a centralized computer-generated random list with a permuted block 
size. He is the only person who know the size of the blocks. 
Participants will be randomly assigned, in a 1:1 ratio, to receive a BIC containing regimen or boosted 
PI containing regimen for 48 weeks, with allocation stratified by country and baseline CD4 cell count 
(<50 cells/μL, 50-199 cells/μL, or ≥200 cells/μL). 

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Randomization will be done at the baseline visit (date of the study treatment initiation). This study is 
open-label; therefore, all investigators, site pharmacists, study nurses and participants will be 
unmasked and aware of the treatment allocation throughout the study. 
3.3 
STUDY SCHEDULE 
 
Procedure 
Screening 
Visit 
Baseline 
Visit2 
Treatment Phase 
Follow 
Up/Early 
Termination 
Visit 
Day -28 to 
Enrolment1 
Week 
4 
(± 7 
days) 
Week 
8 
(± 7 
days) 
Week 
12 
(± 7 
days) 
Week 
24 
(± 7 
days) 
Week 
36 
(± 7 
days) 
Week 
48 
(± 7 
days) 
30 days 
following 
Week 48 
visit 
(± 7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment3 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and social history4 
X 
 
 
 
 
 
 
 
 
ECG5 
X 
 
 
 
 
 
 
 
 
HBV and HCV testing6 
X 
 
 
 
 
 
 
 
 
TB test7 
X 
 
 
 
 
 
 
 
 
Local Resistance testing8 
X 
 
 
 
 
 
 
 
X 
Randomisation 
 
X 
 
 
 
 
 
 
 
Symptom-directed physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis10 
 
X 
 
 
X 
X 
X 
X 
X 
Haematology (including CD4 & CD8 
testing)11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry12 (including urinary 
chemistry) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral load testing13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample collection for central resistance 
testing (deep sequencing)14 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life questionnaire (EuroQoL EQ-
5D-3L) 
 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Symptom Index questionnaire (HIV-
SI/SDM) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing of trial drugs15 
 
X 
 
 
X 
X 
X 
 
 
Adherence16 
 
 
 
 
X 
X 
X 
X 
 
Serum pregnancy test17 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test18 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (including height & 
weight)19 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Assessment sub notes 
Parameters/Notes 
1 
Screening visit 
The maximum time between screening visit and baseline visit is 28 days; however, participants 
should be invited for their baseline visit as soon as reasonably possible in order to start their 
treatment. 
Only the following laboratory assessments are required for screening and historic (up to 28 days 
old) tests results may be used for screening: 
 
HBV and HCV testing 
 
TB test 
 
CD4 & CD8 testing 
 
Platelet count testing 
 
Clinical chemistry (only creatinine, creatinine clearance, eGFR, potassium, sodium, 
ALT, AST is required) 
 
Viral load testing 
 
Resistance testing (the last resistance test carried out can be used) 
A serum pregnancy test is mandatory at the screening visit for women of child bearing potential 
2 
Baseline visit 
For baseline results, all screening tests carried out within 10 days before baseline can be used. 
This includes historic screening results, as long as 
they fall within the 10 day window before baseline. Screening data obtained more than 10 days 
from baseline, must be repeated at baseline. 
3 
Eligibility 
According to the inclusion/exclusion criteria. 
4 
Medical & 
social history 
Including: 
 
Recreational drug use 
 
Smoking history 
 
Alcohol intake 
 
Concomitant diseases 
 
Past & present medical history, including HIV- associated conditions 
 
Review of any medication taken within the last 30 days 
5 
ECG 
12-Lead ECG performed supine. If an ECG is not performed at screening, it must be performed 
by the time of the baseline visit. 
6 
HBV & HCV testing 
HBV antigen test and hepatitis C (HCV) antibodies test (if patient tests positive for HCV 
antibodies, test for HCV RNA, if positive and chronic for either HBV or HCV, add HBV DNA test at 
baseline visit). 
HBV test to be repeated in event of positive result. Participants with active HBV infection at 
study entry will be monitored throughout the study and additional HBV DNA tests performed at 
the Week 24 and 48 visits. For screening, test results 28 days prior to the screening visit can be 
used 
7 
TB Testing 
A TB test (IGRAs e.g. ELISPOT, QuantiFERON) will be performed in patients with expected latent 
TB at the screening visit. For screening, test results 28 days prior to the screening visit can be used. 
Patients can be randomised into the study without having the latent TB screening results available 
at randomisation 
A TB test can be performed at subsequent visits on the basis of clinical suspicion. 
8 
Resistance testing 
(performed locally) 
A local resistance test will be performed at the screening visit. This result is not required for 
eligibility or prior to randomisation. If a HIV resistance test was done previously and results are 
available, the last resistance test carried out shall be considered. 
An additional resistance test will be performed at the ETV for patients with virological failure or 
insufficient virological response. 
9 
Vital Signs 
(10 mins resting) 
Including: 
 
Pulse 
 
Blood pressure 
1 
0 
Urinalysis 
Including: 
 
Urinary creatinine* 
 
Urinary glucose (dipstick test sufficient)* 
 
Urinary proteins* 
 
Albumin (can be obtained from ‘spot’ urine test) 
 
Nitrites (dipstick test sufficient) * 
 
Albumin: Creatinine Ratio (ACR) and Protein: Creatinine Ratio (PCR) 
 
Urinary phosphate 
 
Beta-2 microglobulin 
 
Leukocytes (dipstick test sufficient) 

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* Assessments should be performed as per local site procedure; however, assessments marked 
with an asterisk are mandatory for the study at and after baseline. 
Haematology 
(non-
fasting) 
Including: 
 
Platelet count* 
 
RBC Count (indices MCV & MCH)* 
 
WBC count (absolute)* 
 
CD4 Count and %* 
 
CD8 Count and %* 
 
Haemoglobin* 
 
Haematocrit* 
11 
RBC Count indices: 
 
MCV 
 
MCH 
Automated WBC differentials: 
 
Neutrophils* 
 
Lymphocytes* 
 
Monocytes 
 
Eosinophils 
 
Basophils 
* Assessments should be performed as per local site procedure; however, assessments marked 
with an asterisk are mandatory for 
the study. 
Assessments that have been underlined are required at screening (results up to 28 days old can 
be used). 
 
Urea* 
 
Chloride* 
 
Alkaline phosphatase* 
 
Creatine phosphokinase* 
 
Creatinine* 
 
Calcium* 
 
Phosphate* 
 
Creatinine clearance, eGFR* 
12 
Clinical chemistry 
(non-fasting) 
(Calculations: Cockcroft-Gault (requires weight), MDRD, CX-Epi) 
 
Glucose* 
 
Total* and indirect bilirubin 
 
Potassium* 
 
Total protein* 
 
Sodium* 
 
ALT* 
 
AST* 
 
Albumin* 
 
Cholesterol* 
 
HDL* 
 
LDL* 
 
Triglycerides* 
* Assessments should be performed as per local site procedure; however, assessments marked 
with an asterisk are mandatory for the study at 
and after baseline. 
Assessments that have been underlined are required at screening (results up to 28 days old can 
be used). 
13 
Viral load testing 
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14 
Resistance testing for deep 
sequencing 
(sent to central laboratory) 
In addition to the resistance test performed locally, a resistance testing sample will be taken at 
the Baseline visit, each visit in the treatment phase (Week 4, 8, 12, 24, 36 and 48) and at the ETV 
(for patients with virological failure identified outside of a scheduled visit). 
All resistance testing samples for patients with virological failure will be sent to a central 
laboratory for next generation sequencing to look for low-level pre-existing resistance in cases 
of suspected resistance development. 
15 
Drug dispensing 
There will be four dispensations of the study medication to the patient (Baseline visit, Week 12, 
24 and 36). 
16 
Adherence 
Also performed at the ETV if required. 
17 
Serum pregnancy test 
For women of child bearing potential only (see Appendix 7 for definition). 
18 
Urine pregnancy test 
Dipstick and urine pregnancy test (WOCBP only - see Appendix 7 for definition). This is a 
mandatory assessment. If a urine pregnancy test is not 
possible, a serum pregnancy test can replace this. 
19 
Physical examination 
Weight is required at all visits, as detailed in the appendix 1, however height is only required at 
baseline. 
 
 

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4. SAMPLE SIZE CALCULATION 
In the ANRS 146 OPTIMAL trial [Levy et al.], of late presenters, the proportion of patients with severe 
morbidity (new adverse drug event (ADE), other HIV related diseases, serious non-AIDS events, IRIS 
and death) was estimated at 12.2% per year in the boosted PI arm. The virological failure was 
estimated at 20% at week 48 in the DRV/r group of the IMEA 040 DATA study (Slama L et al) that 
recruited a similar population. As a few subjects will meet more than one of these criteria, we assumed 
a cumulative probability of failure at 25% at 48 weeks in the PI regimen group.  
A total of 404 evaluable subjects, randomized in a 1:1 ratio to 2 treatment groups (202 subjects per 
treatment group), achieves at least 80% power to detect a non-inferiority margin of 1.606 in the 
hazard ratio, which corresponds to a 12% difference in the cumulative probability of failure rate 
between INI-based regimen group (37%) and PI-based regimen group (25%), with 97 events required. 
The sample size and power calculation assume that the cumulative probability of failure is 25% for the 
PI regimen group and 23% for the INI-based regimen group (i.e. the expected hazard ratio is 0.909), 
using a non-inferiority margin of 1.606 in hazard ratio and a two-sided 95% confidence interval (CI). 
The sample size and power calculation were made using the statistical software package nQuery 
Advanced, non-inferiority testing of two survival curves using cox regression module (Version 8.1.2.0).  
With an estimated ~7.5% drop off rate/year, we plan to enrol 220 subjects per group to ensure we 
have sufficient power for this per-protocol analysis.  
Superiority of INI-based regimen group versus PI-based regimen group will be evaluated after the non-
inferiority is established. With an ITT analysis, 440 subjects and 78 events, a two-sided log-rank test at 
an alpha level of 0.05 will achieve at least 80% power to detect a 50% reduction in hazard rate in INI-
based regimen (i.e. the hazard ratio is 0.5). A 50% reduction in hazard rate means that INI-based 
regimen could decrease the risk by 11.6% (25% for PI- vs 13.4% for INI- based regimen). 
5. GENERAL CONSIDERATIONS 
All continuous variables will be summarised using the following descriptive statistics: n (non-missing 
sample size), mean, standard deviation (SD), 1st quartile, median, 3rd quartile, maximum and 
minimum. The frequency and percentages (based on the non-missing sample size) of observed levels 
will be reported for all categorical variables. 
The number of participants and the flowchart of the study will be presented. The period of enrolment 
and the total number of participants screened to be included in the study will be presented. The 
number of ineligible participants and the total number of randomized participants will be presented. 

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The number of participants who never receive the study intervention will also be presented by 
treatment group and those who were included in the full analysis set and the safety analysis set will 
be presented. 
Baseline is considered as the day 1 visit and the baseline data is data collected just before intervention 
at day 1. 
5.1 
TIMING OF ANALYSES 
Before the final analysis is performed, the trial Statistician will write the statistical code needed to 
perform the statistical analyses required by the SAP. A temporary version of the trial database should 
be sent to the Trial Statistician for final SAP and code preparation. The code together with the 
temporary version of the trial database will result in a mock-up report. The Trial Statistician will review 
the mock-up report, and subsequently the SAP will be updated if needed before the final version is 
approved and signed-off. The final analysis will be performed after the database has been locked and 
cleaned and this analysis plan has been validated and signed. 
5.2 
ANALYSIS POPULATIONS 
For the purposes of analysis, the following analysis sets are defined. 
5.2.1 
Full Analysis Population 
Modified Intention-to-treat (mITT) analysis set:  all randomised participants who received at least one 
dose of study drug. Participants will be included in the analyses according to the planned randomised 
intervention. 
The following data points sets are defined:  
- 
DPS1:  All observed data will be included in the analysis set regardless of study intervention 
discontinuation and/or receipt of rescue therapy 
- 
DPS2: For participants who discontinue study intervention and/or receive rescue therapy, 
post-discontinuation or post-rescue observations will be excluded. 
The mITT and DPS1 will be used to estimate the primary endpoints and the all secondary endpoints. 
5.2.2 
Per Protocol Population 
The per-protocol (PP) population will include all participants from the mITT population, with the 
exception of those who did not meet the inclusion/exclusion criteria or who initially received 
treatment assigned to the other group. 
The PP and DPS2 will be used for sensitivity analyses of the primary endpoint. 
5.2.3 Safety Population 

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Safety analysis set: all participants who are exposed to a study intervention. Participants will be 
analysed according to the planned randomised intervention. 
The safety analysis set is used to analyse the endpoints and assessments related to safety. 
Safety analysis set and DPS1 will be used to present safety data. 
5.3 
HANDLING OF MISSING DATA 
The primary and all secondary end points will be analysed on a mITT basis.  
During the study, participants may be lost to follow-up, withdraw or drop out. A participant will be 
considered lost to follow-up if he/she is unreachable for at least two consecutive visits by the study 
site until the end of the study. And so, for these participants, observations will be censored from the 
date of last observation. 
In addition, for participants still being followed in the study but whose observation is missing at 
week 48 and at the 30-day visit after week 48, data will be censored at the last observation. 
Partial dates will be extrapolated. For example, all dates saved as NK/FEB/2020 will be recoded as 
15/FEB/2020 and those saved NK/NK/2020 will be recoded as 30/JUNE/2020. NK means not known. 
For the assessment of HIV RNA viral load reduction at week 12, we will use the last observation 
carried forward approach to fill in missing data at visit 12. 
For all continuous variables used as endpoint, if the value is missing at week 48 and the value at the 
30-day visit after week 48 is not missing, it will be used to replace the missing week 48 value 
whether or not the patient has been switched off the study drug. 
For participants who stop the study prematurely, if the Early Termination Visit (ETV) is performed, 
the value will be used to complete the nearest missing visit. 
For participants for whom the date of onset of the clinical event used as an endpoint is missing, the 
missing date of onset will be replaced by the event reporting date. 
For patients reported outcomes, we will used multiple imputation approach to fill in missing data. 
5.4 
INTERIM ANALYSIS  
No interim analysis for efficacy was planned. However, an independent data monitoring committee 
(DSMB) consisting of independent scientists not otherwise involved in the trial has been appointed 
and has reviewed the data regularly during the study for safety and scientific integrity and has made 
recommendations to the sponsor. 
However, in the event of external evidence of trial interventions, the sponsor may seek advice from 
the DSMB and the DSMB could recommend an interim efficacy analysis based on the observed data 
collected at that time to help make a recommendation. A two-sided Type-I error rate of 5% will be 
used because no formal interim analysis for efficacy is planned. 

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5.5 
MULTIPLE TESTING 
Because all subgroup analyses are designed to detect possible heterogeneity of the treatment effect 
across subgroups, and because they are exploratory and supportive, no adjustment for multiplicity is 
necessary. 
6. SUMMARY OF STUDY DATA 
All continuous variables will be summarised using the following descriptive statistics: n (non-missing 
sample size), mean, standard deviation (SD), 1st quartile, median, 3rd quartile, maximum and 
minimum. The frequency and percentages (based on the non-missing sample size) of observed levels 
will be reported for all categorical variables. 
The number of patients and the flowchart of the study will be presented. The period of enrolment and 
the total number of patients screened to be included in the study will be presented. The number of 
ineligible patients and the total number of randomised patients will be presented. The number of 
patients who never take the study treatment will also be presented by group and those who remained 
on the study treatment up to week 48 will be presented. 
6.1 
SUBJECT DISPOSITION 
The number of participants and the flowchart of the study will be presented as in the CONSORT 
flowchart (Figure 2). 
 
Figure 2: CONSORT flowchart  

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For the analysis, a summary table with the description of the number of included subjects, the number 
of randomized subjects, the number of subjects in whom the treatment was initiated, the number of 
subjects in whom the treatment was not initiated and reasons, the number of subjects who 
discontinued the study and reasons and when, the number of subjects analyzed, and the number of 
subjects excluded from the analysis and reasons, will be prepared by treatment group. The dates of 
the inclusion period will be reported as well as the date of the last follow-up visit. The median (IQR) 
duration of participation and the total number of person-years will also be reported. The person-year 
is the total sum of the number of years that each subject of the study population has been under 
observation. The duration of participation in years for each subject will be calculated by the difference 
between the date of the last observation and the date of randomization divided by 365.25. 
6.2 
PROTOCOL DEVIATIONS  
The following deviations are defined for the purpose of analysis:  
- 
Did not fulfil the eligibility criteria  
- 
Interruption of study treatment for >10% of total time on treatment 
- 
Received treatment from another randomisation group 
- 
Consent withdrawal  
- 
Lost to follow-up (at least 2 consecutive visits missed until the end of the study) 
- 
At least one missed follow-up visits for those not lost to follow-up 
At least one visit for which the viral load is missing for those for whom all visits have been madeA 
summary table by treatment group and overall with the number and percentage of subjects 
presenting deviations will be prepared for the subjects in the mITT population.  
6.3 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS  
The summary of the demographic and baseline characteristics will be performed on the mITT 
population. The data will be summarized overall and by randomisation arm (Integrase inhibitor (BIC) 
versus protease inhibitor (DRV/c)). Baseline data corresponds to all data collected prior to the 
initiation of the study interventions. 
6.3.1 Descriptive statistics  
Demographics and baseline characteristics will be summarized as follows:  
- 
For continuous variables: sample size, mean, standard deviation, median, interquartile range, 
minimum and maximum.  
- 
For categorical variables: sample size, proportion and number of patients in different 
categories.  
6.3.2 Baseline data  
The following demographic characteristics will be summarized by treatment group and overall:  

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- 
Age  
- 
Sex  
- 
Child bearing potential among Female 
- 
Participating country 
- 
Ethnicity (e.g White caucasian; White mixed; Asian, Black; Other) 
- 
Population group (AIDS with any CD4 cell count; Severe bacterial infection and CD4 cell count 
< 200; Asymptomatic with CD4 cell count < 100; Currently receiving treatment for an 
opportunistic infection) 
- 
Body weight and BMI  
- 
Systolic and diastolic Blood Pressure 
- 
Pulse rate 
- 
Alcohol intake (Does not drink alcohol; Drink alcohol) 
- 
Smokers (Never smoked; Current smoker; Ex-smoker) 
- 
Recreational drug use 
- 
Days from HIV diagnosis to treatment initiation 
- 
HIV RNA viral load, log10 copies/mL and in category (<100,000; 100,000-500,000; >500,000) 
- 
CD4+ count (cells/µL) and in category (<50; 50-199; ≥200) and CD4+ (%) 
- 
CD8+ count (cells/µL) and CD8+ (%) 
- 
CD4/CD8 ratio and in category (<0.10; 0.10-0.30; >0.30) 
- 
Positive HBV Antigen; Positive HCV antibody:  
- 
HCV RNA Viral load among those with Positive HCV antibody 
- 
Positive TB testing result 
- 
Red blood cells (10^12/L);  
- 
White blood cells (10^12/L) 
- 
Platelet counts (10^9/L) 
- 
Haemoglobin (g/dL) 
- 
Haematocrit (%) 
- 
MVC (fl) 
- 
MCH (pg) 
- 
Neutrophils (1012/L) 
- 
Lymphocytes (1012/L) 
- 
Monocytes (1012/L) 
- 
Eosinophils (1012/L) 
- 
Basophils (1012/L)Sodium (mmol/L) 
- 
Potassium (mmol/L) 
- 
Total Protein (mmol/L) 
- 
Total Bilirubin (µmol/L) 
- 
Indirect bilirubin (µmol/L) 
- 
ALT (U/L); AST (U/L)Albumin (g/L) 
- 
Creatinine (umol/L); Creatinine clearance (eGFR) (mL/min) 
- 
Alkaline phosphatase (U/L) 
- 
Creatine phosphokinase (U/L) 
- 
Calcium (mmol/L) 
- 
Phosphate (mmol/L) 
- 
Urea (mmol/L) 

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- 
Chloride (mmol/L) 
- 
Total cholesterol (mmol/L); HDL-cholesterol (mmol/L); LDL-cholesterol (mmol/L); Triglyceride 
(mmol/L);  
- 
Glucose (mmol/L) 
- 
Resistance mutations at baseline. Drugs resistance mutations will be identified from the 
Stanford drugs resistance interpretation algorithm (last version at the time of analysis). 
https://hivdb.stanford.edu/dr-summary/mut-scores/NRTI/; 
https://hivdb.stanford.edu/dr-summary/mut-scores/NNRTI/; https://hivdb.stanford.edu/dr-
summary/mut-scores/PI/; https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/. 
6.4 
STUDY TREATMENT COMPLIANCE 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each 
visit. Compliance rate for each participant will be estimated by the response of the following item: 
Thinking about the last week, how often has the subject taken their medication? The response is 
classified in 5 categories (All the time, Most of the time, About half of the time, Very few times, None). 
For participants who reported taking their medication “All the time” during the past week, if it is also 
indicated that they forgot to take their medication at least once since the last visit, they are 
downgraded to the "Most of the time" category. The compliance rate will be done at each visit. A bar 
plot will be presented. 
6.5 
STRATIFICATION FACTOR 
The stratification variable is consisted of two variables: participating country (7 countries: UK, Spain, 
France, Belgium, Germany, Ireland, and Italy) and baseline CD4 cell count (<50, 50-199, ≥200). Overall, 
21 strata will be considered. Based on the large number of strata, we anticipated some few 
participants in some strata. In country that will recruit fewer than 10 participants, we will group 
together some neighboring countries. In addition, with regard to CD4 cell count, we will group 
together participants whose value is between 50-199 and ≥200/µl to obtain 2 categories (<50 versus 
≥50/µl) because of the anticipated small number of participants in the latter category. These new 
variables will be used for adjustments. 
The number and proportion of participants in each stratum will be reported by treatment group and 
overall. The exact list of strata will also be presented. 
7. EFFICACY ANALYSES 
All the efficacy analyses of the primary and secondary endpoints will be conducted on the mITT 
population and a sensitivity analysis of the per-protocol population.  
Time-to-event methods, including Kaplan-Meier, Cox proportional hazard models, and Poisson 
regression models, will be used to account for all participants in the analysis. 

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7.1 
PRIMARY EFFICACY ANALYSIS 
Endpoint 
The primary endpoint is the first occurrence of any of the following components: 
1. Virological failure 
a) Insufficient virological response, either:  
a. HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or 
b. Viral load > 50 HIV-1 RNA copies/mL at week 48  
b) Viral rebound, which is subsequently confirmed at the following scheduled or 
unscheduled visit, defined as either: 
a. Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL  
b. Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose 
viral load has never been suppressed below 50 copies/mL 
2. Clinical events1 
a) Death related to HIV, AIDS, OI/severe BI or complications of therapy including IRIS 
b) Any new or recurrent AIDS defining event on, or after 28 days of therapy 
c) Any new serious non-AIDS defining event documented by the endpoint review 
committee (including severe BI, end stage liver disease, renal failure, cardiovascular 
event, and non-AIDS related malignant disease)  
d) Clinically relevant AEs of any grade or IRIS which require treatment interruption 
(lasting > 5 days) of INI or boosted PI therapy within the first 48 weeks after 
randomisation. Discontinuation of BIC or boosted DRV followed by (within 5 days) 
continuation with another INI or PI, respectively, is not considered as a strategy failure 
or endpoint. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with an event. Kaplan-Meier curves will also be plotted for the 
primary endpoint and its component. 
A table, listing for each participant any event, they may have had as well as the day from baseline to 
event onset, will be generated.  
Statistical methodology 
The proportion of patients with an event will be estimated using the Kaplan-Meier method. Episodes 
of clinical events diagnosed at baseline will not be considered as incident events in the study. For 
virological events evaluation data were censored at the time of treatment discontinuation. 
The follow-up will begin at baseline and continue until the week 48 visit, study discontinuation, loss 
to follow-up, or onset of the composite primary endpoint events; whichever occurs first. Participants 
lost to follow-up or who have discontinued the study when they are endpoint free at time of leaving 
the study will be censored at the date of last observation. 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
                                                 
 

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counts (<50/µL or ≥50/µL), as the sample size would not allow use of the stratification factors of 
randomisation (country and baseline CD4 in three categories (<50; 50-199; ≥200/µL)). An adjusted 
hazard ratio (HR) and the associated 95% Confidence Interval (CI) will be calculated. Separate analyses 
for each component of the primary endpoint will be done. All P-values will be two-tailed with a 
significant level at 5%. 
A sensitive analysis will be performed with the per-protocol population and DPS2. 
7.2 
 SECONDARY EFFICACY ANALYSES 
7.2.1 
Cumulative incidence of the composite primary endpoint 
Endpoint 
Cumulative incidence of the composite primary endpoint. All the observed events for each patient 
over the total duration of follow-up will be considered. Patients with multiple events on a given day 
will be considered as having one event on that day. For virological events only first episode was 
considered and data were censored at the time of treatment discontinuation. 
Descriptive statistics and graphical representation 
The cumulative incidence of the primary composite endpoint will be summarized with the total 
number of events, person-years, and the incidence rates per 100 person-years by treatment group 
(Integrase inhibitor versus Protease inhibitor). 
Statistical methodology 
In this analysis, the event is the sum of all episodes of the composite primary endpoint. For this 
analysis, the entire follow-up will be considered (i.e. follow-up will begin at baseline and continue until 
the 48-week visit, study discontinuation, loss to follow-up; whichever occurs first). All participants will 
be censored on the date of their last observation. 
The cumulative incidence of the composite primary endpoint will be estimated by the total number 
of events divided by the total number of person-years of observation. The person-year is the total sum 
of the number of years that each subject of the study population has been under observation. The 
number of years each subject would have been under observation will be calculated by the difference 
between the date of the last observation and the date of study treatment initiation plus one, divided 
by 365.25. 
The effect of study treatment will be assessed using a Poisson regression model adjusted for the 
stratification factor (country/group of neighbouring countries and baseline CD4 cell counts (<50 or 
≥50/µL). An adjusted incidence rate ratio (IRR) and the associated 95% CI will be calculated. 
All P-values will be two-tailed with a significant level at 5%. 
This analysis will only be performed if it is added additional information: i.e. if the number of 
cumulative episodes is greater than that of the first episode (with at least 10 additional events). 

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7.2.2 
HIV-RNA viral load <50 copies/mL at week 24, 36 and 48 
Endpoint 
The proportion of patients with HIV-RNA viral load <50 copies/mL at week 24, 36 and 48 using the 
snapshot approach. 
Virologic outcome will be determined by the last available measurement while the participant is on 
treatment and continues on trial within the time window. The time window for each timepoint is 
defined in Table A below.  
  
Table A:  Proposed Windows 
Visit 
Window 
(Through 
End-of-Study Week) 
Window (Days) 
24 
18-30 
127-210 
36 
30-42 
211-294 
48 
42-54 
295-378 
 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with an event. 
The proportion of patients with HIV-RNA viral load <50 copies/mL, HIV RNA viral load ≥50 copies/mL, 
discontinuation due to Adverse Event (AE/SAE), discontinuation due to other reasons or on study but 
missing data at analysis time point will be calculated. The evolution over time will be analysed 
graphically using trend analysis. 
HIV-RNA ≥ 50 copies/mL includes: patients who changed any component of background therapy to a 
new drug class, changed background components that were not permitted per protocol, or changed 
any background drug in the regimen because of lack of efficacy (perceived or documented) before 
Week 48; patients who discontinued study drug or study before Week 48 for lack or loss of efficacy 
and patients who are equal to or above 50 copies/mL in the 48-week window. 
AE/SAE includes: patients who discontinued because of adverse event (AE) or death at any time point 
from baseline through the time window if this resulted in no virologic data during the specified 
window.  
Other Reasons includes: withdrew consent, loss to follow-up, moved, among others. 
Statistical methodology 
The proportion of patients with HIV-RNA viral load <50 copies/ml, HIV-RNA viral load ≥50 copies/ml, 
discontinuation due to adverse event (AE/SAE), discontinuation due to other reasons or participating 
in the study but with missing data at the time of analysis will be calculated by dividing the number of 
participants with an event of interest by the total number of participants in the mITT population.  

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The effect of study treatment on the proportion of patients with HIV-RNA viral load <50 copies/ml at 
week 24, 36 and 48 will be assessed using a logistic regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
counts (<50 or ≥50/µL)). An adjusted odds ratio (OR) and the associated 95% Confidence Interval (CI) 
will be calculated.  
In addition, we will use Cochran-Mantel-Haenszel tests to assess the difference between treatments 
in the percentage of participants with HIV-RNA viral load <50 copies/ml at week 48 (ie, response rate 
in BIC group minus the response rate DRV/c group) adjusted for country/group of neighbouring 
countries and baseline CD4 cell counts (<50 or ≥50/µl). All P-values will be two-tailed with a significant 
level at 5%. 
7.2.3 
Genotypic resistance test among patients with virological failure 
Endpoint 
Number and percentage of patients with drugs resistance mutations among patients with virological 
failure. Drugs resistance mutations will be identified from the Stanford drugs resistance interpretation 
algorithm (last version at the time of analysis). 
https://hivdb.stanford.edu/dr-summary/mut-scores/NRTI/ 
https://hivdb.stanford.edu/dr-summary/mut-scores/NNRTI/ 
https://hivdb.stanford.edu/dr-summary/mut-scores/PI/ 
https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/.  
 
Descriptive statistics and graphical representation 
The analyses will be performed on patients with virological failure in the mITT population for whom 
genotypic sequences have been obtained. Data will be summarized with the number and percentage 
of participants with drugs resistance mutations. 
Statistical methodology 
The proportion of participants with drugs resistance mutations will be calculated by dividing the 
number of participants with drug resistance mutations by the total number of participants with 
virological failure for whom genotypic sequences have been obtained. The frequency of each 
resistance mutation will be indicated. 
Fisher’s exact test will be used to compare the presence of at least one drug resistance mutation 
between the 2 groups. 
7.2.4 
Time to reach CD4 cell count >200/µl 
Endpoint 
The median time to reach CD4 cell count >200/µl. 
Descriptive statistics and graphical representation 

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The analyses will be performed with the mITT population with CD4≤200/µL at baseline and DPS1. Data 
will be summarized with the number and percentage of participants achieving a CD4 cell count >200/µl 
and the median (95% CI) time to reach a CD4 cell count >200/µl. Kaplan-Meier curves will also be 
plotted. 
Statistical methodology 
Kaplan-Meier method will be used to estimate the proportion of participants achieving a CD4 cell 
count >200/µl and the median time to achieve a CD4 cell count >200/µl. The follow-up will begin at 
baseline (date of study treatment initiation) and continue until the week 48 visit, study 
discontinuation, loss to follow-up, or onset of a CD4 cell count >200/µl; whichever occurs first. 
Participants lost to follow-up or who have discontinued the study with a CD4≤ 200/µl will be censored 
at the date of last observation. 
The effect of study treatment on the time to reach a CD4 >200/µl will be assessed using Cox regression 
model with adjustments for stratification factor (country/group of neighbouring countries and 
baseline CD4 cell counts (<50 or ≥50/µL)). An adjusted HR and the associated 95% CI will be calculated. 
All P-values will be two-tailed with a significant level at 5%. 
7.2.5 
CD4 cell count <200/µl and <350 at week 4, 8, 12, 24, 36 and 48 
Endpoints 
- The proportion of patients with CD4 cell count <200/µl at week 4, 8, 12, 24, 36 and 48  
- The proportion of patients with CD4 cell count <350/µl at week 4, 8, 12, 24, 36 and 48 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants CD4 cell count <200/µl and <350/µl. The evolution over time 
will be analysed graphically using trend analysis. 
Statistical methodology 
The evolution of the proportion of participants with CD4<200/µl and <350/µl over time will be 
compared between the 2 treatment groups (DRV/c versus BIC) using a Generalized Estimating 
Equation (GEE) models with independent covariance structure, binomial distribution and log link, to 
estimate the relative risk. The models will include treatment group, time, and interaction between 
treatment group and time. Time will be modelled as categorical variable. A relative risk (RR) and the 
associated 95% CI will be calculated. All P-values will be two-tailed with a significant level at 5%. 
7.2.6 
Change in CD4/CD8 ratio from baseline to week 48  
Endpoints 
The change in CD4/CD8 ratio from baseline to week 48. 
Descriptive statistics and graphical representation 

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The analyses will be performed with the mITT population and DPS1. Data will be summarized in tables 
by mean and standard error. The evolution of CD4/CD8 ratio will be described by boxplots for each 
treatment group at each time point. The number of participants with data available at each time point 
will also be reported. 
Statistical methodology 
The mean change in CD4/CD8 ratio from baseline to week 48 will be compared between the 2 
treatment groups using a mixed model with random intercept and slope and spatial power covariance 
structure due to unequal time intervals between visits. The models included treatment group, time, 
and interaction between treatment group and time. Time was modelled as a categorical variable. All 
P-values will be two-tailed with a significant level at 5%. 
7.2.7 
Incidence of IRIS 
Endpoints 
The endpoint is the first occurrence of IRIS over the 48-week visit. IRIS diagnosed at baseline will not 
be considered in the analysis. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with an IRIS. Kaplan-Meier curves will also be plotted. 
Statistical methodology 
The incidence of IRIS will be estimated with the Kaplan-Meier method. The follow-up will begin at 
baseline (date of study treatment initiation) and continue until the week 48 visit, study discontinuation 
or death, loss to follow-up, or onset of IRIS; whichever occurs first. 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
counts (<50 or ≥50/µL)). An adjusted hazard ratio (HR) and the associated 95% Confidence Interval 
(CI) will be calculated. 
7.2.8 
Incidence of hospitalisation 
Endpoints 
The endpoint is the first occurrence of hospitalisation over the 48-week visit. Hospitalisation occurring 
before the initiation of study treatment (baseline) will not be considered in the analysis. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of hospitalised participants. The Kaplan-Meier curves will also be plotted. 
Statistical methodology 

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The incidence of hospitalisation will be estimated with the Kaplan-Meier method. The follow-up will 
begin at baseline (date of study treatment initiation) and continue until the week 48 visit, study 
discontinuation or death, loss to follow-up, or hospitalisation; whichever occurs first. 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
counts (<50 or ≥50/µL)). An adjusted hazard ratio (HR) and the associated 95% Confidence Interval 
(CI) will be calculated. 
7.2.9 
Duration of hospitalisation 
Endpoints 
The endpoint is the duration of the hospitalisation during the 48-week period. The event of interest is 
the occurrence of last discharge (end date of hospitalisation) from hospital. A transfer to a palliative 
care will not be considered a discharge. Hospitalisation occurring before the initiation of study 
treatment (baseline) will not be considered in the analysis. 
Descriptive statistics and graphical representation 
The analyses will be performed with the hospitalised patients in the mITT population and DPS1. Data 
will be summarized with the number and percentage of participants discharged from hospital, and the 
median (95% CI) duration of hospitalisation. The Kaplan-Meier curves will also be plotted. 
Statistical methodology 
The proportion of participants discharged from hospital and the median duration of hospitalisation 
will be estimated using the Kaplan-Meier method. Follow-up will begin at the date of first 
hospitalisation and continue until the week 48 visit, study discontinuation or death, loss to follow-up, 
or last discharge from hospital; whichever occurs first. 
The effect of study treatment will be assessed using Cox regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
counts (<50 or ≥50/µL)). An adjusted hazard ratio (HR) and the associated 95% Confidence Interval 
(CI) will be calculated. 
7.2.10 Rate of relapse recurrence of specific opportunistic infection or bacterial infection 
through week 48 
Endpoint 
The endpoint is the rate of relapse/recurrence of specific opportunistic infection or bacterial infection 
through week 48. 
Descriptive statistics and graphical representation 

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The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with relapse/recurrence of specific opportunistic infection or 
bacterial infection through week 48. 
Statistical methodology 
The rate of relapse/recurrence will be estimated by the number of patients with relapse/recurrence 
divided by the total number patients in ITT population.  
The effect of study treatment on the rate of relapse/recurrence of specific opportunistic infection or 
bacterial infection at week 48 will be assessed using a logistic regression model with treatment group 
and adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 
cell counts (<50 or ≥50/µL)). An adjusted odds ratio (OR) and the associated 95% Confidence Interval 
(CI) will be calculated. 
8. SAFETY ANALYSES 
Endpoints  
Safety endpoints include the following endpoints:  
- 
Cumulative incidence of any adverse events (AEs: grade ≥2), separately grade 2, 3 and 4 AE  
- 
Cumulative incidence grade 3 or AEs 
- 
Cumulative incidence of drug-related AEs (all grade)  
- 
Cumulative incidence of drug-related grade 3 and 4 AEs 
- 
Cumulative incidence of serious adverse events (SAE)  
- 
Cumulative incidence of AE leading to study/treatment  
- 
Cumulative incidence of laboratory toxicities 
- 
Death 
Participants with multiple adverse events on a given day will be considered as having one adverse 
event on that day. Adverse events occurring before the initiation of study treatment (baseline) will 
not be considered in the analysis. 
Descriptive statistics and graphical representation 
All analyses on safety endpoints will be performed on the Safety analysis set. All observed data will be 
included in the analysis set.  
Any AE (grade ≥2), grade 3 or 4 AE, SAE, drug-related SAE, grade  2, 3 and 4 AEs, drug-related grade 
3/4 AE, drug-related AEs (all grade), discontinuation of study/treatment due AEs, laboratory toxicities 
and death will be summarized with the total number of events, number and percentage of participants 
with at least one event and the incidence rates per 100 person-years of these events by treatment 
group (BIC versus DRV/c). The most frequent drug-related grade 3 or 4 AEs will be reported. 
Statistical methodology  
The incidence rates of each endpoint of interest will be calculated by the total number of events from 
baseline to week 48 visit divided by the total number of person-years. In this analysis, the entire 

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follow-up will be considered (i.e. follow-up will begin at baseline and continue until the week 48 visit, 
study discontinuation or death, loss to follow-up; whichever occurs first). The duration in years of 
participation for each subject will be calculated by the difference between the date of the last 
observation and the date of date of study treatment initiation plus one, divided by 365.25. The person-
years is the total sum of the number of years that each member of a study population has been under 
observation. 
The incidence rates of each endpoint will be compared between the treatment groups (BIC versus 
DRV/c) with a Poisson regression model adjusted for stratification factor (country/group of 
neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL)). The incidence rates ratio and 
the associated 95% confidence interval will be calculated. All P-values will be two-tailed with a 
significant level at 5%. 
9. SUBGROUP ANALYSES 
Subgroup analyses for the composite primary endpoints will be performed to assess the consistency 
of the effect of study treatment across the subgroups. The analysis will be performed with the mITT 
population. The following baseline variables will be studied (continuous variables will be categorized 
into terciles):  
- 
age at inclusion (categorized into terciles)  
- 
country 
- 
group of neighbouring countries  
- 
baseline CD4 cell counts (<50 or 50-199 or ≥200/µL) 
- 
baseline CD4 cell counts (<50 or ≥50/µL) 
- 
gender 
- 
transmission group 
- 
ethnic group 
- 
baseline viral load (<100,000, 100,000-500,000, >500,000) 
- 
Current smoker (no or yes) 
- 
adherence (take medication all the time versus not at all) 
If the number of participants is too small (less than 10) within a subgroup, then the subgroup 
categories may be redefined before locking the database. A forest plot will display confidence intervals 
across subgroups. 
We will use a Cox proportional hazard model to calculate the hazard ratio between BIC and DRV/c of 
the incidence of the first episode of the composite primary endpoint event in each subpopulation, 
without adjustments for stratification factors. The heterogeneity of the effect of BIC and DRV/c within 
subgroups will be assessed by including terms for interactions between treatment group and subgroup 
variables in a Cox proportional hazard model. 
10. OTHER ANALYSES 

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10.1 
OTHER SECONDARY ENDPOINTS 
10.1.1 ART and/or opportunistic infection/bacterial infection treatment changes and/or dose 
modifications due to toxicities and/or DDI with ART, and/or IRIS through week 48 
Endpoint 
The endpoint is the proportion of patients with ART treatment changes and/or dose modifications 
due to toxicities and/or DDI with ART, and/or IRIS through week 48. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarised with 
the number and percentage of participants with ART or OI/BI treatment changes or dose 
modifications due to toxicities and DDI and IRIS through week 48. The list of patients with the event 
of interest will be reported in a table, including the previous and the current treatment, start date, 
end date and the reason for change. 
Statistical methodology  
The percentage of patients with ART n treatment changes due to toxicities and/or DDI with ART, 
and/or IRIS will be estimated by the number of patients with the event of interest divided by the total 
number patients in ITT population. The effect of study treatment on the proportion of patients with 
ART treatment changes due to toxicities and/or DDI with ART, and/or IRIS at week 48 will be assessed 
using a logistic regression model with treatment group and adjustments for stratification factor 
(country/group of neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL)). An adjusted 
odds ratio (OR) and the associated 95% Confidence Interval (CI) will be calculated. Similar analyses will 
also be performed separately for each component (toxicities, DDI, and IRIS). If no events were 
observed in a group, the comparison will be made using Fisher's exact test. 
10.1.2 Health care resource use, through week 48 
Endpoint 
The endpoint is the proportion of patients with health care resource use, through week 48. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarised with 
the number and percentage of participants with health care resource use, including total inpatient 
days and emergency room visits through week 48.  
Statistical methodology  
The percentage of patients with health care resource use, including total inpatient days and 
emergency room visits will be estimated by the number of patients with the event of interest divided 
by the total number patients in ITT population.  

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The effect of study treatment on the proportion of patients with health care resource use, including 
total inpatient days and emergency room visits at week 48 will be assessed using a logistic regression 
model with treatment group and adjustments for stratification factor (country/group of neighbouring 
countries and baseline CD4 cell counts (<50 or ≥50/µL)). An adjusted odds ratio (OR) and the 
associated 95% Confidence Interval (CI) will be calculated. 
10.1.3 Quality of life (EQ-5D-3L questionnaire) and HIV Symptoms index 
Endpoints 
The endpoints are: 
- 
Change from baseline in health status score ranging from 0 to 100 (100 being best quality of 
life) and in each of the 5 dimensions of the EQ-5D-3L quality of life questionnaires (mobility, 
self- care, usual activities, pain/discomfort and anxiety/depression). Each dimension has 3 
levels: 1=no problems, 2=some problems, and 3=extreme problems. 
- 
Change from baseline in HIV symptoms index score over time. HIV Symptoms Index 
questionnaire is consisted of 20 selected symptoms. Each symptom has 5 levels: 0=I do not 
have this symptom 1=It doesn't bother me 2=It bothers me a little 3=It bothers me 4=It 
bothers me a lot. The HIV Symptom Index score is the sum of frequency ratings for the 20 
selected symptoms; the score could range from 0 to 80. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population who complete the baseline questionnaire 
and least one of the follow-up questionnaires. 
Data for health status score and HIV Symptoms index will be summarised by mean and standard error. 
The evolution of health status score and HIV Symptoms index will be described by boxplots for each 
treatment group at each time point.  
Data for the 5 dimensions will be summarised with number and percentages per class and Bar plotted 
will also be generated for each of the 5 dimensions. 
The number of participants with data available at each time point will also be reported. 
Statistical methodology  
The changes from baseline in health status score will be compared between the two treatment groups 
using mixed models for repeated measures with random intercept and slope and spatial power 
covariance structure due to unequal time intervals between visits, adjusted for country/group of 
neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL). The model will include treatment 
group, time, interaction between treatment group and time, country/group of neighbouring countries 
and baseline CD4 cell counts (<50 or ≥50/µL). Time will be modelled as categorical variables.  

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The distribution of each of the 5 dimensions (mobility, self- care, usual activities, pain/discomfort and 
anxiety/depression), will be compared between the two treatment groups at each timepoint using 
Chisquare test 
The changes from baseline in Symptom index score will be compared between the two treatment 
groups using mixed models for repeated measures with random intercept and slope and spatial power 
covariance structure due to unequal time intervals between visits, adjusted for country/group of 
neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL). The model will include treatment 
group, time, interaction between treatment group and time, country/group of neighbouring countries 
and baseline CD4 cell counts (<50 or ≥50/µL). Time will be modelled as categorical variables. All p-
values will be two-tailed, with a significant level of 0.05.  
 
10.1.4 discontinuation or modification of study medication due to insufficient virological 
response or resistance mutation development before week 48 
Endpoints 
The endpoint is the proportion of patients with discontinuation or modification of study medication 
due to insufficient virological response or resistance mutation development before week 48. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarised with 
the number and percentage of participants with discontinuation or modification of study medication 
due to insufficient virological response or resistance mutation development through week 48. The 
list of patients with the event of interest will be reported in a table, including the reasons for 
discontinuation or modification of study medication. 
Statistical methodology  
The percentage of patients with discontinuation or modification of study medication due to 
insufficient virological response or resistance mutation development will be estimated by the number 
of patients with the event of interest divided by the total number patients in ITT population.  
The effect of study treatment on the proportion of patients with discontinuation or modification of 
study medication due to insufficient virological response or resistance mutation development through 
week 48 will be assessed using a logistic regression model with treatment group and adjustments for 
stratification factor (country/group of neighbouring countries and baseline CD4 cell counts (<50 or 
≥50/µL)). An adjusted odds ratio (OR) and the associated 95% Confidence Interval (CI) will be 
calculated. 

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The analyses will also be performed separately for each component of the endpoint (insufficient 
virological response and resistance mutation development). If no events were observed in a group, 
the comparison will be made using Fisher's exact test. 
 
10.1.5 Adherence to study medication over time 
Endpoints 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each 
visit. Compliance rate for each participant will be estimated by the response of the following item: 
Thinking about the last week, how often has the subject taken their medication? The response is 
classified in 5 categories (All the time, Most of the time, About half of the time, Very few times, 
None).  
Descriptive statistics and graphical representation 
Analyses will be performed with the mITT population for which data are available at each time point. 
The data will be summarized by the number and percentage of participants per class at each time 
point. A bar chart will be presented.  
Statistical methodology  
The analysis will be descriptive and no inference will be made. 
 
10.1.6 Change from baseline in plasma and urine laboratory parameters 
Endpoints 
The endpoints are the change from baseline plasma and urine laboratory parameters 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DSP1. 
Data will be summarised by mean and standard error. The evolution will be described by boxplots for 
each treatment group at each time point. 
Statistical methodology  
The changes from baseline in haematology, chemistry, lipid and glycaemia will be compared between 
the two treatment groups using mixed models for repeated measures with random intercept and 
slope and spatial power covariance structure due to unequal time intervals between visits, adjusted 
for country/group of neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL). The model 
will include treatment group, time, interaction between treatment group and time, country/group of 
neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL). Time will be modelled as 
categorical variables.  
All p-values will be two-tailed, with a significant level of 0.05.  

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10.2 
EXPLANATORY ENDPOINTS 
10.2.1 Mutations detected by deep sequencing compared with those detected by population 
sequencing 
Endpoint 
The endpoint is the proportion of patients for whom there is a difference in the list of mutations 
(Stanford list last available version) detected by deep sequencing compared with those detected by 
population sequencing. 
Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with difference in the list of mutations detected by deep 
sequencing compared with those detected by population sequencing. 
Statistical methodology 
The proportion of patients with difference in the list of mutations detected by deep sequencing 
compared with those detected by population sequencing will be estimated by dividing the number of 
participants with difference in the list of mutations detected by deep sequencing compared with those 
detected by population sequencing by the total number of participants in the mITT population.  
The effect of study treatment on the proportion patients with difference in the list of mutations 
detected by deep sequencing compared with those detected by population sequencing will be 
assessed using a logistic regression model with treatment group and adjustments for stratification 
factor (country/group of neighbouring countries and baseline CD4 cell counts (<50 or ≥50/µL)). An 
adjusted odds ratio (OR) and the associated 95% Confidence Interval (CI) will be calculated. 
10.2.2 Proportion of patients with HIV RNA viral load <50 copies/mL at week 4, 8, and 12 
Endpoint 
The endpoint is the proportion of patients with HIV-RNA viral load <50 copies/mL at week 4, 8 and 12 
using the snapshot approach. 
Virologic outcome will be determined by the last available measurement while the participant is on 
treatment and continues on trial within the time window. The time window for each timepoint is 
defined in Table B below.  
 
Table B:  Proposed Windows 
Visit 
Window 
(Through 
End-of-Study Week) 
Window (Days) 
4 
2-6 
15-42 
8 
6-10 
43-70 
12 
10-14 
71-98 
 

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Descriptive statistics and graphical representation 
The analyses will be performed with the mITT population and DPS1. Data will be summarized with the 
number and percentage of participants with an event. 
Statistical methodology 
The proportion of patients with HIV-RNA viral load <50 copies/mL will be estimated by dividing the 
number of participants with HIV-RNA viral load <50 copies/mL by the total number of participants in 
the mITT population.  
The effect of study treatment on the proportion patients with HIV-RNA viral load <50 copies/ml at 
week 4, 8, and 12 will be assessed using a logistic regression model with treatment group and 
adjustments for stratification factor (country/group of neighbouring countries and baseline CD4 cell 
counts (<50 or ≥50/µL)). An adjusted odds ratio (OR) and the associated 95% Confidence Interval (CI) 
will be calculated. 
 
10.2.3 Evolution of HIV RNA in individuals with viral load >50 copies/mL at week 48 
Endpoint 
The endpoint is the evolution of HIV RNA between week 48 and week 52 in individuals with viral load 
>50 copies/mL at week 48. 
Descriptive statistics and graphical representation 
Analyses will be performed in participants with HIV RNA viral load >50 copies/mL at week 48. Data will 
be summarized for each treatment group: (i) the number of participants with 50-200 HIV RNA at week 
48 and a viral load increasing by >200 copies/mL, remaining at 50-200 copies/mL or decreasing to <50 
copies/mL at week 52. (ii) the number of participants with >200 HIV RNA at week 48 and a viral load 
remaining at >200 copies/mL, decreasing to 50-200 copies/mL or decreasing to <50 copies/mL at week 
52. The evolution between week 48 and 52 will be analysed graphically using trend analysis. 
Statistical methodology 
A descriptive analysis will be carried out and no statistical inferences will be made. 
 
1. REPORTING CONVENTIONS 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 

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Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) 
will be reported to 3 significant figures.  
2. STATISTICAL SOFTWARE  
Statistical analyses will be performed using SAS® version 9.4 (SAS Institute Inc., Cary, NC, USA). Stata 
version 15.0 (StataCorp, College Station, TX, USA) will be used for graphical representation of 
selected analyses. 
 

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3. REFERENCES 
 
Antinori, A. et al. (2011) ‘Late presentation of HIV infection: A consensus definition’, HIV Medicine, 12(1), pp. 61–64. 
doi: 10.1111/j.1468-1293.2010.00857.x. 
 
Blanc, F. X. et al. (2011) ‘Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis’, New 
England Journal of Medicine, 365(16), pp. 1471–1481. doi: 10.1056/NEJMoa1013911. 
 
Camoni, L. et al. (2013) ‘Late presenters among persons with a new HIV diagnosis in Italy and the regional 
representatives 
of 
the 
HIV 
Surveillance 
System’, 
BMC 
Public 
Health, 
13. 
Available 
at: 
http://www.biomedcentral.com/1471-2458/13/281. 
 
DeJesus, E. et al. (2012) ‘Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus 
ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of 
HIV-1 infection: A randomised, double-’, The Lancet. Elsevier Ltd, 379(9835), pp. 2429–2438. doi: 10.1016/S0140-
6736(12)60918-0. 
 
Demarest, J. et al. (2018) ‘Short Communication: Dolutegravir-Based Regimens Are Active in Integrase Strand Transfer 
Inhibitor-Naive Patients with Nucleoside Reverse Transcriptase Inhibitor Resistance’, AIDS Research and Human 
Retroviruses, 34(4), pp. 343–346. doi: 10.1089/aid.2017.0184. 
 
Gallant, J. et al. (2017) ‘A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, 
vs ABC/DTG/3TC in treatment-naïve adults at week 48’, IAS2017, p. 105. 
 
Hill, A. M. et al. (2018) ‘Risks of cardiovascular or central nervous system adverse events and immune reconstitution 
inflammatory syndrome, for dolutegravir versus other antiretrovirals: Meta-analysis of randomized trials’, Current 
Opinion in HIV and AIDS, pp. 102–111. doi: 10.1097/COH.0000000000000445. 
 
I.E.A.Wijting et al. (2017) ‘Integrase inhibitors are an independent risk factor for IRIS: An athena cohort study’, Topics in 
Antiviral 
Medicine, 
25(1), 
p. 
313s. 
Available 
at: 
http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L616685950%0Ahttp://sfx.library.u
u.nl/utrecht?sid=EMBASE&issn=21615853&id=doi:&atitle=Integrase+inhibitors+are+an+independent+risk+factor+for
+IRIS%3A+An+athena+cohort+study&stitle=To. 
 
M., D. et al. (2017) ‘Initiation of ART based on integrase inhibitors increases the risk of IRIS’, Topics in Antiviral Medicine, 
25(1), 
pp. 
313s-314s. 
Available 
at: 
http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L616685962. 
 
Montlahuc, C. et al. (2013) ‘Impact of late presentation on the risk of death among HIV-infected people in France (2003-
2009)’, Journal of Acquired Immune Deficiency Syndromes, 64(2), pp. 197–203. doi: 10.1097/QAI.0b013e31829cfbfa. 
 
Mussini, C. et al. (2008) ‘Patients presenting with AIDS in the HAART era: A collaborative cohort analysis’, AIDS, 22(18), 
pp. 2461–2469. doi: 10.1097/QAD.0b013e328314b5f1. 
 
P.E. Sax et al. (2017) ‘Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-
dose combination (B/F/TAF) vs dolutegravir (DTG) + F/TAF in treatment-naïve HIV-1 positive adults: week 48 results’, 
IAS2017, p. 201. 
 
Psichogiou, M. et al. (2017) ‘Integrase Strand Transfer Inhibitors and the Emergence of Immune Reconstitution 
Inflammatory Syndrome (IRIS)’, Current HIV Research, 15(6), pp. 405–410. doi: 10.2174/1570162x15666171122155708. 
 
Raffetti, E. et al. (2016) ‘The risk of late or advanced presentation of HIV infected patients is still high, associated factors 
evolve but impact on overall mortality is vanishing over calendar years: Results from the Italian MASTER Cohort’, BMC 
Public Health. BMC Public Health, 16(1). doi: 10.1186/s12889-016-3477-z. 
 
Raffi, F. et al. (2013) ‘Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with’, Lancet (London, 
England). Elsevier Ltd, 381(9868), pp. 735–743. doi: 10.1016/S0140-6736(12)61853-4. 
 
Salim S. Abdool Karim, M.B., Ch.B., Ph.D., Kogieleum Naidoo, M.B., Ch.B., Anneke Grobler, M.Sc., Nesri Padayatchi, M.B., 
Ch.B., Cheryl Baxter, M.Sc., Andrew L. Gray, M.Sc.(Pharm.), Tanuja Gengiah, M.Clin.Pharm., M.S.(Epi.), Santhanalakshmi 
Gengiah, M. A. (Res. P. . and Anushka Naidoo, M.Med.Sci.(Pharm.), Niraksha Jithoo, M.B., Ch.B., Gonasagrie Nair, M.B., 
Ch.B., M.P.H., Wafaa M. El-Sadr, M.D., M.P.H., Gerald Friedland, M.D., and Quarraisha Abdool Karim, P. . (2011) 
‘Integration of Antiretroviral Therapy with Tuberculosis Treatment’, pp. 1492–1501. 
 
Sobrino-Vegas, P. et al. (2012) ‘Educational gradient in HIV diagnosis delay, mortality, antiretroviral treatment initiation 
and response in a country with universal health care’, Antiviral Therapy, 17(1), pp. 1–8. doi: 10.3851/IMP1939. 
 
Walmsley, S. L. et al. (2013) ‘Dolutegravir plus Abacavir-Lamivudine for the treatment of HIV-1 infection’, New England 
Journal of Medicine, 369(19), pp. 1807–1818. doi: 10.1056/NEJMoa1215541. 
 
Zolopa, A. R. et al. (2009) ‘Early antiretroviral therapy reduces AIDS progression/death in individuals with acute 
opportunistic infections: A multicenter randomized strategy trial’, PLoS ONE, 4(5). doi: 10.1371/journal.pone.0005575. 

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4.  LISTING OF TABLES AND FIGURES 
TABLE 1. BASELINE CHARACTERISTICS 
  
Integrase inhibitor 
(N=XXX) 
Protease inhibitor 
(N=XXX) 
Total 
(N=XXX) 
Age (years), median (IQR) 
 
 
 
Gender 
 
 
 
Male 
 
 
 
Female 
 
 
 
Child bearing potential 
 
 
 
Ethnicity 
 
 
 
White caucasian 
 
 
 
White mixed 
 
 
 
Asian 
 
 
 
Black 
 
 
 
African 
 
 
 
Caribbean 
 
 
 
Other 
 
 
 
Prior AIDS-defining event 
 
 
 
No 
 
 
 
Yes 
 
 
 
Days from HIV diagnosis to treatment initiation, 
median (IQR) 
 
 
 
HIV RNA viral load, log10 copies/mL, median (IQR) 
 
 
 
<100,000 
 
 
 
100,000 – 500,000 
 
 
 
>500,000 
 
 
 
CD4+ count (cells/µL) 
 
 
 
<50 
 
 
 
50 – 199 
 
 
 
≥200 
 
 
 
CD4+ (%) 
 
 
 
CD8+ count (cells/µL), median (IQR) 
 
 
 
CD8+ (%) 
 
 
 
CD4/CD8 ratio, median (IQR) 
 
 
 
<0.10 
 
 
 
0.10 – 0.30 
 
 
 
>0.30 
 
 
 
Alcohol intake 
 
 
 
Does not drink alcohol 
 
 
 
Drinks alcohol 
 
 
 
Current Smokers 
 
 
 
Never smoked 
 
 
 
Current smoker 
 
 
 
Ex smoker 
 
 
 
Recreational drug use 
 
 
 
Positive HBV Antigen 
 
 
 
Positive HCV antibody 
 
 
 
HCV RNA VL, median (IQR) 
 
 
 
Positive TB testing result 
 
 
 
Body mass index (BMI, kg/m2) 
 
 
 
Weight, Kg 
 
 
 
Systolic Blood Pressure (mmHg) 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
Pulse rate 
 
 
 
Red blood cells (10^12/L) 
 
 
 
White blood cells (10^12/L) 
 
 
 
Platelet counts (10^9/L) 
 
 
 
Haemoglobin (g/dL) 
 
 
 

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Hematocrit (%) 
 
 
 
MVC (fl) 
 
 
 
MCH (pg) 
 
 
 
Neutrophils (1012/L) 
 
 
 
Lymphocytes (1012/L) 
 
 
 
Monocytes (1012/L) 
 
 
 
Eosinophils (1012/L) 
 
 
 
Basophils (1012/L) 
 
 
 
Potassium (mmol/L) 
 
 
 
Total Protein (mmol/L) 
 
 
 
Sodium (mmol/L) 
 
 
 
ALT (U/L) 
 
 
 
Total Bilirubin (umol/L) 
 
 
 
Indirect bilirubin (umol/L) 
 
 
 
ALT (U/L) ; AST (U/L) 
 
 
 
Albumin (g/L) 
 
 
 
Creatinine (umol/L) 
 
 
 
Creatinine clearance (eGFR) (mL/min) 
 
 
 
Alkaline phosphatase (U/L) 
 
 
 
Creatinine phosphokinase (U/L) 
 
 
 
Calcium (mmol/L) 
 
 
 
Urea (mmol/L) 
 
 
 
Phosphate (mmol/L) 
 
 
 
Chloride (mmol/L) 
 
 
 
Fasting plasma lipids and glucose 
 
 
 
Total cholesterol (mmol/L)  
 
 
 
HDL-cholesterol (mmol/L)  
 
 
 
LDL-cholesterol (mmol/L)  
 
 
 
Triglyceride (mmol/L)  
 
 
 
Glucose (mmol/L) 
 
 
 
 

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TABLE 1B: BASELINE RESISTANCE MUTATIONS 
Characteristic 
  
Integrase 
inhibitor 
(N=XXX) 
Protease 
inhibitor 
(N=XXX) 
Total (N=XXX) 
Resistance testing, n (%) 
    
  
  
  
No  
 
 
  
Yes  
 
 
Resistance mutations to ARV class 
   
 
 
  
NRTI  
 
 
  
NNRTI  
 
 
 
PI  
 
 
 
INI  
 
 
NRTI mutations (Stanford algorthm last version) 
   
 
 
  
  
 
 
  
  
 
 
NNRTI mutations (Stanford algorthm last version) 
   
 
 
  
  
 
 
  
  
 
 
PI mutations (Stanford algorthm last version) 
  
 
 
 
  
 
 
  
  
 
 
 INI mutations (Stanford algorthm last version) 
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
Resistance to DRV (stanford algorithm) 
  
  
  
  
  
Resistance 
 
 
 
  
Intermediate 
 
 
 
  
Sensitive 
 
 
 
Resistance to BIC (stanford algorithm) 
  
 
 
 
  
Resistance 
 
 
 
  
Intermediate 
 
 
 
  
Sensitive 
 
 
 
Resistance to 3TC/FTC (stanford algorithm) 
  
 
 
 
  
Resistance 
 
 
 
  
Intermediate 
 
 
 
  
Sensitive 
 
 
 
Resistance to TAF (stanford algorithm) 
  
 
 
 
  
Resistance 
 
 
 
  
Intermediate 
 
 
 
  
Sensitive 
 
 
 
Resistance to TDF (stanford algorithm) 
  
 
 
 
  
Resistance 
 
 
 
  
Intermediate 
 
 
 
  
Sensitive 
 
 
 
 
 
 
 

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TABLE 2. PRIMARY COMPOSITE ENDPOINT AND ITS COMPONENT 
mITT analysis 
PP analysis 
  
Integrase 
Inhibitor 
Protease 
Inhibitor 
Adjusted 
Hazard ratio 
Integrase 
Inhibitor 
Protease 
Inhibitor 
Adjusted 
Hazard ratio 
N=XXX 
N=XXX 
 
N=XXX 
N=XXX 
 
Primary composite endpoint 
 
 
 
 
 
 
  
 
 
 
 
 
 
Virological failure 
 
 
 
 
 
 
Insufficient virological response 
 
 
 
 
 
 
Viral rebound 
 
 
 
 
 
 
Clinical events 
 
 
 
 
 
 
Any new or recurrent AIDS 
defining event on, or after 28 days 
of therapy 
 
 
 
 
 
 
SAE due to Non-AIDS events 
 
 
 
 
 
 
AE leading to discontinuation 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
Insufficient virologic response: (HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or Viral load > 50 HIV-1 
RNA copies/mL at week 48). 
Viral rebound: confirmed rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 
copies/mL, or confirmed rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose viral 
load has never been suppressed below 50 copies/mL. 
 
 
TABLE 2B. CUMULATIVE INCIDENCE OF THE PRIMARY COMPOSITE ENDPOINT 
 
 
Integrase Inhibitor 
(N=xxx) 
 
 
Protease Inhibitor 
(N=xxx) 
Adjusted 
Incidence  
rate ratio (95% 
CI) 
 
N of 
event  
Person-
years 
IR per 
100 p-y 
 
N of 
event 
Person-
years 
IR per 100 
p-y) 
p-
value 
Composite Primary 
endpoint 
 
 
 
 
 
 
 
 
 
All observed endpoint will be considered in the analysis. In this analysis, the entire follow-up will be considered (i.e. follow-
up began at baseline and continued until the end of the study, study discontinuation, loss to follow-up; whichever occurs 
first). The incidence rates will be calculated by the total number of events from baseline to the end of the study divided by 
the total number of person-years. The incidence rates will be compared between the treatment groups (Integrase inhibitor 
versus Protease inhibitor) with a Poisson regression model adjusted for stratification factor. The incidence rates ratio and 
the associated 95% confidence interval will be calculated. 

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TABLE 3. HIV-RNA VIRAL LOAD <50 COPIES/ML AT WEEK 24, 36 AND 48 
  
  
Integrase Inhibitor 
Protease Inhibitor 
Adjuted OR 
adjusted difference 
  
  
N=XXX 
N=XXX 
(95% CI) 
(95% CI) 
W24 
  
N 
% (95% CI) 
N 
% (95% CI) 
  
  
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change 
in 
backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 
W36 
  
 
 
 
 
 
 
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change in backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 
W48 
  
 
 
 
 
 
 
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change in backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 
 

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TABLE 4. OTHER SECONDARY EFFICACY ENDPOINTS 
  
Integrase 
Inhibitor 
Protease Inhibitor 
Adjusted 
Hazard ratio 
P-value 
N=XXX 
N=XXX 
 
 
Kaplan-Meier estimate of percentage of patients 
with CD4>200/µL, n (%) 
 
 
 
 
Kaplan-Meier estimate of median (95% CI) time to 
reach CD4>200/µL 
 
 
 
 
Kaplan Meier estimate of incidence of IRIS, n (%) 
 
 
 
 
Kaplan-Meier estimate of Incidence of 
hospitalisations, , n (%) 
 
 
 
 
Kaplan-Meier estimate of median (95% CI) 
duration of hospitalisation 
 
 
 
 
 
TABLE 5: EVOLUTION OF CD4 CELL COUNT <200/µL AND <350 AT WEEK 4, 8, 12, 24, 36 AND 48 
 
CD4 cell count <200/µL 
CD4 cell count <350/µL 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
 
n/N (%) 
n/N (%) 
 
n/N (%) 
n/N (%) 
 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
RR (95% CI) from baseline to W4 
 
 
 
 
 
 
RR (95% CI) from baseline to W8 
 
 
 
 
 
 
RR (95% CI) from baseline to W12 
 
 
 
 
 
 
RR (95% CI) from baseline to W24 
 
 
 
 
 
 
RR (95% CI) from baseline to W36 
 
 
 
 
 
 
RR (95% CI) from baseline to W48 
 
 
 
 
 
 
 
TABLE 6: EVOLUTION OF CD4/CD8 RATIO AT WEEK 4, 8, 12, 24, 36 AND 48 
 
CD4/CD8 ratio 
 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between groups 
 
Mean (SD) 
Mean (SD) 
 
0 
 
 
 
4 
 
 
 
8 
 
 
 
12 
 
 
 
24 
 
 
 
36 
 
 
 
48 
 
 
 
Mean (95% CI) difference from baseline to week 4 
 
 
 
Mean (95% CI) difference from baseline to week 8 
 
 
 
Mean (95% CI) difference from baseline to week 12 
 
 
 
Mean (95% CI) difference from baseline to week 24 
 
 
 
Mean (95% CI) difference from baseline to week 36 
 
 
 
Mean (95% CI) difference from baseline to week 48 
 
 
 

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TABLE 7: SAFETY 
Integrase inhibitor (N=XXX) 
Protease inhibitor (N=XXX) 
P-
value 
Person-Year (P-Y): XXX.X 
Person-Year (P-Y): XXX.X 
  
N of 
events 
N of 
pts 
(%) 
Incidence 
rate/100 p-y 
N of 
events 
N of 
pts 
(%) 
Incidence 
rate/100 p-y 
  
Any adverse events (AEs : grade ≥2) 
 
 
 
 
 
 
 
 Grade 2 
 
 
 
 
 
 
 
 Grade 3 
 
 
 
 
 
 
 
 Grade 4 
 
 
 
 
 
 
 
 Grade unknown 
 
 
 
 
 
 
 
Grade 3 or 4 AE 
 
 
 
 
 
 
 
Drug related AEs 
 
 
 
 
 
 
 
Drug related grade ¾ AEs 
 
 
 
 
 
 
 
dress syndrom (rash) 
 
 
 
 
 
 
 
IRIS 
 
 
 
 
 
 
 
IRIS-Kaposis sarcoma 
 
 
 
 
 
 
 
PML-IRIS requiring hospitalisation 
 
 
 
 
 
 
 
progressive rash 
 
 
 
 
 
 
 
transaminitis 
 
 
 
 
 
 
 
worsening symptoms of Progressive 
multifocal leukoencephalopathy 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
AE leading to the study drugs 
interruption 
 
 
 
 
 
 
 
Serious adverse events (SAE) 
 
 
 
 
 
 
 
Laboratory toxicities 
 
 
 
 
 
 
 
Death  
 
 
 
 
 
 
 
 
TABLE 8. OTHER SECONDARY ENDPOINTS 
  
Integrase Inhibitor Protease Inhibitor 
Adjusted OR  
P-value 
N=XXX 
N=XXX 
(95% CI) 
 
Percentage of patients with HIV drug resistance 
mutations among those with virological failure 
 
 
 
 
Proportion of patients with ART treatment 
changes due to toxicities and/or DDI with ART, 
and/or IRIS through week 48 
- due to toxicities 
- due to DDI 
 - due to IRIS 
 
 
 
 
Proportion of patients with with health care 
resource use, including total inpatient days and 
emergency room visits through week 48 
 
 
 
 
Proportion of patients with discontinuation or 
modification of study medication due to 
insufficient virological response or resistance 
mutations development before week 48 
- for insufficient virological response 
 - resistance mutations development 
 
 
 
 
Proportion of patients for whom there is a 
difference in the list of mutations (Stanford list 
last available version) detected by deep 
sequencing compared with those detected by 
population sequencing 
 
 
 
 

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TABLE 9: EVOLUTION OF QUALITY OF LIFE (HEALTH STATUS SCORE) AND HIV SYMPTOMS INDEX 
 
QOL : health status score 
HIV Symptoms index score 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
 
Mean 
(SD) 
Mean 
(SD) 
 
Mean 
(SD) 
Mean 
(SD) 
 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SD) from baseline to W4 
 
 
 
 
 
 
Mean (SD) from baseline to W8 
 
 
 
 
 
 
Mean (SD) from baseline to W12 
 
 
 
 
 
 
Mean (SD) from baseline to W24 
 
 
 
 
 
 
Mean (SD) from baseline to W36 
 
 
 
 
 
 
Mean (SD) from baseline to W48 
 
 
 
 
 
 
 

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TABLE 10: QUALITY OF LIFE DIMENSIONS: MOBILITY AND SELF- CARE 
 
Mobility 
Self- care 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
 
n/N (%) 
n/N (%) 
 
n/N (%) 
n/N (%) 
 
0 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
4 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
8 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
12 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
24 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
36 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
48 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
RR (95% CI) from baseline to W4 
 
 
 
 
 
 
RR (95% CI) from baseline to W8 
 
 
 
 
 
 
RR (95% CI) from baseline to W12 
 
 
 
 
 
 
RR (95% CI) from baseline to W24 
 
 
 
 
 
 
RR (95% CI) from baseline to W36 
 
 
 
 
 
 
RR (95% CI) from baseline to W48 
 
 
 
 
 
 
 

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TABLE 11: QUALITY OF LIFE DIMENSIONS: USUAL ACTIVITIES AND PAIN/DISCOMFORT 
 
Usual activities 
Pain/discomfort 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between 
groups 
 
n/N (%) 
n/N (%) 
 
n/N (%) 
n/N (%) 
 
0 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
4 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
8 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
12 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
24 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
36 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
48 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
 
 
 
RR (95% CI) from baseline to W4 
 
 
 
 
 
 
RR (95% CI) from baseline to W8 
 
 
 
 
 
 
RR (95% CI) from baseline to W12 
 
 
 
 
 
 
RR (95% CI) from baseline to W24 
 
 
 
 
 
 
RR (95% CI) from baseline to W36 
 
 
 
 
 
 
RR (95% CI) from baseline to W48 
 
 
 
 
 
 
 

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TABLE 12: QUALITY OF LIFE DIMENSIONS: ANXIETY/DEPRESSION 
 
Anxiety/depression 
Week 
Integrase 
Inhibitor 
Protease 
Inhibitor 
P-value 
between groups 
 
n/N (%) 
n/N (%) 
 
0 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
4 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
8 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
12 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
24 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
36 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
48 
1=no problems,  
2=some problems, 
3=extreme problems 
 
 
 
 
RR (95% CI) from baseline to W4 
 
 
 
RR (95% CI) from baseline to W8 
 
 
 
RR (95% CI) from baseline to W12 
 
 
 
RR (95% CI) from baseline to W24 
 
 
 
RR (95% CI) from baseline to W36 
 
 
 
RR (95% CI) from baseline to W48 
 
 
 
 

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TABLE 13. HIV-RNA VIRAL LOAD <50 COPIES/ML AT WEEK 4, 8 AND 12 
  
  
Integrase Inhibitor 
Protease Inhibitor 
Adjuted OR 
adjusted difference 
  
  
N=XXX 
N=XXX 
(95% CI) 
(95% CI) 
W4 
  
N 
% (95% CI) 
N 
% (95% CI) 
  
  
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change 
in 
backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 
W8 
  
 
 
 
 
 
 
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change in backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 
W12 
  
 
 
 
 
 
 
HIV-RNA < 50 copies/mL 
 
 
 
 
 
 
  
 
 
 
 
 
 
HIV-RNA ≥ 50 copies/mL 
 
 
 
 
 
 
Data in window not below 
50 copies/mL 
 
 
 
 
 
 
Discontinued for lack of 
efficacy 
 
 
 
 
 
 
Change in backgroud 
therapy 
 
 
 
 
 
 
No virologic data 
 
 
 
 
 
 
Discontinuation due to 
AE/SAE 
 
 
 
 
 
 
Discontinuation due for 
other reason 
 
 
 
 
 
 
On study but missing data 
in window 
 
 
 
 
 
 

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TABLE 14: ADHERENCE TO STUDY MEDICATION OVER TIME 
  
Randomisation 
Integrase inhibitor 
N=xxx 
Protease inhibitor 
N=xxx 
N 
% 
N 
% 
WK12 
How often has patient taken 
medication? 
All the time 
 
 
 
 
Most of the time 
 
 
 
 
About half the time 
 
 
 
 
Very few times 
 
 
 
 
None 
 
 
 
 
Total 
 
 
 
 
WK24 
How often has patient taken 
medication? 
All the time 
 
 
 
 
Most of the time 
 
 
 
 
About half the time 
 
 
 
 
Very few times 
 
 
 
 
None 
 
 
 
 
Total 
 
 
 
 
WK36 
How often has patient taken 
medication? 
All the time 
 
 
 
 
Most of the time 
 
 
 
 
About half the time 
 
 
 
 
Very few times 
 
 
 
 
None 
 
 
 
 
Total 
 
 
 
 
WK48 
How often has patient taken 
medication? 
All the time 
 
 
 
 
Most of the time 
 
 
 
 
About half the time 
 
 
 
 
Very few times 
 
 
 
 
None 
 
 
 
 
Total 
 
 
 
 
 
 

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TABLE 15: CHANGE FROM BASELINE IN LABORATORY RESULTS 
Laboratory parameters 
Week 
Integrase Inhibitor 
N=xxx 
Protease Inhibitor 
N=xxx 
P-value 
between 
groups 
 
 
N 
Mean (SE) 
N 
Mean (SE) 
 
Red blood cells (10^12/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
White blood cells (10^12/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet counts (10^9/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Haemoglobin (g/dL) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 

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8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Hematocrit (%) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
MVC (fl) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
MCH (pg) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 

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Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils (109/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocytes (109/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Monocytes (109/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Eosinophils (109/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 

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12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Basophils (109/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Potassium (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Total Protein (g/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 

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Sodium (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (U/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin (umol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Indirect bilirubin (umol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 

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48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
AST (U/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin (g/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine (umol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance 
(mL/min) 
0 
 
 
 
 
 

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4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase (U/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine phosphakinase 
(U/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Calcium (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 

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Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Urea (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Phosphate (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Chloride (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Total cholesterol (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 

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12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
HDL (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
LDL (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
 
 
 
 
 
 
 
Triglycerides (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 

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Glucose (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to week 
48 
 
 
 
 
 
The mean change in laboratory parameters from baseline to week 48 will be compared between the 2 treatment groups using a mixed model 
with random intercept and slope and spatial power covariance structure due to unequal time intervals between visits. 
 

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TABLE 16: CHANGE FROM BASELINE IN URINE PARAMETERS 
 
Urine parameters 
Week 
Integrase Inhibitor 
N=xxx 
Protease Inhibitor 
N=xxx 
P-value 
between 
groups 
 
 
 
 
 
 
 
Creatinine (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Glucose (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Postive/trace Glusose 
Dipstick, n (%) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Relative risk (RR, 
95% CI) from 
baseline to week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Proteins (mg/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 

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24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin (mg/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin : Creatinine ratio 
(ACR) (mg/mmoL) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Protein : Creatinine ratio 
(PCR) (mg/mmoL) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Phosphate (mmol/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 

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8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2 microglobulin (mg/L) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Mean (SE) difference 
from baseline to 
week 48 
 
 
 
 
 
 
 
 
 
 
 
 
Positive Leukocytes, n (%) 
0 
 
 
 
 
 
 
4 
 
 
 
 
 
 
8 
 
 
 
 
 
 
12 
 
 
 
 
 
 
24 
 
 
 
 
 
 
36 
 
 
 
 
 
 
48 
 
 
 
 
 
 
Relative risk (RR, 
95% CI) from 
baseline to week 48 
 
 
 
 
 
The change in continuous urine parameters from baseline to week 48 will be compared between the 2 treatment groups using a mixed model 
with random intercept and slope and spatial power covariance structure due to unequal time intervals between visits. 
Change in binary parameters from baseline to week 48 will be compared between the 2 treatment groups using a Generalised Estimating 
Equation (GEE) with independent covariance structure, binomial distribution and log link. 
 
 

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5. APPENDICES  
APPENDIX 1 – AIDS-DEFINING CONDITIONS 
From CDC, available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm  
 
Bacterial infections, multiple or recurrent* 
 
Candidiasis of bronchi, trachea, or lungs 
 
Candidiasis of esophagus† 
 
Cervical cancer, invasive§ 
 
Coccidioidomycosis, disseminated or extrapulmonary 
 
Cryptococcosis, extrapulmonary 
 
Cryptosporidiosis, chronic intestinal (>1 month's duration) 
 
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
 
Cytomegalovirus retinitis (with loss of vision) † 
 
Encephalopathy, HIV related 
 
Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis (onset 
at age >1 month) 
 
Histoplasmosis, disseminated or extrapulmonary 
 
Isosporiasis, chronic intestinal (>1 month's duration) 
 
Kaposi sarcoma† 
 
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*† 
 
Lymphoma, Burkitt (or equivalent term) 
 
Lymphoma, immunoblastic (or equivalent term) 
 
Lymphoma, primary, of brain 
 
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary† 
 
Mycobacterium tuberculosis of any site, pulmonary, †§ disseminated, † or extrapulmonary† 
 
Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary† 
 
Pneumocystis jirovecii pneumonia† 
 
Pneumonia, recurrent†§ 
 
Progressive multifocal leukoencephalopathy 
 
Salmonella septicemia, recurrent 
 
Toxoplasmosis of brain, onset at age >1 month† 
 
Wasting syndrome attributed to HIV 
* Only among children aged <13 years. (CDC. 1994 Revised classification system for human immunodeficiency 
virus infection in children less than 13 years of age. MMWR 1994;43[No. RR-12].) 
† Condition that might be diagnosed presumptively. 
§ Only among adults and adolescents aged >13 years. (CDC. 1993 Revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41[No. RR-17].) 
APPENDIX 2 - INISIGHT SERIOUS NON-AIDS EVENTS CRITERIA 
Version 4, August 2012 
ACUTE MYOCARDIAL INFARCTION 

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A. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above 99th 
percentile of upper reference limit (URL) 
 
B. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent 
with myocardial ischemia 
 
C. ECG changes indicative of new ischemia (new ST-changes or new left bundle branch block [LBBB]), 
or development of pathological Q waves on the ECG 
 
D. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
 
E. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or before 
a time when biomarkers appear, along with (1) new ST-changes or new LBB, or (2) evidence of fresh 
thrombus on coronary angiography or at autopsy 
 
F. In patients with percutaneous coronary interventions and normal baseline troponin, increases in 
troponin of three times the 99th percentile of URL 
 
G. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL PLUS at least one of the following: (1) new pathological Q-
waves or new LBBB, (2) angiographically documented new graft or native artery occlusion, or (3) 
imaging evidence of new loss of viable myocardium 
 
H. Pathologic findings of acute myocardial infarction (including acute MI demonstrated as the cause of 
death on autopsy) 
 
I. Development of 1) evolving new Q waves, or 2) evolving ST elevation, preferably based on at least 2 
ECGs taken during the same hospital admission 
 
J. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin 
of five times the 99th percentile of URL 
 
Confirmed: One of the following 5 criteria (adapted from 2007 Universal Definition of Myocardial 
Infarction): 
1. A + (B or C or D) 
2. E 
3. F 
4. G 
5. H 
Probable: B+I or J 
 
CONGESTIVE HEART FAILURE 
 
A. Clinical signs and symptoms compatible with left or right sided heart failure (e.g., paroxysmal 
nocturnal dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative 
explanation 
 
B. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac 
catheterization, or multiple gated acquisition scan showing a decreased ejection fraction of < 45% 
 

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C. Echocardiogram, cardiac catheterization or other studies showing evidence of increased left atrial 
pressure or right heart failure 
 
D. Elevated levels of Brain Natriuretic Peptide (BNP) or NT-proBNP 
 
E. Chest x-ray or other imaging study showing evidence of congestive heart failure, including cardiac 
enlargement 
 
F. Documentation of treatment for congestive heart failure 
 
Confirmed: (A+B) or (A+C) or (A+D) 
Probable: A+E+F 
 
CORONARY ARTERY DISEASE REQUIRING DRUG TREATMENT 
 
A written report in the medical record documenting: 
 
A. Evidence of myocardial ischemia based on either diagnostic imaging (such as a stress 
echocardiogram or thallium scan) or diagnostic changes on an electrocardiogram (such as during stress 
testing or an episode of chest pain) 
 
B. Evidence of coronary artery disease based on coronary angiography or other diagnostic imaging 
 
C. Other evidence of myocardial ischemia and/or coronary artery disease (including that based 
primarily upon symptoms and clinical presentation, such as chest pain with exertion) 
 
D. Use of medication given to treat or prevent angina (e.g., nitrates, beta blockers, calcium channel 
blockers) 
 
Confirmed: (A or B) + D 
Probable: C+D 
 
CORONARY REVASCULARIZATION 
 
Confirmed: A procedure report, hospital discharge summary, or other medical record from the 
hospitalization during which the procedure was performed for treatment of coronary artery disease 
(including coronary artery bypass graft, coronary artery stent implant, coronary atherectomy, and 
percutaneous transluminal angioplasty), or a consultation note from the participant’s cardiologist 
documenting the occurrence of the procedure 
 
Probable: Not applicable 
 
DECOMPENSATED LIVER DISEASE 
 
A. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by one of the following: 
1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy 
2. MRI or CT consistent with cirrhosis 
3. A positive result on transient elastography (FibroScan) or other ultrasound imaging consistent 
with cirrhosis 
 

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B. Clinical evidence of decompensation, as documented by one of the following, and without an 
alternative explanation: 
1. Ascites 
2. Hepatic encephalopathy 
3. Bleeding from gastric or esophageal varices 
4. Spontaneous bacterial peritonitis 
 
Confirmed: A+B 
Probable: B 
 
DEEP VEIN THROMBOSIS 
 
A. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed tomography, 
MRI, or ultrasonography other comparable imaging techniques 
 
B. An elevated D-dimer test OR abnormal plethysmography 
 
C. A score on the Wells Clinical Prediction Rule for DVT of ≥ 3 points 
 
D. Absence of alternative diagnosis as likely or greater than that of deep venous thrombosis 
 
Wells Clinical Prediction Rule for DVT 
One point for each of the following: 
• Active cancer (treatment ongoing or within previous 6 months, or palliative) 
• Paralysis, paresis, or plaster immobilization of lower extremities 
• Recently bedridden for more than 3 days, or major surgery, within 4 weeks 
• Localized tenderness along distribution of the deep venous system 
• Entire leg swollen 
• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm 
below tibial tuberosity) 
• Pitting edema (greater in the symptomatic leg) 
• Collateral superficial veins (non-varicose) 
(Adapted from: Wells PS et al. Lancet 1997;350:1796) 
 
Confirmed: A 
Probable: B+C+D 
 
DIABETES MELLITUS 
 
A. Classic symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose 
concentration >=200 mg/dl (11.1 mmol/l). (Classic symptoms include polyuria and polydipsia; Random 
is defined as any time of day without regard to last meal) 
 
B. 2-hour plasma glucose >=200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (The test 
should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose 
dissolved in water). 
 
C. Repeated abnormal fasting plasma glucose (FPG) and/or abnormal Haemoglobin A1C level (HA1C) 
results using the following criteria: 
1. FPG >=126 mg/dl (7.0 mmol/l) on at least two different dates (Fasting is defined as no caloric 
intake for at least 8 hours). 

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2. HA1C >=6.5% on at least two different dates 
3. An FPG >=126 mg/dl (7.0 mmol/l) PLUS a HA1C >=6.5%, with these tests performed on two 
different dates 
 
D. Documentation of taking an approved anti-diabetic medication to lower glucose levels in the blood, 
such as insulin or oral hypoglycaemic agents. 
 
E. A single abnormal FBS OR a single abnormal HA1C 
 
Confirmed: A or B or C 
Probable: D 
Possible: E 
 
END-STAGE RENAL DISEASE 
 
A. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least three 
months 
 
B. A kidney transplant documented in a clinical note 
 
C. Haemodialysis or peritoneal dialysis documented in a clinical note for a period of at least one month 
and up to the time of death in a patient who dies within three months after dialysis begins 
 
Confirmed: A or B 
Probable: C 
 
NON-AIDS-DEFINING CANCER 
 
A. Diagnosis of cancer other than lymphoma, Kaposi's sarcoma (KS), or invasive cervical cancer in an 
autopsy report 
 
B. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report that 
established the diagnosis 
 
C. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge 
summary or consultation note from the hospitalization or clinic visit during which the diagnosis was 
established 
 
Confirmed: A or B 
Probable: C 
 
PERIPHERAL ARTERIAL DISEASE 
 
A. Compatible clinical signs and symptoms (e.g., intermittent claudication, femoral bruit, decreased 
peripheral pulses, change in colour or temperature of limb suggesting peripheral arterial disease) 
 
B. Positive results on diagnostic imaging studies (e.g., Doppler ultrasound, contrast arteriography, MRI 
arteriography) 
 
C. Ankle Brachial Pressure Index < 0.90 in non-diabetics 
 

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D. A procedure report, hospital discharge summary, or other medical record from the hospitalization 
during which the procedure was performed documenting an invasive procedure for treatment of 
peripheral arterial disease (e.g., percutaneous transluminal angioplasty, endovascular procedures, or 
vascular surgery), or a consultation note documenting the occurrence of the procedure 
 
Confirmed: (A+B) or (A+C) or D 
Probable: A 
 
PULMONARY EMBOLISM 
 
A. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or 
haemoptysis 
 
B. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical CT, 
ventilation-perfusion scan or other comparable imaging studies 
 
C. A diagnosis of pulmonary embolism on autopsy 
D. Results consistent with a diagnosis of deep venous thrombosis on venography, ultrasound, or other 
comparable imaging studies 
 
E. A chest x-ray which, if performed, does not suggest an alternative aetiology for the symptoms 
described in criteria A 
 
Confirmed: (A+B) or C 
Probable: A+D+E  
 
STROKE 
 
A. Acute onset with a clinically compatible course, including unequivocal objective findings of a 
localizing neurologic deficit 
 
B. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms 
 
C. Stroke diagnosed as cause of death at autopsy 
 
D. Positive lumbar puncture compatible with subarachnoid haemorrhage 
 
E. Death certificate or death note from medical record listing stroke as cause of death 
 
Confirmed: (A+B) or C 
Probable: (A+D) or (A+E) 
 
 

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APPENDIX 3 - INSIGHT PROGRESSION OF HIV DISEASE CRITERIA 
Version 2.0, September 2010 
CONFIRMED 
PROBABLE 
CONSTITUTIONAL DISEASE 
HIV wasting syndrome 
None 
A plus B plus C: (A) unexplained, 
involuntary weight loss >10% from 
baseline, (B) persistent diarrhea 
with > 2 liquid stools/d for > 1 
month or weakness for 
> 1 month or fever for > 1 month, 
(C) tests for alternate causes of 
weight loss, such as cancer, TB, 
MAC, cryptosporidiosis or other 
specific causes of weight loss, if 
obtained, should be negative 
INFECTIONS 
Aspergillosis, invasive pulmonary 
A plus B plus C: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy, 
(C) positive culture from lung biopsy or 
sputum collected by any method 
A plus B: (A) CXR abnormality 
compatible with aspergillosis, 
(B) invasive mycelia consistent with 
Aspergillus on lung biopsy or 
positive culture of lung tissue or 
positive culture of sputum collected 
by any method 
Aspergillosis, other invasive 
A plus B plus C: (A) compatible clinical 
course, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
clinical evidence of infection, (C) 
positive culture from the affected tissue 
A plus B: (A) clinical evidence of 
invasive infection, (B) invasive 
mycelia consistent with Aspergillus 
on tissue biopsy or positive culture 
at a normally sterile site (e.g., 
blood) apart from the involved 
tissue 
Bartonellosis 
A plus B: (A) Clinical or histologic 
evidence of bacillary angiomatosis or 
bacillary peliosis, (B) a positive culture 
or PCR for B. quintana or B. henselae 
A plus B: (A) Clinical evidence of 
bacillary angiomatosis or bacillary 
peliosis, (B) positive silver stain for 
bacilli from a skin lesion or an 
affected organ 
Candidiasis of bronchi, trachea, or lungs 
Macroscopic appearance at 
bronchoscopy or autopsy plus 
microscopic evidence of yeasts or 
pseudo hyphae 
None 
Candidiasis, esophageal 
A plus B: (A) Macroscopic 
appearance at esophagoscopy or 
autopsy, 
(B) microscopic evidence of yeasts or 
pseudo hyphae 
A plus B plus C: (A) Recent onset 
of retrosternal pain or difficulty 
on swallowing, (B) a clinical 
diagnosis of oral candidiasis, 
endoscopic visualization of 
candidiasis and/or microscopic 
evidence of yeasts or pseudo 
hyphae from oropharyngeal 
mucosa, 
(C) clinical response to 
treatment 
CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Chagas disease (American 
trypanosomiasis) of the CNS 
Histologic evidence obtained by brain 
tissue biopsy or autopsy 
A plus B plus C plus D: (A) Focal, 
typically hemispheral neurological 

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dysfunction with onset over several 
days or weeks; (B) enhancing focal 
lesion(s) with mass effect, and 
surrounding edema and contrast 
enhancement, typically located in 
grey matter; 
(C) serum antibodies to T. cruzi, (D) 
response to standard therapy with 
documented clinical or radiographic 
improvement (if radiography was 
done, it must be improved), or 
peripheral blood smear or CSF 
smear positive for T. cruzi 
Coccidioidomycosis, 
disseminated or 
extrapulmonary 
From tissue other than lung or hilum, A 
or B or C: (A) Microscopic 
demonstration of spherules, (B) 
positive culture, (C) antigen detection 
None 
Cryptococcosis, meningitis or 
extrapulmonary 
From tissue other than lung or hilum, A 
or B or C or D: (A) microscopic 
demonstration of narrow based 
budding yeast, 
) for meningitis, if done, a positive 
CSF India ink test, 
) positive culture, (D) antigen 
detention 
None 
Cryptosporidiosis 
Diarrhea for > 1 month and positive 
microscopy 
None 
CMV retinitis 
Autopsy demonstration 
Typical appearance on fundoscopy 
of discrete patches of retinal 
whitening, spreading along blood 
vessels, associated with vasculitis, 
hemorrhage and necrosis, 
confirmed by ophthalmologist 
CMV radiculomyelitis 
Autopsy demonstration 
A plus B plus C plus D plus E plus F: 
(A) Loss of sensation, leg weakness, 
or decreased reflexes, (B) 
presentation over 3 days to 3 
weeks, (C) CT, MRI or myelogram 
must be done and all imaging 
studies must not show a mass 
lesion, 
(D) CSF shows > 10 WBC with 
> 50% polymorphs, (E) CSF shows no 
other pathogen, (F) persistence of 
symptoms in the absence of CMV 
treatment, or elevated quantitative 
CMV in the CSF by PCR 
CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
CMV meningoencephalitis 
Autopsy or brain biopsy 
demonstration 
A plus B: (A) Rapid < 4 weeks 
syndrome with progressive delirium, 
cognitive impairment and fever, (B) 
CT/MRI demonstration of 
periventricular abnormalities or 
elevated quantitative CMV DNA in 
the CSF by PCR 
CMV, other disease 
A plus B plus C plus D: (A) compatible 
illness, (B) histologic demonstration of 
inclusion bodies from affected tissue, 
(C) if done, detectible CMV antibodies, 
(D) if done, detectible CMV DNA or 
A plus B plus C plus D: (A) 
Compatible illness, (B) moderate to 
markedly high CMV antigen or CMV 
DNA in blood, (C) response to 
therapy, (D) if done, detectible CMV 

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CMV antigen in blood 
antibodies 
HSV mucocutaneous 
ulceration 
A plus B: (A) Ulceration for > 1 month, 
(B) histology, culture, PCR, or detection 
of antigen from affected tissue 
A plus B: (A) Typical HSV ulceration 
for > 1 month, (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
HSV, bronchitis, pneumonitis, 
esophagitis, or other visceral disease 
A plus B: (A) Compatible symptoms, 
(B) histology, culture, PCR, or 
detection of antigen from affected 
tissue 
None 
HZV, disseminated 
A plus B: (A) multiple ulcerated lesions 
affecting at least 2 non-contiguous 
dermatomes, or with generalized 
cutaneous dissemination; or HZV 
involvement of the lung, liver, brain, 
or other internal organs 
(B) positive culture, PCR, or antigen 
assay from affected tissue 
A plus B: (A) multiple typical 
ulcerated lesions affecting at least 2 
non-contiguous dermatomes, or 
with generalized cutaneous 
dissemination (B) response to an 
antiviral active against HZV unless 
resistance is demonstrated 
Histoplasmosis, disseminated or 
extrapulmonary 
A plus B: (A) Compatible symptoms, 
(B) histology or culture or elevated 
blood or urine antigen levels 
None 
Isosporiasis 
Diarrhea for > 1 month, plus 
microscopic identification of 
Isospora belli 
None 
Leishmaniasis, visceral 
Compatible symptoms, plus 
microscopic identification of 
Leishmania 
Compatible symptoms, plus a 
positive PCR test for Leishmania 
Microsporidiosis 
Diarrhea for > 1 month plus 
Microscopic identification of 
Microsporidia 
None 
CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
MAC and other mycobacterial 
disseminated disease 
A plus B: (A) Fever, fatigue, anemia or 
diarrhea, (B) positive culture from 
blood, body fluids or tissue other than 
pulmonary, hilar or stool 
A plus B plus C: (A) Fever, 
fatigue, anemia or diarrhea, 
(B) AFB or positive direct MAC PCR 
in blood, body fluids or tissue other 
than pulmonary, hilar or stool (C) no 
concurrent non-pulmonary TB 
M. tuberculosis disease, pulmonary 
A plus B: (A) Compatible symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, 
(B) culture or PCR from sputum or 
bronchial lavage or lung tissue 
A plus B plus C plus D: (A) 
Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, 
(B) abnormal chest X-ray, (C) AFBs 
seen in sputum or lavage or lung 
tissue but not grown in culture, (D) 
responds to treatment 
POSSIBLE (pulmonary TB only) 
A plus B plus C plus D: 
(A) Symptoms of fever, dyspnea, 
cough, weight loss or fatigue, (B) 
abnormal chest X-ray compatible 
with pulmonary TB (such as upper 
lobe cavitation, pleural exudate), 
(C) No other etiology for pulmonary 
symptoms and signs identified, (D) 
Responds to anti-tuberculosis 
treatment 
M. tuberculosis disease, 
extrapulmonary 
A plus B: (A) Compatible symptoms, (B) 
culture or PCR from blood or affected 
tissue 
A plus B plus C: (A) Compatible 
symptoms, (B) AFBs seen from 
affected tissue or blood (C) 
concurrent diagnosis of pulmonary 
TB or responds to treatment 
Nocardiosis 
Clinical evidence of invasive infection 
Clinical evidence of invasive 

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plus a positive culture from the affected 
tissue or blood 
infection plus microscopic 
evidence of bronchial weakly acid-
fast organisms from the affected 
tissue 
Penicillium marneffei, 
disseminated 
Culture from a non-pulmonary site 
Known presence in a P. marneffei 
endemic area plus characteristic 
skin lesions plus response to 
antifungal therapy for penicillosis 
CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
PcP 
A plus B: (A) compatible clinical 
syndrome, (B) microscopic or 
histological demonstration of P. jirovecii 
cysts in a pulmonary specimen 
A plus B plus C plus D plus E: 
(A) dyspnea or cough, or fever 
progressive over > 1 week, (B) 
diffuse chest x-ray abnormality or, if 
on inhalational pentamidine, diffuse 
upper lung field abnormality, (C) 
evidence of hypoxia, (D) not 
suggestive of bacterial pneumonia 
(i.e., not purulent sputum or 
hemoptysis, no bacterial pathogen 
identified in blood or bronchial 
wash), (E) response to PcP 
treatment 
Pneumocystis jirovecii, 
extrapulmonary 
Compatible symptoms, plus 
microscopy 
None 
Pneumonia, recurrent bacterial, excludes: 
(a) post- obstructive pneumonias, 
including in those with 
intrapulmonary/bronchial lesions, (b) 
aspiration pneumonia, including in those 
with decreased consciousness levels, (c) 
nosocomial ventilator-associated 
pneumonias 
Both pneumonia episodes must occur 
after enrollment and satisfy criteria (A) 
plus (B) plus (C). The recurrent 
pneumonia must also satisfy criteria (D) 
plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) identification 
of a bacterial pathogen by positive 
blood culture, positive bronchoscopic 
sputum culture, detection of Legionella 
or pneumococcal antigen in urine or 
blood or diagnostic serologic findings, 
(D) the second pneumonia had onset of 
symptoms < 365 days after the first 
episode, (E) there is strong evidence 
that the first episode was cured such as 
an intervening clear CXR or absence of 
symptoms after > 1 month off 
antibacterials effective against 
pathogens commonly producing 
pneumonia 
Both pneumonia episodes must 
occur after enrollment and satisfy 
criteria (A) plus (B). The recurrent 
pneumonia must also satisfy criteria 
(C) plus (D): (A) Signs and symptoms 
suggestive of bacterial pneumonia, 
(B) focal CXR abnormality 
compatible with bacterial 
pneumonia, (C) the second 
pneumonia had onset of symptoms 
< 365 days after the first episode, 
(D) there is strong evidence that the 
first episode was cured such as an 
intervening clear CXR or absence of 
symptoms after 
> 1 month off antibacterials 
effective against pathogens 
commonly producing 
pneumonia 
PML (progressive multifocal 
leukoencephalopathy) 
A or B: (A) positive histology, 
(B) compatible clinical and radiologic 
course and positive CSF PCR for JK 
virus 
A plus B plus C: (A) Consistent 
symptoms, (B) brain image 
consistent with PML, (C) no 
response to toxo treatment or 
toxoplasma seronegative 
CONFIRMED 
PROBABLE 
INFECTIONS (CONTINUED) 
Rhodococcus equi disease 
Clinical evidence of invasive infection 
plus microbiologic identification of the 
organism in the affected tissue or 
blood 
None 
Salmonella septicemia, recurrent 
Both episodes must occur after 
enrollment and met criterion (A). The 
second episode must meet criteria (B) 
None 

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and C: (A) Positive blood or tissue 
culture, (B) the second septicemia had 
onset of symptoms < 365 days after the 
first episode, (C) the second septicemia 
must be due to a different Salmonella 
serotype or there must be strong 
evidence that the first episode was 
cured such as a negative blood culture 
off effective antibacterials for > 1 week 
or absence of symptoms off 
antibacterials for > 1 month 
Toxoplasmosis of brain 
Microscopy 
A plus B plus C: (A) Symptoms of 
focal intracranial abnormality or 
decreased consciousness, 
(B) brain image consistent with 
lesion(s) enhanced by contrast, 
(C) positive toxoplasma serology 
or responds to treatment 
clinically or by scan 
NEOPLASMS 
Cervical carcinoma, invasive 
Histology (NOT carcinoma-in- situ) 
None 
Kaposi sarcoma, (mucocutaneous or 
visceral) 
Histology 
Highly typical appearance and 
persistence for > 1 month 
Lymphoma, primary, of brain 
Histology 
Symptoms consistent with 
lymphoma plus at least one CNS 
lesion with mass effect plus lack of 
clinical and radiographic response 
to at least 2 weeks of treatment 
for toxoplasmosis 
Lymphoma, Hodgkin's 
Histology 
None 
Lymphoma, non-Hodgkin's, all cell 
types 
Histology 
None 
 
 
CONFIRMED 
PROBABLE 
NEUROLOGICAL 
HIV-related encephalopathy (including 
AIDS Dementia Complex) 
None 
Cognitive or motor dysfunction 
interfering with usual activity, 
progressive over weeks or months 
plus no other condition to explain 
the findings plus brain image 
obtained and suggests no other 
causes plus grade 2 or worse 
impairment in at least 2 domains 
by NARS (see below) excluding 
abnormal domains at trial entry. 
(For persons with abnormal 
domains at entry worsening by at 
least two grades meets criteria.) 
 
 
 

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Abbreviated NARS (Neuropsychiatric AIDS Rating Scale) Grading for HIV Encephalopathy  
Adapted from: Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988; 158 (5): 1079- 83, 
and Hughes CP, Berg L, Danziger WL. A new clinical scale for the staging of dementia. Brit J Psych 
1982; 140: 566-92. 
NARS 
stage 
Cognitive-Behavioral Domains 
Orientation 
Memory 
Motor 
Behavior 
Problem 
solving 
Activities 
of 
daily living 
0.5 
fully oriented 
complains of 
memory 
problems 
fully 
ambulatory 
slightly 
slowed 
movements 
normal 
has slight 
mental 
slowing 
slight 
impairment in 
business 
dealings 
1 
fully oriented, 
may have brief 
periods of 
“spaciness" 
mild memory 
problems 
balance, co- 
ordination 
and 
handwriting 
difficulties 
more irritable, 
labile or 
apathetic, 
withdrawn 
difficulty 
planning and 
completing 
work 
can do simple 
daily tasks, may 
need prompting 
2 
some 
disorientation 
memory 
moderately 
impaired, 
new learning 
impaired 
ambulatory 
but may 
require 
walking aid 
some 
impulsivity or 
agitated 
behavior 
severe 
impairment, 
poor social 
judgement, 
gets lost easily 
needs 
assistance 
with ADLs 
3 
frequent 
disorientation 
severe 
memory loss, 
only 
fragments of 
memory 
remain 
ambulatory 
with 
assistance 
may have 
organic 
psychosis 
judgement 
very poor 
cannot live 
independently 
4 
confused and 
disoriented 
virtually no 
memory 
bedridden 
mute and 
unresponsive 
no problem-
solving ability 
nearly 
vegetative 
 
 

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APPENDIX 4 – IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME GENERIC CRITERIA  
 (Revised 01/10/09) 
From ACTG, available under https://actgnetwork.org/IRIS_Case_Definitions  
 
1. Initiation, reintroduction or change in antiretroviral therapy/regimen or therapy for 
opportunistic infections (OI).   
AND 
2. 
1Evidence of:   
a. an increase in CD4+ cell count as defined by ≥50 cells/mm3 or a ≥2- fold rise in CD4+ cell 
count, and/or    
b. decrease in the HIV-1 viral load of >0.5 log10 and/or    
c. weight gain or other investigator-defined signs of clinical improvement in response to 
initiation, reintroduction or change of either antiretroviral therapy/regimen or OI therapy.     
     AND   
3. Symptoms and/or signs that are consistent with an infectious or inflammatory condition.     
     AND  
4. These symptoms and/or signs cannot be explained by a newly acquired infection, the expected 
clinical course of a previously recognized infectious agent, or the side effects of medications. 
AND 
5. For purposes of data collection, the infectious/inflammatory condition must be attributable to 
a specific pathogen or condition. A Clinical Events form should be completed 16 weeks (+ 4 
weeks) after initial report if diagnosis confirmed or changed from initial report 
 
1 If the study participant is being evaluated for an inflammatory condition at a time that is <4 weeks 
after initiation, reintroduction or change in antiretroviral therapy/regimen or OI therapy, items 2a 
through 2c are not required.     
Refer to the “Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes 
(IRIS)” document for specific Opportunistic Infection (OI) and non-pathogen condition diagnosis 
criteria. 

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Criteria for the Diagnosis of Specific Immune Reconstitution Inflammatory Syndromes (IRIS) 
IRIS Focus Group 
Given the paucity of data for a clearly-defined immune reconstitution inflammatory syndrome for each 
opportunistic pathogen, the IRIS Working Group concentrated on developing specific definitions for the 
most well-characterized IRIS in the literature. IRIS events may occur as paradoxical worsening or as an 
unmasking. Paradoxical responses are described as an initial clinical worsening when patients are started 
on pathogen-specific therapy and/or ART simultaneously. Unmasking refers to aberrant clinical 
presentations of previously common OIs such as localized Mycobacterium avium complex (MAC) 
lymphadenitis and Cytomegalovirus (CMV) vitritis occurring within the first weeks of starting ART 
suggesting that patients have sub-clinical disease prior to the initiation of ART. There are specific definitions 
including confirmed and probable for the following specific pathogen IRIS:  Mycobacterium avium complex 
(MAC), Progressive Multifocal Leukoencephalopathy (PML), Cytomegalovirus (CMV), Mycobacterium 
tuberculosis (TB) and Cryptococcus neoformans. All other clinical syndromes attributed to immune 
reconstitution will be treated as probable IRIS events without specific definitions and will include 
Pneumocystis jirovecii pneumonia (PCP), Varicella Zoster (VZV), Herpes Simplex (HSV), Hepatitis B, 
Hepatitis C, Toxoplasmosis, Kaposi’s Sarcoma, Graves’ disease, Sarcoidosis, and other autoimmune 
disorders. For these less well-defined IRIS, key data will be captured on a generic form that includes clinical 
signs/symptoms, CD4, HIV RNA data, and clinical outcomes.  
 
Specific IRIS Case Definitions  
 
1. Cytomegalovirus (CMV): {Ophthalmologic only} IRIS associated with CMV is fairly common; 
syndromes include uveitis, vitritis, extension or new development of retinal opacification, 
proliferative vitreoretinopathy (leading to retinal detachment), neovascularization, macular or 
optic nerve edema and subcapsular cataracts (leading to visual impairment) [1, 2]. The 
inflammatory component is marked, with significant anterior and/or posterior chamber 
inflammation. Vitritis and extension or new development of retinal opacification usually occurs 
within 3-12 weeks of beginning antiretroviral therapy/regimen and/or CMV antiviral therapy; 
uveitis may occur months to years after beginning antiretroviral therapy. Antiretroviral 
therapy/regimen is usually continued; some patients are also treated with anti-CMV drugs, 
especially those with sight-threatening disease. IRIS associated with gastrointestinal or neurologic 
(non-ocular) CMV disease have not be adequately characterized 
 
Confirmed CMV IRIS in patients with a prior history of CMV retinitis:  previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by an experienced ophthalmologist.  
 
Confirmed CMV IRIS in patients without a prior history of CMV retinitis:  the development of 
significant ocular inflammation in the uveovitreal tract, lens or retina attributed to CMV in the 
absence of ophthalmologic findings typical for acute CMV retinitis, with or without visual changes, 
as documented by an experienced ophthalmologist. 
 
Probable CMV IRIS in patients with a prior history of CMV retinitis previous CMV retinitis 
diagnosis by ACTG criteria and improvement of signs/symptoms with anti-CMV therapy, with the 
subsequent development of ocular inflammatory changes in uveovitreal tract, lens or retina, with 
or without associated visual changes, as documented by a non-ophthalmologist clinician 
 

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2. Cryptococcus neoformans. The best described cases of Cryptococcus neoformans IRIS involve 
inflammatory changes developing in patients with recently diagnosed cryptococcal meningitis, 
cryptococcemia or pneumonia who have responded to appropriate antifungal therapy [1, 3,4].  
Most have presented as meningitis, associated with CSF abnormalities (significantly elevated 
protein, lymphocytes, hypoglycorrhachia and cryptococcal antigen titers) with negative cultures. 
CNS imaging may demonstrate new meningeal inflammation. Significant elevations of intracranial 
pressure may occur. Non-CNS presentations are also common and have included the development 
of mediastinal or cervical adenopathy, necrotizing pneumonia, cavitation of previously 
documented pulmonary lesions, focal lymphadenitis and cutaneous abscesses. Biopsies may 
demonstrate granulomatous changes and cryptococci but typically cultures are negative. These 
presentations have occurred anywhere from two weeks to 11 months after initiation of 
antiretroviral therapy/regimen, with most cases occurring within three months. Less well 
described are cases of cryptococcal meningitis presenting only after initiation and response to 
antiretroviral therapy/regimen, also associated with elevated CSF cryptococcal antigen (CRAG) 
titers, negative CSF cultures and significant meningeal enhancement on scan. 
 
Confirmed cryptococcal IRIS in patients with a prior history of cryptococcosis: Cryptococcal 
meningitis or other diagnosis of systemic cryptococcal infection (fungemia, pneumonia) by ACTG 
criteria and improvement of signs/symptoms with antifungal therapy, with the subsequent 
development of new or worsening pulmonary infiltrates, new meningeal enhancement on scan or 
abnormal CSF findings (low glucose, elevated WBC, CSF CRAG with negative fungal culture), 
mediastinal or cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal 
lesions at other sites;  histopathology from non-meningeal site demonstrating inflammatory 
changes and organisms in the absence of a positive culture or positive culture.   
 
Confirmed cryptococcal IRIS in patients without a prior history of cryptococcosis:  the 
development of meningitis with meningeal enhancement on scan with abnormal CSF findings (low 
glucose, elevated WBC, positive CSF CRAG with negative or positive fungal culture), mediastinal or 
cervical lymphadenopathy, pleural effusion, cutaneous abscesses or cryptococcal lesions at other 
sites;  histopathology from non-meningeal site demonstrating inflammatory changes and 
organisms in the absence of a positive culture or positive culture.   
 
Probable cryptococcal IRIS in patients with a prior diagnosis of cryptococcosis:  previous 
cryptococcosis diagnosis by ACTG criteria and improvement of signs/symptoms with anti-cryptococcal 
therapy, and the subsequent development of focal inflammatory site(s); histopathology from involved 
site or sterile body fluid analysis  demonstrating inflammatory changes (e.g., granulomas, 
lymphocytes) in the absence of positive stains or cultures for any other pathogen or any non-infectious 
histopathologic diagnosis; and negative blood cultures for Cryptococcosis; and negative CSF CRAG if 
obtained or development of new onset CNS signs or symptoms with meningeal enhancement or other 
atypical radiographic changes with no evidence of other neurologic disease to explain the findings. 
 
Probable cryptococcal IRIS in patients without a prior diagnosis of cryptococcosis: the subsequent 
development of focal inflammatory site(s); histopathology from involved site or sterile body fluid 
analysis demonstrating inflammatory changes (e.g., granulomas, lymphocytes) accompanied by 
evidence consistent with cryptococcosis in the absence of positive cultures for any other pathogen. 
   
3. Mycobacterium avium complex (MAC). This is one of the best described IRIS. The most common 
presentation is focal lymphadenitis (especially cervical) with high fever, elevated WBC counts and 
negative blood cultures; fistula formation may occur. There is a significant inflammatory 

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component on biopsy with necrotizing granulomas, caseation and AFB. The syndrome usually 
occurs within 3-12 weeks of initiating antiretroviral therapy/regimen and/or anti-mycobacterial 
therapy, although rare cases have been described beyond 6 months with deep tissue foci, e.g. 
psoas abscess. MAC IRIS has presented as diffuse adenopathy, and as focal disease in diverse sites 
(paraspinous, mediastinal, abdominal, vertebral, pulmonary and CNS). [1,5,6]  
 
Confirmed MAC IRIS in patients with a prior history of disseminated MAC (dMAC): previous 
disseminated MAC diagnosis by ACTG criteria and improvement of signs/symptoms with anti-MAC 
therapy, with the subsequent development of focal inflammatory site(s). 
 
Confirmed MAC IRIS in patients without a prior history of dMAC: the development of focal 
inflammatory site(s); histopathology from the involved site demonstrating inflammatory changes 
(e.g., granulomas) accompanied by histologic or culture evidence of AFB consistent with MAC in 
the absence of positive cultures for any other AFB; and may have positive blood cultures for MAC.   
 
Probable MAC IRIS in patients with a prior history of dMAC: previous dMAC diagnosis by ACTG 
criteria and improvement of signs/symptoms with anti-MAC therapy, and the subsequent 
development of focal inflammatory site(s); histopathology from involved site demonstrating 
inflammatory changes (e.g., granulomas) in the absence of positive stains or cultures for any other 
pathogen or any non-infectious histopathologic diagnosis; and negative blood cultures for MAC. 
 
Probable MAC IRIS in patients without a prior diagnosis of MAC: the subsequent development of 
focal inflammatory site(s); histopathology from involved site demonstrating inflammatory changes 
(e.g., granulomas, lymphocytic infiltrates) and without evidence of any other specific pathogen 
(stains may be positive for AFB); and negative blood cultures for MAC. 
 
4. Mycobacterium tuberculosis (TB). Tuberculosis-associated IRIS can present as one of two main 
syndromes: (1) a paradoxical reaction after the start of ART in patients receiving tuberculosis 
treatment (“paradoxical” tuberculosis-associated IRIS), or (2) a new presentation of tuberculosis 
that is “unmasked” in the weeks following initiation of ART with an exaggerated inflammatory 
clinical presentation or complicated by a paradoxical response (“unmasking” tuberculosis 
associated IRIS). A “paradoxical” response to anti-tuberculous therapy was described as far back 
as 1955 in patients initiating therapy. In the HAART era, IRIS associated with TB is common and 
occurs in approximately 8-43% and typically consists of new and persistent fever after starting 
antiretroviral therapy/regimen; worsening or emergence of intrathoracic adenopathy, pulmonary 
infiltrates or pleural effusions, or worsening or emergence of cervical nodes on serial exam or of 
other tuberculous lesions, such as skin and CNS. It usually occurs within the first 4 weeks of 
beginning antimycobacterial therapy with or without antiretroviral therapy/regimen but has been 
described as late as 9 months when the patient is smear-negative. Antiretroviral therapy/regimen 
can usually be continued, often with anti-inflammatory support; corticosteroids have been used in 
those with CNS lesions or who are critically ill [7-12]. 
 
Confirmed TB IRIS in patients with a prior history of TB (paradoxical TB-associated IRIS): There 
are three components to this case-definition (adopted from Lancet Infect Dis 2008, reference 12): 
 
A) Antecedent requirements 

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i) Diagnosis of tuberculosis: previous pulmonary (smear positive or smear-negative) or 
extrapulmonary TB diagnosis by ACTG criteria  
AND 
ii) Initial response with anti-TB therapy (i.e. stabilization or improvement of signs/symptoms with 
appropriate anti-TB therapy prior to initiation of ART)*. For example, there has been cessation or 
improvement of fevers, cough, night sweats).  
* (Note: this does not apply to patients starting ART within 2 weeks of starting tuberculosis 
treatment since insufficient time may have elapsed for a clinical response to be reported) 
 
(B) Clinical criteria 
The onset of tuberculosis-associated IRIS manifestations should be within 3 months of ART 
initiation, re-initiation, or regimen change because of HIV treatment failure. 
 
Of the following, at least one major criterion or two minor clinical criteria are required: 
 
Major criteria 
• New or enlarging lymph nodes, cold abscesses, or other focal tissue involvement—e.g. 
tuberculous arthritis 
• New or worsening radiological features of tuberculosis (found by chest radiography, abdominal 
ultrasonography, CT, or MRI) 
• New or worsening CNS tuberculosis (meningitis or focal neurological deficit; e.g. caused by 
tuberculoma) 
• New or worsening serositis (pleural effusion, ascites, or pericardial effusion) 
 
Minor criteria 
• New or worsening constitutional symptoms such as fever, night sweats, or weight loss 
• New or worsening respiratory symptoms such as cough, dyspnea, or stridor 
• New or worsening abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or 
abdominal adenopathy 
 
 
(C) Alternative explanations for clinical deterioration must be excluded 
• Failure of tuberculosis treatment because of tuberculosis drug resistance 
• Poor adherence to tuberculosis treatment 
• Another opportunistic infection or neoplasm (it is particularly important to exclude an alternative 
diagnosis in patients with smear-negative pulmonary tuberculosis and extrapulmonary 
tuberculosis where the initial tuberculosis diagnosis has not been microbiologically confirmed) 
• Drug toxicity or reaction 
 
Confirmed TB IRIS in patients without a prior history of TB (ART “unmasking” TB-associated IRIS): 
Patient is not receiving treatment for TB when ART is initiated. Active TB is diagnosed after 
initiation of ART and the diagnosis of TB fulfils ACTG criteria for smear-positive pulmonary TB, 
smear-negative pulmonary TB or extrapulmonary TB. Active TB develops within 3 months of 

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starting ART and one of the following criteria is met: heightened intensity of clinical manifestations, 
particularly if there is evidence of a marked inflammatory component. For example, presentations 
may include TB lymphadenitis or TB abscesses with prominent acute inflammatory features; the 
development of pulmonary* or extrapulmonary TB with no evidence of miliary disease 
accompanied by marked focal inflammation; or histopathology from involved site demonstrating 
inflammatory changes (e.g., granulomas, caseation) accompanied by histologic or culture evidence 
of AFB consistent with TB in the absence of positive cultures for any other AFB. 
 
Probable TB IRIS in patients with a prior history of TB: “Probable” status should be assigned for 
cases where criteria A and B are met (see confirmed TB IRIS with a prior history of TB definition) 
but an alternative diagnosis or explanation for clinical deterioration cannot be fully excluded.  
 
Probable TB IRIS in patients without a prior diagnosis of TB: Patient is not receiving treatment for 
TB when ART is initiated. Active TB is diagnosed after initiation of ART and the diagnosis of TB fulfils 
ACTG criteria for smear-positive pulmonary TB, smear-negative pulmonary TB or extrapulmonary 
TB. There is heightened intensity of clinical manifestations but there is not clear evidence of a 
marked inflammatory component to the presentation or the subsequent development of focal 
inflammatory site(s) is beyond 3 months of ART initiation.  
 
5. Progressive Multifocal Leukoencephalopathy (PML). Inflammatory responses to PML usually 
occur within 3 months of beginning antiretroviral therapy. Based on available data, the 
simultaneous diagnosis of PML and IRIS post-HAART initiation is more commonly observed (i.e. 
unmasking IRIS). Furthermore, it appears that paradoxical worsening PML IRIS is identified sooner 
(within 4 weeks) than unmasking PML IRIS. MRI with gadolinium shows contrast enhancement 
suggesting an inflammatory response, and biopsy reveals significant inflammation with gliosis, 
marked intraparenchymal and perivascular infiltration by macrophages and lymphocytic infiltrates 
(especially CD8 T cells), giant cells, with or without demyelination. Intense JC-specific PCR signals 
(or other immunoreactivity to papovavirus antigens) are detected in brain tissue even in the 
absence of positive JC CSF PCR. The clinical responses are mixed:  some improve, and some have 
significant worsening with progression to death. A variable response to steroids has been 
described [1,13,14].  
 
Confirmed PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG 
criteria (consistent CT or MRI scan with positive biopsy or positive CSF JC PCR and the absence of 
any alternative diagnosis), with the subsequent development of new or worsening CT or MRI 
findings with contrast enhancement; brain biopsy shows focal inflammatory changes accompanied 
by histologic or PCR evidence of PML in the absence of another diagnosis.   
 
Confirmed PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in patient with no previously recognized CNS infection or malignancy, 
accompanied by CT or MRI changes showing contrast enhancement; brain biopsy shows focal 
inflammatory changes accompanied by histologic or PCR evidence of PML in the absence of 
another diagnosis. 
 
Probable PML IRIS in patients with a prior history of PML: previous PML diagnosis by ACTG criteria 
(consistent CT or MRI scan with positive biopsy or CSF JC PCR and the absence of any alternative 
diagnosis), with the subsequent development of new or worsening CT or MRI findings with 
contrast in the absence of another diagnosis.   

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Probable PML IRIS in patients without a prior diagnosis of PML: the development of new 
neurologic deficit(s) in a patient with no previously recognized CNS infection or malignancy 
accompanied by CT or MRI changes showing contrast enhancement consistent with PML with no 
brain biopsy obtained. CSF findings cannot be attributable to another pathogen or disease process. 
 
IRIS Diagnoses without Specific Case Definitions 
 
Pathogen-Directed: 
 
1.  Kaposi’s Sarcoma (KS). Rapid KS progression [15] and local swelling with adjacent 
lymphadenopathy [20] have both been reported as a manifestation of immune reconstitution after 
antiretroviral therapy/regimen initiation. Whereas the latter syndrome may truly represent an IRIS 
syndrome, if there is no clear evidence of any characteristic inflammatory component [1, 16], then 
the progression could be due to a failure to reconstitute KSHV-specific immune responses. KS-IRIS 
is defined as a sudden or more dramatic progression of disease than expected as part of natural 
history that occurs within 12 weeks of initiation of ART. ART alone should be continued for 4-6 
weeks to monitor for clinical response. If the lesions stabilize, have a regression of inflammation 
or lesion number or size diminishes, this will be defined as IRIS. Should disease progression 
continue, then this is unlikely to be IRIS and should be defined as progression of disease and 
managed with appropriate KSHV specific therapies. The presence of inflammation on biopsy may 
assist in distinguishing progression of disease vs. IRIS. 
 
 
2. Hepatitis B and C. Significant increase in ALT over baseline (flares) have been documented after 
beginning antiretroviral therapy/regimen with HBV co-infection as well as after interruption of 
antiretroviral therapy/regimen (especially in patients with HBV on a 3TC- or tenofovir-containing 
regimen). After immune recovery HBV "flares" may occur if HBV is not being concomitantly treated, 
although there are other potential reasons to consider. These include: 
 
a) spontaneous HBeAg seroconversion; 
b) treatment induced exacerbation of the underlying disease; 
c) hepatotoxic effects of treatment; 
d) withdrawal of active HBV drug; 
e) development of resistance and return of replication, and/or  
f) superimposed and unrelated acute liver disease (e.g. hepatitis A) 
 
Liver biopsy may be helpful in determining evidence of drug related (eosinophilic infiltrate) vs. 
acute viral hepatitis (hepatocyte swelling with lobular inflammation). 
 
Biopsy may also grade and stage chronic viral hepatitis. IRIS is less well-defined in HCV co-infection, 
and increases in liver enzymes on antiretroviral therapy/regimen may be multifactorial as well.  
 
3. Herpes simplex virus (HSV). The development of unusual presentations of HSV following the initiation 
of antiretroviral therapy/regimen attributed to immune reconstitution have been rarely described. 

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Localized HSV vesicles may occur within 8 weeks of initiating ART among persons with no prior history 
and no new source contact to attribute it to. Symptoms and signs are frequently consistent with a 
primary infection. Chronic erosive or ulcerative lesions of the genitals have been described in 
individuals who had prior histories of genital HSV. The appearance and clinical course of the lesions 
attributed to immune reconstitution appeared inconsistent with these patients’ previous HSV 
presentations. Proctitis has also been reported [1,18,19].  Routine viral cultures may or may not yield 
HSV though histochemistry studies may show evidence of HSV antigens in the absence of a positive 
viral culture. Histopathology in some cases may demonstrate an inflammatory infiltrate with unusual 
prominence of plasma cells and eosinophils. Response to antivirals appears to be variable.  
 
4. Pneumocystis jirovecii pneumonia (PCP). Despite being the most common OI with a relatively high 
CD4 threshold for development, few clear cases of Pneumocystis pneumonia IRIS have been 
documented so far (likely because steroids have been established for the use of severe PCP). Cases 
have been described as worsening of pneumonia and even respiratory failure, although the 
patients reported received suboptimal courses of steroids [20]. To entertain a diagnosis of PCP 
IRIS, bronchoscopy should rule out an intercurrent pulmonary process. 
 
5. Syphilis. New reactive RPR within 12 weeks of starting ART in setting of known previously treated 
syphilis and documented nonreactive within past 2 years without new attributable source. May also 
present serologically as less than or equal to 4-fold change in titer in someone with previous history of 
treated syphilis and no new attributable source. May present with systemic symptoms including 
arthralgia. May improve with anti-inflammatories. 
1. 
 
6. Toxoplasmosis. There is also a very small database for possible toxoplasmosis IRIS. No specific 
clinical pattern has been seen, and there is no clear evidence of an inflammatory component. 
 
7. Varicella Zoster (VZV). The development of herpes zoster after initiation of antiretroviral 
therapy/regimen has been attributed to immune reconstitution. The incidence of zoster appears 
to be 2- to 5-fold greater in those receiving antiretroviral therapy/regimen compared to those not 
receiving antiretroviral therapy/regimen. Most cases occur in the first 16 weeks following initiation 
of antiretroviral therapy/regimen. Those with higher percentage of CD8+ lymphocytes at the time 
of initiation of HAART and at one month following antiretroviral therapy/regimen appeared to be 
at higher risk for zoster [21].  Most cases present as cutaneous dermatomal disease or 
mucocutaneous disease, are mild, occur without systemic symptoms and respond to antiviral 
therapy. Iritis and keratitis have been described rarely [1,22]. It is not clear that cutaneous zoster 
following initiation of antiretroviral therapy/regimen has a significant inflammatory component 
that differentiates this from routine VZV.  
 
8. Other viral dermatoses. Eruptive onset of new common warts, flat warts, or epidermodysplasia 
verruciformis-type warts, or inflammation/rapid growth of previously stable cutaneous or genital 
warts, have been noted during immune restoration [23-24]. In addition, eruptive onset of new 
molluscum contagiosum or inflammation/enlargement of pre-existing mollusca during immune 
restoration has been described [25]. 
 
Non-Pathogen or Unknown Pathogen Directed 
   

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1. Autoimmune disorders. Systemic lupus erythematosus, polymyositis, rheumatoid arthritis, 
relapsing polychondritis and Guillain-Barre have also been attributed to immune reconstitution 
following administration of antiretroviral therapy/regimen [1,26]. 
 
2. Follicular inflammatory eruptions. Sudden onset of follicular papulopustular inflammatory 
eruptions resembling acne vulgaris or acne rosacea have been reported within first 4 months of 
immune reconstitution [27]. Eosinophilic folliculitis, distinguished from acneiform eruptions by 
intense pruritus, an urticarial appearance to the papules, and histopathology showing follicular 
inflammation containing eosinophils, has been documented. An increased incidence of 
eosinophilic folliculitis has been noted in the first 6 months of HAART therapy [28]. 
 
3. Graves’ Disease. New onset of clinically significant Graves’ disease (hyperthyroidism) has been 
reported following the initiation of antiretroviral therapy/regimen. The development of anti-
thyrotropin receptor antibodies in individuals following antiretroviral therapy/regimen, not 
present before antiretroviral therapy/regimen initiation has been described [1, 26]. 
 
4. Sarcoidosis. Worsening of previously diagnosed sarcoidosis or newly diagnosed sarcoidosis following 
antiretroviral therapy/regimen has been reported. Pulmonary involvement as well as extrapulmonary 
involvement (erythema nodosum) has been described [1, 26].