CCTG 594: Engagement and Retention in Care for HIV+, A Multicenter Trial of the California Collaborative Treatment Group
Phase: NA
Conditions: Patient Adherence, HIV Positive
Sponsor: University of California, San Diego

UCSD HRPP Project Number, 130196 
CCTG 594 
Protocol Version 3 (January 12, 2016) 
 
 
 
  
 
 
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CCTG 594 
 
Engagement and Retention in Care for HIV+ 
(Main Study) 
 
 
A Multicenter Trial of the California Collaborative Treatment Group (CCTG) 
 
Sponsored by: 
 
The California HIV/AIDS Research Program (CHRP) 
 
 
CCTG Oversight: 
Sheldon Morris, M.D., MPH 
 
Protocol Co-chairs: 
Maile Karris, M.D. 
 
Katya Corado, M.D. 
Protocol Vice-chairs: 
Eric Daar, M.D. 
 
Joel Milam, Ph.D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 3 
January 12, 2016 
 

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Protocol Version 3 (January 12, 2016) 
 
 
 
  
 
 
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TABLE OF CONTENTS 
 
PROTOCOL TEAM ROSTER  
 p 4 
LIST OF ABBREVIATIONS  
 p 8 
LIST OF TERMS  
 p 9 
SCHEMA  
 p 10 
1.0 HYPOTHESIS AND STUDY OBJECTIVES  
 p 12 
 
1.1 Hypotheses  
 p 12 
 
1.2 Primary Objectives  
 p 12 
 
1.3 Secondary Objectives  
 p 12 
2.0 INTRODUCTION  
 p 13 
 
2.1 Background  
 p 13 
 
2.2 Rationale  
 p 15 
3.0 STUDY DESIGN  
 p 16 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS  
 p 17 
 
4.1 Inclusion Criteria  
 p 17 
 
4.2 Exclusion Criteria  
 p 17 
 
4.3 Enrollment Procedures  
 p 18 
 
4.4 Co-enrollment  
 
 
 
 
 
 
 p 19 
5.0 INTERVENTION  
 p 19 
 
5.1 ALERT Intervention  
 p 19 
6.0 CLINICAL AND LABORATORY EVALUATION  
 p 22 
 
6.1 Table of Schedule of Events  
 p 22 
 
6.2 Definitions for Schedule of Events – Timing of Evaluations  
 p 24 
 
6.3 Special Instructions and Definitions of Evaluations  
 p 27 
 
6.4 End of Study Assessment_______________________________p 29 
7.0 CLINICAL MANAGEMENT ISSUES  
 p 30   
8.0 CRITERIA FOR EARLY TERMINATION  
 p 30 
9.0 STATISTICAL CONSIDERATIONS  
 p 30 
 
9.1 General Design Issues  
 p 30 
 
9.2 Endpoints  
 p 30 
 
9.3 Randomization and Stratification  
 p 31  
 
9.4 Sample Size and Accrual  
 p 31 
 
9.5 Monitoring  
 p 32 
 
9.6 Analyses  
 p 31 
10.0 DATA COLLECTION, MONITORING AND ADVERSE EVENT REPORTING   p 34 
 
10.1 Records to be Kept  
 p 34 
 
10.2 Role of Data Management  
 p 34 
 
10.3 Clinical Site Monitoring and Record Availability  
 p 34 
 
10.4 Serious Adverse Experiences (SAE) Reporting  
 p 34 
11.0 HUMAN SUBJECTS  
 p 35 
 
11.1 Institutional Review Board and Informed Consent  
 p 35 

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11.2 Subject Confidentiality  
 p 36 
 
11.3 Study Discontinuation  
 p 36 
12.0 PUBLICATION OF RESEARCH FINDINGS  
 p 36 
13.0 BIOHAZARD CONTAINMENT  
 p 36 
14.0 REFERENCES  
 p 37 
 
 
 
 
 
 

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PROTOCOL TEAM ROSTER 
 
 
CCTG Oversight 
 
 
 
 
 
Sheldon Morris, M.D., MPH 
Assistant Professor of Medicine 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
Phone 
619.543.8080 
Fax 
619.543.5066 
E-mail 
shmorris@ucsd.edu 
 
 
 
Study Co-Chairs 
 
 
 
 
 
Maile A. Karris, M.D. 
Assistant Professor of Medicine 
University of California, San Diego 
Owen Clinic  
4168 Front St. 3rd Floor 
San Diego, CA 92103 
Phone 
619.543.8080 
Fax 
619.543.5066 
E-mail 
m1young@ucsd.edu 
 
 
Katya Corado, M.D. 
Division of HIV Medicine 
Harbor-UCLA Medical Center 
David Geffen School of Medicine at UCLA 
1124 W. Carson St., CDCRC 203 
Torrance, CA 90502 
Phone 424.2013000 x7316 
Fax 
310.782-2964 
E-mail kcalvo@labiomed.org 
 
Study Vice-Chairs 
 
 
 
 
 
Eric S. Daar, M.D. 
Chief, Division of HIV Medicine 
Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at UCLA 
1124 W. Carson St., CDCRC 205 
Torrance, CA 90502 
Phone 
424.201-3000 x7317 
Fax 
310.782-2964 
E-mail 
edaar@labiomed.org 
 
Joel Milam, Ph.D. 
Assistant Professor of Preventive Medicine 
University of Southern California 
1441 Eastlake Ave. 
Los Angeles, CA 92103 
Phone 
 
Fax 
 
E-mail  
joel.milam@med.usc.edu 
 
 

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Co-Investigators 
 
 
 
 
 
Michael Dubé, M.D. 
Professor of Medicine 
Keck School of Medicine 
University of Southern California 
1300 N. Mission Road, Room 349 
Los Angeles, CA 90033 
Phone 
323.343.8288 
Fax 
323.226.2083 
E-mail mdube@usc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Trials Specialist 
Eric E. Ellorin, MAS 
Research Project Coordinator 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
Phone 
619.543.8080 
Fax 
619.543.5072 
E-mail 
eellorin@ucsd.edu 
 
Biostatistician 
 
Sonia Jain, Ph.D. 
Director, CCTG Biostatistics Core 
Co-Director, Biostatistics Research Center (BRC) 
Associate Professor, Division of Biostatistics and Bioinformatics 
Department of Family and Preventive Medicine 
University of California, San Diego 
9500 Gilman Dr., MC 0717 
La Jolla, CA 92093-0717 
Phone 
858.822.2388 
E-mail 
sojain@ucsd.edu 
 
Study Monitor and Data Unit 
 
Edward Seefried, R.N. 
Medical Monitor, CCTG Data Unit 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
Phone 
619.543.8080 
E-mail 
eseefried@ucsd.edu 
 
HIV Active Linkage, Engagement, and Retention to Treatment (ALERT) specialist 
Kelly Walsh 
ALERT Specialist, UCSD 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
Phone 
619.543.8080 
Fax 
619.543.5072 
E-mail 
krwalsh@ucsd.edu 

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Daisy Villafuerte 
ALERT Specialist, USC 
University of Southern California 
Rand Schrader Clinic – 5P21 
1300 North Mission Road, Room 349 
Los Angeles, CA 90033 
Phone 
323.343.8284 
E-mail 
dvillafu@usc.edu 
 
Janisse Mercado 
ALERT Specialist, USC - LA County Emergency Department 
LAC/USC Medical Center 
Department of Internal Medicine 
Division of Infectious Diseases 
1300 North Mission Road 
Los Angeles, CA 0033 
Phone 
619.543.8080 
Fax 
619.543.5072 
E-mail 
janissem@usc.edu 
 
Lab Technician 
 
DeeDee Pacheco 
Phlebotomist and Lab Manager 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
Phone 
619.543.8080 
E-mail 
dmpacheco@ucsd.edu 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALERT 
Active Linkage, Engagement, and Retention to Treatment 
ART 
Antiretroviral Therapy 
ARV 
Antiretroviral 
CCTG 
California Collaborative Treatment Group 
CD4 
CD4 Lymphocytes 
CRF 
Case Report Form 
CT 
Chlamydia 
DSMB 
Data Safety and Monitoring Board 
GC 
Gonorrhea 
HIV-1 
Human Immunodeficiency Virus – 1 
ITT 
Intention to Treat 
LTFU 
Lost to Follow Up 
MSM 
Men who have Sex with Men 
NAAT 
Nucleic Acid Amplification Test 
PID 
Patient Identification Number 
PLWH 
Persons Living With HIV/AIDS 
RPR  
Rapid Plasmin Reagin 
SAE 
Serious Adverse Event 
SOC 
Standard of Care 
STI 
Sexually Transmitted Infection 
TPPA 
Treponema Pallidum Particle Agglutination Assay 
VDRL  
Venereal Disease Research Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF TERMS 
 
Lost to follow up: no visit with a prescribing HIV provider in the last 180 days   
 
Out of care: no visit with a prescribing HIV provider in the last 180 days and not on a stable 
antiretroviral regimen 
 
Retention in care: maintaining at least one visit with a prescribing HIV provider within 180 days 
 
Newly diagnosed patient : someone who has never engaged in HIV care 
 
Patient returning to care: a patient previously seen at least once by a prescribing HIV provider 
who has not seen a prescribing HIV provider in the last 180 days and is not on a stable 
antiretroviral regimen 
 
Prescribing HIV provider: a licensed HIV care provider who is able to prescribe HIV medications 
(e.g. an HIV specialty MD, Nurse practitioner, or Physician Assistant) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
Design: 
CCTG 594 is a controlled, un-blinded, two-arm, randomized (1:1) clinical 
trial to evaluate the effectiveness of a clinic-based HIV Active Linkage, 
Engagement, and Retention to Treatment (ALERT) specialist on improving 
endpoints of retention in care and maintenance of antiretroviral therapy 
(ART) as compared to the current standard of care (SOC) in HIV primary 
care clinics.  
 
Duration: 
Each subject will receive follow-up of at least 48 weeks.  Follow-up for 
enrolled patients will continue until the last enrolled patients has been 
on study for 48 weeks 
 
Sample Size: 
A total of 300 subjects will be randomized, 150 per arm. 
 
Study Population: 
Eligible subjects will include 1) newly diagnosed HIV-infected individuals 
entering primary HIV care at one of the CCTG clinics, or 2) previously 
diagnosed HIV-infected individuals who are “out of care” defined as 
having no visit with a prescribing HIV provider in the last 180 days and 
not on a stable ARV regimen.  
 
Stratification: 
Subjects will be stratified based on study site and if they are newly 
diagnosed or returning to care.   (See Diagram 1) 
 
Intervention: 
Subjects will be randomized (1:1) to either the ALERT Enhanced Retention 
Intervention Arm or the SOC Arm. Subjects placed into the ALERT 
Intervention Arm will receive aggressive engagement efforts by the 
ALERT specialist to ensure visit continuity and retention into care. The 
ALERT specialist will also administer an education intervention consisting 
of 5 retention modules designed to improve HIV knowledge and self-
efficacy, and will also monitor health care visits and intervene via 
methods to track, find, and re-engage patients during the study. Patients 
placed into the SOC arm will receive the HIV care clinic’s current standard 
of care retention services.  
 
Outcomes: 
 
 
Primary Outcome: 
Time to “lost to follow up” (LTFU) defined as the time from study entry to 
no visit with a prescribing HIV provider in the last 180 days   
 
 

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DIAGRAM 1: CCTG 594 STUDY SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Positive 
ALERT Study 
(CCTG 594) 
ALERT Intervention 
- Intensive continuous retention 
efforts with use of tracking 
database 
- Education intervention consisting 
of 5 retention modules  
Data abstraction q3 month to evaluate for primary endpoint  
Time to LTFU 
Randomize 1:1 
Clinical Standard of Care  
(SOC) 
Test and Link 
(CCTG 593) 
Social Networks 
(CCTG 596) 
- New positive 
diagnosis from other 
sources 
- Known HIV positive 
patients returning to 
care 
Secondary outcome measures 
- Time to ART initiation 
- Viral suppression 
- Other secondary measures 
HIV Negative 
PrEP Study 
(CCTG 595) 

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1.0 HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 Hypotheses 
 
1.1.1 
Primary hypothesis 
 
 
Subjects randomized to the ALERT specialist arm will have higher levels of 
“retention in care,” defined as maintaining at least one visit with a prescribing 
HIV provider within 180 days, compared to subjects in the SOC arm. 
 
1.1.2 
 
Secondary hypotheses 
 
 
1.1.2.1 
Subjects randomized to the ALERT specialist arm will have 
higher ART uptake compared to subjects in the SOC arm. 
 
 
1.1.2.2 
Use of detailed assessments at study entry will allow for the 
identification of covariates associated with poor retention and 
initiation of ART. 
 
 
1.1.2.3     
Use of an ALERT specialist and a structured retention module 
intervention will modify the impact of covariates on retention 
and initiation of ART. 
 
1.2 Primary objective 
 
1.2.1 
To evaluate the effect of an ALERT specialist on retention in care, based on time 
to LTFU. 
 
 
1.3 Secondary objectives 
 
1.3.1 
To evaluate the effect of an ALERT worker on the time to initiation of ART per 
DHHS guidelines. 
 
1.3.2 
To assess factors predictive of loss to care, such as demographic, 
socioeconomic, and psychosocial factors, risk behavior, substance use and 
psychiatric illness. 
 
1.3.3 
To assess if the ALERT intervention mitigates the impact of psychosocial barriers 
on retention in care and initiation of ART. 
 
1.3.4  
To compare in the intervention vs. SOC arm (assessed at 12 month intervals): 
 
 
1.3.4.1 
Baseline and annual scores on standardized assessments of HIV 
literacy, disclosure and social support, perception of stigma, 
barriers to care,  ART adherence and Intention to Adhere, Beck 
Depression Index, substance use evaluations, HIV high-risk 

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transmission behaviors, and measures of self-efficacy 
 
 
1.3.4.2 
Number of visits per year with HIV prescribing provider per year 
 
 
1.3.4.3  
HIV RNA < 50 and 200 copies/mL at 12 months and every 12 
months thereafter 
 
 
1.3.4.4 
CD4 cell counts and changes from baseline in CD4 at 12 months 
and every 12 months thereafter 
 
1.3.4.5   
Time to AIDS diagnosis or death 
 
1.3.5  
To describe the reasons identified in the refusal survey why patients who are 
eligible for the study decline study participation 
 
 
2.0 INTRODUCTION 
 
2.1 Background 
 
Over the last 30 years, HIV infection has evolved from a progressive disease with high mortality 
to a manageable chronic infection in those patients who adhere to ART with regular 
appointments for care. Yet, as the Gardner cascade has revealed, progressive gaps in care 
delivery remain, from the identification of the HIV positive community to adherence to ART 
resulting in an undetectable viral load (1). Studies suggest that only two thirds of HIV- infected 
people aware of their serostatus receive HIV care (2), 56% of patients eligible for ART actually 
receive it (3), and an estimated 20% of HIV-infected persons in the US achieve an undetectable 
viral load (1).   
 
At community, state, and national levels, a formalized focus on retention assures that HIV-
infected populations have improved engagement in their care to assure virologic response to 
ART and improved health outcomes.  Active participation in healthcare, assessed as routine 
attendance with medical provider visits, improves the likelihood that HIV- infected patients will 
initiate ART, have improved virologic response and lower mortality (4-8).  
 
In order to improve the success of programs designed to identify HIV- infected individuals 
earlier in the course of disease, through “test, link to care, plus treat” (TLC+), the focus of 
research must shift to the primary care HIV clinic to promote interventions which identify 
barriers and improve retention (9, 10). 
 
2.1.1   
Theoretical Framework 
 
Using the guiding framework of the modified ‘Behavioral Model for 

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Vulnerable Populations’, we will construct a responsive behavioral model 
aimed to improve patient engagement in care (11).  This model posits 
that both patient level [education (literacy), perception of HIV 
risk/diagnosis/stigma, social support] and clinic level [available services 
on site (e.g., psychiatric), reminder phone calls] factors are critical 
barriers to patient engagement with healthcare (6, 10).  Addressing a 
single level or factor of this model is inadequate to sustain meaningful 
improvement in patient care.  Thus, by addressing multiple factors and 
the complex interplay between them through a structured behavioral 
intervention, we aim to improve overall patient care linkage and 
retention. 
 
2.1.2   
Factors associated with retention in care 
 
A complex interplay of patient, structural, and process factors result in 
synergistic barriers to engagement in care (6, 10, 11).  For example, social 
marginalization, active substance use (6) (12) and racial disparities (8) 
have been identified as predictors of retention in care. HIV related stigma 
and difficultly navigating the health system can also contribute to poor 
retention (13), and patients have reported the importance of clinic 
outreach as a vehicle to improve their HIV knowledge and provide a 
supportive network (14).   
 
For people with HIV, low health literacy has been associated with lower 
CD4 counts, higher HIV viral loads, increased hospitalizations, and poorer 
self-reported health (15), yet rates of health literacy among HIV-infected 
patients are low, ranging from 15- 49% (16-23). Remarkably, in one study, 
two thirds of HIV-infected patients with a low health literacy level did not 
know how to take their medications correctly and 75% did not 
understand the meaning of CD4 cell count and HIV viral load levels (21). 
In several studies African American and Hispanic patients had significantly 
lower health literacy rates compared with other groups (OR of 2.78 and 
4, respectively) (22). In another study, African American HIV infected 
patients were found to be statistically more likely to be non-adherent to 
ART, yet this difference became non-significant when health literacy 
levels were included in the model (20). These populations represent a 
growing proportion of patients with HIV in the US and are highly 
represented in the CCTG sites proposed in this application (24). 
 
Interventions targeting health literacy have been shown to improve 
clinical outcomes by our group (25, 26),  resulting in a significant 
sustained increase in knowledge of ART and gain in CD4 cell counts.  

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Thus, improving health and HIV literacy are potential pathways to 
successful engagement in, and optimization of HIV care.   
 
Facilitating patient navigation of the complex health system (System 
Literacy) (27) allows better use of available resources, improves 
communication and can sustain HIV care over time (engagement).  One 
study in 333 HIV-infected found that 71% of the patients needed at least 
one support service that was ostensibly available to them through their 
clinic.  Services were not accessed due to lack of information (47%) or 
other logistical barriers (33%; such as confusing instructions or long 
waiting lists for services) (28). Similarly, in the UC San Diego Health 
Systems HIV retention project (29), system navigation was frequently 
cited as the reason for lack of retention.  
 
Finally, people with HIV report fear of disclosure of their diagnosis and 
potential stigma as significant barriers to care (13, 30), and to accessing 
social support networks (31).  Behavioral models identify stigma and lack 
of social support as important factors in an individual’s risk for poor 
engagement, particularly within vulnerable populations (11, 32).  
Qualitative studies also identify stigma and family support as key factors 
in patients’ ability to engage in HIV care (33), and studies have 
demonstrated associations between lack of HIV disclosure to support 
networks and poorer psychosocial, adherence, immunologic, and 
virologic outcomes (31, 32, 34) (34-38).  Furthermore, minority patients 
are more likely to have concerns about stigma and are more likely to 
change clinics (30, 39) which may contribute to disparities seen in HIV 
outcomes in minority patients (40, 41).    
 
We hypothesize that an ALERT specialist, who has access to a tracking database, outreach 
activity, and a structured behavioral intervention to address the above retention barriers, will 
improve successful continuity of care and ART initiation.   
 
2.2 Rationale 
 
2.2.1   
Study population 
 
 
The goal of this study is to enhance retention in care amongst those 
diagnosed with HIV who are at high risk of being LTFU.  Based upon the 
Gardner cascade there is a major drop off from those diagnosed who 
encounter care and are retained in care over time (1). Thus, we will target 
those that are encountering care for the first time since HIV diagnosis or 
who have already met the criteria of having been LTFU, having not been 

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seen for at least 180 days since first entering care. 
 
2.2.2   
Rationale for the use of an ALERT specialist 
 
Retention in care should be defined by both measures of adherence to 
medical appointments and maintaining visits at regular defined intervals 
(42, 43). A demonstration project to promote retention in HIV primary 
care used outreach, advocacy, and support services in a sample of 773 
HIV-infected subjects. Participants with nine or more contacts during the 
first 3 months of their program were half as likely to have gaps in care 
(defined as 4 months or more) during their first 12 months of follow up 
(44).  In another large non-randomized engagement program including 
the use of mobile technologies, health educators to facilitate navigation 
of the health care system, case management to coordinate services, 
support groups, and peer support, 83% of subjects were still engaged at 
12 months. Findings also included improvement of health outcomes as 
measured by decrease in hospital and ER use (p<0.0001) and increases in 
ART use (p<0.001) (45). 
 
In summary, current literature highlights potential improvements in retention in care, ART use 
and clinical outcomes in response to various patient engagement interventions.  The efficacy of 
these approaches needs to be determined with randomized clinical trials to evaluate their 
sustained impact.  
 
3.0 STUDY DESIGN 
 
The CCTG 594 Study is a randomized, two-arm, unblinded, controlled clinical trial to evaluate 
the effect of an enhanced engagement strategy using an ALERT specialist, as compared to local 
clinics’ SOC, on sustainable engagement in care and uptake of ARVs in a variety of southern 
California clinical settings.  Eligible patients will include those with a new HIV diagnosis and 
those with prior diagnoses who are out of care.  Patients randomized to the intervention arm 
will have multiple contacts with the ALERT specialist in the form of 5 standardized educational 
sessions as well as continuous aggressive retention efforts.  Engagement and retention efforts 
in the ALERT arm will follow the algorithm we developed in the pilot project (29). Once a 
patient has a scheduled appointment, attendance will be tracked.  Failed appointments will 
trigger follow up by an ALERT specialist.  Standardized assessments at study initiation and 
annually will be used to evaluate the psychosocial factors associated with successful retention 
in care and evaluate the effect of an ALERT specialist on those factors.  The primary endpoint 
will be time to LTFU.  The secondary endpoint will include other relevant markers of success in 
care, including time to initiation of ART.   
 
 

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4.0 SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 Inclusion Criteria 
 
4.1.1  
HIV-1 infection, as documented by any licensed screening antibody test, 
such as ELISA, and confirmed by a second antibody test, such as Western 
blot, or detectable plasma HIV-1 RNA at any time prior to study entry. If 
an ELISA or Western blot is not available, HIV infection may be 
documented by two HIV RNA values ≥2000 copies/mL, drawn at least 24 
hours apart.  The RNA assays must have been run at a CLIA-approved 
laboratory or equivalent.  
 
4.1.2 
18 years of age or older. 
 
4.1.3  
Able to give written informed consent. 
 
4.1.4  
New patient to the clinic (defined as someone who has never engaged in 
HIV care) or a patient returning to care (defined as a patient previously 
seen at least once by a prescribing HIV provider who has not seen a 
prescribing HIV provider in the last 180 days and is not on a stable ARV 
regimen).  
 
4.1.5  
English or Spanish Speaking. 
 
4.1.6  
Registered to receive HIV primary care services at one of the identified 
CCTG-affiliated clinic, i.e. the Owen Clinic at UC San Diego Health System, 
Harbor-UCLA Medical Center clinic or Rand Schrader clinic at USC. 
 
4.2 Exclusion Criteria 
 
4.2.1  
Unstable neurologic, psychiatric, or physical condition which, in the 
opinion of the investigator, would limit participation with study 
procedures for the duration of the study. 
 
4.2.2  
A level of drug or alcohol use that, in the opinion of the investigator, 
would preclude safe participation in the study. 
 
4.2.3  
 
Resident of nursing home or skilled facility. 
 
4.2.4  
 
Pregnant or breastfeeding 
 
4.2.5  
Patient’s first primary care visit (for new patients) or return to care visit 

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(for patients returning to care) occurred >60 days ago 
 
4.3 Enrollment Procedures 
 
4.3.1  
Prior to implementation of this protocol, sites must have the protocol 
and consent form approved by their local Institution Review Board (IRB). 
Sites must be registered with and approved by the CCTG Data Center. Site 
registration must occur before any subjects can be enrolled in this study. 
 
4.3.2  
Once a candidate for study entry has been identified, details of the study 
will be discussed with the subject. The subject will be asked to read and 
sign the consent form that was approved by both the local IRB and the 
CCTG Data Center.   
 
4.3.3  
A patient identification number (PID) will be assigned to each patient 
screened for the study. PIDs should not be reassigned even if the patient 
fails to enter the study. The PID must be included on every CRF and 
patient blood sample. Each site must maintain a master list of PID’s in a 
central location. The patient registration and inclusion/exclusion CRF 
must be completed on the online system.  
 
4.3.4  
Once enrolled, participants will respond to the baseline assessment 
survey, administered with assistance of the study coordinator or ALERT 
specialist. 
 
4.3.5  
Once the survey is completed, participants will be randomized (1:1) to 
either the ALERT Intervention Arm or the SOC Arm. Subjects randomized 
to the ALERT Intervention Arm will receive the contact information for 
the ALERT specialist and will be notified that the ALERT specialist will be 
contacting them to ensure visit continuity and retention into care.  
Participants placed into the SOC arm will be notified that they will receive 
the clinic’s current SOC services.  
 
4.3.6  
Refusal Survey Administration 
 
 
Patients who meet the inclusion and exclusion criteria of the Engagement 
and Retention in Care for HIV+ study who decline to participate in the 
study will be offered a refusal survey. The refusal survey will be 
administered to patients who verbally consent to participate in the 
refusal survey administration. The survey will be administered either in 
written or verbally. No personal health identifying information will be 
collected as part of this survey. The refusal survey includes questions 
about age and categorical questions about gender, new to HIV care or 

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out of care for more than 6 months, race, ethnicity, and the reasons for 
not participating. 
 
4.37 
 
End of Study Assessment 
 
 
Study participants in the standard of care and ALERT arms will be 
contacted at end of study and asked to complete either in person or over 
the phone a questionnaire about their experiences in the study.  
 
4.4 Co-enrollment 
 
Co-enrollment will be allowed in CCTG 593 and CCTG 596 (Networks Sampling study).  For all 
other studies, co-enrollment will require permission from the CCTG 594 study team. 
 
5.0 INTERVENTION 
 
5.1 ALERT Intervention 
 
 
5.1.1   
Overview 
 
Building from methods previously developed in our pilot retention 
project (29) we will expand the role of our ALERT specialist to provide on-
going engagement in care monitoring and outreach as well as a 
structured behavioral intervention.  
 
Core training for ALERT specialists will be provided at all consortium care 
sites.  The ALERT specialist should have experience with phone 
solicitation, customer service, database management and language and 
cultural competence.   During the initial training, skills for navigation of 
the health systems at each of the three sites will be emphasized.  The 
ALERT specialist will cross train with many clinic personnel to better 
understand barriers to care; training will include work with the front 
desk, medical assistants, phone operators, triage nurses and 
administrative support. The ALERT specialist will also be trained to inform 
patients about aspects of care including: appropriate estimated visit 
duration, optimal methods to initiate contact with their provider and 
education about symptoms which should necessitate immediate health 
evaluation.  A site-appropriate toolbox will be developed (from our pilot 
retention experience) that includes an algorithmic approach to locate lost 
patients, a standardized telephone script, creation of a secure visit 
tracking database, establishment of a secure line for messages from 
patients to the ALERT specialist and brochures that emphasize 
engagement awareness.  

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A summary of the roles, responsibilities, procedures, algorithms, and 
protocols for the ALERT worker can be found in the Manual of Operating 
Procedures [MOP CCTG 594]. 
 
 
5.1.2   
Initial visit 
 
The study coordinator or ALERT specialist will interview patients 
following their completion of consent and baseline assessment. The 
ALERT specialist will collect additional pertinent information relative to 
outreach [MOP CCTG 594: 3.0 Baseline ALERT Specialist Patient Contact 
Information]. This patient survey will be completed on all patients 
regardless of randomization to the intervention or the SOC arm. 
Following survey completion, patients who receive the SOC will receive 
on-going clinic standards regarding outreach and retention activity. For 
patients who are randomized to the intervention arm, they will be given a 
brief overview of the intervention: including anticipated reminder calls 
about upcoming or needed appointments, follow up outreach for missed 
visits, and delivery 5 monthly one hour modules related to our HIV 
coaching intervention. 
 
Patients will also select their preference for communication and outreach 
activities including: text, voice message, phone call, email, other.  
Patients will provide optimal secondary recommended approaches for 
outreach including the ability of the ALERT specialist to contact friends, 
family, partners, or other persons, and location. Patients will be pro-
actively requested to identify and share perceived barriers to 
engagement in care. 
 
 
5.1.3  
Retention Modules related to our HIV coaching intervention  
 
 
(intervention arm subjects only) 
 
Each patient will receive a one hour coaching intervention starting 
between 2 weeks and four weeks following enrollment in the study. The 
coaching intervention will occur in person at the clinic at the time of a 
routine clinic visit when available and by phone when more convenient to 
the patient. Each module will provide information and skills that are 
highly pertinent to HIV care delivery. As part of the 5 retention modules 
which deliver the HIV coaching intervention, key attention will be to build 
patient self-efficacy through the use of open ended questions and 
confidence building. The 5 retention modules include HIV literacy, HIV 
health systems, Disclosure, Medication adherence and Continuation with 

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Care, and Self-Efficacy [MOP CCTG 594: 5.0 The 5 Retention Modules for 
the ALERT specialist]. Consented participants receiving one of the five 
retention modules may be audio recorded as part of the quality 
improvement process. 
 
 
5.1.4   
Tracking and outreach 
 
The ALERT specialist will be responsible for tracking the on-going 
engagement of patients who are randomized into the intervention arm.  
Patients will be expected to complete visits at a minimum of every 6 
months. However, the ALERT specialist will also review chart notes to 
review the interval that the provider recommended a medical visit. The 
ALERT specialist will track that the patient makes and keeps an 
appointment with their primary provider at the suggested interval. If the 
patient misses a visit at the recommended interval, the ALERT specialist 
will perform outreach to schedule a return visit, and again track to see 
that the visit is kept. The ALERT specialist will use a tracking database in 
order to track patient engagement, their outreach efforts and delivery of 
the retention modules. The ALERT specialist will record contacts 
(categorically) both successful and unsuccessful. They will also utilize the 
baseline patient contact information as well as other key notes in this 
tracking database.  Patients who meet the LTFU primary end point, 
regardless of study arm will have outreach activity initiated by the ALERT 
specialist. This will include following the retention tracking algorithm 
including evaluating whether the patient is incarcerated, providing 
outreach calls to the patient, and reviewing the medical record.  Patients 
who meet the primary endpoint and are found to be incarcerated will be 
removed from the study and censored effective at the time of their 
incarceration. Those who are incarcerated but then return to care upon 
release, prior to reaching a primary endpoint will be allowed to remain in 
study.  Patients who are confirmed to have changed care provider to an 
external health facility (such as a different clinic system or a nursing 
facility) will be assessed for their current engagement in care; those who 
have completed a clinic visit with a HIV prescribing clinician within the 
180 days will be considered engaged in care, and will not be considered 
LTFU.  The ALERT specialist will request access to the patient’s new HIV 
prescribing provider in order to assess continued follow-up care during 
the course of the study.  In addition, if possible, these patients will 
continue to come to study site for the annual study visit. 
 
 

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6.0 CLINICAL AND LABORATORY EVALUATION 
6.1 Table 1: CCTG 594 Schedule of Events 
 
Schedule of 
Evaluations 
 
Screen 
 
On Study Evaluations 
 
Wk 
01 
Mo 
12 
Mo 
22 
Mo 
32 
Every 
3 
months 
Mo 
42 
Mo 
52 
Mo 
62 
Mo 
12 
Every 
12 
Months5 
Primary 
Endpoint 
EOS 
Assessment 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Examination 
(targeted) 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Randomizati
on 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV RNA 
  
X4 
 
 
 
X4 
 
 
 
X4 
X4 
X4 
 
CD4 cell 
counts 
  
X4 
 
 
 
X4 
 
 
 
X4 
X4 
X4 
 
ALERT 
Specialist 
retention 
modules3 
 
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
Plasma 
Storage 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Subject self-
reported 
Assessments 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Data 
abstraction 
(via chart 
review, no 
visits) 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
In person or 
phone call  
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 Entry must be within 30 days of screening 
2 Planned for monthly intervals but can be done at patient’s convenience during course of first year 
3 Interventions only for those in ALERT specialist arm 
4 Abstracted from chart review 
5 annual visits and annual labs should occur within a window of +/- 60 days from the due date.  Labs and study 
visit do not need to occur on the same day. 
EOS – End of Study 
 
 
Figure 2:  Detailed flow diagram of CCTG 594 with scheduled events 
Legend: 
Blue Dot: ALERT Specialist 
Red Dote: Study Coordinator 

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6.2 Definitions for Schedule of Events – Timing of Evaluations 
 
6.2.1   
Screening Assessment 
 
Screening visit must occur within 60 days, the patient’s first primary care 
visit (for patients new to care) or their first primary care re-entry visit (for 
patients returning to care). 
 
A PID will be assigned to each patient screened for the study. PID’s 
should not be reassigned even if the patient fails to enter the study. The 
PID must be included on every CRF and patient blood sample. Each site 
must maintain a master list of PID’s in a central location. The patient 
registration and inclusion/exclusion CRF must be completed on the online 
system. 
 
 
Screening will be conducted by the study coordinator, Alert specialist or a 
trained member of the study team and will include medical history, 
confirmation of HIV test results, evaluation of Inclusion/Exclusion criteria, 
and signing of study consent form. 
 
Patients who meet the study eligibility but decline to participate will be 
offered participation in a brief refusal survey. Patients who verbally 
consent to participate in the refusal survey will be administered the 
questionnaire in written or verbal format. Patients who were not 
previously offered will be re-approached while attending their Primary 
Care clinic visit and will be offered participation in the brief refusal 
survey. 
 
 
6.2.2  
Entry Evaluations and Randomization  
 
Entry must occur within 60 days of the patient’s first primary care visit (for 
patients new to care) or their first primary care re-entry visit (for patients 
returning to care).  At study entry, baseline surveys will be collected 
utilizing the web-based, computer-assisted system on the study specific 
portal (to view baseline survey, see Attachment 5, iPad Assessments for 
CCTG 594).  The portal will allow private completion of questionnaires 
without concern that clinic or study personnel can view the subject’s 
responses in order to encourage candor.  
 
Subjects will be randomized (1:1) to SOC or ALERT Intervention study 
arm. Randomization will be stratified by clinic site and whether the 
subject is newly diagnosed or returning to care.  A total of 300 subjects 

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(150 per arm) will be randomized and followed for a minimum of 48 
weeks. SOC will be the clinic standard.   
 
Samples of plasma will be stored for future assays. 
 
6.2.3  
On-Study Evaluations 
 
Study specific follow-up visits for each subject will be kept to a minimum 
in order not to bias the outcome of lost to follow up. Our experience 
suggests that involvement in a research protocol, with the extra effort 
the coordinators exert to ensure study follow-up, could easily impact on 
attendance to clinical care.  Thus, for SOC patients, study specific visits 
will occur yearly preferably in conjunction with a regularly scheduled 
clinic visits (see below, yearly study visits).  
 
In the ALERT intervention arm, the ALERT specialist will conduct 5 
monthly educational retention modules (in person or by phone).  The 
ALERT specialist will also continuously monitor and track all health care 
visits to ensure healthcare continuity, and will intervene using described 
tools/methods when the subject does not have a visit within a pre-
determined interval (see Attachment 4, Manual of Operating Procedures, 
for ALERT Specialist job description, methods, and Retention Modules).  
 
 
6.2.4  
Data Abstraction  
 
It is expected that subjects new or returning to care will have regular 
primary care visits at least 3-4 times in the first year. The ALERT specialist 
will use the clinic medical record system to abstract data on clinic visits, 
ART medications, serial HIV RNA and CD4 values, routine CBC and 
chemistry values, HIV-related and AIDS diagnoses and other medical 
diagnoses. Data will be entered into the study electronic database. 
Abstraction will be done at least quarterly for each subject.  The ALERT 
specialist will track the status of each subject and record retention and 
outreach in the study database.  Using data abstracted from the primary 
care clinic medical records system, the ALERT specialist will record all 
visits with a prescribing HIV provider, which will document retention as 
related to the primary study endpoint.   For patients in the SOC arm, 
contact information will be collected for use in the event that the person 
meets the primary endpoint.  Subjects in either arm who reach criteria 
for the LTFU primary endpoint will be identified by the ALERT specialist. 
The ALERT specialist will then contact the subject to assure that the 
patient is not incarcerated or receiving care from an HIV provider at 

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another facility.  Once LTFU is confirmed, the ALERT worker will try to 
bring the patient in for a primary endpoint visit. All patients will continue 
to be followed after the primary endpoint (ITT) for assessment of 
secondary endpoints.   
  
Education Contacts (weeks 1-24).  The ALERT specialist will complete a 5 
session educational curriculum called a retention module either in person 
or by phone to the subjects randomized to the ALERT Intervention arm.  
The 5 retention modules include instruction about the navigation of HIV 
health systems, HIV literacy, Disclosure, Medication adherence and 
Continuation with Care, and Self-Efficacy [MOP CCTG 594: 5.0 The 5 
Retention Modules for the ALERT specialist]. The goal will be to present 
the majority of the material within the first 6 months, however 
scheduling flexibility will be allowed up to the 12 month time-point in 
order to maximize opportunities for patients to receive the intervention.  
Subjects that complete all 5 modules will be asked about their reasons 
motivating them to 1) participate in the study and 2) completing the 5 
modules. 
 
Ongoing Retention Efforts.  The ALERT specialist will continuously 
monitor visit records on all patients in the ALERT specialist Intervention 
arm and will utilize all tools developed for clinic specific re-engagement 
to aggressively track, find, and re-engage patients during the study. 
Monitoring will include missed visits and intervals between scheduled 
visits. In addition to continuous monitoring for missed appointments, the 
ALERT specialist will screen the charts of all enrolled subjects every 3 
months to evaluate the number of clinic contacts, missed visits, missed 
attendance of the retention modules, and any other risks for falling out of 
care. 
 
Yearly Study Visits.  For both arms, a study-specific visit will be conducted 
at yearly intervals from the enrollment date.  The annual visits must 
occur within a 60 day window before or after the due-date. At the annual 
study visits the baseline study assessments will be repeated along the 
collection of plasma which will be stored for future assays. Efforts will be 
made to have these study visits occur around a regularly scheduled clinic 
visit.   
 
Though every effort will be made to bring all patients in for annual visits 
within the 60 day window, subjects may remain in the study if the annual 
visit is missed (i.e., not completed within the 60 day window).     
 

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Compensation. Study participants will be compensated for their time at 
intake, annual, and endpoint visits which are anticipated to require 1-2 
hours for questionnaires and collection of lab specimens.  
 
6.2.5  
Primary endpoint visit 
 
When a participant reaches the primary endpoint of LTFU, every effort 
will be made to return the participant for an endpoint study visit.  If the 
patient is willing, this visit will include the same assessments and 
procedures as the annual study visits. 
 
6.3 Special Instructions and Definitions of Evaluations 
 
6.3.1  
Documentation of HIV 
 
Documentation of HIV-1 infection will be confirmed by reviewing a 
positive test from any licensed screening antibody test, such as ELISA, 
and confirmed by a second antibody test, such as Western blot, or 
detectable plasma HIV-1 RNA at any time prior to study entry. If an ELISA 
or Western Blot is not available, HIV infection may be documented by 
two HIV RNA values > 2000 copies/mL, drawn at least 24 hours apart. The 
RNA assays should have been run at CLIA approved laboratory or 
equivalent. 
 
6.3.2  
Medical and Laboratory History 
 
At screening, a medical history will be obtained and must be recorded in 
the source documents. The medical history should include any previous 
HIV-related diagnoses, malignancies, and AIDS-defining events which will 
be recorded on the electronic CRF. History will include date of HIV 
diagnosis, date of last HIV clinic visit (for those returning to care), 
antiretroviral (ARV) history (if any), concomitant medical conditions, 
substance use history.     
 
6.3.3  
Medication History 
 
At screening, a medication history (only of those taken within the last 30 
days prior to entry) with actual or estimated start and stop dates should 
be obtained and recorded in the source documents and the concomitant 
medication CRF, including: 
 
 
All prescription medications, including medications taken for the 

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treatment or prophylaxis of opportunistic infections. 
 
Non-prescription medications. 
 
Alternative therapies and/or dietary supplements. 
 
Allergies to any medications and their formulations must be 
documented. 
 
6.3.4  
Concomitant Medications 
 
At annual study visits concomitant medications of interest taken since the 
last visit will be recorded in the source documentation and entered into 
the concomitant medication log CRF. 
 
6.3.5  
ARV Modifications 
 
All modifications of ART, including initiation of ART, will be recorded on 
the CRF’s at the 3 month data extractions: including initial doses, patient-
initiated interruptions, modifications, and permanent discontinuations.  
ART will also be reviewed and confirmed at the annual study visits. 
 
 
 
 
6.3.6 
Clinical Assessments 
 
 
 
Height and Weight 
 
Height and weight should be documented at study entry and weight 
documented at annual visits. 
 
 
 
 
 
Treatment-Limiting Toxicity and Diagnoses  
 
The following should be recorded on the CRFs at the annual study visits, 
and upon reaching the primary endpoint of LTFU (if possible): AIDS-
defining events, ART-limiting toxicity, CV events or non-AIDS-related 
malignancies, STI diagnoses, new medical conditions and death.  The 
source document must include date of diagnosis and date of resolution. 
 
6.3.7  
Immunologic and Virologic Studies 
 
 
 
Nadir CD4+ T-Cell Count 
 
 
 
The subject’s prior nadir CD4+ cell count (absolute value and date) should 
be documented during screening and, when possible, a copy of nadir 
CD4+ cell count report should be included in the source document. If this 
documentation is not available, then subject recollection will suffice. For 

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Subjects who do not know the exact nadir value and for whom there is no 
source documentation, then recall of the categorical nadir (e.g., < 50, < 
100, < 200 cells/mm3) will suffice. 
 
 
 
CD4/CD8 and HIV-1 RNA 
 
At baseline, at all annual study visits, and upon reaching the primary 
study endpoint (if possible), a CD4/CD8 count and percentage and HIV-1 
RNA will be recorded.  The results may be obtained via chart extraction, if 
available from a CLIA-certified laboratory within 60 days of the study 
visit.  If a result is not available within a 60 day window, it will be drawn 
at the study visit. 
To avoid the need for extra blood draws, efforts will be made, via 
communication with the Primary Care Provider, to have the patient’s 
routine primary care blood draws occur within the 60 day window of the 
annual study visits.    
  
6.3.8  
 Antiretroviral resistance testing 
 
If patients have had an antiretroviral resistance test during routine care, 
that data will be collected via chart abstraction.   
 
6.3.9  
Stored Samples 
 
Stored plasma will be collected at study entry, the annual study visits, 
and upon reaching the primary study endpoint (if possible).  Specimen 
collection will be encouraged but not mandated. Specimens will be 
stored at the site’s local laboratory and batched shipped to the central 
laboratory (UCSD) after completion of the study. 
 
 
 
Blood volume for stored plasma: 15mL 
 
6.4 End of Study Assessment 
 
6.41 
At end of study subjects will be asked (in person or by phone) to  
 
 
complete a short questionnaire assessing the  subjects’ experiences over  
 
 
the course of the study. Subjects in the intervention will be asked  
 
 
specifically about the different components of the intervention and about  
 
 
other aspects of care that may impact their retention in care. Subjects in  
 
 
the standard of care arm will be asked about aspects of care that may  
impact retention in care.  The survey will be administered to patients 
who verbally consent to participate. No personal health identifying 

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information will be collected as part of this survey. 
 
 
 
 7.0 CLINICAL MANAGEMENT ISSUES 
 
7.1 Toxicity 
 
No toxicities are anticipated as no treatment or invasive procedures are being performed as 
part of this study. 
 
 
8.0 CRITERIA FOR EARLY TERMINATION 
 
8.1 Criteria for Study Subject Discontinuation  
 
8.1.1  
Pregnancy or initiation of breastfeeding during the study.  
 
8.1.2  
Subject request to withdraw participation. 
 
8.1.3 
Primary care provider request for subject withdrawal based on the 
provider’s belief that study participation is no longer in subject’s best 
interest. 
 
8.1.4 
Medical provider belief that the patient has life threatening clinical 
condition. 
 
8.1.5   
By the discretion of the site IRB, CCTG, or investigator. 
 
8.1.6 
 
The patient is found to be incarcerated at the time of reaching the 
primary endpoint. 
 
9.0 STATISTICAL CONSIDERATIONS 
 
This section briefly describes the planned statistical analysis. The Statistical Analysis Plan (SAP) 
provides details. If the language in this section differs from the language in the SAP, the SAP 
takes precedence. 
 
9.1 General Design Issues 
 
This is a 48-week, un-blinded, 2-arm, randomized (1:1) controlled clinical trial. 
 
9.2 Endpoints 
 

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Primary Outcome:  The CCTG 594 primary outcome is “time to LTFU” defined as the time from 
baseline visit to meeting the primary endpoint (LTFU defined as: no visit with a prescribing 
provider for more than 180 days). 
 
9.3 Randomization and Stratification 
 
 
Once eligibility and consent are confirmed and the baseline survey is completed, randomization 
will occur using the web-based CFAR BIT data management system. Participants will be 
randomized (1:1) to either the ALERT Enhanced Retention Intervention Arm or the SOC Arm by 
the study coordinator or ALERT specialist.   
 
We will stratify randomization by whether the patient is a new HIV diagnosis or a prior 
diagnosis returning to care and by HIV primary care clinic site.   
 
9.4 Sample Size and Accrual 
 
 
9.4.1  
Power and Sample Size Justification 
 
The primary outcome for this study is to compare the time to LTFU.  A 
secondary outcome is time to initiation of ART.  Sample size calculations 
were based on a two-sided, two-sample log-rank test to compare the 
differences in time to the primary endpoint proportions between the 
intervention arm and the standard of care arm. 
 
Since attrition is a component of the composite endpoint, attrition rates are not used as an 
adjustment in the power calculations. Assuming 150 subjects per group in each of the two 
groups (for a total of 300 subjects), we have 
87% power to detect a difference of 15%, 
assuming a time without a composite 
endpoint rate of 70% in SOC arm and that the 
intervention arm will increase the time 
without an endpoint (to a rate to 85%). This 
corresponds to a hazard ratio of 2:19. Table 5 
shows other possible standard of care rates 
between arms (and hazard ratios), and 
corresponding statistical power. The 
calculations assume that the hazard rates are 
proportional. 
 
 
 
9.5 Monitoring 
Composite 
rate without 
Endpoint in 
SOC (%)
Composite rate 
without 
Endpoint in 
Intervention 
(%)
Corresponding 
Hazard Ratio 
(HR) 
Statistical 
Power (%)
65
80
1.93
82
65
85
2.65
97
70
85
2.19
87
75
87.5
2.15
78
75
90
2.73
92
80
92.5
2.86
87
80
95
4.35
97
Table 5: Power based on a two-sided, log-rank test with 
alpha=0.05 and N=150 per arm (total N = 300)

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Monitoring will be conducted monthly by the core protocol team to assess for accrual and data 
completeness.  
 
9.6 Analyses 
 
9.6.1  
Statistical Analysis Plan 
 
In general, analyses will incorporate the intent-to-treat principle, namely, 
all randomized participants will be included in the analysis. The primary 
analysis compares the ALERT Intervention to the SOC arm.  For all 
secondary analyses of interest, no adjustments for multiple comparisons 
will be made, and a p-value of 0.05 will be considered statistically 
significant.  Demographic and baseline measurement variables will be 
summarized via standard descriptive statistics. 
 
 
9.6.2   
Analysis of Primary Outcome 
 
A survival analysis of “time to LTFU” will be conducted. LTFU is defined as 
no visit with a prescribing HIV provider in the last 180 days. Time-to-LTFU 
will be calculated as total days between the first visit and the date when 
the participant reaches the definition of LTFU.   
For example, a subject has his first visit on Jan 1, 2013, and another visit 
on Mar 1, 2013. If the subject does not have any visits thereafter, or does 
not have any visits until >180 days later, the subject will be counted as 
reaching the primary endpoint of LTFU. In this case, the subject would be 
LTFU if no visit occurred before Aug 27, 2013, (which is 180 days past Mar 
1st). The “time-to-LTFU” will be the time period between Jan 1, 2013 and 
Aug 27, 2013. 
 
At the end of the study, patients who have not reached the primary 
endpoint will be censored at the time of their last quarterly data 
extraction. 
 
Patients who meet the primary endpoint and are found to be incarcerated 
will be removed from the study and censored effective at the time of their 
incarceration. Those who are incarcerated but return to care upon release, 
prior to reaching a primary endpoint, will be allowed to remain in study.  
Patients who change care provider to an external health facility (such as a 
different clinic system or a nursing facility) will be assessed for their 
current engagement in care; those who have completed a clinic visit with 
a prescribing clinician within the 180 days will be considered engaged in 

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care, and will not be considered LTFU.  If possible, these patients will 
continue to come in for annual study visits. 
 
The null hypothesis is that the median time-to-LTFU estimated using the 
Kaplan-Meier method will be identical in both groups. The log-rank test 
will be used to test the null hypothesis against the alternate hypothesis 
that the median time-to-LTFU is not the same between the groups.  
 
In addition, to assess the factors associated with time-to-LTFU, Cox 
regression models will be performed on two subgroups, looking at each 
arm separately. The model will have time to LTFU as the outcome, 
baseline variables such as demographic, socioeconomic, psychosocial 
factors, risk behavior, substance use and psychiatric illness as predictors. 
 
Randomization will be stratified by clinic site and whether the subject is 
newly diagnosed or returning to care.  A total of 300 subjects (150 per 
arm) will be randomized and followed for a minimum of 48 weeks. SOC 
will be the clinic standard.  
 
 
9.6.3   
Analysis of Secondary Outcomes 
 
Main Secondary Outcome:  The CCTG 594 secondary outcome is time to 
initiation of ART.  A survival analysis of time to initiation of ART will be 
conducted. Time to initiation of ART will be calculated as total days 
between the first visit to the ART start date. For those participants who 
do not start ART, the time to initiation of ART will be censored to the 
participant's last visit date. 
 
The NULL hypothesis is that the median time to initiation of ART 
estimated using the Kaplan-Meier method will be identical in both groups. 
The log-rank test will be used to test the null hypothesis against the 
alternate hypothesis that the median time to initiation of ART is not the 
same between the groups.  
 
In addition, to assess the factors associated with time to initiation of ART, 
Cox regression models will be performed on two subgroups, looking at 
each arm separately. The model will have time to initiation of ART as the 
outcome, baseline variables such as demographic, socioeconomic, 
psychosocial factors, risk behavior, substance use and psychiatric illness 
as predictors. 
 
 
9.6.4   
Other Secondary Analyses 

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Descriptive analyses will be conducted for all the secondary analyses 
including comparisons between randomized groups on the following 
measures: 
 
 
Baseline and follow-up scores on HIV and health literacy 
assessments, disclosure rates, adherence, and measures of self-
efficacy 
 
Number of primary care visits per year 
 
HIV RNA < 50 and <200 copies/mL at years 1 and 2  
 
CD4 cell counts and changes from baseline in CD4 at years 1 
through 2 
 
Scores on Beck Depression Index 
 
Substance use   
 
HIV high-risk transmission behaviors   
 
Time to AIDS diagnosis or death 
 
Reasons eligible patients decline study participation 
 
For patients who meet the primary endpoint (LTFU) but subsequently 
return to care, secondary analyses will measure the proportion returning 
in the intervention vs. SOC arm and the time between their last and 
return visit with a prescribing provider. 
 
Fisher's exact test will be used for categorical variables; T-test (or 
Wilcoxon Rank Sum test, if parametric assumptions fail) will be used for 
continuous variables.  
 
10.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
10.1 Records to be kept 
 
Case report forms (CRF’s) will be provided for each subject. Subjects must not be identified by 
name on any CRF’s. Subjects will be identified by the PID provided by the CCTG Data Unit upon 
registration and the linkage to the PID will be kept in paper copy only in a locked cabinet in a 
secure office at the study sites available only to the site investigators. Surveys performed 
electronically will be automatically stored in the electronic database secured by the CFAR BIT 
group for the CCTG. 
 
The contact information collected by the ALERT specialist will be collected on a paper form. This 
will be stored in a secured locked file cabinet within a locked office at the AVRC. 
  
10.2 Role of Data Management 

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10.2.1 
Instructions concerning the recording of study data on CRF’s will be 
provided by the CCTG Data Unit. 
 
 
10.2.2 
It is the responsibility of the CCTG Data Unit to assure the quality of 
computerized data for this study. 
 
 
10.3 Clinical Site Monitoring and Record Availability 
 
 
10.3.1 
Site monitors provided by the CCTG will visit participating clinical 
research sites to review the individual subject records, including consent 
forms, CRF’s, supporting data, laboratory specimen records, and medical 
records (physicians’ progress notes, nurses’ notes, individuals’ hospital 
charts), to ensure protection of study subjects, compliance with the 
protocol, and accuracy and completeness of records. The monitors also 
will inspect sites’ regulatory files to ensure that regulatory requirements 
are being followed.  
 
With their permission, consented participants receiving one of the five 
retention modules may be audio recorded as part of the quality 
improvement process related to the ALERT Specialist. The audio 
recording will not have any participant related identification. This 
recording will be securely disposed and not used directly for research 
purposes.    
 
 
10.3.2 
The investigator will make study documents (e.g., consent forms and 
CRF’s) and pertinent hospital or clinic records readily available for 
inspection by the local IRB or the site monitors. 
 
10.4 Serious Adverse Experience (SAE) Reporting 
 
Serious adverse events are not expected in this study. All serious adverse experiences must be 
documented on the Serious Adverse Experience (SAE) Reporting Form within 5 working days of 
site awareness of the event and submitted to the CCTG Data Unit. 
 
11.0 HUMAN SUBJECTS 
 
11.1 IRB Review and Informed Consent 
 
 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for the oversight of the 

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study. A signed consent form will be obtained from the subject. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the subject. 
 
Patients who meet the inclusion and exclusion criteria who decline to participate in the 
Engagement and Retention in Care for HIV+ study will be offered a refusal survey. The refusal 
survey will be administered to patients who verbally consent to participate in the refusal survey. 
 
11.2 Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
stripped of any patient identifiers (name, birthdate, medical record number) and identified by 
the coded PID only to maintain subject confidentiality. All records will be kept locked. All 
computer entry and networking programs will be done with coded numbers only and analyzed 
centrally without any possibility of linking subject identity with subject data. Clinical 
information will not be released without written permission of the subject, except as necessary 
for monitoring by IRB and governmental agencies. 
 
 
11.3 Study Discontinuation 
 
The study may be discontinued at any time by the IRB or other government agencies as part of 
their duties to ensure that research subjects are protected. 
 
12.0 PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by CCTG policies.  
 
13.0 BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and the National Institutes of Health. 
 
All infectious specimens will be transported using packaging mandated in the Federal Code of 
Regulations, CDC 42 CFR Part 72. Please also refer to individual carrier guidelines, e.g., FedEx, 
Airborne, for specific instructions. 
 
 
 
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