Intensive Combination Approach to Rollback the Epidemic in Nigerian Adolescents: UH3 Phase
Phase: NA
Conditions: Adolescent HIV Infection
Sponsor: Northwestern University

iCARE Nigeria 
 
Version 6.0 
 
 
8 March 2024 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
a 
 
 
Version 
Information 
Summary of Revisions Made 
Rationale 
Version 2.0 
1. The study timelines associated 
with Study 1 and Study 2 were 
corrected to be consistent with the 
Study Schema (i.e., Time 1=0-24 
weeks) 
 
2. In Study 2, the inclusion criterion 
for language ability was revised to 
include two additional languages: 
Hausa and Pidgin English  
1. The study timelines are now 
consistent with the Study Schema. 
 
 
2. In Study 2, the inclusion criterion for 
language ability now includes the 
primary languages reflected in the 
study population. 
Version 3.0 
1. We have removed the enrollment 
cap of only 35% suppressed 
participants at clinic sites. 
2. The inclusion criteria were revised 
to allow participation of non-
emancipated 15-year-old youth, 
with parental consent.  
3. Exclusion criteria were revised to 
exclude non-emancipated 15-year-
old youth who do not have parental 
consent.  
4. We have removed a reference to 
DNA extraction in the description of 
DBS procedures. 
5. We have added a requirement for 
parental consent to the consent 
procedures. 
6.We have revised the consent 
process for participants who are 
assented at enrollment, to consent 
them as the earliest opportunity 
after they reach the age of consent. 
1. The proportion of suppressed 
patients varies by clinic site and thus 
there is no one proportion suppressed 
that is representative for all clinics. 
2. We have broadened the inclusion 
criteria for youth who have reached 
an age of transition to adult care at 
age 15, but who are not emancipated.  
3. Exclusion criteria were revised to 
make it clear that non-emancipated 
15-year-old youth who do not have 
parental consent are excluded. 
4. The reference to DNA extraction in 
the description of DBS procedures was 
an error.  
5. The inclusion of non-emancipated 
15-year old youth in clinical research 
in Nigeria requires parent consent. 
6. We will consent patients who were 
assented at enrollment to promote 
their autonomy to consent for 
research participation.  

iCARE Nigeria 
 
Version 6.0 
 
 
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Version 4.0 
1. We have updated the description 
of sample size in study 2 to N=560. 
 
2. In study 1, we have revised the 
protocol to include abstraction of 
HIV testing, behavioral and 
demographic data from sexual 
partners of eligible individuals 
tested via iCARE, regardless of sex 
and age (see updated Consent 
Statement, Version 2, March 11, 
2022). 
 
3. We have updated reporting of 
SAEs such that only SAEs that are 
unanticipated, and related or 
possibly related to the study will be 
reported to the IRB and the DSMB 
within 7 working days of the study 
team becoming aware of its 
occurrence. All SAEs (regardless of 
whether they are unanticipated or 
related or possibly related to the 
study) will be reported to the 
Northwestern team and the NIH 
Program Officer within 3 days of 
occurrence. 
 
4. With Study PI approval, a remote 
verbal consent addendum was 
added to allow HIV treatment arm 
participants who have moved or are 
otherwise not available for an in-
person follow up study visit at their 
study site to complete the viral load 
testing and questionnaires from 
their current location (see Verbal 
Consent Addendum, Version 1, 
March 11, 2022).    
1.  The study sample size has been 
updated for specificity and to align 
with the Study Schema 
2. HIV testing data from sexual 
partners of eligible cases provides an 
opportunity to collect additional 
information on HIV related risk for the 
target population. 
 
 
 
3. The SAE reporting criteria were 
revised to be consistent with reporting 
requirements at site IRBs, which only 
require reporting of SAEs that meet 
these criteria and to respond to the 
DSMB preference for reporting.   
 
 
 
 
4.  Remote completion of a follow-up 
study visit will be allowed on rare 
occasions to limit loss-to-follow-up for 
the primary endpoint (viral load).      
Version 5.0 
1. We have added questions 
about HIV prevention, including 
Pre-exposure prophylaxis to the 
study measures in Study 1 
(Testing arm). 
 
1. Adding questions on HIV 
prevention preferences will 
inform future HIV prevention 
intervention development for the 
study population. 

iCARE Nigeria 
 
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Version 6.0 
1. We have added questions 
about human papillomavirus 
(HPV) and HPV vaccination to 
the study measures in Study 1 
(Testing arm). 
 
1. Adding questions on HPV and 
HPV vaccination will inform 
future HPV prevention 
intervention development for 
the study population. 

iCARE Nigeria 
 
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NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
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Intensive Combination Approach to Rollback the Epidemic in Nigerian 
Adolescents: UH3 Phase 
 Protocol Number: iCARE Nigeria UH3  
National Clinical Trial (NCT) Identified Number:  NCT04950153 
Nigerian Clinical Trial Registry (NCTR) 
Principal Investigators (PI):  
Local PIs:            Olayinka Omigbodun, MBBS, MPH, FAS University of Ibadan, University 
College Hospital, Infectious Disease Institute (IDI/CoMUI) 
 
 
Alani Sulaimon Akanmu, MBBS, Lagos University Teaching Hospital (LUTH) 
Agatha David, MBBS, MPH, FMCPaed, Nigerian Institute of Medical Research 
(NIMR) 
 
 
Akinsegun Akinbami, MBChB Lagos State University Teaching Hospital  
(LASUTH) 
 
Oche O. Agbaji MBBS, MPH, MD, FMCP, Jos University Teaching Hospital 
(JUTH) 
Folashade Adekanmbi, Olabisi Onabanjo University Teaching Hospital, Sagamu 
(OOUTH/Sagamu) 
Study  PIs/Institutions:   
Babafemi Taiwo, MBBS, FAS Northwestern University  
Robert Garofalo, MD, MPH, Lurie Children’s Hospital 
Sponsor:  NIH/NICHD 
Grant Title: Prevention and Treatment through a Comprehensive Care Continuum for HIV-
affected Adolescents in Resource Constrained Settings (PATC3H) (UG3/UH3) 
Grant Number*: UH3HD096920 
Funded by: Eunice Kennedy Shriver National Institute of Child Health and Human 
Development   
Version Number:  6.0  
8 March 2024 

iCARE Nigeria 
 
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Summary of Changes from Previous Version:  
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.1 
 
 
5.1 
1. The study timelines associated with Study 1 
and Study 2 were corrected to be consistent 
with the Study Schema (i.e., Time 1=0-24 
weeks) 
 
2. In Study 2, the inclusion criterion for 
language ability was revised to include two 
additional languages: Hausa and Pidgin English 
 
1. The study timelines are now consistent 
with the Study Schema. 
 
2. In Study 2, the inclusion criterion for 
language ability now includes the primary 
languages reflected in the study population. 
4.1, 5.1, 5.5 
 
 
5.1 
 
5.2 
 
 
8.1 
 
 
10.1.1.1,  
 
10.1.1.2 
 
 1. We have removed the enrollment cap of 
only 35% suppressed participants at clinic sites. 
 
2. The inclusion criteria were revised to allow 
participation of non-emancipated 15-year-old 
youth, with parental consent.  
3. Exclusion criteria were revised to exclude 
non-emancipated 15-year-old youth who do 
not have parental consent.  
 
4. We have removed a reference to DNA 
extraction in the description of DBS 
procedures. 
 
5. We have added a requirement for parental 
consent to the consent procedures. 
6.We have revised the consent process for 
participants who are assented at enrollment, to 
consent them as the earliest opportunity after 
they reach the age of consent 
1. The proportion of suppressed patients 
varies by clinic site and thus there is no one 
proportion suppressed that is representative 
for all clinics. 
2. We have broadened the inclusion criteria 
to include youth who have reached an age of 
transition to adult care at age 15, but who 
are not emancipated.  
3. Exclusion criteria were revised to make it 
clear that non-emancipated 15-year-old 
youth who do not have parental consent are 
excluded. 
4. The reference to DNA extraction in the 
description of DBS procedures was an error.  
 
5. The inclusion of non-emancipated 15-year 
old youth in clinical research in Nigeria 
requires parent consent. 
6. We will consent patients who were 
assented at enrollment to promote their 
autonomy to consent for research 
participation. 

iCARE Nigeria 
 
Version 6.0 
 
 
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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
4.1 
 
 
5.1 
 
 
8.2.5 
1. We have updated the description of sample 
size in study 2 to N=560. 
 
2. In study 1, we have revised the protocol to 
include abstraction of HIV testing, behavioral 
and demographic data from sexual partners of 
eligible individuals tested via iCARE, regardless 
of sex and age (see updated Consent 
Statement, Version 2, March 11, 2022). 
3. We have updated reporting of SAEs such that 
only SAEs that are unanticipated, and related 
or possibly related to the study will be reported 
to the IRB and the DSMB within 7 working days 
of the study team becoming aware of its 
occurrence. All SAEs (regardless of whether 
they are unanticipated or related or possibly 
related to the study) will be reported to the 
Northwestern team and the NIH Program 
Officer within 3 days of occurrence. 
 
 
1.  The study sample size has been updated 
for specificity and to align with the Study 
Schema 
2. HIV testing data from sexual partners of 
eligible cases provides an opportunity to 
collect additional information on HIV related 
risk for the target population. 
 
 
3. The SAE reporting criteria were revised to 
be consistent with reporting requirements at 
site IRBs, which only require reporting of 
SAEs that meet these criteria and to respond 
to the DSMB preference for reporting.   
8.1 
 
 
1. We have added questions about HIV 
prevention, including Pre-exposure 
prophylaxis to the study measures in Study 
1 (Testing arm). 
 
1. Adding questions on HIV prevention 
preferences will inform future HIV 
prevention intervention development 
for the study population. 
8.1 
1. We have added questions about human 
papillomavirus (HPV) and HPV vaccination 
to the study measures in Study 1 (Testing 
arm). 
 
1. Adding questions on HPV and HPV 
vaccination will inform future HPV 
prevention intervention development 
for the study population. 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 

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approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule of Activities .......................................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background ........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 9 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 10 
4 
STUDY DESIGN ........................................................................................................................................... 12 
4.1 
Overall Design .................................................................................................................................... 12 
4.2 
Scientific Rationale for Study Design .............................................................................................. 15 
4.3 
Justification for Intervention ............................................................................................................. 16 
4.4 
End-of-Study Definition ..................................................................................................................... 16 
5 
STUDY POPULATION ................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................................................... 17 
5.3 
Lifestyle Considerations .................................................................................................................... 17 
5.4 
Screen Failures .................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 18 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 18 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 18 
6.2 
Fidelity ................................................................................................................................................. 20 
6.2.1 
Interventionist Training and Tracking .......................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 20 
6.4 
Study Intervention/Experimental Manipulation Adherence .......................................................... 20 
6.5 
Concomitant Therapy ........................................................................................................................ 21 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................... 21 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 21 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 21 
7.3 
Lost to Follow-Up ............................................................................................................................... 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 21 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 21 

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8.2 
Safety Assessments .......................................................................................................................... 23 
Adverse Events and Serious Adverse Events .................................................................................................. 24 
8.2.1 
Definition of ADVERSE EVENTS AND Serious Adverse Events ........................... 24 
8.2.2 
Classification of an Adverse Event .............................................................................. 24 
8.2.3 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 24 
8.2.4 
Adverse Event Reporting .............................................................................................. 24 
8.2.5 
Serious Adverse Event Reporting ............................................................................... 24 
8.2.6 
Reporting Events to Participants ................................................................................. 25 
8.2.7 
Events of Special Interest ............................................................................................. 25 
8.2.8 
Reporting of Pregnancy ................................................................................................ 25 
8.3 
Unanticipated Problems .................................................................................................................... 25 
8.3.1 
Definition of Unanticipated Problems .......................................................................... 25 
8.3.2 
Unanticipated Problems Reporting .............................................................................. 26 
8.3.3 
Reporting Unanticipated Problems to Participants ................................................... 26 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 26 
9.1 
Statistical Hypotheses ....................................................................................................................... 26 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses ............................................................................................................................ 27 
9.4.1 
General Approach .......................................................................................................... 27 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 27 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 28 
9.4.4 
Safety Analyses .............................................................................................................. 28 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 28 
9.4.6 
Planned Interim Analyses ............................................................................................. 29 
9.4.7 
Sub-Group Analyses ..................................................................................................... 29 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 29 
9.4.9 
Exploratory Analyses ..................................................................................................... 29 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 29 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 29 
10.1.1 
Informed Consent Process ........................................................................................... 29 
10.1.2 
Study Discontinuation and Closure ............................................................................. 31 
10.1.3 
Confidentiality and Privacy ........................................................................................... 31 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.5 
Key Roles and Study Governance .............................................................................. 31 
10.1.6 
Safety Oversight ............................................................................................................. 32 
10.1.7 
Clinical Monitoring .......................................................................................................... 32 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 32 
10.1.9 
Data Handling and Record Keeping ............................................................................ 32 

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10.1.10 
Protocol Deviations ........................................................................................................ 33 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 33 
10.1.12 
Conflict of Interest Policy .............................................................................................. 33 
10.2 
Additional Considerations ................................................................................................................. 33 
10.3 
Abbreviations and Special Terms ................................................................................................... 33 
10.4 
Protocol Amendment History ........................................................................................................... 34 
11 
REFERENCES ............................................................................................................................................. 36 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
• 
The Nigerian National Code for Health Research Ethics (www.nhrec.net) 
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) must 
be obtained before any participant is consented. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form(s) 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances that this 
study will be conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local legal and regulatory requirements and applicable US federal regulations 
and ICH guidelines. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name*:  
 
Title*:  
 
Investigator Contact Information 
Affiliation*: 
Address: 
Telephone: 
Email: 
 
 
Signed: 
 
Date: 
 
 
Name:  
 
Title: 
 
 
Affiliation: 
 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Intensive Combination Approach to Rollback the Epidemic in 
Nigerian Adolescents (iCARE Nigeria): UH3 Phase  
 
Grant Number: 
 
UH3HD096920 
 
Study Description: 
 
Two combination interventions, each with mHealth and Peer 
Navigation components, will be evaluated in a randomized, 
stepped wedge trial among youth in Ibadan, Lagos, Sagamu, and 
Jos, Nigeria. Study findings will demonstrate whether or not the 
combination interventions, which were found to be efficacious in 
our prior UG3 trial, will remain efficacious if scaled as proposed 
in this UH3 trial, across multiple sites. 
 
 
Objectives: 
 
 
 
The primary objective of the HIV Testing Intervention is to 
determine the effect of Social Media Engagement + Peer 
Navigation on HIV seroprevalence among young men across 
multiple testing sites. A secondary objective is to determine the 
effect of the intervention on linkage of newly diagnosed young 
men to a clinic for antiretroviral therapy (ART). 
 
The primary objective of the HIV Treatment Intervention is to 
determine the efficacy of the combination of SMS + Peer 
Navigation to improve viral suppression among youth with HIV 
receiving ART across multiple sites. Secondary objectives are to 
determine the effect of the intervention on medication adherence 
and retention in care. A tertiary objective is to test ART adherence 
and retention in care as mediators of the intervention effect as 
well as age, gender, and mode of transmission as potential 
moderators of the intervention effect across multiple sites.  
 
An exploratory objective is to identify and describe the barriers 
and 
facilitators 
of 
iCARE 
intervention 
readiness 
and 
implementation (both interventions) across multiple sites and to 
describe intervention costs. 
 
Endpoints: 
 
The primary endpoint for the HIV Testing Intervention is the 
change in HIV seroprevalence during the intervention period in 
comparison to the control period. 
 
The primary endpoint for the HIV Treatment Intervention is rate 
of viral suppression, defined as viral load <200 copies/mL, during 
intervention period compared to the control period.  
 

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Study Population:                
 
The population for the HIV Testing Intervention is the total 
number of HIV tests completed, and resulting seroprevalence, 
among youth in/around Ibadan, Lagos, Sagamu and Jos.  
 
The study population for the HIV Treatment Intervention are 
youth living with HIV and receiving antiretroviral therapy (ART) at 
IDI/CoMUI, LUTH, NIMR, LASUTH, OOUTH Sagamu and JUTH, 
or their satellite clinics. 
 
Phase or Stage: 
This is the UH3, second phase of the iCARE Nigeria study 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
HIV Programs at IDI/CoMUI, LUTH, NIMR, LASUTH, OOUTH 
Sagamu and JUTH are supported by the APIN Public Health 
Initiatives to provide ART to persons living with HIV (PLWH). 
Description of Study 
Intervention/Experimental 
Manipulation: 
 
The combination intervention in each of the studies includes peer 
navigation and mHealth components 
 
 
Study Duration:  
 
The study duration is 96 weeks (from start of data collection to 
end of data collection) in the stepped wedge design. Additionally, 
abstraction of HIV Testing surveillance data and HIV Treatment 
medical data will continue through 120 weeks, respectively, in 
order to explore the durability of the intervention effects post-
intervention. 
 
 
 

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1.2 
SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Intervention Phase 
 
Intervention Phase 
 
Post-Intervention Phase 
 

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1.3 
SCHEDULE OF ACTIVITIES  
 
Study 1 (HIV Testing Intervention and Linkage to Care) 
 
 
Pre-intervention 
Intervention Phase 
Post-intervention 
Activities  
• 
Collect HIV testing 
seroprevalence data 
from each site for 
young men ages 15-
24 for the period 
preceding 
intervention  
 
• 
Collect 
questionnaire and 
qualitative data 
(focus groups, key 
informant interviews) 
on intervention 
readiness from 
study staff and CBO 
representatives 
 
• 
Social Media 
Engagement 
 
• 
Community Outreach 
and Peer Navigation 
including HIV Testing 
 
• 
Collect measures of 
intervention 
implementation from 
study staff and CBO 
representatives 
 
• 
Collect intervention 
cost data from site 
administrative 
records and through 
interviews with 
stakeholders 
• 
Collect 
questionnaire and 
qualitative data 
on intervention 
implementation 
from study staff 
and CBO 
representatives 
 
 
 
 

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Study 2 (HIV Treatment Intervention)  
 
 
 
Pre-
intervention 
(Control Sites) 
Baseline 
(Intervention 
Phase) 
Week 24- 
Intervention 
Phase 
Week 48 – 
Intervention 
Phase 
Post-
intervention 
Informed consent 
X 
X 
 
 
 
Blood draw for viral load 
X 
X 
X 
X 
Xa 
Blood draw for CD4 count 
Xb 
Xb 
 
 
 
Blood draw for future studies 
(stored; virologic resistance 
testing and other studies)  
 
X 
X 
X 
X 
 
Adherence Assessment: Dried 
Blood Spot (DBS), Pharmacy 
Pick-up Records Abstraction, 
Self-Report 
 
       X 
X 
X 
X 
 
Xc 
Computer Assisted Personal 
Interviewing Questionnaires d 
X 
X 
X 
X 
 
Implementation Assessment e 
X 
X 
X 
X 
X 
Cost Assessment f 
X 
X 
X 
X 
X 
SMS + Peer Navigation   
 
Baseline through week 48 
 
SMS Text Initiation 
X 
 
 
 
Peer Navigation Enrollment 
X 
 
 
 
 
 
 
 
 
 
 a Per medical chart abstraction of standard of care viral load 
quantification 
b CD4 quantification will be performed only at the first study 
visit (either pre-intervention in Jos, Lagos, Sagamu), or 
baseline (in Ibadan) 
c Medical records abstraction only (no self-report, no DBS) 
d Computer assisted personal interviewing (CAPI): 
Demographic Characteristics, HIV Treatment Knowledge, 
HIV Medication Self-Efficacy, HIV Stigma, Substance Use, 
Depressive Symptoms, Intervention Satisfaction and 
Acceptability 
e Includes Questionnaires, Key Informant Interviews, and 
Focus groups with study and clinic staff, CBO representatives 
f Includes abstraction of cost data from site administrative 
records and through interviews with stakeholders 
 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
There is a need for effective interventions to improve HIV diagnosis and treatment among high-risk youth 
in Nigeria.  
2.2 
BACKGROUND  
 
Nigeria has more than 1.9 million people living with HIV/AIDS (PLWH; 1.5%),1 the second highest 
in the world, however, it has been largely neglected as a focus of public health efforts compared to other 
“hot spots” in sub-Saharan Africa.2 In 2018, Nigeria had 130,000 new HIV infections and 53,000 AIDS 
related deaths.1 Progress towards UNAIDS 95-95-95 goals in Nigeria is slow, with an estimated 67% of 
PLWH aware of their status, 55% on antiretroviral therapy (ART), and 42% virally suppressed.3    
Nigeria has a mixed epidemic; meaning that risk of acquiring of HIV as well as access to HIV-testing and 
treatment services are not evenly distributed across demographic groups. Specifically, with regard to 
availability and uptake of HIV testing - a critical strategy in helping Nigeria achieve the UNAIDS 95-95-
95 goals – youth and key populations such as men who have sex with men (MSM) are among those with 
disproportionate impacts.  
Since 2016, guidelines in Nigeria, Africa’s most populous country, have recommended antiretroviral 
treatment regardless of CD4 cell count for all people with HIV.4 Effective ART suppresses HIV-1 
replication, which curbs AIDS-related morbidity and mortality, limits viral transmission, and is essential to 
end the epidemic.5-7 Consistent with the global trend, youth (15-24 years of age) in Nigeria have not 
benefited from ART as much as adults.8-11 In 2017, fewer than half of the youth with HIV (YWH) at the 
Infectious Diseases Institute, University College Hospital, Ibadan, Nigeria (IDI/CoMUI) were virally 
suppressed, similar to the experience at other ART centers in the country (unpublished data). Evidence-
based interventions are needed to optimize ART outcomes in YWH.12  
Mobile phones are potentially powerful tools for ART intervention,13,14 and there were over 190 
million active mobile phone subscriptions in Nigeria in April 2020.15 The widespread use and preference 
for text messaging among youth make it uniquely promising for youth-directed HIV prevention and ART 
interventions. In 2016, the United States (U.S.) Centers for Diseases Control (CDC) endorsed an 
innovative two-way text message reminder intervention (TXTXT) for promoting ART adherence in YWH.16 
This endorsement was based on a study by Garofalo et al., in which 16-29-year-olds who received the 
TXTXT intervention were more than twice as likely to report >90% adherence to ART over the 6-month 
intervention period, and the improvements were sustained at 6-months post intervention.17 To date, 
TXTXT has not been evaluated outside the U.S.  
Engagement of peers is another potential way to improve HIV testing and ART outcomes in youth, 
particularly adolescents (10-19 years of age) because peer influences on health and well-being are 
greatest during adolescence.18-20 Interventions that affect the attitudes, values, and behaviors of the peer 
group have the greatest impact during this stage of life.21 Indeed, peer navigation and support is an 
evidence-based approach that is recommended by the World Health Organization (WHO) to improve 
outcomes for youth across the HIV care continuum.22 Peer support ranks high among potential facilitators 
of ART adherence  among YWH in sub-Saharan Africa,23,24 which harbored 78% of the global population 
of YWH in 2017.25 
Studies of interventions to improve ART outcomes among 15-24-year-olds in sub-Saharan Africa 
have failed to demonstrate improvement in ART adherence or other outcomes, even when the same 
interventions were effective in older individuals.26-28  While these results reflect the unique struggles of 
youth, they may also indicate to the limitations of single interventions in addressing complex multi-

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dimensional determinants of ART success. There is evidence to suggest that combining multiple 
interventions may be more effective than single interventions,29 but this is not a consistent finding.30   
The Intensive Combination Approach to Rollback the Epidemic in Nigerian Adolescents Study 
(iCARE Nigeria) is a two-phase trial with HIV testing and treatment intervention arms, each incorporating 
both mobile health technology (mHealth) and peer navigation components. iCARE Nigeria was adapted 
for Nigerian youth through broad input from local youth living with HIV and other stakeholders.31 Results 
from the UG3 phase of the iCARE study suggest both preliminary efficacy and feasibly of our combination 
intervention approach. In the HIV testing arm, during the 12-month intervention period, the iCARE 
intervention increased by >30% the number of HIV tests completed among the young men, ages 15-24 
at IDI/CoMUI and increased the seropositivity rate among cases to 4.9%, compared to 1.7% in the 6-
month period prior to the intervention. In the HIV treatment arm, the proportion of patients with a 
suppressed viral load (VL<200 copies/mL) increased by 71% over the 48-week intervention period, from 
35% at baseline to 60% at 48 weeks, a statistically significant change (McNemar test, OR = 6.00, p = 
0.013. Self-reported adherence (≥90%) increased from baseline at both 24 weeks (63%, p = 0.008) and 
48 weeks (68%, p = 0.031). Medication possession ratio (MPR) ≥90% increased numerically at both 
weeks 24 and 48 (85% and 80%, respectively), achieving statistical significance at 24 weeks only (p = 
0.022). Retention in care at 48 weeks was 87.5%.  Satisfaction as rated by individuals who completed 
HIV tests and participants in the HIV treatment intervention was over 90%.  
 
2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
 
The primary risk to participation in this study is breach of confidentiality (related to being MSM identified 
or to HIV status). However, the risk to the participant is no greater than that encountered in standard 
counseling or HIV treatment services. The risk associated with the collection of blood from a vein in the 
arm (for viral load quantification), include pain or discomfort at the site of collection, temporary bruising 
at that site and very rarely, the site of blood collection may become infected or need medical treatment.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The purpose of this study is to determine whether the combination iCARE interventions, which were 
found to be efficacious across the HIV care continuum among youth ages 15-24 in the UG3 trial, will 
remain efficacious if scaled as proposed in this UH3 trial, across multiple sites in Nigeria. The results of 
the UG3 trial suggest potential beneficial effects of the intervention to improve rates of HIV testing and 
identification of seropositive cases, and to improve viral load suppression among youth living with HIV.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Protection Against Risks 
For Study 1, the HIV Testing and Linkage to Care intervention, we will not enroll participants in research 
activities in order to reduce the potential risk of breach of confidentiality among YMSM given the 
criminalization of same-sex sexual behavior in Nigeria. In Study 2, The HIV Treatment Intervention, to 
protect the integrity of the youth’s data, staff will assign each individual a unique patient identification 
number (PID) at study enrollment, linked to their name and medical records number (for medical records 
abstraction). This code number will be used for all study data. Only staff who have been trained in human 

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subjects protection will have access to these PIDs.  
 
Importance of the Knowledge to be Gained 
Possible risks (i.e. potential confidentiality breaches) are outweighed by the new knowledge gained from 
testing this intervention among the study population across multiple sites, a population at very high risk 
of poor HIV outcomes.  
3 
OBJECTIVES AND ENDPOINTS  
 
Study 1:  HIV Testing and Linkage to Care Intervention 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS 
OF ACTION 
Primary 
 
 
 
To determine the effect of 
Social Media Engagement 
+ Peer Navigation on HIV 
testing and seroprevalence 
among young men across 
multiple sites 
 
 
 
 
 
 
 
 
 
HIV seroprevalence 
among the tested 
young men during 
the intervention 
period (calculated 
as the number of 
confirmed HIV 
cases divided by 
the total number of 
tests). Repeat 
testing in youth who 
initially test 
negative will be 
analyzed 
separately. 
 
 
 
While the focus of this 
study is young men who 
have sex with men 
(YMSM), the social 
conditions in Nigeria make 
it difficult to collect reliable 
data from this population. 
Data from young men in 
general will be collected to 
overcome this obstacle.  
An increase in HIV testing 
among male youth 
regardless of their sexual 
orientation is also 
desirable to stem the HIV 
epidemic 
 
 
The 
investigational 
intervention will 
alleviate 
barriers to HIV 
testing among 
young men, 
including 
YMSM  
 
 
 
 
 
Secondary 
 
 
 
To evaluate linkage of 
newly diagnosed young 
men to a clinic for ART 
The percentage of 
young men who are 
linked to HIV care 
within 30 days of an 
HIV confirmatory 
test. This is defined 
as registering and 
completing a clinic 
visit where ART or 
opportunistic 
infection treatment 
is provided within 
30 days of a 
confirmatory HIV 
test. 
Ideally, all HIV diagnosed 
individuals would be linked 
to care; the public health 
goal is for 90% of HIV 
diagnosed individuals to be 
linked to care 
Peer navigation 
will facilitate 
linkage to care 
Tertiary/Exploratory 
 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS 
OF ACTION 
To identify and describe 
the barriers and facilitators 
of iCARE intervention 
readiness and 
implementation across 
study sites and to describe 
intervention costs 
This objective is 
exploratory and 
descriptive in 
nature, therefore 
there are no 
specific endpoints 
N/A 
N/A 
 
 
Study 2: HIV Treatment Intervention  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
 
 
 
To determine the efficacy 
of the combination of SMS 
+ Peer Navigation to 
improve viral suppression 
among youth receiving 
ART across multiple sites 
Viral 
suppression, 
defined as viral 
load <200 
copies/mL at 
week 48 of 
intervention 
exposure 
Viral suppression to levels 
below 200 copies/mL is a 
commonly used measure 
of successful ART. In 
addition, the public health 
tenet of U=U is based on 
evidence that HIV 
transmission does not 
occur when viral load is < 
200 copies/mL. In 
addition, viral suppression 
is one of the indicators 
included in the UNAIDS 
95-95-95 declaration 
The investigational 
intervention will improve 
adherence to ART which 
will in turn increase the 
odds of achieving and/or 
maintaining viral 
suppression  
Secondary 
 
 
 
To determine the effect of 
the intervention on 
medication adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ART adherence 
as measured by:  
 
a) Pharmacy 
drug pick-up 
(90% of days 
with medication) 
at week 48 
 
b) Antiretroviral 
(ARV) drug 
concentration in 
Dried Blood Spot 
sufficient for viral 
suppression at 
week 48 
 
Pharmacy drug pick -up 
records and ARV drug 
concentration are 
objective indirect 
measures of adherence 
while self-report is a 
complimentary subjective 
measure.  
 
 
 
 
 
 
 
 
 
Practical assistance and 
other support provided 
by peer navigation 
combined with text 
message reminders lead 
to ART adherence  
 
 
 
 
 
 
 
 
 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
 
 
 
 
 
 
To determine the effect of 
the intervention on 
retention in care.  
 
 
 
 
 
 
 
c) Self report on 
a visual analogue 
scale of 90% at 
week 48 
 
 
Retention 
defined as at 
least two care 
(non-study) visits, 
including youth 
clinic, in the prior 
24-week period 
at week 48 
 
 
 
 
 
 
 
 
Retention in care is a 
surrogate marker of 
treatment success 
 
 
 
 
 
 
 
 
 
 
 
Practical assistance and 
other support provided 
by peer navigation will 
lead to retention in care  
 
 
Tertiary/Exploratory 
 
 
 
A tertiary objective is to 
test ART adherence and 
retention in care as 
mediators of the 
intervention effect AND 
age, gender, and mode of 
transmission (perinatal vs. 
behavioral) as potential 
moderators of the effect 
across multiple sites  
 
 
 
 
An exploratory objective is 
to identify and describe the 
barriers and facilitators of 
iCARE intervention 
readiness and 
implementation across 
multiple sites and to 
describe intervention costs 
 
Statistically 
significant 
(P<.05) 
mediation and/or 
moderation of the 
intervention 
effect on viral 
suppression 
 
 
 
 
 
 
This objective is 
exploratory and 
descriptive in 
nature, therefore 
there are no 
specific 
endpoints 
Evidence of mediation of 
the intervention effect 
provides an indication of 
how the effect is 
transferred to changes in 
viral load suppression. 
Differences in the 
intervention effect by 
subgroups of age, gender 
and mode of transmission 
indicate for whom the 
intervention works. 
 
 
N/A 
The investigational 
intervention will improve 
adherence to ART and 
retention in care, which 
will in turn lead to viral 
suppression, the effect of 
which may differ by age, 
gender and mode of 
transmission 
 
 
 
 
 
N/A 
4 
STUDY DESIGN 
4.1 OVERALL DESIGN 
Two randomized stepped wedge trials will be conducted to investigate two interventions (each with 
mHealth + Peer Navigation components). A stepped wedge design is a type of cluster-randomized design 

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in which clusters are randomized to one of several different sequences which dictate when the cluster 
will switch from a control condition to an intervention condition. An advantage of this design is that all 
clusters receive the intervention and individual-level randomization is not required. This is a pragmatic 
design that is typically used to evaluate how interventions would work in real-world settings. Study 1 will 
test a combination intervention that targets HIV testing and linkage to care while Study 2 will test a 
combination intervention that targets HIV treatment outcomes (retention, adherence and viral 
suppression). These studies will be implemented concurrently. The exploratory, implementation science 
objective, to identify and describe the implementation barriers and facilitators of both iCARE interventions 
across all study sites will be studied using mixed methods, which include data collection via closed-ended 
questionnaires, as well as key informant and focus group interview data collection. 
In Study 1 (HIV Testing and Linkage to Care), we hypothesize that using the same primary outcome 
as in the UG3 phase, the combination intervention, will remain efficacious across multiple sites. With the 
combination intervention of Social Media + Peer Navigation, i) the change in HIV seroprevalence in the 
intervention versus control period will be OR≥2.0. We will continue the intervention in each site after the 
intervention period to explore longer-term uptake and efficacy of the intervention.   
 
 
 
 
 
 
 
Trained Testing Peer Navigators (including an Outreach Coordinator) will conduct HIV testing outreach 
to at-risk youth using social media platforms to promote HIV testing. The Outreach Coordinator and Peer 
Navigators will be male or female young adults who are staff members (not volunteers), with experience 
working with key populations. For youths who express an interest in HIV testing, the peer will navigate 
them based on the youth’s preference to any of the local HIV testing locations or the peer navigator will 
perform the HIV test wherever the participant feels most comfortable (e.g., home, community location, 
clinic or office). Youth who are navigated to HIV testing will be asked to complete an optional, brief, 
anonymous and self-reported questionnaire regarding their demographic characteristics, HIV testing and 
risk behavior, and satisfaction with the intervention. Those diagnosed with HIV will be linked to their 
STUDY 1 – HIV TESTING 
~Year 01a 
~Year 02 
~Year 03 
STUDY WEEKS 
-24-0 
0-24 
25-48 
49-72 
73-96 
97-120 
TIME PERIOD 
TIME 0 
TIME 1 
TIME 2 
TIME 3 
TIME 4 
TIME 5 
Cluster 1:  Ibadan (not 
randomized) 
 
 
 
 
 
 
Cluster 3: RANDOM SELECTION 
(Jos+Sagamu vs. Lagos) 
 
 
 
 
 
 
Cluster 2: RANDOM SELECTION 
(Jos+Sagamu vs. Lagos) 
 
 
 
 
 
 
a Study years are approximate given the use of 24 week intervals 
Study Start-Up Phase 
 
 
Pre-intervention Phase 
 
 
Intervention Phase 
 
 
Post-Intervention Phase  
 
 

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preferred HIV treatment clinic. While peer navigators will include youth men and women, the primary 
target of this study is YMSM. 
To determine efficacy of the combination intervention, the change in HIV seroprevalence will be 
compared between the intervention and control period. HIV testing data for all young men as opposed to 
YMSM alone will be utilized mainly because HIV testing records do not routinely contain valid data on 
same-sex behavior. 
 
As a secondary objective, we will assess the percentage of newly diagnosed youth who are linked to care 
for ART. As an exploratory objective we will assess barriers and facilitators of iCARE intervention 
readiness and implementation across multiple sites and describe intervention costs. 
 
In addition, we will describe the seroprevalence of tested young men after the intervention period, which 
will provide an assessment of longer-term uptake of the intervention.  
In Study 2 (HIV Treatment Intervention), the combination of Short Message Service (SMS; via 
adaptation of the TXTXT intervention) + Peer Navigation will be investigated to evaluate their effect on 
HIV treatment outcomes (viral suppression, ART adherence, and retention in care) across all sites. We 
hypothesize that viral suppression (defined as < 200 copies/mL) will be greater during the intervention 
period relative to the control period, reflecting an OR≥1.5. After the end of the intervention period, in each 
site, we will continue to measure outcomes via medical records abstraction to explore the longer-term 
durability of the intervention effect.   
 
 
 
 
 
 
 
 
We will enroll approximately 560 youth in total, ages 15-24 at the six sites (including virologically 
suppressed and viremic individuals) with HIV regardless of gender, who have been on ART for at least 3 
months at the HIV clinics in IDI, LUTH, NIMR, LASUTH, JUTH, Sagamu or their satellite clinics. 
Enrollment will be monitored to ensure a representative proportion of suppressed versus viremic 
participants at study entry.  
STUDY 2 – HIV TREATMENT 
~Year 01a 
~Year 02 
~Year 03 
STUDY WEEKS 
-24-0 
0-24 
25-48 
49-72 
73-96 
97-120 
TIME PERIOD 
TIME 0 
TIME 1 
TIME 2 
TIME 3 
TIME 4 
TIME 5 
Cluster 1:  Ibadan (not 
randomized) 
 
 
 
 
 
 
Cluster 2: RANDOM SELECTION 
(Jos+Sagamu vs. Lagos) 
 
 
 
 
 
 
Cluster 3: RANDOM SELECTION 
(Jos+Sagamu vs. Lagos) 
 
 
 
 
 
 
a Study years are approximate, given the use of 24 week intervals 
Study Start-Up Phase 
 
 
Pre-Intervention Phase 
 
 
Intervention Phase 
 
 
Post-Intervention Phase 
 
 

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Trained Treatment Peer Navigators (one for 5 participants) will be selected from the clinics using the 
following criteria: i) on ART, ii) virologically suppressed with viral load <200 copies/mL based on viral load 
in the preceding 12 months, if available, iii) 18 to 30 years of age, and iv) “doing well” according to their 
physician’s subjective assessment. Peer Navigators will be carefully selected to represent diversity in 
each clinic population including by religion, primary language, gender, age and other important 
characteristics. Each Peer Navigator will navigate 5 youths, by providing practical assistance and other 
support to optimize adherence. Provided support will be determined through a structured Needs 
Assessment process that will be conducted immediately prior to beginning the intervention. In addition, 
peer navigators will foster a sense of community among the participants in their respective groups. 
Participants will receive SMS text messages, adapted from the CDC recommended TXTXT, which 
includes daily, free, bi-directional and personalized text messages, delivered using a secure platform 
provided by Dimagi CommCare. The SMS will be personalized to remind and encourage the youth to 
adhere to their ART. Each participant will be exposed to the intervention for 48 weeks. 
The primary efficacy measure for this combination intervention is the proportion of participants with viral 
load <200 copies/mL during the intervention period in comparison to the control period. Those with viral 
load ≥200 copies/ml at study entry, or at weeks 24 and/or 48 of intervention exposure, may have 
resistance testing done to better understand their viral non-suppression.  In addition, per the clinical 
standard of care, youth with persistent viremia despite enhanced adherence counselling will be reviewed 
for change to second or third line ART regimens. 
The secondary measures of efficacy are: i) adherence (based on pharmacy pick up records, self-report, 
and DBS drug levels) and, ii) retention in care based on medical records during the intervention period 
in comparison to the control period. 
We will explore the implementation science objective, to identify and describe the implementation barriers 
and facilitators of both iCARE interventions across all study sites using mixed methods, which include 
data collection via closed-ended questionnaires, as well as key informant and focus group interview data 
collection. In addition, we will continue to abstract primary and secondary outcomes, from the medical 
record after the intervention period to describe the durability of the intervention effect.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
 
Evidence supports the combination of peer navigation and SMS reminders to improve HIV 
outcomes. In South African adults, Steward and colleagues used a cluster 3-arm randomized controlled 
trial (SOC/Standard of Care vs. SMS only vs. SMS + peer navigation) to evaluate the value of a combined 
intervention using peer navigation and SMS check-in messages in improving HIV treatment outcomes.32 
In the study, peers were trained to help other patients navigate HIV care and prevention through a 
minimum of monthly in-person meetings, phone and SMS contact as needed (minimum biweekly check-
ins) and accompanying patients to clinic appointments as needed.33,34 In addition to the SMS text check-
in reminder with peer navigators, patients in the combination intervention arm also received SMS text 
“healthy living” reminders as well as reminders for clinic appointments. In comparison to the SOC arm, 
participants in SMS + peer navigation arm were almost twice as likely (OR 1.83, p<0.01) to be retained 
in care at 12 months (with retention defined for those on ART as at least 4 care visits within 12 months 
and for those not on ART defined as 2 or more visits in 12 months).32 There was no significant difference 

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in retention between the SMS alone vs. SOC arms. Consistent with this finding in adults, SMS alone 
failed to improve adherence to ART and co- trimoxazole prophylaxis in the only randomized trial of this 
intervention in youth\recently reported from Uganda.35 These data suggest that combination interventions 
may be necessary in youth. Indeed, the combination of SMS text + peer navigation may be particularly 
suited to youth because it aligns with their developmental and social needs for peer engagement & 
acceptance and affinity for telecommunication, thus holding promise across the HIV care continuum. 
Results from the UG3 phase of the iCARE study suggest both preliminary efficacy and feasibly of 
our combination intervention approach. In the HIV testing arm, during the 12-month intervention period, 
the iCARE intervention increased by >30% the number of HIV tests completed among the young men, 
ages 15-24 at IDI/CoMUI and increased the seropositivity rate among cases to 4.9%, compared to 
1.7% in the 6-month period prior to the intervention. In the HIV treatment arm, the proportion of patients 
with a suppressed viral load (VL<200 copies/mL) increased by 71% over the 48-week intervention 
period, from 35% at baseline to 60% at 48 weeks, a statistically significant change (McNemar test, OR 
= 6.00, p = 0.013).  Self-reported adherence (≥90%) increased from baseline at both 24 weeks (63%, p 
= 0.008) and 48 weeks (68%, p = 0.031). Medication possession ration (MPR) ≥90% increased 
numerically at both weeks 24 and 48 (85% and 80%, respectively), achieving statistical significance at 
24 weeks only (p = 0.022). Retention in care at 48 weeks was 87.5%. Satisfaction as rated by 
individuals who completed HIV tests and participants in the HIV treatment intervention was over 90%.  
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
Youth, particularly YMSM, are weak links in Nigeria’s response to the HIV epidemic. While there are 
many complicated factors that fuel the epidemic in these groups, a void of evidence-based interventions 
is remediable and necessary to advance the UNAIDS 95-95-95 goals. Therefore, we will investigate 
evidence-based youth-specific approaches that include peer navigation and mHealth components, which 
have shown initial evidence of efficacy and feasibility in the UG3 pilot, across multiple sites.   
 
4.4 
END-OF-STUDY DEFINITION 
These studies are part of the second (UH3) phase of the iCARE, Nigeria study. If the hypotheses of this 
UH3 phase are met, the sustainability plan will be activated to maintain the intervention beyond the 
study context.  
 

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5 
STUDY POPULATION 
The population for Study 1 is the total number of HIV tests completed, and resulting HIV seroprevalence, 
among youth in/around Ibadan, Lagos, and Jos.  
 
The study population for Study 2 comprise youth living with HIV and receiving antiretroviral therapy (ART) 
at IDI, LUTH, NIMR, LASUTH, OOUTH Sagamu, and JUTH and their satellite clinics. 
5.1 
INCLUSION CRITERIA 
Study 1 (Testing and Linkage to Care) 
HIV tests of young men ages 15-24 residing in Ibadan, Lagos, Jos and surrounding areas in the pre-
intervention period (24 to 72 weeks prior to the launch of the intervention in each site, depending on 
randomization) and during the intervention period (48 weeks) will be abstracted from surveillance records 
of each clinic for analysis. In addition, HIV testing records for sexual partners of eligible cases, tested via 
iCARE (i.e., per national partner testing guidelines), will also be abstracted regardless of sex or age.  
 
NB: For the HIV testing and linkage intervention, no human subjects will be enrolled and no identifying 
data will be collected. Routine HIV testing data from surveillance records at each site/clinic will be 
abstracted in a de-identified format. Demographic, behavioral and intervention satisfaction data will be 
collected in anonymous format for eligible cases and their sexual partners. 
 
Study 2 (Treatment Intervention)  
 Inclusion criteria:  
1. Age 15-24 years; if 15 years old must have parental consent or be emancipated i.e., has been 
granted status of adulthood by a court order, has lived independent of parental guidance for at 
least a year, is married, living on the street, or is head of a household 
2. Living with HIV infection 
3. Registered in the study clinics or their satellite clinics  
4. On ART for at least 3 months. Participants may be virologically suppressed or viremic/failing on 
ART.  We will monitor enrollment to ensure a representative proportion of suppressed versus 
viremic participants. 
5. Understands and can read basic English, Hausa, Pidgin English, or Yoruba 
6. Willing and able to provide informed assent or consent.  
7. Intention to remain a study clinic patient during the study observation and intervention period (up 
to 96 weeks).  
 
NB: There are no eligibility criteria specific to ART adherence or retention since these are subject to 
variation over time in youths, cell phone ownership is not required; cell phones will be provided to 
participants without one. 
5.2 
EXCLUSION CRITERIA 
Study 2: Exclusion criteria 
1. Inability to provide informed assent or consent. 
2. Youths who are 15 years old and do not receive parental consent or are not emancipated  
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
 

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5.4 
SCREEN FAILURES 
Participants who do not meet the eligibility criteria will not be enrolled into the study.  
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
The HIV testing and linkage study will reach at-risk youth through social media and in-person outreach 
conducted by peer navigators, who will be trained to implement the manualized combination intervention, 
focused on promoting HIV testing and linkage to care. 
In the HIV treatment outcomes study, a sampling frame will be created for eligible patients from medical 
records at each of the six sites (and satellite sites) and stratified by status as virally suppressed versus 
viremic. Eligible patients will be contacted from each stratum or approached in clinic and screened for 
eligibility until the accrual target is reached, while ensuring a representative proportion of suppressed 
versus viremic participants.  
 
A screening log will be maintained to track ineligible cases and reasons for ineligibility, as well as refusals 
and no-shows.  
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
Study 1: (HIV testing and linkage to care Intervention) includes social media engagement and peer 
navigation.   
Social media engagement: Outreach and testing will be done using a targeted approach. Trained HIV 
Testing Peer Navigators (male and female youth) will conduct outreach and engagement on social media 
platforms that are used and trusted by YMSM (e.g., Whatsapp, Grindr, Facebook). Testing Peer 
Navigator’s activities will include using existing or creating new closed groups on these platforms, plus 
respondent-driven new invitations in order to generate a following. The Outreach Coordinator and Testing 
Peer Navigators will be male or female young adults who are regular staff (not volunteers), with 
experience working with key populations.  
Prior to deployment, the Testing Peer Navigators will be trained on 1) profile set-up; 2) scripts for 
messaging, and instructions for structuring the interaction (e.g., how many times to message before 
moving on, providing responses as quickly as possible); 3) FAQs to guide unscripted interaction (e.g., 
Don’t exchange personal information/photos; Do stick to pre-approved themes). The social media 
interactions will promote HIV testing. 
Peer navigation: Testing Peer Navigators will also be trained to conduct community-based outreach and 
HIV testing, with emphasis placed on flexibility, building trust and maintaining confidentiality. In addition, 
they will be trained in pre and post-test counseling and in the management of reactions to the test results. 
HIV testing will be promoted via social media and in-person interactions, e.g., at locations where young 
people may socialize locally. Social media messaging by Testing Peer Navigators will focus on the 
benefits of HIV testing, management of stigmatization of HIV testing, and peer-based social support. The 
navigator will emphasize the advantages of HIV tests, e.g., “know your status,” autonomy for self-

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management, benefits of early diagnosis and treatment. In addition, the navigator will emphasize free 
testing and confidentiality of treatment.  
For individuals who express interest in HIV testing, the Testing Peer Navigators will navigate them based 
on the youth’s preference to either i) IDI/CoMUI, LUTH, NIMR, LASUTH, OOUTH Sagamu, or JUTH 
testing site, ii) another testing site that the youth prefers, or iii) HIV test performed by the peer navigator 
at a location the youth finds comfortable. Youth who are navigated to HIV testing will be asked to complete 
an optional, brief, anonymous and self-reported questionnaire regarding their demographic 
characteristics, HIV testing and risk behavior, and satisfaction with the intervention. Youth who have a 
negative test result will be counseled to return for follow-up testing and reminded to do so according to 
the national guidelines and local surveillance practices. Youth with a positive HIV test will be navigated 
to the IDI/CoMUI, LUTH, NIMR, LASUTH, OOUTH Sagamu, or JUTH clinic (or any other treatment site 
preferred by the youth) for confirmatory testing and linked to care for ART initiation according to national 
guidelines.  
Study 2: HIV treatment intervention (retention, ART adherence and viral suppression) 
Intervention, also includes two components- peer navigation and SMS text messaging  
Peer Navigation: The Treatment Intervention Peer Navigators in this pilot study are defined as HIV 
positive, medication adherent role models living with a shared experience and a shared community 
membership as the populations with whom they will work. The Treatment Peer Navigators will be selected 
from the IDI, LUTH, NIMR, LASUTH, OOUTH Sagamu and JUTH, or their satellite clinics using the 
following criteria: i) HIV-1 viral load < 200 copies/mL within the preceding 12 months (if available), ii) 
subjectively assessed as “doing well” by their physician, based on the categories- doing well, doing 
poorly, or variable, iii) willingness to volunteer as navigator, iv) successful completion of comprehensive 
training that includes modules on privacy and confidentiality. A designated clinic/study staff, assisted by 
the Treatment Peer Navigator, will conduct a Needs Assessment and ART education for participants. 
The navigator will initiate a minimum of two encounters per month (at least once every two weeks) with 
each of their assigned participants (in person or by texting/voice call/social media). 
Treatment Peer Navigators are tasked with optimizing treatment outcomes by:  
1) Assessing and addressing barriers to care engagement (e.g., transportation to clinic).  
2) Providing referrals and linkage to supportive services.  
3) Attending appointments with participants as needed.  
4) Enabling early detection of those at risk of poor outcomes; and  
5) Fostering community and providing supportive care (e.g., medication adherence support, 
support for disclosure of HIV status).  
Each Treatment Peer Navigator will meet in person or by phone at least every two weeks with a 
designated clinic staff to discuss emerging issues with their assigned peers and formulate practical 
solutions including allocation of funds to participants based on the findings of the Needs Assessment. 
This meeting may occur in a group-based format with other navigators. 
 Funds that are available to the clinic, and are not study-provided (e.g., through philanthropy or 
indigent fund), may be used to address some of the needs of study participants, based on availability. 
Peer navigators will receive a small stipend, which includes funds for their transportation/communication 
costs. 
SMS text message reminders: This study will utilize a locally adapted version of our CDC-
recommended, TXTXT intervention.17 Messaging will consist of daily, bi-directional and personalized text 
messages that will be delivered, using a platform provided by Dimagi CommCare. All text-related data 

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will be securely stored by Dimagi per their privacy policy. The SMS messages will promote adherence 
and the content will be selected by and for the participant themselves with consideration given to each 
person’s need for privacy and confidentiality and timed to coincide with individual dosing schedule.  
Trained Treatment Peer Navigators will use a structured text message tailoring form to elicit 
message content and then set up automated messages in the Dimagi platform, i.e., set-up daily 
reminders according to the participants’ dosing schedule and preferred message content. To protect 
privacy and confidentiality, we will encourage participants to delete text messages after taking 
medication, to use confidential messages that do not reveal HIV status or mention medications, and we 
will encourage them to use a passcode on their phone to protect confidentiality. Participants will have the 
option to choose a personalized message that may be changed as requested throughout the study 
period.  
Bi-directionality is reflected in a series of follow-up messages. Participants will be asked to send 
a text message response indicating they have successfully taken their ART per schedule.  An automated 
response system provides options for responding, including: 1) “Yes” or 2) “No.” If the participant 
responds, “Yes” an affirmative and encouraging message will be sent in reply (e.g., “Well done!”); a “No” 
response will trigger an acknowledging and encouraging message (e.g., “You can do it!”). This 2-way 
message system provides a positive feedback to promote motivation, self-efficacy, and support.  
Participants will use their own cell phones for receipt of messages, however, we will provide 
phones to those who do not have them (estimated to be approximately 40% of clinic population based 
on UG3 findings), to ensure broad participation. Peer navigator will maintain logs of contacts with 
participants and phone-related problems 
6.2 
FIDELITY 
Intervention fidelity will be determined by the proportion of intervention tasks completed, using a fidelity 
checklist.  
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
All Peer Navigators will undergo training prior to deployment. The training curriculum for research staff 
includes human subjects education, privacy and confidentiality, participant safety, and intervention and 
data collection training.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
In the stepped wedge design, the Ibadan site will not be randomized because it already began the 
intervention in the UG3 period, however, the other study sites will be randomized in two clusters: one 
cluster will include the Lagos sites (LASUTH, LUTH, NIMR) and the other cluster will include OOUTH  
Sagamu and JUTH. Randomization of the two remaining clusters will reduce bias for observation of the 
control period in comparison to the intervention period. The randomization assignments will be generated 
by computer algorithm by the study statistician and will remain concealed until after data has been 
collected in the observation period, before launch of the intervention in randomized sites.  
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
N/A 

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6.5 
CONCOMITANT THERAPY 
N/A 
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
The study will terminate upon completion of the funding period unless a no-cost extension is secured or 
premature termination is mandated by the IRB, the NICHD, or other constituted authority. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants may withdraw or be discontinued from the Study 2 at any time for any of the following 
reasons: 
i) 
Withdrawal of consent for any reason 
ii) 
Potential for harm to the participant in the opinion of the site investigator or their physician 
 
Peer navigators in either of the studies will be discharged if there are concerns about their conduct on 
study, including violation of privacy and confidentiality requirements. Peer navigators who quit the study 
prematurely will be replaced. 
7.3 LOST TO FOLLOW-UP 
Participants will be considered lost to follow-up in Study 2 if they do not complete the week 48 visit of the 
intervention period. Measures to be taken by Treatment Peer Navigators to prevent loss to follow-up are 
similar to those already in place in the site clinics, including maintaining contact information up-to-date, 
using multiple methods of contact, and providing reminders for study visits.  
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Study 1 (HIV Testing and Linkage to Care)  
Study HIV Testing data will be collected in 24-week increments for up to 96 weeks during the study 
period.  
 
The primary endpoints for the combination intervention for HIV testing/linkage study is the HIV 
seroprevalence, calculated as the number of confirmed HIV cases divided by the total number of tests 
during the intervention versus control period. To achieve this, HIV testing data for all young men, ages 

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15-24, will be abstracted from surveillance records at each site in each observation and intervention 
periods.   
 
Secondary endpoints include linkage to care of newly HIV diagnosed youth who undergo testing through 
IDI, LUTH, NIMR, LASUTH, OUTH Sagamu, and JUTH (i.e. tested on site at the clinic or by a Peer 
Navigator during community outreach). This is defined as registering and completing a clinic visit where 
ART or opportunistic infection treatment is provided within 30 days of a confirmatory HIV test. These data 
will be captured in HIV testing encounter forms used for surveillance purposes and tracked using an 
anonymous identification number. 
 
 
The anonymous self-reported questionnaire will include items that reflect demographics, behavior, 
experiences with HIV testing and HIV prevention (including pre-exposure prophylaxis, both oral and long-
acting injectable options), human papilloma virus infection (HPV; including HPV vaccination), and 
satisfaction and will be collected in paper-and-pencil format or (as connectivity allows), deployed on a 
mobile device via the secure data capture system, REDCap, hosted at Northwestern University. 
Aggregate social media tracking data and HIV testing encounter data will be entered into REDCap and 
stored for analysis.  
 
 
Study 2 (HIV Treatment Intervention) 
Study data will be collected at enrollment and at 24-week increments during the study period, up to 96 
weeks per the stepped wedge design (See Schedule of Events, Section 1.3) 
The primary endpoint for the HIV treatment intervention study is viral suppression defined as HIV < 200 
copies/mL during the intervention period versus control period.  We will collect blood via venipuncture for 
HIV viral load quantification at all study visits. Two tubes of blood, each 8-10 mL (total 16-20 mL) will be 
collected. One tube will be used for viral load, dried blood spot (DBS), and CD4 quantification (CD4 
completed at the first study visit only); the other tube will be stored for viral resistance testing (select 
samples) and future potential studies. Viral load and CD4 quantification will be performed at designated 
HIV laboratories. Additional abstraction of viral load lab values from the medical records will occur post-
intervention, through 120 weeks, to assess the duration of the intervention effect.     
 
 
Secondary endpoints will be captured to measure both secondary effects and mediation of the 
intervention effect and include: 
1) Adherence based on:   
• 
Dried Blood Spot (DBS):  From one tube of the collected blood sample (i.e., 8-10 mL), five 
50µL spots on protein saver cards will be used for measurement of ART levels. The 
samples will be dried out at room temperature for 24 hours, then sealed tightly with 
desiccant and a humidity indicator, and stored at -20 degrees Celsius until analysis.   
 
• 
ART pharmacy pick-up: Pharmacy records of ART pick-up are captured as part of routine 
care at each clinical site and will be abstracted from the medical record at all study visits 
(for the 24-week period prior to the visit). Additional data abstraction will occur post-
intervention, through 120 weeks, to assess the duration of the intervention effect. These 
data will be used for calculation of MPR. 
 
• 
Self-report of ART adherence via 30-day visual analogue scale (VAS), 30-day number of 
missed doses, and 4-day missed doses.36  
  

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2) Retention in care 
• 
This is defined as at least two care (non-study) visits, including youth club visits, to the 
clinic in a 24 week period.  Visit dates are captured as part of routine care at each clinical 
site and will be abstracted from the medical record at all study visits (for the 24 week 
period prior to the visit). Eligible visits include “Youth Club” visits that take place in the HIV 
clinic or any other non-study-mandated visit. Additional data abstraction will occur post-
intervention, through 120 weeks, to assess the duration of the intervention.32  
 
Other assessments 
1) Implementation Assessment 
Anticipated variations in local practices, strengths and challenges at intervention sites will create an 
opportunity to measure and understand: 1) how the interventions are implemented across the study sites 
and reflect key study outcomes, and 2) the contextual factors that impact the efficacy of the intervention. 
We will use the RE-AIM framework to evaluate our implementation strategies,37  and explore 
implementation contextual factors using relevant domains from the Consolidated Framework for 
Implementation Research (CFIR).38 These frameworks were chosen based on relevance and have been 
used in low and middle income countries, and in evaluating and understanding the success and 
challenges of implementation to accelerate success to achieve 95-95-9539  
We will assess indicators of intervention implementation, including satisfaction and acceptability40 among 
study participants via study questionnaire data. Additional indicators of implementation feasibility, reach, 
and adoption, as well as study cost will be collected from administrative records and tracking logs.  Finally, 
questionnaire, key informant, and focus group data will be collected with study staff and clinic staff, as 
well as representatives from community-based organization (CBOs) before, during, and after the 
implementation of the intervention in each site to elicit perceptions of barriers and facilitators of 
intervention implementation.  These findings will inform practice-based implementation and sustainability 
after the end of the study. 
2) Demographic, Medical History & Psychosocial Assessments  
Demographic and medical history data, including age, gender and mode of infection will be collected via 
study participant computer assisted personal interviewing (CAPI) questionnaires and via medical records 
abstraction to describe the sample and test moderators of the intervention effect. In addition, 
psychological assessments will be collected to fully describe characteristics often associated with HIV 
outcomes, including measures of HIV treatment knowledge,41 HIV medication self-efficacy42, HIV 
stigma,43 depressive symptoms,44 alcohol and drug use45. 
 
8.2 
SAFETY ASSESSMENTS 
 
Participant safety will be monitored through weekly review of peer navigation activity logs and encounter 
forms and monthly tallies of completed satisfaction questionnaires. In addition, study staff will be trained 
to report concerns about safety directly to the local Principal Investigator at each site. If any study staff 

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member discovers any untreated condition (e.g., onset of physical or mental health condition), they will 
refer the participant for appropriate treatment immediately. The study multiple Principal Investigators at 
the lead site (Profs. Robert Garofalo and Babafemi Taiwo) will be informed of any significant safety 
concerns within 24 hours of the site PI becoming aware of the event. Participant safety will be discussed 
at weekly all team research meetings, and a written log of all safety events will be maintained. 
 
Since breach of confidentiality is a potential safety concern in these studies, all study personnel and peer 
navigators will be trained regarding privacy and confidentiality.  The training will include reviewing 
possible scenarios and key questions to assess risk. We will train staff to err on the side of caution and 
to contact the clinical supervisor or site investigator as needed. Under the guidance and direction of 
clinical supervisors (or site investigator), study staff will be trained when, if appropriate, to escort 
participants to the nearest emergency room or clinic in the event of an emergency.  
 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.2.1 DEFINITION OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
While an adverse event (AE) is typically defined as any untoward medical occurrence in a participant 
enrolled in a study, for the purpose of these studies in which no study drugs are provided or clinical care 
rendered, reportable AEs are limited to the events of special interest in section 8.2.7.   
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect   
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 
8.2.2 CLASSIFICATION OF AN ADVERSE EVENT 
AEs and SAEs will be classified by the site investigator as related or not related to the study. 
8.2.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Unanticipated problems will be tracked in problem and adverse event logs throughout the study and 
managed according to local IRB or ethics board requirements. 
8.2.4 ADVERSE EVENT REPORTING  
 
AEs, including SAEs, will be collated and presented as part of the study reports. 
8.2.5 SERIOUS ADVERSE EVENT REPORTING  

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All SAEs will be reported to the Northwestern team and the NIH Program Officer within 3 days of 
occurrence. SAEs that are unanticipated and related or possibly related to the study will be reported to 
the IRB and the DSMB within 7 working days of the study team becoming aware of its occurrence.  
8.2.6 REPORTING EVENTS TO PARTICIPANTS  
In consultation with the site IRB(s) and the NIH Program Officer, the study team will notify participants 
and/or implement modifications to the study protocol.  
 
8.2.7 EVENTS OF SPECIAL INTEREST  
Potential AEs include inadvertent disclosure of HIV status and significant negative emotional or social 
consequences of interactions and interventions that occur during the study. In addition, though unlikely 
based on findings of the recent UG3 phase, there is a risk of arrest, incarceration or similar legal jeopardy 
as a result of the social and legal environment for young men who have sex with men. These events will 
be reported as outlined in 8.2.1, 8.2.4 and 8.2.5 
 
Disruptions 
Disruptions to a research study can be brought on by a multitude of unpredictable events, i.e. political 
unrest, strikes, disease outbreaks. When such an event occurs, the local PI at each site will meet with 
the Co-Investigators and other study staff to formulate a plan to continue study data collection, while 
ensuring the safety of study participants. The study MPIs (Drs. Taiwo, Garofalo) will be informed of any 
significant disruptions within 24 hours of the site PI becoming aware of the event. In some cases, the 
necessary changes may require deviating from the study protocol. Participants should be kept informed 
of changes to the study that could impact them. The sites will report all such events to their IRB and 
sponsoring agencies.  
8.2.8 REPORTING OF PREGNANCY  
 
Pregnancies that occur in the course of the study will be described in study reports. Since ART is not 
provided in this study, pregnancy outcomes will not be tracked by the study team.  
8.3 
UNANTICIPATED PROBLEMS 
 
8.3.1 DEFINITION OF UNANTICIPATED PROBLEMS 
Unanticipated problems involving risks to subjects or others include, in general, any incident, experience, 
or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent documents; and (b) the characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 

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• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.3.2  UNANTICIPATED PROBLEMS REPORTING  
All events that meet the criteria for an unanticipated problem will be reported to the site IRB and the NIH 
Program Officer within 7 days of the study team becoming aware of its occurrence. 
 
 
 
8.3.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
In consultation with the IRB and Program Officer, the study team will implement participant notification 
and/or modifications to the study protocol.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Study 1: HIV Testing and Linkage to Care 
 
Primary Endpoints:  
 
HIV Testing Hypotheses:  the effect size in HIV seroprevalence during the intervention versus control 
period will be OR≥2.0. 
 
Secondary Endpoints: 
 
Linkage to Care Hypothesis: There will be at least 90% linkage to care among those with newly diagnosed 
HIV  
 
 
Study 2 HIV Treatment Intervention  
Primary Endpoint:  
 
We hypothesize that the rate of viral suppression (defined as < 200 copies/mL) during intervention period 
will be greater relative to control period, reflecting an OR≥1.5.  
 
Secondary Endpoints: 
 
Retention in Care Hypothesis: Retention in care during the intervention period will be greater relative to 
the control period. Eligible visits include the monthly “Youth Club” that takes place in the HIV clinic or 
any other non-study-mandated visit. 
 
Adherence Hypothesis: Adherence will be greater during the intervention period in comparison to the 
control period. Adherence will be compared both for ART concentration, via dried blood spot, pharmacy 

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pick-up records (100 minus percentage of days alive but without medication), and self-report (30-day 
visual analogue scale adherence, 4-day missed doses) 
 
Tertiary Endpoint:  
Medication adherence and retention in care will mediate the intervention effect on viral load 
suppression. We further hypothesize that there will be no significant moderation effect by age, gender 
and mode of infection, that is, the intervention effect in subgroups will be not be of differing strength or 
directionality.  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Power analysis For Study 1, small to moderate correlation within clusters (ICC = 0.10), there is sufficient 
power (0.805) to detect the OR of 2.0 in positivity rate with 315 tests completed on average in each 
cluster. For Study 2, with a small to moderate within cluster correlation and moderate individual auto-
correlation (0.50), this analysis will have adequate power (power = 0.945) to detect an OR of 1.5 in the 
proportion of participants achieving viral suppression with at least 90 participants per site. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The population for Study 1 is the total number of HIV tests completed, and resulting seroprevalence, 
among youth in/around Ibadan, Lagos, and Jos.  
 
For Study 2, the population will include youth on ART at the IDI, LUTH, NIMR, LASUTH, JUTH, OOUTH 
Sagamu and their satellite clinics.  
 
9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
 
For descriptive statistics, percentages will be presented for dichotomous outcomes (e.g., viral 
suppression vs. non-suppression) and means will be presented for continuous outcomes (e.g., 
medication adherence). Similarly, changes between intervention and control periods will be 
summarized via odds ratios. For Study 1, generalized linear models (GLM) will be used. For Study 2, 
generalized estimating equations (GEE) will be used to account for multiple observations of 
participants. For both studies, a binomial distribution and logit link function will be used to evaluate the 
statistical significance of the intervention effect, while controlling for secular trends in the outcomes over 
time and clustering within clusters. This analysis will follow the principles of intention to treat analysis 
and will be evaluated by examining the statistical significance of the regression coefficient for the 
intervention on the two primary outcomes of the studies. For differences in HIV seroprevalence in Study 
1 and differences in viral load suppression in Study 2, we will compare intervention and control periods 
at the end of the intervention period, i.e. 48 weeks.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 

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Study 1 
A GLM will be used to estimate difference in seroprevalence between intervention and control periods 
by examining the statistical significance of the intervention effect (i.e., identifying interventions periods), 
with a fixed effect for cluster, and a fixed categorical for fixed effect to account for secular changes in 
seropositive rates over time. An odds ratio of ≥2.0 will indicate satisfactory evidence of the intervention 
on seroprevalence. 
 
 
Study 2 
A GEE will be used to estimate the difference in viral suppression (<200 copies/mL) between intervention 
and control periods with participant as the cluster level effect, fixed effect for cluster, and a fixed 
categorical effect to account for secular changes in viral suppression over time. An odds ratio value ≥1.5 
will be considered satisfactory evidence of efficacy of the intervention on viral suppression.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Study 1 
Linkage to Care: To estimate the effect of the intervention on linkage to care we will compute the 
percentage of HIV positive individuals that are linked to care. GLMs will be used to compare intervention 
versus control periods and will be evaluated in identical models to those of the primary endpoints. 
 
Study 2: 
Retention in Care: To estimate the effect of intervention on retention in care we will examine we will 
analyze GEEs to account for multiple observations of participants and fixed effects to account for the 
clusters. We will compare change in the proportion of participants retained versus not retained, with 
retention defined as at least two clinic visits in the prior 24 weeks.  
 
Adherence: To estimate the effect of the intervention on adherence we will examine GEEs to account for 
multiple observations of participants and fixed effects to account for the clusters. We will compare change 
in the proportion of participants adherent to ART based on 90% adherence on the VAS, number of days 
possessing medication and level of ART medication in DBS samples. 
 
Mediation analyses 
Mediation analysis will be conducted using a structural equation modeling to examine the indirect effect 
of the intervention on viral suppression via adherence. The statistical significance of the indirect effect 
will be evaluated to examine mediation. Cluster membership will be accounted for using a fixed effect.    
 
9.4.4 SAFETY ANALYSES 
 
Safety issues that occur in the course of the studies will be described in annual reports to the IRBs and 
DSMB.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
We will describe age, gender, and mode of infection, as well as ethnicity/tribal affiliation, religion, 
employment, highest level of education, and marital/partnership status using measure of central tendency 
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9.4.6 PLANNED INTERIM ANALYSES  
 
Interim analysis of study endpoints will be performed at the end of year 2. 
 
 
9.4.7 SUB-GROUP ANALYSES 
 
Moderation of the intervention effect will be analyzed by subgroups of age, gender and mode of infection. 
This will be evaluated by examining interaction effects between the fixed effect for the intervention and 
age, gender, and mode of infection as part of a GEE. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
 
9.4.9 EXPLORATORY ANALYSES 
 
Implementation assessment data from questionnaires and abstracted from administrative and 
programmatic records will be analyzed using descriptive statistics, including measures of central 
tendency and dispersion. As relevant, multivariate regression models accounting for clustering at the site 
level will be used to explore individual-level factors (of study participants and staff) associated with 
measures of implementation feasibility, acceptability and satisfaction. In addition, we will explore the 
relationship between implementation indicators and overall effectiveness and factors modifying these 
associations to understand variability between sites or subpopulations.  Qualitative data from focus group 
and key informant interviews will be audio recorded, transcribed verbatim, and when needed, translated 
into English. Dedoose46 software will be used to store interview data and facilitate analysis using 
deductive and inductive content analysis. The coding structure will start with the CFIR domains relevant 
to the implementation and focus on understanding success, challenges and variability in key indicators 
of implementation.  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
In Study 1, while no individuals will be enrolled for the purposes of assessment of primary outcomes, 
individuals who complete HIV testing will be consented prior to completion of the brief demographic, 
behavioral and satisfaction survey (via a consent statement with waiver of documentation of consent).   
 
For human subjects research in Study 2, no research data will be collected prior to informed assent or 
consent.  Consent is conducted in a private room, by trained research staff. The consenting process will 

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ensure autonomy of the youth by explicitly stating that participation in the research is voluntary, and that 
the youth is free to participate or withdraw at any time. The consenting procedure, among other elements, 
will cover: a) sources of potential harm (e.g., inadvertent disclosure even if the possibility is remote, or 
routine risks such as from blood draw); and b) importance of the knowledge to be gained (e.g. findings 
may improve understanding of how to improve the health for youths living with HIV). 
 
While telephones will be provided to approximately 40% youths who do not have one (based on findings 
from the UG3) and a small sum will be made available to facilitate provision of practical support (based 
on needs assessment) in Study 2, there will no overt or covert coercion, enticement or intimidation of the 
participants.  
 
All participants in the implementation assessment, including study staff and CBO representatives will be 
consented prior to participation using written consent (if identifying data are collected) or via a consent 
statement with waiver of documentation of consent (for anonymous data collection).  
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Determining Capacity.   The cognitive capacity of youths will be carefully assessed as part of the 
consenting process.  The trained Study Coordinator will proceed through each component of the consent, 
written to Nigerian primary school or below reading level, and will make an assessment of the youth’s 
decisional capacity to consent prior to signing.  Potential participants will be asked questions designed 
to assess their capacity to understand what the study is about, appreciate, reason with, and express a 
choice about participation in the protocol.   
 
Parental consent   
Parental consent is required for unemancipated minors, but not for emancipated minors to participate in 
Study 2. In compliance with the 2014 Federal Ministry of Health Guidelines for Young Persons’ 
Participation in Research and Access to Sexual and Reproductive Health Services in Nigeria, youths 16 
years and older or emancipated minors aged 15 years are exempt from parental consent. This guidance 
defines an emancipated minor as a person under the age of 18 years who has been granted status of 
adulthood by a court order, has lived independent of parental guidance of at least a year, is married, 
living on the street, or is head of a household.   
 
Parental consent may decrease participation rates of emancipated minors because some youth will fear 
that their HIV status may be “outed” as a result of participation.  Furthermore, the nature and scope of 
the proposed research do not pose more than “minimal risk” to participants. To compensate for waiver of 
parental consent or emancipated minors, minor participants receive a formal individual assessment of 
capacity to consent to ensure their understanding of study goals, procedures, and risks from disclosure 
of sensitive information.   
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent as described above must be obtained and documented before any human subjects 
research. This applies to completion of the consent statement in Study 1 (HIV Testing Intervention) prior 
to the demographic, behavioral, and satisfaction questionnaire, and the assent or consent form for Study 
2 (HIV Treatment Intervention), as well as consent for participation in the implementation assessment. 
Youths who are assented for participation with parental permission will be consented for participation at 
the next available visit after their sixteenth birthday.  

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10.1.2 STUDY DISCONTINUATION AND CLOSURE 
The study will be discontinued when all data are complete, including HIV testing surveillance data in 
Study 1 and abstraction of HIV treatment data from medical records in Study 2, collected after the end of 
the intervention period in order to assess durability of the intervention effect.  
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
To protect the integrity of the participant’s data, staff will assign each individual a unique participant 
identification number (PID) at study enrollment.  This code number will be used for all study data.  We 
will maintain a list of participants with links between identifying information and code numbers to avoid 
any duplication in cases and to facilitate follow-up in Study 2. Only staff who have been trained in human 
subjects protection will have access to these lists, which will be kept on a secure server with password 
protected access.  Consents are stored in a locked cabinet away from workstations and are only 
accessed in the event of a consent amendment or an audit.  Locator files are kept in a locked cabinet in 
the research area, separate from data files, and are updated at each research visit. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Drug resistance testing will be used to determine whether a participant with HIV has a mutated form of 
the virus that does not respond to ARTs, and as a result, could not have benefited from this 
intervention. We will collect and store venous blood and plasma at each study time point. Select 
participants will be identified and their samples sent to a reference laboratory for testing. Findings from 
resistance testing will be made available to the site and may be used to guide selection of an HIV 
regimen when initiating or changing ART and inform standard of care practices after the intervention 
period. We will store blood plasma samples indefinitely (with participant consent) for future studies as 
proposed by study investigators.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Site 
Site PI 
Email Address 
University of Ibadan/IDI 
Prof. Olayinka Omigbodun 
olayinka.omigbodun@gmail.com 
fouryinkas@yahoo.co.uk 
 
LUTH 
Prof. Alani Sulaimon Akanmu 
asulaimona@gmail.com 
 
LASUTH 
 
Prof. Akinsegun Akinbami  
segun.akinbami@lasucom.edu.ng  
NIMR 
 
Dr. Agatha David 
nkiru_d@yahoo.com 
 
JUTH 
 
Prof. Oche Agbaji 
oagbaji@yahoo.com 
 
OOUTH (Sagamu) 
 
Dr. Folashade Adekanmbi  
wonlash@yahoo.com 
 

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The PIs at each of the six study sites will oversee all study activities.  
10.1.6 SAFETY OVERSIGHT 
 
All study personnel and Peer Navigators will be trained regarding privacy and confidentiality.   They will 
err on the side of caution and contact the clinical supervisor or site investigator and, if appropriate, 
escort participants to the nearest emergency room or clinic in the event of an emergency. Both study 
staff and Peer Navigators will report concerns about safety directly to the PI at their respective site. If 
any study staff discovers any untreated condition (e.g., onset of physical or mental health condition), 
they will refer the participant to appropriate treatment immediately. The MPIs (Profs. Garofalo and 
Taiwo) will be informed of any significant safety concerns within 24 hours of the site PIs becoming 
aware of the event.  
 
Participant safety will be discussed on weekly team calls, and a written log of all safety events will be 
maintained, including AEs, SAEs and Unanticipated Problems. Safety will also be monitored through 
weekly review of peer navigation activity logs, participant encounter forms and monthly tallies of 
completed satisfaction questionnaires. 
 
AEs and SAEs will be classified by the site PI as related or not related to the study and will be reported 
to the study team.  All serious AEs that are unanticipated will be reported to the IRB, NIH Program Officer, 
and the DSMB within 3 working days of the study team becoming aware of its occurrence.  In consultation 
with the IRB, the NIH Program Officer, and the DSMB, the study team will notify participants and/or 
implement modifications to the study protocol. 
 
10.1.7 CLINICAL MONITORING 
Clinical monitoring will occur according to the local standard of care. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure accuracy of collected data, a monthly data audit will be conducted.  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
We have developed systematic protocols for data handling and storage over multiple cohort studies.  We 
maintain both paper files and computer files for each participant.  Paper files include: 1) locator 
information, 2) informed consent, 3) any paper data forms.  The first two have identifying information and 
are linked to the data by the patient identification number (PID).   
 
Computer files consist of the tracking data base, and study data files. Tracking files are maintained in 
REDCap at Northwestern University, a highly secure web-based research database.  This database is 
used to schedule and track study visits; it is completely password protected.  Computer data files never 
have any identifying information and are encrypted for transfer between study sites.  Data files do not 
include information that could be used to identify the participant from the data file alone. 
 

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Dimagi will provide a private cloud server for the SMS application content and user data for the duration 
of the application deployment. This is a secure system and will be further protected by login credentials 
for limited access, to protect participant confidentiality. To protect privacy and confidentiality, we will 
encourage participants to delete text messages after taking medication, to use confidential messages 
that do not reveal HIV status or mention medications, and we will encourage each participant to protect 
cell phone confidentiality with a passcode.  
 
 
 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Data files are exported from REDCap and imported into SPSS database for storage and analysis.  
 
10.1.10 
PROTOCOL DEVIATIONS   
 
Deviations from this protocol will be reported to the study MPIs and local IRBs as required by local 
practices. 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
This protocol will adhere to publications, and data and resource sharing policies of the PATC3H 
consortium and will be consistent with the relevant NIH policies, laws and regulations. 
  
10.1.12 
CONFLICT OF INTEREST POLICY 
Study investigators at IDI/CoMUI, LUTH, NIMR, LASUTH, OOUTH Sagamu, JUTH, and Northwestern 
University will adhere to their institutional policies for reporting conflicts of interest.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
As described in the protocol. 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
A Summary of Changes table for the current amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
22 March 2021 
1. The study timelines associated with 
Study 1 and Study 2 were corrected to 
be consistent with the Study Schema 
(i.e., Time 1=0-24 weeks) 
 
2. In Study 2, the inclusion criterion 
for language ability was revised to 
include two additional languages: 
Hausa and Pidgin English 
1. The study timelines are now 
consistent with the Study Schema. 
 
 
 
2. In Study 2, the inclusion 
criterion for language ability now 
includes the primary languages 
reflected in the study population. 
3.0 
07 June 2021 
1. We have removed the enrollment 
cap of only 35% suppressed 
participants at clinic sites. 
 
 
 
2. The inclusion criteria were revised 
to allow participation of non-
emancipated 15-year-old youth, with 
parental consent.  
 
 
3. Exclusion criteria were revised to 
exclude non-emancipated 15-year-old 
youth who do not have parental 
consent.  
 
 
4. We have removed a reference to 
DNA extraction in the description of 
DBS procedures. 
 
5. We have added a requirement for 
parental consent to the consent 
procedures. 
 
 
6.We have revised the consent 
process for participants who are 
assented at enrollment, to consent 
them as the earliest opportunity after 
they reach the age of consent. 
1. The proportion of suppressed 
patients varies by clinic site and 
thus there is no one proportion 
suppressed that is representative for 
all clinics. 
 
2. We have broadened the inclusion 
criteria to include youth who have 
reached an age of transition to adult 
care at age 15, but who are not 
emancipated.  
 
3. Exclusion criteria were revised 
to make it clear that non-
emancipated 15-year-old youth 
who do not have parental consent 
are excluded. 
 
4. The reference to DNA extraction 
in the description of DBS 
procedures was an error.  
 
5. The inclusion of non-
emancipated 15-year old youth in 
clinical research in Nigeria requires 
parent consent. 
 
6. We will consent patients who 
were assented at enrollment to 
promote their autonomy to consent 
for research participation. 

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4.0 
01 March 2022 
1. We have updated the description of 
sample size in study 2 to N=560. 
 
 
2. In study 1, we have revised the 
protocol to include abstraction of HIV 
testing, behavioral and demographic 
data from sexual partners of eligible 
individuals tested via iCARE, 
regardless of sex and age (see updated 
Consent Statement, Version 2, March 
11, 2022). 
 
3. We have updated reporting of 
SAEs such that only SAEs that are 
unanticipated, and related or possibly 
related to the study will be reported to 
the IRB and the DSMB within 7 
working days of the study team 
becoming aware of its occurrence. All 
SAEs (regardless of whether they are 
unanticipated or related or possibly 
related to the study) will be reported 
to the Northwestern team and the NIH 
Program Officer within 3 days of 
occurrence. 
 
4. With Study PI approval, a remote 
verbal consent addendum was added 
to allow HIV treatment arm 
participants who have moved or are 
otherwise not available for an in-
person follow up study visit at their 
study site to complete the viral load 
testing and questionnaires from their 
current location (see Verbal Consent 
Addendum, Version 1, March 11, 
2022).    
1.  The study sample size has been 
updated for specificity and to align 
with the Study Schema 
 
2. HIV testing data from sexual 
partners of eligible cases provides 
an opportunity to collect additional 
information on HIV related risk for 
the target population. 
 
 
 
 
3. The SAE reporting criteria were 
revised to be consistent with 
reporting requirements at site IRBs, 
which only require reporting of 
SAEs that meet these criteria and to 
respond to the DSMB preference 
for reporting.   
 
 
 
 
 
 
 
4.  Remote completion of a follow-
up study visit will be allowed on 
rare occasions to limit loss-to-
follow-up for the primary endpoint 
(viral load).      
5.0 
05 May 2023 
1. We have added questions about 
HIV prevention, including Pre-
exposure prophylaxis to the study 
measures in Study 1 (Testing 
arm). 
1. Adding questions on HIV 
prevention preferences will 
inform future HIV prevention 
intervention development for 
the study population. 
6.0 
8 March 2024 
1. We have added questions about 
human papillomavirus (HPV) 
and HPV vaccination to the study 
measures in Study 1 (Testing 
arm). 
1. Adding questions on HPV and 
HPV vaccination will inform 
future HPV prevention 
intervention development for 
the study population. 
 
 
 
 
 
 
 
 
 
 
 
 

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