HIV HOspital TEsting: Bringing the Hidden to Light in the Hospital Setting: A Monocentric Observational Cross-Sectional Study
Conditions: Hiv, HIV Infections, AIDS
Sponsor: Castagna Antonella

 
 
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CLINICAL STUDY PROTOCOL 
 
Study Code: HIV-HOTE (HIV Hospital Test) 
 
Title: HIV testing: bringing to light the hidden burden in the intra-hospital setting 
 
Principal Investigator: Silvia Nozza, MD 
 
 
 
CLINICAL STUDY PROTOCOL 
Title: HIV testing: bringing to light the hidden burden in the intra-hospital setting 
 
Study Identifier 
HIV-HOTE (HIV Hospital Test) 
RSO number 
NA 
Other Protocol Codes 
NCT06282328 
Version 
1.0 
Date 
27-Nov-2023 
 
 
Sponsor 
Ospedale San Raffaele  
Authorized Sponsor 
Representative 
Antonella Castagna 
Professor 
Infectious Diseases Unit,  
IRCCS Ospedale San Raffaele Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy 
Principal Investigator 
Silvia Nozza, MD 

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DISCLAIMER 
This material is strictly private, confidential and property of the Sponsor. Its contents must not 
be disclosed or used except as authorized in writing by the Sponsor. 
 
 
Infectious Diseases Unit, 
IRCCS Ospedale San Raffaele, Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy 
Co-Investigator 
Angelo Roberto Raccagni, MD 
Infectious Diseases Unit, 
IRCCS Ospedale San Raffaele, Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy 
Vita-Salute San Raffaele University, Milan 

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VERSION HISTORY 
 
 
 
 
Protocol 
version n. 
Reason of changes 
Date issued 
 
 
 
 
 
 
1.0 
First Version submitted to the Ethics Committee (EC) 
27 Nov 2023  

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PROTOCOL SIGNATURE PAGE 
 
Study Title: HIV testing: bringing to light the hidden burden in the intra-hospital setting 
Study Code: HIV-HOTE (HIV Hospital Test) 
Protocol Version and Date: 1.0 27 Nov 2023 
 
The undersigned has read and understood all the aspects of the protocol detailed within this 
document and agrees to supervise and conduct the study in accordance with the protocol, the 
Declaration of Helsinki, Guideline for Good Clinical Practice ICH E6 (R2), and all applicable 
regulatory requirements. 
 
 
 
 
 
Silvia Nozza 
 
____________________ 
Principal Investigator 
Name 
 
 
 
 
_________________ 
Signature 
 
 
 
 
U.O. Infectious Diseases, 
IRCCS Ospedale San 
Raffaele  
___________________ 
Affiliation 
 
 
 
 
 
09 Feb 2026 
_________ 
Date 
 
 
 
Antonella Castagna 
 
 
 
U.O. Infectious 
Diseases, 
IRCCS Ospedale San 
Raffaele 
 
09 Feb 2026 
Authorized Sponsor 
Representative Name 
 
 
Signature 
 
Affiliation 
 
 
Date 

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TABLE OF CONTENTS 
1. 
KEY STUDY CONTACTS ................................................................................................................................................. 8 
2. 
SYNOPSIS ............................................................................................................................................................................ 8 
3. 
ABBREVIATIONS AND DEFINITIONS .......................................................................................................................... 14 
3.1. 
Abbreviations ................................................................................................................................................... 14 
3.2. 
Definitions ............................................................................... Errore. Il segnalibro non è definito. 
4. 
BACKGROUND AND RATIONALE ............................................................................................................................... 14 
5. 
OBJECTIVES AND ENDPOINTS ................................................................................................................................... 16 
6. 
STUDY DESIGN ................................................................................................................................................................. 18 
6.1. 
Study duration ................................................................................................................................................. 18 
7. 
STUDY POPULATION ...................................................................................................................................................... 18 
7.1. 
Study Participants .......................................................................................................................................... 18 
7.2. 
Inclusion Criteria ............................................................................................................................................. 18 
7.3. 
Exclusion Criteria ............................................................................................................................................ 19 
7.4. 
Screening Failures ............................................................. Errore. Il segnalibro non è definito. 
8. 
STUDY OBJECT  ............................................................................................................................................................... 19 
8.1. 
Study object description ................................................ Errore. Il segnalibro non è definito. 
9. 
STUDY PROCEDURES ..................................................................................................................................................... 19 
9.1. 
Informed Consent .......................................................................................................................................... 21 
9.2. 
Subject Recruitment and Screening ........................ Errore. Il segnalibro non è definito. 
9.3. 
Subject Identification ....................................................... Errore. Il segnalibro non è definito. 
9.4. 
Baseline Assessments ..................................................... Errore. Il segnalibro non è definito. 
9.5. 
Visits and Follow Up .......................................................... Errore. Il segnalibro non è definito. 
9.6. 
Definition of End of Study ............................................... Errore. Il segnalibro non è definito. 
9.7. 
Premature termination or suspension of a studyErrore. 
Il 
segnalibro 
non 
è 
definito. 
10. 
DISCONTINUATION AND WITHDRAWAL ............................... Errore. Il segnalibro non è definito. 
11. 
SAMPLE HANDLING .................................................................................................................................................... 21 

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12. 
PATIENT SAFETY .......................................................................................................................................................... 21 
13. 
DATA MANAGEMENT ............................................................................................................................................... 22 
13.1. 
Definition of source data and source documentsErrore. 
Il 
segnalibro 
non 
è 
definito. 
13.2. 
Documentation of data in Case Report Forms (CRFs) ............................................................ 22 
13.3. 
Data Recording and Record Keeping ................................................................................................. 23 
13.4. 
Data Protection .............................................................................................................................................. 23 
14. 
STATISTICS .................................................................................................................................................................. 23 
14.1. 
Description of Statistical Methods ....................................................................................................... 23 
14.2. 
Sample Size Determination...................................................................................................................... 24 
14.3. 
Analysis Populations ........................................................ Errore. Il segnalibro non è definito. 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................................... 24 
15.1. 
Responsibilities of the Investigator(s) ............................................................................................... 24 
15.2. 
Ethics Committee (EC) Approvals ...................................................................................................... 25 
15.3. 
Other Ethical Considerations ....................................... Errore. Il segnalibro non è definito. 
16. 
GENDER MEDICINE IN RESEARCH PROTOCOL .................... Errore. Il segnalibro non è definito. 
17. 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................................... 25 
17.1. 
Deviation from study protocol .................................... Errore. Il segnalibro non è definito. 
17.2. 
Surveillance for observational studies with additional procedureErrore. 
Il 
segnalibro non è definito. 
18. 
FINANCE AND INSURANCE .................................................................................................................................... 26 
18.1. 
Funding .................................................................................... Errore. Il segnalibro non è definito. 
18.2. 
Patient Insurance .......................................................................................................................................... 26 
19. 
END OF CLINICAL STUDY ........................................................................................................................................ 26 
19.1. 
Summary of the results of the clinical study .................................................................................. 26 
20. 
INTELLECTUAL PROPERTY ....................................................................................................................................... 26 
21. 
PUBLICATION POLICY .............................................................................................................................................. 26 
22. 
REFERENCES ................................................................................................................................................................ 26 

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23. 
APPENDIX A:  AMENDMENT HISTORY ..................................... Errore. Il segnalibro non è definito. 
24. 
APPENDIX B:  LIST OF CLINICAL SERVICES / LABORATORIESErrore. Il segnalibro non è 
definito. 
25. 
APPENDIX C:  LIST OF ENROLLING SITES ............................... Errore. Il segnalibro non è definito. 
 
 
 

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1. 
KEY STUDY CONTACTS 
 
 
Sponsor 
Ospedale San Raffaele 
Via Olgettina, 60 
20132 – Milano, Italy 
 
Authorized Sponsor 
Representative 
Antonella Castagna 
Professor 
Infectious Diseases Unit,  
IRCCS Ospedale San Raffaele Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy  
Tel 02-26437934 
Email: castagna.antonella@hsr.it 
Principal Investigator 
Silvia Nozza, MD 
Infectious Diseases Unit, 
IRCCS Ospedale San Raffaele, Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy  
Tel 02-26437934 
Email: nozza.silvia@hsr.it 
Study Clinical Unit  
U.O. Infectious Diseases, IRCCS Ospedale San Raffaele, 
Tel 0226437934, 0226432276 
Email: carini.elisabetta@hsr.it, bagaglio.sabrina@hsr.it 
Clinical Trial Center 
Email: ctc.firstcontact@hsr.it; ctc.trialstartup@hsr.it; 
ctc.datamanagement@hsr.it; ctc.quality@hsr.it 
 
2. SYNOPSIS 
 
Study Identifier 
HIV-HOTE (HIV Hospital Test) 
Study Title 
HIV testing: bringing to light the hidden burden in the intra-
hospital setting 
 

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Protocol Version and 
Date 
1.0 27 Nov 2023 
Sponsor  
IRCCS Ospedale San Raffaele 
Principal Investigator 
Silvia Nozza, MD 
Infectious Diseases Unit, 
IRCCS Ospedale San Raffaele, Milan 
Via Stamira D’Ancona, 20 
20127 Milan, Italy 
Study Description 
Considering that 1 out of 3 HIV diagnoses occur among people 
with symptoms or diseases attributable to the infection, the 
number of late presenters could be reduced by implementing 
new testing strategies also at the hospital level (intra-hospital 
setting). HIV testing is already regularly performed for people 
with AIDS-defining clinical conditions that are strictly associated 
with HIV infection; however, there are further clinical conditions 
that, although not directly associated with an AIDS stage, can 
be considered indicators of HIV infection. 
The "HIV indicator conditions" (hereafter HIV-IC) are a series of 
clinical, radiological and laboratory conditions, which include, in 
addition to all AIDS-defining conditions, many non-AIDS-
defining conditions. 
HIV-IC can be used as a warning sign for performing HIV 
testing; these are associated with HIV infection because they 
share the same risk factors (as for example in the case of 
infection with hepatotropic viruses) or develop following 
early/late immunosuppression (as for example herpes zoster). 
Moreover, the use of HIV-IC, in combination with behavioural risk 
factors, represents a valid strategy to apply to hospital clinical 
practice. In the extra-hospital setting, access to testing is based 
only on behavioural risk factors and is therefore often limited to 
key populations, with a disparity in access to testing. The intra-
hospital setting instead ensures the possibility of combining 
information on risk behaviours with numerous clinical, 
radiological and laboratory data, available during standard 
clinical practice. This strategy could allow access to HIV testing 
to be expanded to new populations, while still ensuring an 
evidence-guided strategy, individualized to the single person. 
The purpose of this study is to evaluate the prevalence of HIV 
infection, previously unknown, in the hospital setting (in the 
different inpatient wards of medical or surgical areas) in people 

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with the presence of at least one HIV-IC and/or risk behaviours. 
The prevalence will be estimated in relation to the different HIV-
IC and risk behaviours and, finally, the predictive performance 
of the HIV-IC and risk strata for the presence of HIV infection will 
be assessed. 
Study Design 
.Cross-sectional, single-center study, with an additional 
procedure. 
The study provides for the collection of clinical and laboratory 
data on people with the presence of at least one HIV-IC and/or 
behavioural risk factor for HIV infection, admitted to a Hospital 
Operating Unit of San Raffaele Hospital in Milan, for any reason 
(Appendix B). 
Primary Objective 
 To estimate the 
prevalence of HIV 
infection previously 
unknown (new HIV 
infection) in the hospital 
setting among people 
with the presence of at 
least one HIV-IC and/or 
risk behaviours. 
Primary Endpoint 
The primary endpoint will 
be assessed by calculating 
the proportion of people 
with newly diagnosed HIV 
infection 
previously 
unknown in the hospital 
setting, confirmed (positive 
HIV test), out of the total 
number of people included 
in the study and tested for 
HIV. 
 
 Time point(s)  
Primary 
endpoint 
detection 
times 
At 
the 
end 
of 
the 
planned 
enrollment procedure 
Secondary Objectives 
. 
• 
Assess the 
association between the 
presence of newly 
diagnosed HIV infection 
and the different HIV-IC 
categories. 
• 
Assess the 
association between the 
presence of newly 
diagnosed HIV infection 
and the different 
behavioural risk factors. 
Secondary Endpoints 
 The secondary objectives 
will 
be 
assessed 
by 
calculating: 
• 
Proportion 
of 
people 
with 
newly 
diagnosed HIV infection in 
relation 
to 
the 
presence/absence of the 
different HIV-IC (class 1, 2 
or 3). 
• 
Proportion 
of 
people 
with 
newly 
diagnosed HIV infection in 
relation 
to 
the 
Time point(s)  
Secondary endpoints detection 
times 
At 
the 
end 
of 
the 
planned 
enrollment procedure 

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• 
Assess the 
association between the 
presence of newly 
diagnosed HIV infection 
and the number of HIV-
IC and behavioural risk 
factors present. 
• 
Assess the 
number of new HIV 
infections according to 
the Hospital Operating 
Unit (medical or 
surgical). 
• 
Assess the 
association between the 
stage of newly 
diagnosed HIV infection, 
assessed on the basis of 
HIV-RNA and CD4+ 
lymphocyte level, and 
the different HIV-IC and 
behavioural risk factors. 
presence/absence of the 
different behavioural risk 
factors. 
• 
Mean 
number 
of 
"HIV-IC and/or behavioural 
risk 
factors" 
present 
in 
people 
with 
newly 
diagnosed HIV infection. 
• 
Proportion 
of 
people 
with 
newly 
diagnosed 
HIV 
infection 
according to the Hospital 
Operating Unit. 
• 
Mean 
HIV-RNA 
value 
and 
CD4+ 
lymphocytes 
at 
HIV 
diagnosis (proportion of 
late presenters). 
 
Study Population 
People admitted to different Hospital Operating Units of San 
Raffaele Hospital (medical or surgical area) will be included. 
Inclusion Criteria 
• 
People older than 14 years. 
• 
People with at least one of the following criteria: 
• 
Presence of at least one HIV-IC. 
• 
Presence of behavioural risk factors for HIV infection. 
• 
People who provide specific written informed consent for 
the study, or if minors whose parents or legal guardians provide 
specific written informed consent for the study 
Exclusion Criteria 
• 
People who do not provide specific written informed 
consent for the study. 
• 
People with known HIV infection. 
PROCEDURE 
Procedure(s) 
Patients will be actively recruited into the study in the different 
Hospital Operating Units (medical or surgical) of San Raffaele 
Hospital. After the patient has provided and dated/signed their 
informed consent to participate in the study, the clinical and 

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laboratory information relevant to the study, as well as study-
specific blood samples, will be collected. The assessment of 
clinical, radiological and laboratory parameters already 
available during the hospital admission will allow the presence 
of at least one HIV-IC to be established 
Additional procedure 
Immediately after the patient has provided and dated/signed 
their informed consent to participate in the study, the 
hospitalized patient will be asked some questions (Appendix C) 
aimed at identifying the presence of behavioural risk factors for 
HIV infection. In case of the presence of at least one HIV-IC or a 
behavioural risk factor, the person will be eligible for inclusion in 
the clinical study and the capillary rapid HIV test will be 
performed. 
If the capillary blood rapid HIV test is positive, on the same day, 
according to clinical practice, the antigen/antibody test (using 
the Cobas 6800® method) and HIV Western Blot on venous 
blood will be performed for confirmation of infection. HIV tests 
and Western Blot will be performed at the virology laboratory of 
San Raffaele Hospital in Milan. 
In case of confirmed HIV infection (positive HIV test and positive 
Western Blot test), according to good clinical practice, an 
infectious diseases specialist will perform a patient evaluation, 
within 48 hours of diagnosis and before discharge, in order to: 
• 
request the determination of: viral load (HIV-RNA), CD4+ 
lymphocyte count, presence of other co-infections with 
hepatitis viruses (in particular HBV and HCV), according to 
clinical practice; 
• 
refer the person to an outpatient follow-up pathway, 
after discharge, according to clinical practice, at the Infectious 
Diseases Unit of San Raffaele Hospital. 
In case of a negative capillary HIV test, the patient will be 
informed of the negative result of the test. 
Signing the informed consent, collection of clinical and 
laboratory data, questions on behavioural risk factors and 
performance of the HIV test will be carried out on the same day. 
Sample Size  
It is planned to enrol 1000 people admitted to the different 
Hospital Operating Units of San Raffaele Hospital. An HIV 
infection finding is estimated in 3% of people tested on the basis 
of HIV-IC and risk behaviours. Under the hypothesis that the 
prevalence of HIV is 3%, a sample size of 1000 people allows a 

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two-sided 95% confidence interval for this prevalence between 
1.9% and 4.1% to be obtained. 
Statistical Design 
Statistical analyses will be carried out internally within the Infectious 
Diseases Unit of San Raffaele Hospital. 
The median (first and third quartile) and frequency (percentage) will be 
used to describe the characteristics of people with or without HIV 
infection, HIV-IC and risk behaviours. 
The assessment of the primary endpoint involves estimating the 
proportion of people with previously unknown HIV infection and the 
corresponding two-sided 95% confidence interval. 
Characteristics of subjects with and without HIV infection will be 
compared with Fisher’s exact/chi-square test or the Mann-Whitney test. 
The assessment of HIV-IC and/or risk behaviours as risk factors for HIV 
infection will be evaluated through a univariate logistic regression. 
The presence of a linear trend in the proportion of people with HIV 
infection and the number of HIV-IC and/or risk behaviours will be 
evaluated through the Cochran-Armitage test for trend. 
Two-sided p-values <0.05 will be considered statistically significant. 
Statistical analyses will be performed with SAS software, version 9.4 
(SAS Institute, Cary, NC). 
 
 
Duration of the Study 
Overall study duration: 24 months. 
Enrolment duration: 20 months. 
Duration of extraction and review of clinical and biochemical 
data: 2 months. 
Duration of statistical analysis: 1 month. 
Duration of results writing: 1 month. 

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3. ABBREVIATIONS AND DEFINITIONS 
3.1. Abbreviations 
. 
 
CIOMS 
Council for International Organization of Medical Science 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
CTC 
Clinical Trial Center 
DPIA 
Data Protection Impact Assessment 
EC 
Ethics Committee 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
LVLP 
Last Visit of Last Patient 
MedDRA 
Medical Dictionary for Regulatory Activities 
OSR 
Ospedale San Raffaele 
PI 
Principal Investigator 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
 
 
4. BACKGROUND AND RATIONALE 
According to the Italian bulletin of 2020 (COA ISS), 60% of new HIV diagnoses were found among 
people with advanced infection or late presenters (people with a CD4+ lymphocyte count 
below 350 cells/microL), reaching 67% among heterosexual women. Reducing the number of 
late diagnoses is crucial to achieve better clinical outcomes and reduce secondary 
transmission. 
The proportion of late presenters has been increasing since 2015 despite screening efforts both 
in hospital and in territorial (community-based) settings aimed at the general population 
(extra-hospital setting). These strategies mainly target people at high risk of HIV infection, 
based on sexual behaviours (such as men who have sex with men, MSM) or use of narcotic 

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substances (people who use substances intravenously, IDU), while not reaching those who do 
not belong to key populations. Consequently, strategies to strengthen access to HIV testing are 
needed. 
Considering that 1 out of 3 HIV diagnoses occur among people with symptoms or diseases 
attributable to the infection, the number of late presenters could be reduced by implementing 
new testing strategies also at the hospital level (intra-hospital setting). HIV testing is already 
regularly performed for people with AIDS-defining clinical conditions that are strictly associated 
with HIV infection; however, there are further clinical conditions that, although not directly 
associated with an AIDS stage, can be considered indicators of HIV infection. 
The "HIV indicator conditions" (hereafter HIV-IC) are a series of clinical, radiological and 
laboratory conditions, which include, in addition to all AIDS-defining conditions, many non-
AIDS-defining conditions. 
The indicators are grouped into 3 different categories: 
• 
AIDS-defining conditions; 
• 
Conditions associated in the literature with HIV infection in >0.1% of cases (non-AIDS-
defining); 
• 
Conditions in which undiagnosed HIV infection would lead to serious adverse conditions 
(non-AIDS-defining). 
The complete list of HIV-IC is presented in Appendix A. 
HIV-IC can be used as a warning sign for performing HIV testing; these are associated with HIV 
infection because they share the same risk factors (as for example in the case of infection with 
hepatotropic viruses) or develop following early/late immunosuppression (as for example 
herpes zoster). 
Moreover, the use of HIV-IC, in combination with behavioural risk factors, represents a valid 
strategy to apply to hospital clinical practice. In the extra-hospital setting, access to testing is 
based only on behavioural risk factors and is therefore often limited to key populations, with a 
disparity in access to testing. The intra-hospital setting instead ensures the possibility of 
combining information on risk behaviours with numerous clinical, radiological and laboratory 
data, available during standard clinical practice. This strategy could allow access to HIV testing 
to be expanded to new populations, while still ensuring an evidence-guided strategy, 
individualized to the single person. 

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The purpose of this study is to evaluate the prevalence of HIV infection, previously unknown, in 
the hospital setting (in the different inpatient wards of medical or surgical areas) in people with 
the presence of at least one HIV-IC and/or risk behaviours. The prevalence will be estimated in 
relation to the different HIV-IC and risk behaviours and, finally, the predictive performance of 
the HIV-IC and risk strata for the presence of HIV infection will be assessed. 
5. OBJECTIVES AND ENDPOINTS 
Primary objective. 
The primary objective of the study is to estimate the prevalence of HIV infection previously 
unknown (new HIV infection) in the hospital setting among people with the presence of at least 
one HIV-IC and/or risk behaviours. 
Primary endpoint. 
The primary endpoint will be assessed by calculating the proportion of people with newly 
diagnosed HIV infection previously unknown in the hospital setting, confirmed (positive HIV 
test), out of the total number of people included in the study and tested for HIV. 
Secondary objectives. 
• 
Assess the association between the presence of newly diagnosed HIV infection and the 
different HIV-IC categories. 
• 
Assess the association between the presence of newly diagnosed HIV infection and the 
different behavioural risk factors. 
• 
Assess the association between the presence of newly diagnosed HIV infection and the 
number of HIV-IC and behavioural risk factors present. 
• 
Assess the number of new HIV infections according to the Hospital Operating Unit 
(medical or surgical). 
• 
Assess the association between the stage of newly diagnosed HIV infection, assessed 
on the basis of HIV-RNA and CD4+ lymphocyte level, and the different HIV-IC and behavioural 
risk factors. 
Secondary endpoints. 
The secondary objectives will be assessed by calculating: 
• 
Proportion of people with newly diagnosed HIV infection in relation to the 
presence/absence of the different HIV-IC (class 1, 2 or 3). 
• 
Proportion of people with newly diagnosed HIV infection in relation to the 
presence/absence of the different behavioural risk factors. 
• 
Mean number of "HIV-IC and/or behavioural risk factors" present in people with newly 
diagnosed HIV infection. 

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• 
Proportion of people with newly diagnosed HIV infection according to the Hospital 
Operating Unit. 
• 
Mean HIV-RNA value and CD4+ lymphocytes at HIV diagnosis (proportion of late 
presenters). 
 
 
 
Objectives 
Endpoints 
Time point(s)  
Primary Objective 
To estimate the prevalence of 
HIV infection previously unknown 
(new HIV infection) in the 
hospital setting among people 
with the presence of at least 
one HIV-IC and/or risk 
behaviours 
Primary Endpoint 
The primary endpoint will be assessed 
by calculating the proportion of 
people with newly diagnosed HIV 
infection previously unknown in the 
hospital setting, confirmed (positive 
HIV test), out of the total number of 
people included in the study and 
tested for HIV. 
 
Primary 
endpoint 
detection times 
At the end of the 
planned 
enrollment 
procedure 
Secondary Objectives 
Assess the association between 
the presence of newly 
diagnosed HIV infection and the 
different HIV-IC categories. 
• 
Assess the association 
between the presence of newly 
diagnosed HIV infection and the 
different behavioural risk 
factors. 
• 
Assess the association 
between the presence of newly 
diagnosed HIV infection and the 
number of HIV-IC and 
behavioural risk factors present. 
• 
Assess the number of 
new HIV infections according to 
Secondary Endpoints 
The secondary objectives will be 
assessed by calculating: 
• 
Proportion 
of 
people 
with 
newly diagnosed HIV infection in 
relation to the presence/absence of 
the different HIV-IC (class 1, 2 or 3). 
• 
Proportion 
of 
people 
with 
newly diagnosed HIV infection in 
relation to the presence/absence of 
the different behavioural risk factors. 
• 
Mean 
number 
of 
"HIV-IC 
and/or 
behavioural 
risk 
factors" 
present 
in 
people 
with 
newly 
diagnosed HIV infection. 
• 
Proportion 
of 
people 
with 
newly 
diagnosed 
HIV 
infection 
Secondary 
endpoint 
detection times 
At the end of the 
planned 
enrollment 
procedure 

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the Hospital Operating Unit 
(medical or surgical). 
• 
Assess the association 
between the stage of newly 
diagnosed HIV infection, 
assessed on the basis of HIV-
RNA and CD4+ lymphocyte 
level, and the different HIV-IC 
and behavioural risk factors. 
according to the Hospital Operating 
Unit. 
• 
Mean 
HIV-RNA 
value 
and 
CD4+ lymphocytes at HIV diagnosis 
(proportion of late presenters). 
 
 
 
6. STUDY DESIGN 
Cross-sectional, single-center study, with an additional procedure. 
The study provides for the collection of clinical and laboratory data on people with the presence 
of at least one HIV-IC and/or behavioural risk factor for HIV infection, admitted to a Hospital 
Operating Unit of San Raffaele Hospital in Milan, for any reason (Appendix B). 
6.1. 
Study duration  
Overall study duration: 24 months. 
Enrolment duration: 20 months. 
Duration of extraction and review of clinical and biochemical data: 2 months. 
Duration of statistical analysis: 1 month. 
Duration of results writing: 1 month. 
 
7. STUDY POPULATION 
7.1. Study Participants  
 
People admitted to different Hospital Operating Units of San Raffaele Hospital (medical 
or surgical area) will be included. 
 
7.2. Inclusion Criteria  
• 
People older than 14 years. 

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• 
People with at least one of the following criteria: 
• 
Presence of at least one HIV-IC. 
• 
Presence of behavioural risk factors for HIV infection. 
• 
People who provide specific written informed consent for the study, or if minors 
whose parents or legal guardians provide specific written informed consent for the 
study. 
 
7.3. Exclusion Criteria  
• 
People who do not provide specific written informed consent for the study. 
• 
People with known HIV infection. 
 
 
8. STUDY VARIABLES 
The information collected during the hospital admission that will be verified and recorded is 
(Appendix D): 
• 
Gender and age; 
• 
General clinical assessment (e.g., symptoms, new clinical events, including adverse 
events, vital signs); 
• 
Results of the most recent laboratory tests; 
• 
Abdominal circumference and weight; 
• 
Systolic and diastolic blood pressure; 
• 
HIV test result; 
• 
If HIV infection is confirmed (according to clinical practice): viral load (HIV-RNA), CD4+ 
lymphocyte count, co-infection with hepatitis viruses (in particular HBV and HCV), history of 
AIDS-defining events; 
• 
Smoking habit, alcohol consumption; 
• 
Comorbidities (including cancers, diabetes, cardiovascular, renal and liver diseases, 
psychiatric disorders (with a focus on depression), sexually transmitted diseases); 
• 
Risk behaviours (e.g., use of substances intravenously, sexual habits); 
• 
Concomitant medications. 
9. STUDY PROCEDURES 
 

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Patients will be actively recruited into the study in the different Hospital Operating Units (medical 
or surgical) of San Raffaele Hospital. After the patient has provided and dated/signed their 
informed consent to participate in the study, the clinical and laboratory information relevant to 
the study, as well as study-specific blood samples, will be collected. The assessment of clinical, 
radiological and laboratory parameters already available during the hospital admission will 
allow the presence of at least one HIV-IC to be established. 
ADDITIONAL PROCEDURES OR ANALYSES: Immediately after the patient has provided and 
dated/signed their informed consent to participate in the study, the hospitalized patient will be 
asked some questions (Appendix C) aimed at identifying the presence of behavioural risk 
factors for HIV infection. In case of the presence of at least one HIV-IC or a behavioural risk 
factor, the person will be eligible for inclusion in the clinical study and the capillary rapid HIV 
test will be performed. 
If the capillary blood rapid HIV test is positive, on the same day, according to clinical practice, 
the antigen/antibody test (using the Cobas 6800® method) and HIV Western Blot on venous 
blood will be performed for confirmation of infection. HIV tests and Western Blot will be 
performed at the virology laboratory of San Raffaele Hospital in Milan. 
In case of confirmed HIV infection (positive HIV test and positive Western Blot test), according 
to good clinical practice, an infectious diseases specialist will perform a patient evaluation, 
within 48 hours of diagnosis and before discharge, in order to: 
• 
request the determination of: viral load (HIV-RNA), CD4+ lymphocyte count, presence 
of other co-infections with hepatitis viruses (in particular HBV and HCV), according to clinical 
practice; 
• 
refer the person to an outpatient follow-up pathway, after discharge, according to 
clinical practice, at the Infectious Diseases Unit of San Raffaele Hospital. 
In case of a negative capillary HIV test, the patient will be informed of the negative result of the 
test. 
Signing the informed consent, collection of clinical and laboratory data, questions on 
behavioural risk factors and performance of the HIV test will be carried out on the same day. 
 
 
Procedures 
Day 0 
Informed consent 
X 
Demographics 
X 
Survey on behaviours 
X 
Assessment of HIV-IC 
X 
HIV rapid test 
X 
 

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9.1. Informed Consent 
The study will be conducted in accordance with the ethical principles deriving from the 
Declaration of Helsinki and with the current regulations on Observational Studies. 
The investigators involved will conduct the study in accordance with this protocol and the 
applicable GCP. 
Before the formal activation of the study, approval by the Ethics Committee of IRCCS Ospedale 
San Raffaele is planned. 
All patients will be informed as exhaustively as possible about all aspects concerning the study 
in a language and in terms totally understandable to them. Before the patient’s participation, 
specific written informed consent for the study will be obtained. 
The signed and dated informed consent form will be filed in the Trial Master File; a copy of the 
consent will be delivered to each participating subject. 
10. SAMPLE HANDLING 
No ad hoc collection of biological samples is planned for this study. Capillary rapid HIV tests will 
be destroyed immediately after the test is performed. The venous blood drawn in case of a 
possible positive rapid HIV test will be destroyed at the end of the study. 
The venous blood HIV test and the possible Western Blot will be performed on venous blood 
already available and drawn for hematochemical tests prescribed according to clinical 
practice by the ward treating physician. No storage of samples beyond the usual laboratory 
practice in force at San Raffaele Hospital is planned. 
 
11. PATIENT SAFETY 
The participant may feel intimidated or uncomfortable in answering some personal questions 
such as those related to their sexual habits or substance use. The possibility will be given to 
answer the questions autonomously on a paper sheet. On the paper sheet, the participant’s 
name, nor any other information that could identify them, will be reported, but only an 
identification number that will allow the data to be identified within the study. 
Blood sampling: The HIV test will be performed on capillary blood and, in case of a positive test, 
the HIV antigen/antibody test and the HIV test on venous blood will be performed. For this 
reason, there are no additional risks resulting from the procedures of this study beyond those 
related to blood draws performed during admission and which are: 
• 
there is the possibility of experiencing discomfort if bleeding, swelling, dizziness or 
bruising occurs when the needle is inserted into the arm; 

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• 
fainting or infections may rarely occur; 
• 
very rarely, vascular or nerve lesions may occur which can result in permanent damage 
in individual cases. 
Social risks: The study staff undertakes to implement every action to protect participants’ 
privacy. Following confirmation of HIV infection, regular follow-up of the patient at an Infectious 
Diseases outpatient center for the treatment of the infection will be necessary after the study: 
this could reveal problems in the social sphere. When a participant becomes aware of being 
HIV positive, they may feel depressed and suicidal. During follow-up outpatient visits, the 
patient’s infectious diseases specialist will try to assess these aspects and, when necessary, 
support the patient also through counselling. 
 
12. DATA MANAGEMENT   
The data recorded in medical records and the study variables will be collected in an eCRF and 
reported in pseudonymized form, and used in this way for statistical analysis. Such data will be 
processed in compliance with the patient’s rights and the Sponsor’s right to rework and publish 
them for scientific purposes, after appropriate anonymization or pseudonymization, depending 
on the case and on the scientific needs to be met. 
Responsibility for data collection 
Data collection will be the responsibility of the staff involved in the clinical trial under the 
supervision of the Principal Investigator of the study. During the conduct of the study, the 
Investigator will maintain complete and accurate documentation. 
Clinical documents and data archiving 
Data collection will be the responsibility of the staff involved in the clinical trial under the 
supervision of the Principal Investigator of the study. The data will be reported in an accurate, 
complete and legible manner, exactly as recorded in the original documents (medical records, 
reports, etc.). 
The entered data may be modified by the Principal Investigator or by a person delegated by 
them for data entry, in accordance with the modalities provided by GCP. 
All data and documents related to the research will be kept and protected from unauthorized 
access in the Study Trial Master File. 
12.1. Documentation of data in Case Report Forms (CRFs)  

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All relevant data collected during the study for all of the patients enrolled in the study shall be 
entered in the CRF by the principal investigator or someone authorized by the investigator in a 
timely manner (as soon as possible after the information is collected) to ensure that they are 
clear and legible. The physician shall confirm the completeness, correctness, plausibility, and 
compliance with the ICH guidelines and the institutional SOPs of the data by dated signature. 
An explanation must be provided for any and all missing data. The entries shall be made with 
black ballpoint pen. 
The properly filled in CRF will remain in the study site; in case of electronic CRF, a copy of all 
pages will be conserved in the study site. 
12.2. Data Recording and Record Keeping 
The investigator shall arrange for the retention of Essential Documents for the Conduct of a 
Clinical study (e.g., patient files, other source data, and the Trial Master File/Investigator Site 
File) after the completion or discontinuation of the study according to institutional procedures 
and applicable laws. 
 
12.3. Data Protection  
Information related to study subjects will be kept confidential and managed according to the 
relevant provisions (D.L. 196/30 June 2003 and subsequent amendments and additions and EU 
Regulation 679/2016; Privacy Authority Guidelines of 24/07/2008). 
Each patient will be assigned an identification code and the data collected during the Study, 
except for the name, will be recorded, processed and stored together with this code, age, sex, 
weight, height and all clinical data relating to health status. Only the study physician and 
authorized persons may link the code to the name and will not provide third parties with the 
data of patients included in the study. Therefore, all those who conduct research activities on 
the information collected within the study will treat the information in coded form (use of the 
code for each patient). 
13. STATISTICS 
It is not performed by a CRO. 
 
13.1. Description of Statistical Methods 
 Statistical analyses will be carried out internally within the Infectious Diseases Unit of San 
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The median (first and third quartile) and frequency (percentage) will be used to describe the 
characteristics of people with or without HIV infection, HIV-IC and risk behaviours. 
The assessment of the primary endpoint involves estimating the proportion of people with 
previously unknown HIV infection and the corresponding two-sided 95% confidence interval. 
Characteristics of subjects with and without HIV infection will be compared with Fisher’s 
exact/chi-square test or the Mann-Whitney test. 
The assessment of HIV-IC and/or risk behaviours as risk factors for HIV infection will be 
evaluated through a univariate logistic regression. 
The presence of a linear trend in the proportion of people with HIV infection and the number of 
HIV-IC and/or risk behaviours will be evaluated through the Cochran-Armitage test for trend. 
Two-sided p-values <0.05 will be considered statistically significant. Statistical analyses will be 
performed with SAS software, version 9.4 (SAS Institute, Cary, NC).  
13.2. Sample Size Determination 
It is planned to enrol 1000 people admitted to the different Hospital Operating Units of San 
Raffaele Hospital. An HIV infection finding is estimated in 3% of people tested on the basis of 
HIV-IC and risk behaviours. Under the hypothesis that the prevalence of HIV is 3%, a sample size 
of 1000 people allows a two-sided 95% confidence interval for this prevalence between 1.9% and 
4.1% to be obtained. 
14. ETHICAL AND REGULATORY CONSIDERATIONS 
This clinical study will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments established by the 
World Medical Assemblies, and the ICH guidelines for Good Clinical Practice.  
This clinical study will be conducted in compliance with all international laws and regulations; 
national laws and regulations of the country in which the clinical study is performed; as well as 
any other applicable guidelines. 
 
14.1. Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) the responsibility to perform the study in accordance with this 
Protocol, Good Clinical Practice, and the applicable regulatory requirements. The Investigator is 
required to ensure compliance with the investigational product schedule, visits schedule, and 

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procedures required by the protocol. The Investigator agrees to provide all information 
requested in the Case Report Form (CRF) in an accurate and legible manner. The investigator 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to study subjects without prior EC approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and, if appropriate, the proposed 
protocol amendment(s) should be submitted. The investigator must have available an 
adequate number of qualified staff and adequate facilities for the foreseen duration of the 
study to conduct the study properly and safely. 
 
14.2. 
Ethics Committee (EC) Approvals  
This clinical study protocol as well as the Informed Consent are to be submitted to the 
appropriate Ethics Committee, and it is mandatory to obtain the written and dated approval, 
signed by the chairman with Ethics Committee(s) composition. 
The clinical study the documents reviewed, the list of voting members and their qualifications, 
and the date of the review should be clearly stated on the written Ethics Committee approval. 
 
 
15. QUALITY ASSURANCE AND QUALITY CONTROL 
As this is an observational study that provides for the execution of the following additional 
procedure: capillary HIV test, a study “surveillance” activity will be carried out. 
To guarantee study quality, the Sponsor will implement the following operating modalities: 
• 
The Sponsor’s CTC-Quality Unit sets up the TMF/ISF with the related forms (delegation 
log, subject log, AE/SAE log, etc.) using its own templates; 
• 
The PI organizes a study kick-off meeting (also via telematics) with the coordinating 
center team. The PI presents the protocol and CTC-Quality explains document management, 
the Informed Consent collection process, and patient safety management. CTC-Quality will 
minute and share the meeting minutes with participants. 
• 
The PI must communicate to CTC-Quality any SAE and major deviations from the 
protocol and GCP; 
• 
CTC-Quality may request periodic updates from the PI and conduct audits of the study 
to verify correct application of the protocol, applicable regulations and institutional procedures. 
 
 

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16. FINANCE AND INSURANCE 
16.1. Patient Insurance 
Given the observational nature of the proposed study, insurance coverage is not necessary. 
The study is non-profit and does not receive dedicated funding. No additional costs are expected for 
administering questionnaires on sexual behaviours and for collecting and performing data analysis. 
Expenses for any resources required (capillary rapid HIV tests) will be covered by funds available to the 
Infectious Diseases Unit. 
17. END OF CLINICAL STUDY 
In accordance with applicable regulation, ICH GCP and SOPs, the PI shall notify the end of the 
clinical study within 15 days from the end of the clinical study and the reasons for such action. 
17.1. Summary of the results of the clinical study 
Irrespective of the outcome of a clinical study, within one year from the end of a clinical study, 
the PI shall submit a summary of the results of the clinical study.  
 
18. INTELLECTUAL PROPERTY  
The data and results generated by the study are the property of IRCCS Ospedale San Raffaele. 
 
19. PUBLICATION POLICY 
Study results will be made public in anonymous form through conference presentations and 
scientific publications. In no case is the publication of data that allow recognition of the patient 
envisaged. 
The results of this study will be submitted to national and international journals; posters and 
oral communications will be submitted to national and international congresses. All 
publications and communications regarding the study will be approved in advance by the PI. 
The Sponsor/Principal Investigator of the study is responsible for preparing an annual report on 
the clinical study to be sent to the Ethics Committee and for preparing a final report on the 
clinical study. After the data have been completely analyzed, they will be communicated, in 
anonymous form, to all researchers involved in the study. 
 
20. REFERENCES 

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O'Byrne P. HIV self-testing: A review and analysis to guide HIV prevention policy. Public 
Health Nurs. 2021 Sep;38(5):885-891. doi: 10.1111/phn.12917. Epub 2021 May 27. PMID: 34043831. 
2. 
Bogers SJ, Schim van der Loeff MF, Davidovich U, Boyd A, van der Valk M, Brinkman K, de 
Bree GJ, Reiss P, van Bergen JEAM, Geerlings SE; HIV Transmission Elimination AMsterdam (H-
TEAM) Consortium. Promoting HIV indicator condition-guided testing in hospital settings 
(PROTEST 2.0): study protocol for a multicentre interventional study. BMC Infect Dis. 2021 Jun 
2;21(1):519. doi: 10.1186/s12879-021-06183-8. PMID: 34078315; PMCID: PMC8173796. 
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Gómez-Ayerbe C, Martínez-Sanz J, Muriel A, Pérez Elías P, Moreno A, Barea R, Polo L, Cano 
A, Uranga A, Santos C, Casado JL, Quereda C, Robledillo G, Díaz-de Santiago A, Vivancos MJ, 
Dronda F, Navas E, Moreno S, Pérez Elías MJ. Impact of a structured HIV testing program in a 
hospital emergency department and a primary care center. PLoS One. 2019 Aug 
1;14(8):e0220375. doi: 10.1371/journal.pone.0220375. PMID: 31369594; PMCID: PMC6675098. 
4. 
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at: 
https://www.epicentro.iss.it/aids/notiziario-coa 
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Lazarus JV, Hoekstra M, Raben D, Delpech V, Coenen T, Lundgren JD; HIV in Europe 
Initiative Steering Committee. The case for indicator condition-guided HIV screening. HIV Med. 
2013 Aug;14(7):445-8. doi: 10.1111/hiv.12022. Epub 2013 Mar 10. PMID: 23480600. 
6. 
Cerini C, Casari S, Donato F, Porteri E, Rodella A, Terlenghi L, Compostella S, Apostoli A, 
Brianese N, Urbinati L, Salvi A, Rossini A, Agabiti Rosei E, Caruso A, Carosi G, Castelli F. Trigger-
oriented HIV testing at Internal Medicine hospital Departments in Northern Italy: an 
observational study (Fo.C.S. Study). Infect Dis (Lond). 2016 Nov-Dec;48(11-12):838-43. doi: 
10.3109/23744235.2016.1169551. Epub 2016 Aug 11. PMID: 27622515. 
7. 
Horsley Downie J, Pegler M, Widdrington J, Price DA, Premchand N, Chadwick DR. Late HIV 
diagnosis and missed opportunities for testing: piloting a standardised, multi-source review 
process. Int J STD AIDS. 2020 Mar;31(3):208-213. doi: 10.1177/0956462419868637. Epub 2020 Jan 
22. PMID: 31969058. 
8. 
D’Arminio Monforte A. et al. Milan fast track city: study on HIV prevalence in two different 
settings. Presented at ICAR 2021 Congress. 
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Picarelli C. May administering routine HIV test be useful to uncover the iceberg in a 
University Hospital setting? Our experience. Presented at ICAR 2020 Congress. 
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Galli M, Borderi M, Viale P. HIV policy in Italy and recommendations across the HIV care 
continuum. Infez Med. 2020 Mar 1;28(1):17-28. PMID: 32172257. 
11. 
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ated%20JUN2016_mlj.pdf 

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12. 
Bull L, Rayment M. HIV-indicator-condition-driven HIV testing: clinically effective but still 
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