Strategic Antiretroviral Therapy and HIV Testing for Youth in Rural Africa
Phase: NA
Conditions: HIV
Sponsor: University of California, San Francisco

Strategic Antiretroviral Therapy and HIV Testing for 
Youth in Rural Africa
The SEARCH Youth Study
Protocol Co-Chairs:
Diane Havlir, MD
       Moses Kamya, MBChB, MPH, PhD
       Theodore Ruel, MD
Sponsor: University of California, San Francisco
Grant Title: Strategic antiretroviral therapy and HIV testing for youth in rural 
Africa
Grant Number: UG3 HD96915-01
Funded by: National Institute of Child Health and Human Development
National Institutes of Child Health 
Version Number:  v.4.1
27 October 2022
NCT03848728

ii
Summary of Changes from Previous Version:
Affected 
Section(s)
Summary of Revisions Made
Rationale
8.1.6
Updated Assessment of Infant Outcomes 
section to include details on additional viral 
load testing of participating mothers and 
facilitation of standard care HIV testing of 
infants as needed.
To include a final measurement of viral 
load suppression among this subset of 
participants and ensure their infants have 
completed all required HIV testing 
according to country programs.
8.1.7, 9.4.3.7
Added Assessment of Mental Health 
procedures for participants in the RCT at 
both clinics and intervention sites, including 
the analytic approach for statistical analysis.
To understand the effect of the 
intervention on participants’ mental 
health and any major life events at the 
end of their study participation.
Throughout 
protocol
Minor typographical corrections.
To make minor edits for to correct 
typographical errors.

iii
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recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award. 

iv
PROTOCOL TEAM ROSTER
Diane Havlir, MD
Protocol Co-Chair
Professor of Medicine, Chief, HIV, Infectious Diseases and Global Medicine Division, University of 
California, San Francisco
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A.
Phone Number:  +1-415-476-4082 ext. 424
Email:  diane.havlir@ucsf.edu
Moses R. Kamya, MBChB, MMed, PhD 
Protocol Co-Chair
Professor and Chair of Medicine; Dean, School of Medicine, Makerere University
Address: Department of Medicine, P.O. Box 7072, Kampala, Uganda  
Phone Number: +256-414-533200
Email: mkamya@infocom.co.ug
Theodore Ruel, MD
Protocol Co-Chair
Professor, Department of Pediatrics, University of California, San Francisco
Address:  UCSF Box 0434, San Francisco, CA 94143-0136, U.S.A.
Phone Number:  +1-415-476-9197
Email:  theodore.ruel@ucsf.edu
Edwin Charlebois, PhD, MPH
Investigator, University of California, San Francisco
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A
Phone Number:  +1-415-476-6241
Email:  edwin.charlebois@ucsf.edu
Laura Balzer, PhD
Investigator and Protocol Statistician, University of Massachusetts, Amherst
Address:  School of Public Health and Health Sciences, Amherst, MA 01003-9304, U.S.A.
Phone Number:  +1-203-558-3804
Email:  lbalzer@umass.edu
Dalsone Kwarisiima, MBChB, MPH
Investigator, Infectious Diseases Research Collaboration
Address:  P.O. Box 7072, Kampala, Uganda
Phone Number:  +256-772-607274
Email:  dkwarisiima@idrc-uganda.org
Janet Nakigudde, PhD, MS
Investigator, Makerere University
Address:  Department of Psychiatry, P.O. Box 7072, Kampala, Uganda
Phone:  +256-414-542803
Email:  jnanbi@muip.mak.ac.ug 
James Ayieko, MBChB, MPH

v
Investigator, Kenya Medical Research Institute
Address:  P.O. Box 517-20107, Njoro, Kenya
Phone Number:  +254-720-925262
Email:  jimayieko@gmial.com
Elizabeth Bukusi, MBChB, M.Med, MPH, PhD 
Investigator, Kenya Medical Research Institute
Address:  Box 54840, Nairobi, Kenya
Phone Number: +254-733-617503
Email:  ebukusi@rctp.or.ke
Carol Camlin, PhD, MPH
Investigator, Social Sciences/Qualitative Studies, University of California, San Francisco
Address: ANSIRH Program, 1330 Broadway, Suite 1100, Oakland, CA 94612
Phone Number:  +1510 986-8981
Email:  carol.camlin@ucsf.edu
Starley Shade, PhD
Investigator, Cost Effectiveness, University of California, San Francisco
Address:  Box 0886, San Francisco, CA 94143-0886, U.S.A.
Phone Number:  +415-476-6362
Email:  starley.shade@ucsf.edu
Catherine Koss, MD
Investigator, University of California, San Francisco
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A
Phone Number:  +1-415-476-4082 ext. 441
Email:  catherine.koss@ucsf.edu 
Sarah Puryear, MD, MPH
Investigator, Alcohol Studies, University of California, San Francisco
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A
Phone Number:  +1-415-502-1765, ext. 423
Email:  sarah.puryear@ucsf.edu 
Bill Kapogiannis, MD
Program Officer, National Institute of Child Health and Human Development
Address:  Box 7510, Bethesda, MD 20892-7510, U.S.A.
Phone Number:  +1-301-402-0698
Email:  kapogiannisb@mail.nih.gov

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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...................................................................................................................................................4
1.3
Schedule of Activities .............................................................................................................................5
2
INTRODUCTION.................................................................................................................................................6
2.1
Study Rationale ......................................................................................................................................6
2.2
Background ............................................................................................................................................6
2.3
Risk/Benefit Assessment........................................................................................................................8
2.3.1
Known Potential Risks ........................................................................................................8
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....................................................................................................13
4.3
Justification for Intervention................................................................................................................13
4.4
End-of-Study Definition........................................................................................................................13
5
STUDY POPULATION .......................................................................................................................................13
5.1
Inclusion Criteria ..................................................................................................................................14
5.2
Exclusion Criteria..................................................................................................................................14
5.3
Lifestyle Considerations .......................................................................................................................14
5.4
Screen Failures .....................................................................................................................................14
5.5
Strategies for Recruitment and Retention ...........................................................................................15
6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S)..................................................................15
6.1
Study Intervention(s) or Experimental Manipulation(s) Administration..............................................15
6.1.1
Study Intervention or Experimental Manipulation Description .......................................16
6.1.2
Administration and/or Dosing ..........................................................................................17
6.2
Fidelity..................................................................................................................................................17
6.2.1
Interventionist Training and Tracking...............................................................................17
6.3
Measures to Minimize Bias: Randomization and Blinding ...................................................................17
6.4
Study Intervention/Experimental Manipulation Adherence................................................................18
6.5
Concomitant Therapy...........................................................................................................................18
6.5.1
Rescue Therapy ................................................................................................................18
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.............................................................................................................................18
7.1
Discontinuation of Study Intervention/Experimental Manipulation....................................................18
7.2
Participant Discontinuation/Withdrawal from the Study ....................................................................18
7.3
Lost to Follow-Up .................................................................................................................................19
8
STUDY ASSESSMENTS AND PROCEDURES.......................................................................................................19
8.1
Endpoint and Other Non-Safety Assessments .....................................................................................19
8.1.1
Community Testing and Linkage.......................................................................................19
8.1.2
SEARCH YOUTH Intervention and ClinIcal Outcomes .......................................................19
8.1.3
Identification of Barriers and Facilitators of the SEARCH Youth Intervention..................20

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8.1.4
Incremental Costs and Gains of the SEARCH Youth Intervention.....................................23
8.1.5
ASSESSMENT of ALCOHOL USE and its effect ON viral suppression.................................24
8.2
Safety Assessments..............................................................................................................................24
8.3
Adverse Events and Serious Adverse Events........................................................................................25
8.4
Unanticipated Problems.......................................................................................................................25
8.4.1
Definition of Unanticipated Problems..............................................................................25
8.4.2
Unanticipated Problems Reporting ..................................................................................25
8.4.3
Reporting Unanticipated Problems to Participants..........................................................26
9
STATISTICAL CONSIDERATIONS.......................................................................................................................26
9.1
Statistical Hypotheses ..........................................................................................................................26
9.2
Sample Size Determination..................................................................................................................26
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)..................................................................................28
9.4.3
Analysis of the Secondary Endpoint(s) .............................................................................28
9.4.4
Safety Analyses.................................................................................................................31
9.4.5
Baseline Descriptive Statistics ..........................................................................................31
9.4.6
Planned Interim Analyses .................................................................................................32
9.4.7
Sub-Group Analyses..........................................................................................................32
9.4.8
Tabulation of Individual Participant Data.........................................................................32
9.4.9
Exploratory Analyses ........................................................................................................32
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................................................32
10.1
Regulatory, Ethical, and Study Oversight Considerations ....................................................................32
10.1.1
Informed Consent Process................................................................................................32
10.1.2
Study Discontinuation and Closure...................................................................................33
10.1.3
Confidentiality and Privacy...............................................................................................33
10.1.4
Future Use of Stored Specimens and Data.......................................................................34
10.1.5
Key Roles and Study Governance .....................................................................................35
10.1.6
Safety Oversight................................................................................................................35
10.1.7
Clinical Monitoring ...........................................................................................................35
10.1.8
Quality Assurance and Quality Control.............................................................................35
10.1.9
Data Handling and Record Keeping ..................................................................................36
10.1.10
Protocol Deviations ..........................................................................................................37
10.1.11
Publication and Data Sharing Policy .................................................................................38
10.1.12
Conflict of Interest Policy..................................................................................................38
10.2
Additional Considerations....................................................................................................................38
10.3
Abbreviations and Special Terms .........................................................................................................38
10.4
Protocol Amendment History ..............................................................................................................40
11
REFERENCES....................................................................................................................................................41
APPENDIX 1:  Randomization Principals and Procedures............................................................................................43
APPENDIX 2:  Costing Principals and Procedures ........................................................................................................44

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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). 
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: Diane Havlir, MD
Title: Professor of Medicine
Chief, Division of HIV, Infectious Diseases & Global Medicine
Associate Chair for Clinical Research
Department of Medicine
University of California, San Francisco
Zuckerberg San Francisco General Hospital

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1
PROTOCOL SUMMARY
1.1
SYNOPSIS 
Title:
Strategic Antiretroviral Therapy and HIV Testing for Youth in Rural 
Africa
Grant Number:
UG3 HD96915-01
Study Description:
A cluster randomized study to evaluate the effect on HIV viral 
suppression of a combination intervention designed to address the 
structural barriers,  psychological and social needs of HIV-positive 
youth in rural Uganda and Kenya.
Objectives:
Primary Objective: To determine the effectiveness of the SEARCH Youth 
intervention in increasing long-term retention and virologic 
suppression
Secondary Objectives:
1.
To investigate barriers and facilitators of the SEARCH Youth 
intervention
2.
To estimate incremental costs and gains of the SEARCH Youth 
intervention
3.
To evaluate the effectiveness of the youth HIV testing and 
referral strategy to SEARCH youth clinics 
4.
To characterize alcohol use and its effect on viral suppression 
among HIV-positive youth
5.
To evaluate the impact of SEARCH Youth intervention on HIV-
free survival of infants born to participants 
Endpoints:
Primary Endpoint: Proportion of study participants with virologic 
suppression (HIV RNA <400 c/mL) at 2 years of follow-up
Secondary Endpoints include
1.
Retention in care
2.
Sustained viral suppression
3.
Virologic failure
4.
Cost of care delivery 
5.
Uptake and yield of community outreach to identify new HIV 
infections 
6.
Alcohol use
7.
HIV-free survival among infants born to participants
Study Population:
Approximately 2000 HIV-positive youth, ages 15-24, in rural Uganda 
and Kenya
Phase or Stage:
Phase IV
Description of 
Sites/Facilities Enrolling 
Participants:
28 health centers in rural Southwestern Uganda and Western Kenya 
serving HIV-positive patients 

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Description of Study 
Intervention/Experimental 
Manipulation:
The intervention consists of 3 components:
1.
Life-stage assessment tool and provider e-collaboratives
2.
Structured choice clinic access
3.
Rapid viral load (VL) feedback
Study Duration:
5 years 
Participant Duration:
At least 2 years beyond enrollment until end of the study 
1.2
SCHEMA 
 
 
 
Randomization
28 communities in Kenya and SW Uganda
Screen Participants and Conduct Informed Consent Process
Intervention
N = 14 communities
Approximately 1000 participants 
Control
N = 14 communities
Approximately 1000 participants 
Baseline VL testing
Baseline Intervention Visit
Life-stage assessment
Access choice
Rapid VL response 
Baseline VL Testing
Follow-Up Intervention Visits
Life-stage asses. Q 3 months
Access choice annually
Rapid VL testing Q 6 months
Standard of Care
2-Year Follow-up VL Testing

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1.3
SCHEDULE OF ACTIVITIES 
1.
Regular study visits in intervention and control sites will coincide with participants’ standard 
care visit schedule, which is generally every 3 months
2.
The Life-Stage Assessment will occur every 3 months, or more frequently as needed
3.
The structured clinic access choice review will occur at least annually, but participant choice may 
be updated more frequently as needed
4.
Rapid VL testing and feedback will occur every 6 months when the participant is suppressed; 
however participants with detectable VLs will be tested roughly every 2-4 weeks by clinician 
decision, with feedback and support, until suppression is achieved or until a time point that the 
participant is not amenable to changing adherence or medications as advised by the provider
5.
Provider consultation and discussion via WhatsApp will occur for detectable VL test results and 
for any other issue or barrier to adherence identified by the study staff as requiring 
consultation, as needed
Baseline1
3 months1
6 months1
9 months1
12 months1
15 months1
18 months1
21 months1
24 months1
Every 3 
months1
INTERVENTION AND CONTROL SITES
Eligibility Screen
X
Informed Consent
X
Baseline Questions
X
2-Year Follow-Up VL
X
INTERVENTION SITES
Life-Stage Assessment2
X
X
X
X
X
X
X
X
X
X
Structured Choice Clinic 
Access Review3
X
X
Baseline VL and Rapid 
Feedback
X
Follow-Up Rapid VL and 
Feedback4
X
X
X
X
Every 
6 mo.
Provider Consultation via 
WhatsApp5
As 
needed
As  
needed 
As 
needed
As 
needed
As 
needed
As 
needed
As 
needed
As  
needed
As  
needed
As needed
CONTROL SITES
Baseline VL
X
Standard Care
X
X
X
X
X
X
X
X
X
X

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2
INTRODUCTION
2.1
STUDY RATIONALE 
Adolescents and young adults with HIV (AYAH) represent a growing share of people living with the 
disease in sub-Saharan Africa (SSA). AYAH have lower HIV testing rates, engagement in care and viral 
suppression (VS) compared to adults.1-5 We postulate that to achieve successful testing and longitudinal 
care of AYAH, interventions must be tailored to the dynamic social and cognitive needs of AYAH as they 
pass through life-stages, including both in- and out-of-health facility components.  SEARCH Youth will be 
the first rigorously tested combination HIV intervention for AYAH in rural SSA that:  a) incorporates 
youth in testing outreach, b) is grounded on contemporary understandings of social development with 
its life-stage approach, and c) includes AYAH new to care, re-engaging in care and already in care, d) has 
viral load (VL) as primary endpoint, and  e) is designed to address the specific psychological, social, and 
gender needs of AYAH, in way that is cost effective and scalable for implementation in rural settings. 
Our proposed work is addressing 2 significant gaps: 1) Individual, clinic and/or community/ system level 
combination interventions to improve outcomes on the HIV care continuum for youth living with HIV), 
and 2) Implementation of youth friendly strategies to improve uptake of biomedical interventions (HIV 
testing and linkage for ART) for infected and/or at-risk youth.
2.2
BACKGROUND 
An estimated 2.2 million adolescent and young adults are living with HIV in sub-Saharan Africa. In a 
study of 4 countries in SSA, the proportion of youth aged 15-24 years (n=53,244) who initiated ART by 1 
year was only 25% compared to 46% among 25-54 year old adults (n=240,440).1  Compared to adults, 
AYAH in SSA are 1.6-1.8 x more likely to be lost to follow up,1,2 twice as likely to report lapsed 
adherence3, and 1.5-3.2 times more likely to be viremic,3-5 and adolescent girls and young women have 
four times the HIV prevalence of their male counterparts.6 In rural settings where the burden of HIV 
among youth is substantial, additional challenges exist. In Kenya, 70% of people living with HIV reside in 
rural areas.7  Mortality rates are higher among HIV- infected persons in rural vs urban SSA.8,9 AYAH 
attending clinics outside of urban areas have higher attrition (RR: 1.2) 1 year after linkage.1  Barriers in 
rural areas include distance to clinics10 transportation costs,11 decreased access to lab services12 and 
other social influences.13  Our strategic combination HIV intervention aims to engage, retain-in-care and 
increase VS among AYAH to reduce new infections and mortality in rural East Africa. We will generate 
evidence-based approaches aimed to direct resources towards what works and divert funding away 
from those that do not. We will additionally use mixed methods and costing studies to understand 
mechanisms of intervention components and to provide information for countries considering using this 
strategy for AYAH.

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AYAH face barriers to HIV testing and long-term care that vary by life-stage, gender, and individual 
context. Between the ages of 10 and 24 years, AYAH go through a series of distinct life-stages that 
impact their decision making, healthcare-seeking behavior and outcomes. As described in the 
conceptual framework of Sawyer et al14, and recently highlighted by the WHO,15 cognitive and social role 
changes interact with social determinants to impact AYAH health behaviors and outcomes throughout 
this period (Table 1).
Table 1. Conceptual Framework of AYAH Life-Stage, Development, Events, and Barriers
Life-Stage
Cognitive 
Development
Social Development
Life Events
Barriers to HIV Testing and Care
Early 
Adolescence
(10-14 years)
Moving from 
concrete to 
abstract 
thought
Immediacy
Struggle with identity 
Worry about being 
normal 
Conflict with parents
Desire for 
independence and 
privacy 
Lives at home 
or move to 
boarding school 
Orphaned 
Concern for consequences of 
testing on identity 
Worry that clinic attendance and 
medications leads to disclosure in 
school settings & stigma
Standard counseling based on long 
term life goals not effective
Late 
Adolescence 
(15-19 years)
Abstract 
thinking 
Goal setting 
Moral 
reasoning
Intense self-
involvement
Distancing from 
parents and new 
responsibilities 
Increasing influence 
of peers
increasing interest in 
sex
Sexual debut;
Boarding 
school, first 
employment, 
migration
Marriage
Young 
Adulthood 
(20-24 years)
Can delay 
gratification 
Increasing 
concern for 
future
Firmer sense of 
identity, increased 
concern for others, 
developing more 
serious relationships
Marriage and 
then children, 
responsibility to 
others about 
life outcome
Shifting social and support systems 
from families, to peers, to partners 
means evolving needs for disclosure
Increased sexual activity and 
marriage lead to different 
counselling needs (STI to 
contraception to safe conception)
Change in daily schedules and 
residence– home / school / work - 
lead to shifts optimal timing and 
locations of clinic visits
Table adapted from Sawyer et al.14
Formative Research with AYAH in East Africa Has Identified Significant Barriers to HIV Care. In 
developmental research with AYAH in Uganda and Kenya, we interviewed AYAH to learn what they 
perceived as the barriers and facilitators to successful engagement in care and adherence (Table 2). We 
surveyed 20 clients aged 15-24 years. Respondents had a median age of 20.5 years, 16(80%) were 
female, 10(50%) were married, and 6(30%) were in school. Issues around stigma, particularly in the 
home environment, were prevalent barriers to clinic attendance and medication adherence. Several 
reported transport difficulties and distance to clinic were deterrents to visits. AYAH valued their 
relationships with providers, with 89% reporting they liked meeting with their providers when at clinic. 
Only 30% felt they had enough information about HIV; all expressed preference to learn more in 
conversations with their own provider.

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Table 2. Barriers to Medication Adherence and Clinic Attendance
Barrier
AYAH Comments
SEARCH Youth 
Intervention 
Component
Mechanism of Action
Life-stage 
changes
(marriage, 
school) that 
affect 
adherence
Question: what makes taking medication HARDER?
“I am still young and most friends are not taking any drugs.”
“Eventually I got married and had to stop medication for the 
sake of my husband as I had not disclosed my status.”
“Sometimes I couldn’t get time to go for the drugs without 
being seen. They still don’t know my status.”
Predisposing:
Life-stage specific 
counseling; 
facilitated 
disclosure
Structured re-
evaluation of life-stage 
enables providers to 
promptly act when 
social structures and 
change  
Structural 
barriers to 
care
What makes attending appointments HARDER?
“People knowing that you are going to a HIV clinic.”; “There is a 
long distance to clinic”;“ My school is very far from the clinic”
“Sometimes I don't want other people to see me when I come 
on my day of convenience”; “It disrupts my work.”
What makes attending appointments EASIER?
“Attending clinic in late evening”; A majority said that early 
and late hours would make attendance easier
Enabling:
Choice of clinic 
access
1. alternative-
hours
2. option for 
    phone visits 
3. provider choice
Choice respects 
developing sense of 
autonomy among 
AYAH; multiple options 
allow clinic access be 
tailored to the case-
specific pressures
Feedback/ 
motivation 
for 
adherence
Do you think that knowing your viral load helps you take your 
medications better? 
- 88% replied yes
“It helps me because it gives me courage to take my 
medication”
Reinforcing:
Rapid VL feedback 
& Counseling
Prompt identification 
of adherence issues. 
Concept of viremia 
adapts to abstract 
thinking development.
The SEARCH Youth combination HIV intervention was developed using the proven PRECEDE 
Implementation Science Framework. To improve engagement in care and increase viral suppression we 
developed the SEARCH Youth combination HIV intervention structured on the empirically-validated 
PRECEDE model.16 This model has shown that health promotion strategies are most effective when they 
address: (1) “predisposing factors” comprised of knowledge, attitudes or beliefs that affect behavior; (2) 
“enabling factors” that facilitate change by making the behavior “easier”; and (3) “reinforcing factors” 
which include anticipated consequences following a behavior. Use of a proven implementation science 
framework enhances both the scientific rigor of the intervention research and likelihood of success. 
Although this life-stage based approach using PRECEDE has not been tested in HIV care, there are data 
that multi-level interventions based on behavioral theories work in other diseases such as diabetes in 
youth17.
2.3
RISK/BENEFIT ASSESSMENT 
2.3.1
KNOWN POTENTIAL RISKS 

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The SEARCH Youth intervention works through provider behavior change, health systems changes: more 
flexible clinic hours and same day viral load testing – none of which pose significant risk to participants. 
Participants in our study all receive HIV antiretroviral therapy recommended by the ministries of health 
in Uganda or Kenya.  There are neither “experimental” drugs nor un-recommended uses of standard 
medications in this study. Participants will have access to second and third line ART as per country 
guidelines. The primary immediate and long-term risk for youth is therefore loss of confidentiality. This 
could occur during  testing, clinic-based care, or through the use of WhatsApp by the providers.
2.3.2
KNOWN POTENTIAL BENEFITS 
AYAH enrolled at clinics randomized to the intervention arm might benefit from improved retention and 
virologic suppression from the components of the intervention, including increased access to clinic,  
access to ancillary services such as reproductive health, counseling based on the assessments and 
feedback from the more frequent viral load testing.  Knowledge gained from this study could improve 
strategies for viral suppression and retention outcomes among AYAH. 
2.3.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
It is necessary to collect a minimal level of potentially sensitive information in order to practically conduct 
the study.  We will seek to protect participants against the risk to confidentiality as follows:
Risk of HIV Status Disclosure: Given the sensitive and private nature of the HIV-status of participants of 
the randomized controlled trial (RCT), extra measures will be put in place to ensure maintenance of 
privacy, confidentiality and security of the data obtained.  Contact mobile numbers will be re-checked to 
insure they are updated. 
Use of WhatsApp:  We are implementing a number of measures will protect the privacy of participants 
discussed on WhatsApp. First, participation in WhatsApp chats will be strictly limited to the providers 
participating in this study.  As such, participant clinical information will remain within providers of the 
same health system, a practice generally considered acceptable when the goal is to improve medical 
care. Second, all participating providers will be required to attend a training in which they review and 
are tested on Standard Operating Procedures which outline specifically the acceptable and unacceptable 
information for discussion.  For example, the use of names, birthdays, specific locations or any other 
potentially participant specific information is prohibited.  Chats will be monitored by study staff to 
ensure that these guidelines are being adhered to.  Finally, all transmissions of WhatsApp are encrypted, 
greatly reducing the risk that someone outside of the chat could intercept and read transmitted 
messages.
Data Security: All information will be recorded using study identification numbers, rather than 
participant names, and stored securely in locked offices at a study data center. All study computers will 
be password encrypted and kept in locked offices.

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Institutional Review Board Approval: The proposed research study will be reviewed and approved by the 
IRBs of all the participating institutions in the U.S., Uganda and Kenya. This includes the UCSF Committee 
on Human Research (CHR), the Makerere University School of Medicine - Research and Ethics 
Committee (SOM-REC), the Uganda National Council of Science and Technology (UNCST), the Kenya 
Medical Research Institute (KEMRI).
Considering the minimal risk involved in this study and the potential benefit to health care providers and 
the scientific community, the investigators have determined that the potential information gained 
outweighs the risk of study participation.
3
OBJECTIVES AND ENDPOINTS 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To determine the effectiveness of 
the SEARCH Youth intervention in 
increasing long-term retention and 
virologic suppression. We will 
compare the proportion of AYAH 
with virologic suppression (HIV RNA 
<400 c/mL) in each of the 14 clinics 
randomized to intervention versus 
those in 14 clinics randomized to the 
control condition, adjusting for 
clustering within clinics.
Proportion of study 
participants with virologic 
suppression (HIV RNA <400 
c/mL) at 2 years of follow-
up
This measure captures care 
outcomes that the 
combination SEARCH Youth  
intervention has been 
designed to achieve
Secondary
1. To investigate barriers and 
facilitators of the SEARCH Youth 
intervention, we will use a mixed-
methods approach of qualitative 
analysis of in-depth interviews (45 
participants, 15-20 family members, 
12-24 care providers and 6 key 
informants) at baseline and follow-
up years combined with focus 
groups, quantitative process and 
fidelity data. In addition, focus 
groups and provider interviews will 
inform intervention development for 
HIV prevention among high risk 
youth. 
1.a. Qualitative interview 
and focus group data
1.b Quantitative process 
measures 
Understanding the perception 
of participants and providers 
will inform the future 
implementation and 
refinement of the 
intervention.
2. To estimate incremental costs and 
gains of the SEARCH Youth 
2.a.  Health facility level 
costs
Knowing which elements of 
the combined intervention 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
intervention over the continuum of 
care associated with the SEARCH 
Youth intervention using micro-
costing and time-in-motion analyses.
2.b.  Health gains (as per 
primary study outcome, 
disability-adjusted life 
years (DALYs) 
were implemented with high 
fidelity might increase 
understanding of which are 
the most important to the 
primary outcome
Quantitative cost and cost-
effectiveness data will help 
inform stakeholder decision 
makers about the value and 
feasibility of the intervention
3. To evaluate the effectiveness of the 
youth HIV testing and referral 
strategy for ART.
3.a. Uptake of HIV testing 
(total number tested)
3.b. Yield (percentage of 
individuals testing HIV-
positive with a new or out-
of-care HIV diagnoses)
These are the key metrics 
generally used to assess the 
efficacy of testing programs
4. To characterize alcohol use and 
investigate its impact on viral 
suppression, we will measure 
alcohol use by self-report and blood-
based biomarker and assess 
associated risk factors in participants 
randomized to the intervention at 
scheduled study visits
4.a. Self-reported alcohol 
use ( by Alcohol Use 
Disorders Identification 
Test-Consumption (AUDIT-
C) score)
4.b. Biomarker-measured 
alcohol use (by 
phosphatidylethanol 
(PEth))
Knowing the relative 
contribution of alcohol use to 
viral non-suppression may 
inform future implementation 
and refinement of the 
intervention
 
5. To evaluate the effect of the 
SEARCH Youth intervention on HIV-
free survival among infants born to 
participants
5.a.  Proportion of infants 
who remain alive and HIV-
free at 1 and 2 years
5.b. Proportion of infants 
who complete country-
specific testing programs 
for HIV-exposed infants
A larger portion of women 
deliver children during this 
age period.  The SEARCH 
youth intervention could 
improve outcomes by 
reducing vertical transmission 
via higher rates of maternal 
virologic suppression, and 
increased participation in 
exposed infant follow up 
programs. 
4
STUDY DESIGN

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4.1
OVERALL DESIGN
The goal of this study is to evaluate the effect of the SEARCH Youth combination intervention on long-
term HIV viral load (VL) suppression among HIV-infected adolescents/young adults 15-24 years of age in 
28 HIV clinics in western Kenya and southwest Uganda. SEARCH Youth is a multi-level combination HIV 
intervention based on the PRECEDE model of behavioral change that is targeted towards adolescent and 
young adult behavior described above.
The study design is a cluster-randomized trial where the unit of randomization is the HIV clinic: 14 clinics 
randomized to the intervention and 14 to the optimized country standard of care (Differentiated ART 
care, standard clinic hours, routine VL monitoring, access to 2nd and 3rd line ART), balanced within 
country. Our target enrollment for the intervention is approximately 2000 (50-100 AYAH in each clinic).
The primary endpoint of the full RCT is the proportion of adolescents and young adults achieving VL 
suppression two years after the start of the intervention. Secondary endpoints include: a) Retention in 
care, and other virologic outcomes (sustained virologic suppression, virologic failure), b) costing and 
cost-effectiveness, and c) yield of community testing programs to identify persons with new HIV 
diagnosis. 
Figure 1. RCT Study Design and SEARCH Youth Combination HIV Intervention Components
Clinics will be randomized using a stratified randomization with strata of total clinic participant load size 
(<300, >300) and region (Kenya or Uganda). Fourteen (14) clinics will be randomized to the intervention 
condition (SEARCH Youth intervention) and 14 clinics randomized to the control condition (optimized 
country standard of care).

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4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The randomized-controlled trial design was chosen to avoid the potential confounding to which single 
arm observational trials of clinic-based outcomes are particularly vulnerable.  The choice to cluster by 
clinic was made because implementing the components of the intervention on an individual participant 
level would be logistically challenging, not approximate the real-life implementation and risk 
contamination of the control arm as providers and participants in the same clinic would be aware of 
intervention vs control.  It was felt important to have a true contemporaneous standard of care arm to 
demonstrate the costs and values added from the intervention, particularly in relation to any other 
changes that could occur over this period of time (e.g. changes in national treatment guidelines.)
4.3
JUSTIFICATION FOR INTERVENTION
To increase the feasibility and generalizability of the intervention, its elements (counseling, viral load 
testing) were designed to occur in accordance with standard clinical practice and visit frequencies in the 
participant countries.  Because loss-to-follow up is part of the primary study outcome measure, it is 
difficult to state a “minimum acceptable” participation necessary to assess the intervention, but by that 
logic, the minimum could simply be considered completion  of the enrollment visit. 
4.4
END-OF-STUDY DEFINITION
The end of the study is defined as the completion of the last participant reaching the 2-year follow-up VL 
assessment among all participants in the SEARCH Youth intervention RCT.
5
STUDY POPULATION
 
The study population will consist of:

HIV-infected youth taking part in the SEARCH Youth intervention RCT; a subset will also take part 
in in-depth interviews, focus group discussions, patient satisfaction surveys, or alcohol use 
surveys and alcohol blood-based biomarker measurement

Community members who are tested as part of youth testing activities 

Family members/partners of a subset of HIV-infected youth taking part in the intervention RCT 
who will participate in an in-depth interview

Care providers in clinics taking part in the intervention RCT or providing pre-exposure 
prophylaxis (PrEP) who will participate in an in-depth interview

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
Community/regional health officers with responsibility for care at clinics taking part in the 
intervention RCT who will take part in an in-depth interview

HIV-uninfected youth in the community who will take part in focus group discussions to elicit 
input on the concept and design of community-based PrEP delivery interventions to foster PrEP 
uptake and adherence 

Infants born to study participants during the study period
5.1
INCLUSION CRITERIA
In order to participate in the SEARCH Youth intervention RCT study, individuals must meet all of the 
following criteria:
1.
HIV infection diagnosed according to country testing guidelines
2.
Age 15-24 years
3.
Enrolled in care in a study clinic
4.
Ability and willingness to provide informed consent
Eligibility requirements for participants taking part in in-depth interviews and focus group discussions 
will meet minimal inclusion criteria described in the section 8.1.3.
Eligibility requirements for participants taking part in the alcohol sub-study will meet minimal inclusion 
criteria described in the section 8.1.5.
Eligibility requirements for infants are being born to a study participant, as described in section 8.1.6.
5.2
EXCLUSION CRITERIA
N/A.
5.3
LIFESTYLE CONSIDERATIONS
N/A.
5.4
SCREEN FAILURES
The entry criteria for inclusion in the SEARCH Youth intervention RCT or in-depth interviews will be 
determined prior to obtaining informed consent. 

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5.5
STRATEGIES FOR RECRUITMENT AND RETENTION
A total of 28 rural clinics will participate in the study with 14 located in Uganda and 14 in Kenya. The clinics 
that will be chosen serve at least 10,000 people in their catchment area and are staffed typically by a 
medical doctor, a clinical officer, and a nurse. Study clinics will be selected with the cooperation of regional 
health directors for southwestern Uganda (outside Mbarara) and western Kenya (outside Homa Bay town) 
ensuring comparability in populations served, community HIV prevalence, HIV services and staffing within 
each region/country. Geographic location of clinics will be selected to reduce cross clinic “contamination.”
Strategies for recruitment will be tailored to specific communities, such as youth-lead testing and linkage 
strategies, strengthening of efforts at clinics to reengage AYAH who have been lost to follow-up, and 
recruitment of AYAH engaged in care at the clinic.  To reach youth at the highest risk of HIV infection, we 
will implement testing programs that take place outside of the clinic, or augment or coordinate with 
existing testing programs.  High-risk populations include, but are not limited to, recently married women, 
adolescent girls, youth working in the casual sector (maids, motorcycle taxi drivers, field workers), school 
drop outs, men-who-have-sex-with-men (MSM), informal and commercial sex workers (SW).  The 
community-tailored approaches to recruitment might include youth testing teams comprised of clinic 
providers and local youth leaders; youth testing programs such as PrEP “seed” youth to encourage testing 
among peers and youth club and public event mobile testing; and a mobile testing team resources to 
facilitate linkage.
Target enrollment will vary by clinic and community size, averaging approximately 50-100 AYAH in each 
of the 28 rural clinics, to achieve a total of approximately 2,000 participants overall. 
Inclusion of children: Youth aged 15-24 years will be enrolled in the study, therefore minors <18 years of 
age will be included.  The study is considered of minimal risk to participants, including minors.  The Uganda 
National Council for Science and Technology (UNCST) has determined that individuals aged ≥ 14 years are 
able to provide independent consent for research if they have a sexual transmitted infection, and the 
National AIDS and STI Control Programme (NASCOP) and Kenya Medical Research Institute (KEMRI) state 
that individuals aged ≥ 12 years are able to provide independent consent for research.  In both Uganda 
and Kenya, children of the age represented in this study can obtain HIV testing services and HIV care 
without parental consent, and including parental accompaniment could significantly inhibit youth from 
accessing these services.  As with adults, AYAH <18 years will be given sufficient time to read or be read 
the consent form in their language and to ask any questions. 
Infants of participants enrolled in the SEARCH Youth RCT at clinic sites randomized to the intervention 
and control, born during the study period, may also be enrolled in an assessment of outcomes via 
medical record data collection and maternal report.  Women who have delivered will be approached for 
this data collection and, if interested, provide informed consent.  Mothers <18 years will take according 
to the same guidelines described above.

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6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S)
6.1
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION
6.1.1
STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION
The randomized controlled trial (RCT) will evaluate the effect of the SEARCH Youth intervention on long-
term HIV viral load (VL) suppression among HIV-infected adolescents/young adults. 
SEARCH Youth Intervention Components
The components of the SEARCH Youth intervention might include the following:
Life-stage assessment tool. The “life-stage assessment tool,” is a checklist-driven structured evaluation 
of life issues at the beginning of each visit that a) links to life-stage specific actions (Table 3), and b) puts 
subsequent medical discussions in an appropriate context.
a)
Providers will receive initial or refresher training with country-approved curriculum on the 
development of youth from age 15 years, through adolescence and into adulthood and associated 
medical issues (e.g. 
contraception, alcohol use). 
After initial greetings, 
providers are prompted by 
the “life-stage” checklist to 
record: i) life status ii) major 
life events iii) support system 
iv) behaviors v) HIV 
disclosures. This checklist is 
updated at least every 6 
months or more often as 
needed.
Structured Choice Clinic Access. 
To lower barriers to remaining in care, participants will also have a choice to schedule visits during 
routine clinic or before/after standard clinic hours, or in a location other than the clinic, as resources 
allow. There will be a minimum frequency of visits directed by medical needs and national standards. 
Participants can also elect to have phone-only visits between in-person visits.
Rapid VL Feedback.  Participants will be provided with viral load results as soon as available, but always 
aiming to occur within 72 hours (to accommodate Friday-weekend visits and home visits for participants 
who don’t have phones).  Rapid viral load testing will be performed with  technology such as the 
Table 3. Life-Stage Checklist Components   
Life-Stage Assessment Area
Examples of linked care action
Life status: age strata, student, work, marital 
status, residence
Care coordination plan, school care 
transfer plan, family planning
Major life events: start or stop school or 
employment, financial strain, marriage, divorce 
or relationship strife, change in residence, new 
sexual partner or break-up, family death
Counseling, linkage to support 
groups and community services 
Support system: supporting persons, feeling 
lonely or isolated, feeling bullied or ostracized
Counseling, peer support linkage 
Behaviors: alcohol, STI risks 
Alcohol counseling, reproductive 
health appointment and counseling 
Completed and desired HIV disclosures: 
family, partner, friends
Facilitated Disclosure 
Priority issues for participant: list
Issue specific action plans 

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Cepheid GeneXpert device to provide immediate feedback on their HIV suppression and engage AYAH in 
their overall health.
Provider E-Collaboratives Providers will also participate in “e-collaboratives,” that comprises chat group 
using WhatsApp or similar secure messaging application.  This gives providers an opportunity to solicit 
input about this new provider-participant approach and to provide suggestions for any challenging 
clinical situations. To ensure confidentiality of participants, providers are trained, and the use of names 
or any potentially identifying information is avoided.
6.1.2
ADMINISTRATION AND/OR DOSING
All intervention components will be conducted in clinics randomized to the intervention. Participants will 
meet with clinicians on a one-on-one basis and will not interact with other participants as part of the 
intervention.
Life-stage assessment tool: The life-stage assessment tool is designed to be performed at routine visits, 
typically every 3 months at routine visits.   
Structured Choice Clinic Access:  Initial selection visit time and location will occur at the first study visit.  
Participant preferences will be reviewed and, if needed, updated at least annually with each participant.
Rapid VL Feedback: Rapid VL testing will be performed at least every 6 months.  Participants with 
detectable VL results will be tested roughly every 2-4 weeks according to clinician decision, until he or she 
is undetectable (according to the assay’s lower limit of detection) or until a time point that the patient is 
not amenable to changing adherence or medications as advised by the provider.
Provider E-collaboratives:  The WhatsApp e-collaboratives tool will be utilized as needed, for challenging 
issues including discussion of solutions to treatment barriers, detectable VL values, or other situations in 
which consultation with experts outside the clinic is needed.
6.2
FIDELITY
6.2.1
INTERVENTIONIST TRAINING AND TRACKING
We will collect quantitative process and fidelity measures corresponding to each of the components of 
the intervention through chart review of medical records, study case report forms, survey, and review of 
administrative records, and archives of the WhatsApp secure messaging conversations. Survey measures 
may include brief survey questionnaires of patient satisfaction
Feedback on key recruitment, data collection and VL suppression metrics will be provided via regular 
data reports to study sites.

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6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
Clinics will be paired using clinic population size, socioeconomic, and geographic characteristics, then 
randomized using computer-generated randomization list with a random seed. Fourteen (14) clinics will 
be randomized to the intervention condition (SEARCH Youth intervention) and 14 clinics randomized to 
the control condition (optimized country standard of care). 
6.4
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE
Because the intervention is primarily being implemented by providers, adherence will be encouraged by 
training at the outset of the study, and periodic monitoring of activity in clinics to ensure that the life stage 
counseling, rapid viral load assays with communication of results, and e-collaboratives are being utilized. 
6.5
CONCOMITANT THERAPY
N/A.
6.5.1
RESCUE THERAPY
N/A.
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION
Participants who discontinue from the SEARCH Youth intervention will also be discontinued from the 
overall study, however they may continue to receive care at the clinic according to country standard care 
guidelines.  Section 7.2 describes participant discontinuation from the study.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time upon request.  An investigator 
may discontinue a participant from the study for the following reasons:

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
The participant meets a previously unrecognized exclusion criterion

Significant non-compliance with the study

Any event or situation that occurs such that continued participation would not be in the best 
interest of the participant
The reason for discontinuation and date of discontinuation will be documented on the SEARCH Youth 
Participant Withdrawal/Move case report form (CRF).
7.3
LOST TO FOLLOW-UP
A participant who misses clinic visits will not be considered lost to follow-up and can resume participation 
at any time while study activities are ongoing.  If the participant fails to return to the clinic for a study visit, 
the study staff will attempt to contact the participant by telephone or via home tracking to reschedule 
the visit.  
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS
8.1.1
COMMUNITY TESTING AND LINKAGE
  
Community-tailored youth testing and linkage strategies for ART will be implemented to recruit youth 
for the SEARCH Youth combination intervention RCT.  Strategies to reach youth at the highest risk of HIV 
infection will be implemented. To enable evaluation of the effectiveness of these programs, we will 
collect data about the numbers of youth tested, the numbers of new diagnosis, and the number 
successfully linking to Care. Those individuals who test HIV-positive will be referred to the local clinic for 
HIV treatment services and, if they otherwise meet entry criteria, to the SEARCH Youth study for 
possible inclusion.  Participants who are HIV-negative and who meet criteria for PrEP will be referred to 
PrEP services at the study clinic, if available.
8.1.2
SEARCH YOUTH INTERVENTION AND CLINICAL OUTCOMES 
Clinic Sites Randomized to SEARCH Youth Intervention

Participants will be screened to determine if they meet eligibility criteria.  These participants 
may be already engaged in care, newly re-engaged or recently diagnosed participants, including 
those who have linked from youth testing activities.  A waiver of consent will be obtained to 
confirm eligibility during the screening process.

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
If participants meet eligibility criteria, they will be approached to discuss the study and, if 
interested, provide informed consent.

Contact information will be collected, including home location and mobile phone number(s) if 
available.

Baseline information will be collected including but not limited to education, occupation, and 
ART status.

The SEARCH Youth Intervention will be provided (see section 6.1.1.):
i.
A Life-Stage Assessment will be performed at the initial visit and at subsequent care 
visits, generally every 3 months, or more often as needed
ii.
Participants will be offered visits during routine clinic hours or after standard hours, 
determined at the initial visit and updated at least annually
iii.
Participants will undergo VL testing at the baseline and every 6 months thereafter, via 
rapid point-of-care testing technology.  Results will be provided to participants as soon 
as possible and ideally within 72 hours by mobile phone, via home tracking visits or by 
scheduled return clinic visit; undetectable results may be provided at the next clinic visit 
for participants who cannot be reached by mobile phone
iv.
As needed, providers and local investigators will participate in WhatsApp secure 
messaging to discuss approaches and solicit feedback for challenging participant-related 
situations, including but not limited to detectable VL results or barriers to adhering to 
clinic visits
Clinic Sites Randomized to Control

Participants will be screened to determine if they meet eligibility criteria.  These participants 
may be already engaged in care, newly re-engaged or recently diagnosed participants, including 
those who have linked from youth testing activities.  A waiver of consent will be obtained to 
confirm eligibility during the screening process.

If participants meet eligibility criteria, they will be approached to discuss the study and, if 
interested, provide informed consent.

Participants will undergo VL testing at the initial visit, either by routine testing or performed by 
the study.  The results from this testing will be provided to participants at their next routine visit 
as per standard clinic care.

Data from participants’ clinic medical records will be collected for at least a 2 year period 
following enrollment, including but not limited to VL results, ART medications, adherence, and 
illnesses.

2 years after enrollment and baseline VL, participants will undergo VL testing, either by routine 
testing or performed by the study.
8.1.3
IDENTIFICATION OF BARRIERS AND FACILITATORS OF THE SEARCH YOUTH 
INTERVENTION

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Identification of barriers and facilitators may use qualitative interviews with AYAH participants and their 
family members, key stakeholders including care providers, administrators, HIV control program officers 
and community leaders, combined with focus groups, quantitative process measures and programmatic 
data. We will identify mechanisms of action and barriers and facilitators of SEARCH Youth study 
implementation at the community, clinic organization, provider and patient levels using mixed methods 
qualitative and quantitative assessments.
Qualitative Study Populations
We will compose six qualitative cohorts for in-depth semi-structured interviews and focus group 
discussions in select communities at baseline and/or at follow up years 1 or 2 after intervention start.  A 
systematic approach to sampling research participants using probability methods will be undertaken 
prior to approaching potential participants. 
1.
Patient cohort:

Initial interviews: We will purposively select 45 patients in each region (Uganda and 
Kenya) (intervention n=30; control n=15), with sampling balanced by life-stage, 
gender, and treatment status (1. new diagnosis; 2. known diagnosis but out of care in 
past 6 months; and 3. known diagnosis, successfully engaged in care). The patient list 
will be randomly ordered, and participants will be systematically recruited and 
consented until the target number for each category is reached. Interviews will 
explore multiple domains of influence on HIV care engagement, including specific 
elements of the SEARCH Youth intervention for any interviews done in follow up 
years. 

Follow up interviews: In the follow up year interviews, we will resample n=45 patients 
in each region (Uganda and Kenya) (intervention n=30; control n=15), with sampling 
by life-stage (age), gender, and treatment status in the control and in the intervention 
sampling by life-stage (age), gender, and viral suppression at follow up. We will 
maintain many of the baseline patients that fall within the new sampling criteria, and 
will recruit new patients to achieve our sampling categories. 
2.
Family member cohort:

Initial interviews: We plan to select a sample of 15-20 family members in each region 
Uganda and Kenya) of 45 AYAH in the patient cohort for in-depth interview in select 
communities to investigate influences of family members. Members of the patient 
cohort will be asked to provide a list of family members involved with their care 
seeking, and family members will be recruited. Interviews will explore attitudes 
toward AYAH (stigma, support), perceived needs of AYAH, attitudes towards HIV care 
and treatment.

Follow up interviews: We will sample 15-20 family members in each region (Uganda 
and Kenya) of 45 of the new AYAH in the patient cohort (at follow up). We will include 
family members of patients who have been successful at achieving viral suppression 

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as well as patients who are having challenges either achieving and/or maintaining viral 
suppression. These family interviews will explore AYAH support, perceived needs of 
AYAH, attitudes towards AYAH, care and treatment, and elements of the SEARCH 
Youth Intervention.
3.
Provider cohort:

Initial interviews:  We plan to perform in-depth interviews with a sample of 12-24 care 
providers in each region (Uganda and Kenya) from 3 intervention health facilities, with 
each including the SEARCH Youth provider clinical officer or nurse, the director or 
head of HIV care in the facilities this role exits, and peer navigators with one male and 
female peer where possible. Study staff will work with local partners to identify a 
cadre of personnel in study clinics to select the purposive sample. Attitudes towards 
AYAH patients, perceived burden, professional identity/intrinsic vs. extrinsic 
motivations, and specific elements of the SEARCH Youth intervention in any interviews 
done in follow up years.

Follow up interviews: We will conduct follow up in-depth interviews with all providers 
who were interviewed at baseline year, as well as any new additional providers that 
may have been hired and are providing care and/or support to AYAH in the SEARCH 
Youth study. Similar to the baseline year, interviews will explore provider perceptions 
of HIV/STIs and AYAH, provider views on providing care, perceived burden, 
professional identity/intrinsic vs. extrinsic motivations, and specific elements of the 
SEARCH Youth intervention.

PrEP provider interviews: We will conduct in-depth interviews with up to 10 clinicians 
that provide PrEP (up to 5 in Uganda and 5 in Kenya) in SEARCH Youth communities to 
discuss experiences in the provision of PrEP and elicit input on possible future PrEP 
delivery interventions.
4.
Key informant cohort: Six community/regional health officers or leaders with responsibility 
for care at intervention sites may be selected at the beginning of the trial (3 Kenya and 3 
Uganda) to obtain their perspectives on system-level barriers and facilitators, and 
sustainability of intervention elements. 
5.
Youth cohort with HIV focus group discussion: Beginning in follow up year 1, we will conduct 
annual focus group discussions (FGDs) with two cohorts of patients selected in intervention 
communities within each region (Uganda and Kenya) to assess the extent to which the 
intervention has affected care engagement. FGDs will take place with the following two 
groups: virally suppressed and virally unsuppressed. Further, within each FGD, we will 
ensure a balance by life stage (using age as a proxy) and treatment status (newly in care vs. 
previously in care), as well as a balance of current treatment status (engaged in care vs. 
lapsed care). The focus groups will explore individual, interpersonal, and social factor 
influencing care engagement and retention. Each FGD will have up to 15 participants. 
6.
HIV-uninfected youth cohort focus group discussion: We will conduct focus group 
discussions to understand the perspectives of young people on HIV prevention and elicit 
input on the design of future community-based PrEP delivery interventions (such as clubs) 

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to increase PrEP uptake and adherence, as well as desired concurrent health services and 
educational content. We will conduct up to 12 focus group discussions (6 in Uganda and 6 in 
Kenya), each with approximately 8-12 HIV-uninfected youth (ages 15-24 years), stratified by 
gender, who are recruited from SEARCH Youth communities, including clinics and testing 
events.  Each focus group participant will also be asked to take part in a brief survey to 
collect information on demographics and prior PrEP use.
Interview Guides
The interview guides will seek to elicit responses to broad areas of inquiry, including across various 
guides, patients’ attributions for their “success” or “failure” with HIV care engagement, family members’ 
support and influence on AYAH care engagement, providers’ perceptions of AYAH needs and perceived 
burdens and motivations for care-giving of AYAH, and barriers and facilitators of implementation of the 
intervention. Baseline guides establish key domains of influence on care engagement among AYAH, 
while follow up interview guides in select communities will investigate perceptions, experiences and 
reactions to each of the components of the SEARCH Youth intervention among each of the cohorts and 
samples, in addition to peer and social support and intimate partner/relationships areas of inquiry. The 
PrEP provider interview guides will focus on the experiences and opinions of clinicians providing PrEP.
Focus Group Discussion Guides
The focus group guides will seek to explore community norms and perceptions about HIV/STIs and 
adolescent sexual health. It will seek to surface norms, barriers, and potentially challenges are the 
community and peer level that may impact care seeking and engagement among AYAH. Further, the 
guides will explore youth’s reasons for, barriers to, and facilitators of HIV care engagement, support of 
family/peers, and interactions with the SEARCH Youth intervention, including clinic spaces, providers, 
and other peer/network supports. The focus group guides for HIV-uninfected youth will seek to 
understand the community context and concerns about HIV, knowledge and experiences related to 
PrEP, and elicit input on the concept and design of  PrEP delivery interventions to help youth initiate and 
adhere to PrEP.
WhatsApp Provider Survey
Providers involved in the study will be asked to complete an anonymous survey on advantages and 
disadvantages of engaging in WhatsApp group discussions to solicit input and provide suggestions for 
study participant clinical or social issues.
Patient Satisfaction Survey
We will also administer a brief patient satisfaction survey to all participants after 2-years of follow-up.  
8.1.4
INCREMENTAL COSTS AND GAINS OF THE SEARCH YOUTH INTERVENTION
We will use rigorous methods to determine costs of the SEARCH Youth intervention and assess its 
efficiency and cost-effectiveness as cost per participant, cost per additional participant with viral 
suppression and cost per DALY gained. We will use standard micro-costing techniques and time-in-

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motion (T&M) studies to measure the cost of optimized testing and each component of the SEARCH 
Youth intervention. 
Costs Analysis
We will assess costs at least twice in each health facility: once before and once after adoption of the 
SEARCH Youth intervention, in order to estimate incremental costs of SEARCH Youth implementation 
and to compare costs of the intervention to standard of care. “Economic” costs (the true value of 
resources consumed or “opportunity cost”) will be assessed by identifying the value of subsidized or 
donated resources with information from data bases (e.g. wage rates) and donors, and, as needed, 
three price quotes from appropriate market sources.
 
Health Effects
To quantify health effects, we will use directly measured health-related study outcomes (e.g. viral 
suppression).  Second, we plan to integrate the health impact of achieving viral suppression using 
disability-adjusted life years (DALYs), including years of life gained and the collective disability effects of 
living with HIV. We might be estimated as DALYs gained for the short term (during the trial) and the 
long-term (5, 10, and 20 years) using data from the trial, as well as morbidity and mortality attributed to 
un- or partially- treated HIV disease. 
8.1.5
ASSESSMENT OF ALCOHOL USE AND ITS EFFECT ON VIRAL SUPPRESSION  
Assessment of alcohol use among SEARCH-Youth intervention participants may include use of surveys, 
validated alcohol self-report tools (e.g. AUDIT-C), and alcohol biomarker measurement (e.g. 
phosphatidylethanol [PEth], a blood-based biomarker). We will characterize alcohol use and assess the 
relationship with viral suppression, accounting for sex and life-stage using the data obtained in the 
SEARCH Youth intervention (see section 6.1.1). 
Participants who are enrolled in the SEARCH Youth RCT at clinic sites randomized to the intervention will 
be eligible to participate. Potential participants will be approached to discuss the study and, if 
interested, provide informed consent.
 
Initial visit: We will administer a questionnaire that will measure alcohol use by self-report and will 
explore multiple domains of influence on alcohol use and related behaviors. We will collect a blood 
sample to measure PEth, a biomarker of alcohol use.
Subsequent visits: We will reassess alcohol use and/or risk factors by survey every 3 months for at least 
12 months. We will collect blood samples for PEth measurement 12 months after the initial PEth sample 
is collected. 

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8.1.6
ASSESSMENT OF INFANT OUTCOMES  
Infants of participants enrolled in the SEARCH Youth RCT at clinic sites randomized to either the 
intervention and control arms, born during the study period, will be eligible to participate.  Women who 
have delivered will be approached for this data collection and, if interested, provide informed consent.  
A waiver of informed consent for recruitment purposes will be utilized in order to assess the 
completeness of standard care clinic records prior to meeting with participants.  No data will be 
recorded before informed consent is obtained.
Infant outcomes will be characterized using data collected by the study team using the medical records 
of the child in the exposed infant care programs and by maternal report.  They outcomes of interest 
include participation in scheduled visits in the HIV-exposed infant programs, receipt of antiretroviral 
medications as prophylaxis (drugs and duration), duration of breast feeding, HIV test results and 
mortality, at 1 and 2 years of life (for those who reach that duration during the study period).  
In addition, viral load (VL) testing may be performed on participating mothers prior to transitioning off 
study if they do not have recent VL testing in the medical record.  Staff may also help facilitate standard 
of care HIV testing of the infants if they have not completed the country’s Early Infant Diagnosis 
(EID)/HIV Exposed Infant (HEI) program; there will be no extra testing of infants for the purpose of this 
study.
8.1.7
ASSESSMENT OF MENTAL HEALTH  
A subset of study participants will take part in a one-time survey on symptoms of mental health and life 
event issues during a visit at the study clinic or by phone.  The standard mental health assessment tool 
Patient Health Questionnaire (PHQ-9) will be administered to participants who take part, along with 
additional questions on major life events and pressures.
Potential participants will be approached to discuss the survey in the study clinic or by phone call and, if 
interested, be asked to provide verbal consent to take part. A subset of participants enrolled in the 
SEARCH Youth RCT at clinic sites randomized to either the intervention or control arms will be eligible to 
participate.
Participants with score ≥ 5 on the PHQ-9 portion of the survey, or those with a suicidal ideation, have 
moderate to severe symptoms and will need to be evaluated for therapy including pharmacological 
therapy. The study coordinator to arrange for urgent referral for mental health care to the regional 
referral hospital.

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8.2
SAFETY ASSESSMENTS
Participants’ VL results will be measured regularly as part of the SEARCH Youth intervention.  All other 
safety assessments will be performed according to country standard of care.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
N/A.
8.4
UNANTICIPATED PROBLEMS
8.4.1
DEFINITION OF UNANTICIPATED PROBLEMS
This protocol uses the definition of Unanticipated Problems (UPs) as defined by the Office for Human 
Research Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or 
others to 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 Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant 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
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized
8.4.2
 UNANTICIPATED PROBLEMS REPORTING 
The investigator will report unanticipated problems to the reviewing Institutional Review Board (IRB) 
and study sponsor. The UP report will include the following information:
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number
•
A detailed description of the event, incident, experience, or outcome 
•
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP

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•
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP
UPs will be reported using the following timeline:  
•
UPs that are serious adverse events (SAEs) or protocol violations will be reported to the IRBs 
within 7-10 working days of the investigator becoming aware of the event (see section 10.1.10 
for individual IRB reporting timelines).
8.4.3
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
Participants will be informed of any UP that changes the study’s risk/benefit ratio and/or requires 
modification to the informed consent.  The nature of the UP will determine how and when participants 
will be notified.
9
STATISTICAL CONSIDERATIONS 
9.1
STATISTICAL HYPOTHESES
Primary Endpoint(s): Proportion of study participants with virologic suppression (HIV RNA <400 c/mL) at 
2 years of follow-up.  
The null hypothesis is there will be no difference in the proportion of participants with virologic 
suppression at 2 years, between participants who receive the SEARCH Youth intervention and 
participants in the control arm.
9.2
SAMPLE SIZE DETERMINATION
Because the intervention is delivered at the clinic-level (changing the policies and procedures of the 
clinic and all clinicians caring for AYAH within the clinic) randomization and evaluation must be done at 
the clinic-level and incorporate randomization of entire clinics. For the design and power calculations for 
this study we have taken the rigorous extra step of actually measuring the clustering effect on HIV 
virologic suppression of clinic level performance for AYAH in 16 clinics in Kenya and Uganda. Using a 
conservative estimate of the upper 95% CI bound on the measured ICC from the clinic using ICC 
estimates from both a one-way random-effects model and a one-way Analysis of Variance approaches 
(ICC=0.055) we have calculated that with 28 clinics (14 randomized to intervention and 14 to control) 
and an average cluster size of 50-100 AYAH our study would have a 83% or greater power to detect a 
significant difference between the control and intervention clinics if the proportion with HIV virologic 

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suppression among AYAH in the control clinics is 64% and the proportion with suppression in the 
intervention clinics is 88%  In addition, if the study were to lose the ability to evaluate up to 2 clinics due 
to unforeseen events, the study would still retain 80% power to detect the 64% control vs. 88% 
intervention difference.
9.3
POPULATIONS FOR ANALYSES
Intervention Randomized Controlled Trial
AYAH ages 15-24 years enrolled in care at study clinic of ~ 2,000 participants, including ART-naïve and 
experienced participants.
Identification of Barriers and Facilitators
Sample of patient cohort participants, focus group participants, family members, care providers and 
clinic directors, and 6 community/regional health officers or leaders. Additionally, all participants will be 
asked to complete a brief Patient Satisfaction Survey.
Incremental Costs and Gains
AYAH trial participants and outcome data clinic administrative and financial records.
Effectiveness of the Youth HIV Testing and Referral Strategy 
Young persons ages 15-24. The testing team will maintain a registry of tests performed and work with 
clinics to determine  outcomes of linkage efforts.   Interviews of key informant youth.
Alcohol Use and Impact on Viral Suppression
AYAH trial participants enrolled in care at study clinics randomized to the SEARCH Youth intervention 
who consent to additional questionnaires and alcohol biomarker testing
Infants outcomes 
Infants born to women in intervention and control arms during the study period.
9.4
STATISTICAL ANALYSES
9.4.1
GENERAL APPROACH
The primary analysis of the full RCT will be an adjusted comparison of the proportion of AYAH with HIV 
virologic suppression (HIV-1 RNA copies<400/mL) at 2 years on study between those enrolled at clinics 
randomized to the intervention condition (n=14 clinics) versus those enrolled at clinics randomized to the 
control condition (n=14 clinics).  To identify mechanisms of action and barriers and facilitators of the study 
intervention implementation we will examine emergent qualitative themes (perceived benefits, 
acceptability, gender and life-stage issues, reduced burdens, improved communication, etc.), and for each 

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of the individual components of the intervention to identify which components worked and did not work 
and for whom. The incremental costs and gains associated with the intervention will be estimated using 
micro-costing, time-and-motion (T&M) studies, calculation of disability-adjusted life years (DALYs) gained, 
estimation of efficiency (cost per patient, costs per additional patient with viral suppression), cost-
effectiveness analysis (cost per DALY gained). The efficacy of testing and linkage strategies will be 
estimated using yield and proportion who link to treatment clinics. Alcohol use patterns will be described 
and life-stage-specific, and sex-specific prevalence of each pattern will be calculated. The effect of alcohol 
use on viral non-suppression (HIV-1 RNA copies >400/mL) at 1 year will be estimated using causal 
inference techniques by comparing the proportion of AYAH with viral non-suppression between those 
with no alcohol use and those with various patterns of use. The effect of intervention on infants born to 
participants will be examined through (i) the proportion who remain alive and HIV-free at 1 and 2 years, 
and (ii) the proportion of who complete their testing programs for HIV-exposed infants.
9.4.2
ANALYSIS OF THE PRIMARY ENDPOINT(S)
Primary Outcome: Proportion of study participants with virologic suppression (HIV RNA <400 c/mL) at 2 
years of follow-up 
Primary Predictor: Clinic Randomized Arm (intent-to-treat), Intervention or Control.
Analytic Plan: The primary analysis of the full RCT will be an adjusted comparison of the proportion of 
AYAH with HIV virologic suppression (HIV-1 RNA copies <400/mL,) measured at 2 years on study 
between those enrolled at clinics randomized to the intervention condition (n=14 clinics) versus those 
enrolled at clinics randomized to the control condition (n=14 clinics). The primary analysis will restrict to 
participants enrolled prior to December 1, 2019; secondary analyses will include all participants. Viral 
suppression will be compared between arms using Two-Stage TMLE, an approach that appropriately 
accounts for the dependence of outcomes within clinics. In the first stage, viral suppression will be 
estimated for each clinic, using TMLE to adjust for possibly incomplete ascertainment of viral loads. In 
the second stage will use a cluster-level TMLE to estimate intervention effectiveness by comparing the 
clinic-specific endpoints between randomized arms, while accounting for the randomization scheme. 
We will test the null hypothesis that the intervention did not impact viral suppression with a two-sided 
test at the 5% significance level. To understand effect heterogeneity, we will repeat these analyses 
within the following pre-specified subgroups: country, baseline care status, baseline viral suppression 
status, gender, age group, and pregnancy or live birth during the study (among women).
9.4.3
ANALYSIS OF THE SECONDARY ENDPOINT(S)
9.4.3.1
SECONDARY CLINICAL OUTCOMES 

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Secondary Outcomes include retention: Not more than 90 days late to scheduled visit; sustained 
virologic suppression (< 400 and < 200 c/mL), virologic failure, death, transfer to other medical facility 
and change to second line therapy.
Secondary Predictors include country, baseline care status, gender, age, pregnancy, education, 
occupation, marital status, alcohol use, mobility, and other variables captured in the Life-stage 
(assessment tool; intervention arm only).
Analytic Plan:  The secondary clinical outcomes will be examined using analogous Two-Stage approach, 
described in section 9.4.2. In secondary analyses, we will also evaluate predictors of sub-optimal 
outcomes using TMLE (primary) and with univariate associations (secondary), overall and stratified by 
intervention arm. Based on our prior studies with HIV clinics and follow-up in the two regions we 
anticipate a 2-year LTFU rate of less than 8%. Regardless of the LTFU level, we will implement enhanced 
participant tracking procedures that have proven successful in our group at re-engaging participants in 
care.
Secondary Analyses for Exploring Intervention Component Mediation and Moderation: To explore 
mechanisms by which the multiple intervention components effect changes in study outcomes, 
secondary analyses will investigate whether measures of intervention component activities delivered to 
study participants listed in Table 4 mediate relationship between intervention group assignment (study 
arm) and viral suppression, and whether sex, age, and region moderate those associations. In line with 
recent NIH guidelines recommending consideration of sex as a biological variable, participant gender will 
be a key moderator in these analyses. Mediation and moderation will be assessed using the causal 
inference-based approach of Valeri and VanderWeele, which yields optimal estimates of indirect effects 
in the presence of non-continuous (e.g. binary) outcomes and moderator-mediator interactions.20 Mplus 
will be used to fit causal mediation models because it can adjust standard errors for clustering of 
participants within communities and clinics/providers, a feature of the proposed study, and because it 
can include multiple mediators simultaneously. 21,22 For each mediator, we will include the proportion of 
the total effect explained by the mediator.
Table 4. Intervention Component Mediators and Measures
Potential Mediators 
(Intervention Component)
Mediator Measures
SEARCH Youth-1 Predisposing

Life-stage identification and counseling 

Technology enabled e-collaboratives for 
providers
o
Life-Stage Tool Completeness (% visits w/ filled out tool)
o
% Life-Stage Events with Corresponding Plan or Counseling
o
% of Plans Enacted
o
# Life-Stage Events (total)
o
% Provider Engagement with Discussions
o
# Discussions with Provider Participation
o
# Discussion specific to Participant
SEARCH Youth-2 Enabling 

Structured Choice Clinic Access 
o
# Documented offers of clinic hours & provider choice
o
% Uptake of Structured Choice Options
o
# Provider changes 

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SEARCH Youth-3 Reinforcing

Rapid VL Feedback
o
# Visits with Receipt of Rapid- VL Testing & Counseling
o
Mean Participant Self-Report of VL Results Impact Score
9.4.3.2
 IDENTIFICATION OF BARRIERS AND FACILITATORS
Analytic Approach: Mixed-methods approach of qualitative analysis of key informant interviews 
combined with quantitative process and fidelity measures and trial outcome data.
Primary Research Questions: Investigations will be focused on three main areas: 1) overall mechanisms 
of action of the intervention that result in success or failure (suppressed or unsuppressed at one and 
two years), 2) key issues impacting the effectiveness of individual components of the intervention, and 
3) barriers and facilitators of implementation of the intervention from the care delivery side.
To identify mechanisms of action and barriers and facilitators of the SEARCH Youth intervention 
implementation we will examine emergent qualitative themes (perceived benefits, acceptability, gender 
and life-stage issues, reduced burdens, improved communication, etc.), and for each of the individual 
components of the intervention to identify which components worked and did not work and for whom. 
We will look for evidence in qualitative data and quantitative process measures for each component to 
see if - and for which subgroups of AYAH - the proposed predisposing, enabling, and reinforcing 
mechanisms are supported by identified qualitative themes and are echoed in the quantitative 
utilization, success, and fidelity data. For qualitative data analysis translated data will be imported into 
Atlas.ti24 guided by grounded theoretical approaches23, in which research team members iteratively 
review , use theory as well as inductive analysis of empirical findings to develop a common set of codes 
describing patterns observed in the data, and iteratively refine codes as new themes emerge during the 
data collection process.
Table 5. Process Measures for Fidelity & Mechanisms of Action
Component
Process and Fidelity Measures
SEARCH Youth-1
  Life Stage 
  Identification & 
  Plan
  WhatsApp 
  E-collaboratives
Proportion of trainings completed + attendance
Life-Stage tool use: frequency & completeness
Action plan: completeness, counseling & care changes made
Communication frequency: # messages & content (themes)
Participation measures: % of clinic providers initiating & involved
Action plan: completeness, counseling & care changes made
SEARCH Youth-2
  Structured Choice
  Clinic Access
Documentation of structured choice offer (off-hours and flexible 
location)
Off-hours visit utilization
Participant satisfactionsurvey
Number & frequency of phone visits
SEARCH Youth-3
  Rapid viral 
  Load & Counseling
Time to viral load results communication to AYAH
Viral Load counseling received
Action plan: completeness, counseling & care changes made

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9.4.3.3
INCREMENTAL COSTS AND GAINS 
Primary Research Questions: In order to generate evidence that can address key questions concerning 
optimal resource allocation and provide guidance to policymakers, we will use rigorous methods to 
determine costs of the SEARCH Youth intervention and assess its efficiency and cost-effectiveness as 
cost per participant, cost per additional participant with viral suppression and cost per DALY gained. We 
will use standard micro-costing techniques and T&M studies to measure the cost of optimized testing 
and each component of the SEARCH Youth intervention.
Analytic Approach: Micro-costing, time-and-motion (T&M) studies, calculation of disability-adjusted life 
years (DALYs) gained, estimation of efficiency (cost per participant, costs per additional participant with 
viral suppression), cost-effectiveness analysis (cost per DALY gained).
Efficiency and Cost–effectiveness
We plan to calculate efficiency and cost-effectiveness (CE) ratios as net cost per additional person 
achieving viral suppression and net cost per DALY gained, with net costs equal to program costs adjusted 
for changes in health care costs due to the intervention. We plan to conduct extensive univariate and 
multivariate sensitivity analysis. Importantly, if the intervention yields net savings (i.e., negative net 
costs) as well as health benefits, the intervention is classified as “dominant” and no CE ratio is 
calculated.
9.4.3.4
EFFECTIVENESS OF THE YOUTH HIV TESTING AND REFERRAL STRATEGY FOR ART
Primary Research Questions:  The effectiveness of strategies will be examined during the study and at the 
conclusion and shared with community testing teams to allow them to refine efforts.
Analytic Approach: Uptake of HIV testing (total number tested) and Yield (percentage of individuals 
testing HIV-positive with a new or out-of-care HIV diagnosis). Estimates of rates and proportions will be 
determined and compared using standard methods25 within individual and across communities, 
examining predictors such as gender, age, marital status, employment and educational status. Mixed-
methods approach of qualitative analysis of key informant interviews combined with quantitative 
process and fidelity measures and testing/linkage outcome data.
9.4.3.5
ASSESSMENT OF ALCOHOL USE AND ITS EFFECT ON VIRAL SUPPRESSION 
Primary Research Questions:  The developmental changes of youth influence risk-taking behavior and 
increase their likelihood of alcohol use, which may be a key contributor to poor HIV outcomes. However, 
there are substantial knowledge gaps on the scope, context, and impact of alcohol use on HIV outcomes 
among AYAH in SSA.  Alcohol use among AYAH will be characterized and its longitudinal effects on viral 
suppression will be determined to allow further refinement of the intervention and identify potential 
foci of future interventions. 

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Analytic Approach: We will calculate the baseline prevalence of various alcohol use patterns, including 
life-stage-specific and sex-specific prevalence. We will summarize predictors of each alcohol use pattern 
and estimate the relative risks of any alcohol use associated with each predictor using targeted 
maximum likelihood estimation (TMLE). These analyses will be repeated varying definitions of alcohol 
use, incorporating both self-report (AUDIT-C) and biomarker measured use (PEth), to account for 
potential underreporting. We will estimate and compare the proportions of AYAH with viral non-
suppression among non-drinkers versus baseline drinkers, using TMLE to account for potential 
confounders. 
9.4.3.6
ASSESSMENT OF INFANT OUTCOMES
Primary Research Question:  Does the SEARCH Youth intervention result in a higher rate of HIV-free 
survival?  We will also investigate potential steps in the causal pathway, including participation in HIV-
exposed infant care programs, receipt of antiretroviral medications, and duration of lactation.
Analytic Approach: We will compare the proportion of infants who remain alive and have HIV-free at 1 
and 2 years of life between randomized arms using the Two-Stage approach, described in section 9.4.2.  
We will also investigate the intervention effects on elements of postnatal care including the rates of 
participation in HIV-exposed infant care programs, receipt of antiretroviral medications (agents and 
durations), and duration of lactation.
9.4.3.7
MENTAL HEALTH
Primary Research Question:  Does the SEARCH Youth intervention result in a lower rate of depression? 
We hypothesize that additional engagement with providers would facilitate better identification and 
management of mental health issues like depression.
Analytic Approach: We will compare the proportion of participants with depression at the time of study 
end, using the PHQ-9 survey, between randomized arms using the Two-Stage approach, described in 
section 9.4.2.  We also evaluate the association of depression with recent life events.
9.4.4
SAFETY ANALYSES
N/A.
9.4.5
BASELINE DESCRIPTIVE STATISTICS
Intervention and control groups will be summarized on baseline characteristics including such features as 
age, gender, care status, and viral load suppression.

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9.4.6
PLANNED INTERIM ANALYSES 
N/A
9.4.7
SUB-GROUP ANALYSES
Subgroup analyses for primary and secondary endpoints will be performed by region, gender, age group, 
HIV care status, viral suppression status, and peripartum status (among women). 
9.4.8
TABULATION OF INDIVIDUAL PARTICIPANT DATA
N/A
9.4.9
EXPLORATORY ANALYSES
N/A.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
 
10.1.1 INFORMED CONSENT PROCESS
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS
Informed consent will be obtained for the SEARCH Youth RCT participants and for participants of the 
qualitative in-depth interviews and focus groups to better understand youth attitudes and barriers to 
care. Both Uganda and Kenya allow individuals over the age of 14 to consent for participation in 
research, without involvement of their parents, if it concerns the treatment of a sexual transmitted 
disease. The Uganda National Council for Science and Technology (UNCST) has determined that 
individuals aged ≥ 14 years are able to provide independent consent for research if they have a sexual 
transmitted infection, and Kenya’s National AIDS and STI Control Programme (NASCOP) states that 
individuals aged ≥ 12 years are able to provide independent consent for research while Kenya Medical 
Research Institute (KEMRI) allows mature minors to consent independently for research. For the 
qualitative activities, informed consent will be obtained from those interviewed or taking part in focus 
group discussions, including patient cohort participants, family members, providers or clinic directors 

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involved in the SEARCH Youth intervention and clinicians providing PrEP,  community/regional health 
leaders, and members of focus groups among the patient cohort and HIV-non-infected youth.
 
The following informed consent form (ICF) materials will be used in this study:

SEARCH Youth Intervention ICF

SEARCH Youth Control ICF

Testing Referral Verbal Consent Form

Patient Qualitative Cohort ICF

Provider Qualitative Cohort ICF

Key Informant Qualitative Cohort ICF

Family Member Qualitative Cohort ICF

Focus Group Discussion Patient Cohort ICF

PrEP Focus Group Discussion ICF

PrEP Provider Interview ICF

Alcohol Study Cohort ICF

Infant Outcome ICF
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION
All consent forms will be translated into the local language and back translated into English to ensure 
correct use of language. Consent forms will be read aloud to participants by trained staff. The informed 
consent will describe the purpose of the study, all the procedures involved, and the risks and benefits of 
participation. Interviewers will ask participants to summarize the study and explain the reasons why they 
want to participate. Either a signature or a thumbprint (for those who cannot read) will be acceptable to 
confirm informed consent for participation in the study, in the case of written consent forms.
10.1.2 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Notification documenting the reason for study suspension or termination will be provided to study 
participants, the funding agency, and regulatory authorities.
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor. This confidentiality is extended to the data being collected as part of this study. Data 
that could be used to identify a specific study participant will be held in strict confidence within the 

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research team. No personally-identifiable information from the study will be released to any unauthorized 
third party without prior written approval of the sponsor/funding agency. 
All research activities will be conducted in as private a setting as possible.
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, institutional policies, or sponsor/funding agency 
requirements.
Data Security
All information will be recorded using study identification numbers, rather than participant names, and 
stored securely in locked offices at a study data center. All study computers will be password encrypted 
and kept in locked offices.
Risk of HIV Status Disclosure
Given the sensitive and private nature of the HIV-status of participants of the RCT, extra measures will 
be put in place to ensure maintenance of privacy, confidentiality and security of the data obtained.  
Contact mobile numbers will be re-checked to insure they are updated. 
Use of WhatsApp
As described in section 2.3.3., participation in WhatsApp will be limited to providers taking part in the 
study, who will be required to attend an in service to review SOPs and be trained on appropriate 
information that can be included in the discussions.  The chats will be encrypted and take place under 
the oversight of study staff to ensure compliance with confidentiality requirements.  All mobile devices 
used in WhatsApp discussions will have security measures enabled to access the device and chats, and 
investigators will ensure discussions are deleted from individual devices when the study is complete or 
staff member leaves the study.  Information shared in discussions will not include identifiers and will be 
limited to the minimum needed for productive exchanges of ideas.
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies 
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 
traceable to a specific study participant). Plans for archiving and long-term preservation of the data will 
be implemented, as appropriate.
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 

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Samples for PEth testing will be collected after participants complete the initial alcohol survey and again 
12 months later. These samples will be used to prepare dried blood spot cards at the designated in 
country laboratory facilities. Dried blood spot cards will be stored until shipment to the United States 
Drug Testing Laboratory (USDTL) in the United States. The DBS card will be tested for PEth level at 
USDTL using liquid chromatography-tandem mass spectrometry (LC/MS/MS). We will obtain a Materials 
Transfer Agreement to ship the DBS to the U.S.; no laboratories in Africa conduct this test.  All samples 
will be labeled only with the participants’ study ID number, initials, and the date of collection.  A 
database that links these samples to other identifiers will be accessed only by study investigators and 
personnel and will be password protected. Any remaining specimen will be discarded.
10.1.5 KEY ROLES AND STUDY GOVERNANCE
Protocol Co-Chair
Protocol Co-Chair
Protocol Co-Chair
Diane Havlir, MD, Professor of 
Medicine
Moses R. Kamya, MBChB, MMed, 
PhD, Chair of the Department of 
Medicine
Theodore Ruel, MD, Associate 
Professor
University 
of 
California, 
San 
Francisco
Makerere University
University of California, San 
Francisco
UCSF Box 0874, San Francisco, CA 
94143-0874, U.S.A.
P.O. Box 7072, Kampala, Uganda
Box 0434
550 16th Street, 4th Floor
San Francisco, CA 94158-0434
+1-415-476-4082 ext. 424
+256-414-533200
+1 415-476-9197
diane.havlir@ucsf.edu
mkamya@infocom.co.ug
Theodore.ruel@ucsf.edu
10.1.6 SAFETY OVERSIGHT
Safety oversight in this minimal risk study will be led by the study investigators and by adherence to the 
quality management plan (QMP) described in section 10.1.8.
10.1.7 CLINICAL MONITORING
N/A.
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion. All sites will follow a common quality management plan.
Quality control (QC) procedures will be implemented as follows:

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Informed Consent
Study staff will review both the documentation of the consenting process as well as a percentage of the 
completed consent documents.  This review will evaluate compliance with GCP, accuracy, and 
completeness.  Feedback will be provided to the study team to ensure proper consenting procedures 
are followed. 
Data
Data will be captured on source documents or entered directly onto electronic CRFs (see section 10.1.9).  
To ensure accuracy study staff will compare a representative sample of source data against the 
database, targeting key data points in that review.  Reports based on recent data will be made available 
to study staff and investigators.
Intervention Fidelity
Consistent delivery of the study interventions will be monitored throughout the study. Procedures for 
ensuring fidelity of intervention delivery are described in section 6.2.1. 
Protocol Deviations
The study team will review protocol deviations on an ongoing basis and will implement corrective 
actions when the quantity or nature of deviations are deemed to be at a level of concern.
As required, the investigators will provide direct access to all trial related sites, documents, and 
regulatory records for the purpose of monitoring and auditing by local regulatory authorities.
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data management for this study will be overseen by the Infectious Diseases Research Collaboration (IDRC) 
Data Management Center located in the main IDRC research complex in Nakasero, Kampala, Uganda.  The 
Data Management Center (DMC) is also responsible for providing IT support to all staff members.
Data Management System
For any study components using paper data collection, IDRC has designed and developed a custom Data 
Management System that is used to manage the data, using Microsoft SQL Server as the backend for all 
data storage.  MS Access is used for double data entry and SAS programs are used for comparing 1st and 
2nd entry and generating discrepancy reports.  In addition, the DMC has developed custom Visual Basic 
programming for direct survey and data entry of data in the field. Data Transformation Services/ SQL 
Server Integration Services (DTS/SSIS) packages are used to automatically import/export any new data 
and stored procedures written in T-SQL are used to automatically generate new data queries on a daily 
basis.  There is a web interface to the whole system written in ASP.NET to allow users to view the data, 

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view reports, and even modify the data they are authorized to access.  With regular backups and a full 
audit trail, the whole system is regulatory compliant (21 CFR Part 11).
Data Quality Assurance Process
The data management system is designed to collect, transfer and store data for Data Management 
Center studies. Data from any paper records will be 100% double entered into the system via Microsoft 
Access Databases or Web-based data entry screens. Locally collected data is compressed, password-
protected, and then securely uploaded to a cloud based server (Network Solutions, Inc) using secure-FTP 
via the FileZilla application.   Cloud-based uploads are downloaded daily to the Kampala DMC.  After the 
data has been input into the Data Management Center server, it is electronically verified and is then 
written to the SQL database. Edit checks or queries are run nightly and the results are posted to a secure 
clinical trials website so that the sites can electronically address problems with the data the next day. 
The site corrects data via the website and the database is updated automatically.
In order to ensure data security and integrity, the following measures will be implemented:

All members of the study team will be educated in the study protocol prior to the onset of the 
study. 

Detailed Standard Operating Procedures (SOPs) will be written for all project activities and be 
provided to relevant team members. 

Team members will be thoroughly trained on the SOP’s. 

Where applicable, team members will receive additional training on the use of tablet 
computers. 

All data transcribed from paper will be double data entered or verified. 

All electronic data will be backed up regularly. 

All data will be transferred to the main Data Center in Kampala to the secure server. This sever is 
backed up on a daily basis and a monthly backup is stored off-site. 

All computers, including the tablets, will be password protected. 

All computers, including tablets, will be locked in a secure room each night. 

Any Log Books and CRF’s will be locked in a secure room each night.
10.1.9.2 STUDY RECORDS RETENTION 
Data archives will be kept for periods based upon the terms of the agreement between the funding 
organization and IDRC. Datasets that are required to be retained for periods as prescribed by law will 
also be kept following the respective durations as set in the enacted laws of Uganda.  In general, study 
data will be kept electronically for a period of at least 5 years post completing of the study.  Data will 
remain on the password secured IDRC servers and on the system of annual USB physical backup drives.  
After 5 years from the close of the study, all paper records will be destroyed and the electronic records 
will be removed from the server, but retained on Archival, password-protected USB drives.

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10.1.10
PROTOCOL DEVIATIONS  
It will be the responsibility of the site investigators and staff to use continuous vigilance to identify 
deviations or violations and report violations that meet the IRB definition of reportable events.  Protocol 
violations that occur at UCSF will be reported to the UCSF CHR IRB within 10 working days of the PI’s 
awareness.  Protocol violations that occur on-site will be reported to the SOMREC IRB  within 7 working 
days.  SOPs will describe the process for communicating with study coordinators and investigators and 
the event reporting procedures.
10.1.11
PUBLICATION AND DATA SHARING POLICY 
The findings from this study may be published in a medical journal. No individual identities will be used 
in any reports or publications resulting from the study. The researchers will publish results of the study 
in accordance with NICHD, UCSF, UNCST, KEMRI and Makerere University guidelines.
10.1.12
CONFLICT OF INTEREST POLICY
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. The study leadership in conjunction with the NICHD 
has established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest.
10.2 ADDITIONAL CONSIDERATIONS
N/A.
10.3 ABBREVIATIONS AND SPECIAL TERMS
ART
Antiretroviral Treatment
AYAH
Adolescents and Young Adults with HIV
CE
Cost Effectiveness
CFR
Code of Federal Regulations
CHR
Committee on Human Research (UCSF)
CMP
Clinical Monitoring Plan
CRF
Case Report Form
DALY
Disability-Adjusted Life Year(s)
DMC
Data Management Center

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eCRF
Electronic Case Report Forms
GCP
Good Clinical Practice
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH
International Council on Harmonisation 
IDRC
Infectious Diseases Research Collaboration (Uganda)
IRB
Institutional Review Board
KEMRI
Kenya Medical Research Institute
LTFU
Lost to Follow-Up
NASCOP
National AIDS and STI Control Programme
NCT
National Clinical Trial
NICHD
National Institute of Child Health and Human Development (NIH)
NIH 
National Institutes of Health
NIH IC
NIH Institute or Center
OHRP
Office for Human Research Protections
PEth
Phosphatidylethanol
PI
Principal Investigator
PrEP
Pre-Exposure Prophylaxis
Q
Every
QA
Quality Assurance
QC
Quality Control
QMP
Quality Management Plan
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
SOA
Schedule of Activities
SOM-REC
School of Medicine Research and Ethics Committee (Makerere University)
SOP
Standard Operating Procedure
SSA
Sub-Saharan Africa
T&M
Time and Motion
UNCST
Uganda National Council on Science and Technology
UCSF
University of California, San Francisco
UP
Unanticipated Problem
US
United States
VL
HIV Viral Load

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10.4 PROTOCOL AMENDMENT HISTORY
Version
Date
Description of Change 
Brief Rationale
1.2
21-Dec-2018
Initial approved protocol version
N/A
2.0
21-Nov-2019
Updated with details on additional 
and revised qualitative activities, 
to add new and revised data 
collection instruments, and to 
clarify planned target enrollment.
To provide new and updated 
tools to understand barriers 
and facilitators to care and the 
study intervention, explore HIV 
prevention perspectives, and 
clarify enrollment targets.

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11
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Sawyer SM, Afifi RA, Bearinger LH, et al. Adolescence: a foundation for future health. Lancet. 
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Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure-mediator interactions and 
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APPENDIX 1:  RANDOMIZATION PRINCIPALS AND PROCEDURES
The location of the facility where the randomization event takes place should be a central venue that 
has been agreed upon by the local health leaders. The randomization strategy must be both scientifically 
valid and transparent to the community stakeholders and uses local idioms to make the concept of 
randomization easily understood by traditional leaders and community members.  The random 
assignment within matched pairs of each site’s communities to intervention or control status could 
employ a public lottery of community names to achieve maximum public acceptance of the 
randomization results by enhancing transparency and spreading ownership of the process. A computer 
randomly designates the randomization status for each pair of study communities only as the 
community name that would be ‘picked up’ or ‘not picked up’ in the public lottery.   The lottery may be 
a public event with members of the CAB and local leadership present along with guests from other 
organizations with relationship to the health community. 
The lottery could be conducted in a series of draws, one for each of the matched pairs of communities 
by their local leaders. For each drawing, the two clinic names are written on a separate piece of paper or 
card and folded in half to obscure the name from view. For the draw, the names of each matched pair 
could be placed in a sealed box with a hand hole cut out of the top of the box. A flip of a coin could be 
used to decide which of the two community leaders will pick the community name from the box. The 
unselected leader could be responsible for holding and shaking the selection box. The leader then draws 
a paper from the box without looking into the box and the picked-up community name was read aloud 
by both of the community leaders in turn. If the randomization protocol indicated that the “picked-up” 
community was to receive the intervention (i.e., the SEARCH Youth intervention components described 
in the protocol implemented for enrolled participants), then the host country Principal Investigator 
would announce the drawn clinic as an intervention clinic. If the protocol called for the “picked-up” 
clinic to be the control (i.e., community health campaigns and standard ART initiation), then the host-
country PI would announce it as a comparison clinic. This process would assure equal chance of being 
randomized to the intervention or comparison arm, and eliminates any residual fears of bias or rigging.

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APPENDIX 2:  COSTING PRINCIPALS AND PROCEDURES
The costing team uses the standardized micro-costing workbook as the data collection tool to quantify 
the resources and associated unit costs to deliver the SEARCH Youth intervention components. These 
costs mainly consist of direct costs but also include some indirect costs such as infrastructure, 
administration, etc. Cost information will be gathered through examination of expenditure records, 
discussion with program staff and providers, care delivery logs, and other program documents. Each 
resource item used to deliver the SEARCH Youth intervention components will be enumerated under 
standard expenditure categories – personnel, recurrent goods (supplies), capital goods and equipment, 
services, and facility. The number of units consumed and unit cost of each resource item during the 
specified costing period will also be entered into the micro-costing workbook. The costing approach 
emphasizes resources used for service delivery and will include the value of all resources used even if 
not paid for by the SEARCH Youth study. The costing team will assign the full value to donated or 
subsidized resource items based on market price or existing data from similar costing analysis. The 
information sources (e.g., key informants and program documents) and the dates when the cost data 
were obtained are clearly documented in the micro-costing workbook. The costing team will also save 
relevant program documents and email communications for quality check and future references. The 
details of the costing process is outlined in a detailed SOP, which is used for training of staff and 
standardizing the process across all regions and clinics.
Costs Analysis
We will assess costs at least twice in each health facility: once before and once after adoption of the 
SEARCH Youth intervention, in order to estimate incremental costs of SEARCH Youth implementation 
and to compare costs of the intervention to standard of care. “Economic” costs (the true value of 
resources consumed or “opportunity cost”) will be assessed by identifying the value of subsidized or 
donated resources with information from data bases (e.g. wage rates) and donors, and, as needed, 
three price quotes from appropriate market sources.
 
Health Effects
To quantify health effects, we will use directly measured health-related study outcomes (e.g. viral 
suppression).  Second, we plan to integrate the health impact of achieving viral suppression using 
disability-adjusted life years (DALYs), including years of life gained and the collective disability effects of 
living with HIV. We might be estimated as DALYs gained for the short term (during the trial) and the 
long-term (5, 10, and 20 years) using data from the trial, as well as morbidity and mortality attributed to 
un- or partially- treated HIV disease.