Effects of 12-weeks of High-intensity Resistance Aerobic Circuit Exercise Training on Epigenetic Aging and Inflammation in Older HIV-infected Veterans
Phase: NA
Conditions: HIV Infection
Sponsor: VA Office of Research and Development

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Research Protocol
EdϬϰϭϬϯϱϵϯ 
Title: 
Effects of 12-weeks of High-intensity Resistance Aerobic Circuit Exercise Training on 
Epigenetic Aging and Inflammation in Older HIV-infected Veterans 
Sub-title: 
Functional Interval Training for Veterans Exercising through Telehealth (FIT VET) 
Principal Investigators (PI) 
Kris Ann Oursler, MD 
Salem VAMC site PI 
Alice Ryan, PhD  
Baltimore VAMC site PI 
Vince Marconi, MD 
Atlanta VAMC site PI 
Funding 
VA Office of Research and Development (ORD) 
Rehabilitation Research and Development 
I01 RX002790 (Oursler/Ryan/Marconi) 
Version 1.8 
Approval Date: 2-10-23 

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Table of Contents  
1 
BACKGROUND 
1.1 SUMMARY AND STUDY DESIGN 
1.2 RATIONALE AND SIGNIFICANCE 
1.3 HYPOTHESIS AND STUDY AIMS 
 
2 
STUDY STRUCTURE AND GOVERNANCE  
 
2.1 
OVERVIEW 
 
2.2 
COMMUNICATION PLAN 
 
 
2.2.a 
Roles and Responsibilities 
 
 
2.2.b 
Investigators 
2.2.c 
Staff Coordination and Training 
 
2.3 
DATA HANDLING AND ANALYSIS 
 
2.3.a 
Data Management 
 
 
2.3.b 
Data Entry 
 
 
2.3.c 
Data Storage and Access 
 
 
2.3.d 
Data Security and Confidentiality 
 
 
2.3.e 
Statistical Plan 
 
 
2.3.f 
Data Sharing and Publications 
 
 
2.3.g 
Data Safety Monitoring Plan and Reporting 
 
3 
STUDY METHODS 
 
3.1 
STUDY DESIGN 
 
3.2 
COORDINATING CENTER AT THE SALEM VAMC 
 
 
3.2.a 
Exercise Intervention 
 
 
3.2.b 
Randomization 
 
3.3 
ENROLLMENT SITES: ATLANTA VAMC (AVAMC) AND BALTIMORE VAMC (BVAMC) 
 
 
 
3.3.a 
Participant Enrollment: Recruitment, Informed Consent, and Eligibility 
 
 
3.3.b 
Testing Procedures at Enrollment Sites 
 
 
3.3.c 
Risks and Benefits of Procedures at Enrollment Sites 
 
 
3.3.d 
Measures to Minimize Risk 
 
 
3.3.e 
Benefits 
 
 
3.3.f 
Costs/Compensation 
 
 
 
 
 
 

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1. 
BACKGROUND 
1.1 
Summary and Study Design 
The goal of the study is to provide a high-intensity exercise program for older Veterans that can 
be widely disseminated and attenuates processes underlying aging. The study is a randomized trial of 
12-weeks of high-intensity functional circuit exercise that will be broadcasted from the Salem VAMC to 
older Veterans living with HIV in the Atlanta and Baltimore VAMCs. Our primary objective is to 
determine the effect of VTEL exercise compared to sedentary controls on cardiorespiratory fitness, 
anaerobic threshold, and O2pulse based on gas exchange at peak exercise (Aim 1) in addition to 
sarcopenia and frailty (Aim 2). We also will investigate the effect of VTEL exercise on DNA methylation as 
a biomarker of advanced aging and determine correlates with biomarkers of systemic inflammation (Aim 
3). The sedentary control group will be offered the 12-week exercise training and follow-up testing in a 
delayed entry design to ensure equity of the benefits of exercise to all participants.  
 
1.2 
Rationale and Significance  
Treated HIV infection is a chronic disease with numerous elements of biological aging and age-
related conditions that are advanced or accelerated.1–4 Not surprisingly, adults living with HIV (HIV+ 
adults) have an increased risk of disability with reduced cardiorespiratory fitness5 and increased 
sarcopenia6. The VHA is the largest U.S. HIV health provider with 64% of these Veterans 50+ years of 
age.7 Effective and feasible exercise rehabilitation programs are needed to prevent widespread disability 
in these Veterans. Our findings and the work of others support the argument that higher intensity 
exercise may be needed to reverse the putative mechanisms of aging.8–11 Our goal is to provide a high-
intensity exercise program for older Veterans that can be widely disseminated and attenuates processes 
underlying aging.   
Effective strategies for high-intensity exercise in older adults remain a challenge.12 Circuit 
exercise, which involves quick transitions between exercises, is a high-intensity training approach that 
can increase cardiorespiratory fitness (VO2peak) and strength in adults 65+ years of age13,14 but has yet 
to be tested in HIV+ adults. At the Salem and Baltimore VA Medical Centers (VAMCs), Veterans 65+ 
years of age participate in a center-based exercise program, Gerofit, that increases endurance and 
strength.15–17 We recently converted Gerofit into video telehealth (VTEL) circuit exercise classes that are 
functional (no stationary equipment), yet improve endurance and strength. The objective of this project 
is to adapt our center-based high-intensity aerobic (AEX) and resistance training (RT) intervention in 
older HIV+ Veterans into a VTEL-delivered high-intensity circuit exercise program that has the potential 
for large-scale implementation into VAMCs nationwide.   
With increasing age, epigenetic alterations occur that affect transcription in reproducible 
patterns of DNA methylation (DNAm).18,19 DNAm Age is an estimate of epigenetic age based on 353 
methylation sites which Horvath derived and validated in diverse populations and multiple tissues.20 
DNAm Age is expressed in units of years that can be compared to chronologic age, thus providing a 
concrete measure of advanced aging. Recent molecular studies support DNAm Age as a comprehensive 
biomarker of advanced aging.21 We and others found that HIV+ adults have increased DNAm Age 
compared to age-matched adults without HIV.22,23 In adults without HIV increased DNAm Age is 
associated with physical inactivity,24,25 weakness25 and frailty.26 Our preliminary data show that DNAm 
Age correlates with the VACS Index,27 a measure of frailty in HIV+ adults. However, the impact of 
exercise training on DNAm Age has yet to be determined in any patient population. 
In observational studies of HIV+ adults, systemic inflammation independently predicts 
cardiovascular events,28 sarcopenia, and frailty.29 However, the anti-inflammatory response to exercise 
varies in HIV+ adults, likely affected by comorbidity and lifestyle factors.30–33 Methylation profiles in 
candidate genes have been identified that are associated independently with aging phenotypes (age-
related diseases, frailty)34 and lifestyle factors (smoking, physical activity).35,36 Many of these candidate 

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genes encode pro-inflammatory cytokines.37 Further, randomized exercise trials demonstrate epigenetic 
changes that downregulate pro-inflammatory cytokines.38–41 Significant methylation changes in DNA 
isolated from blood leukocytes can occur after acute exercise42 and only 8 weeks of training.43  Yet, the 
effect of exercise on methylation in HIV+ adults is unknown.  
This study leverages our exercise training experience in HIV and VTEL, availability of 3,000 HIV+ 
Veterans at Atlanta and Baltimore VAMCs, and the VA VTEL infrastructure.  Results will impact the fields 
of exercise rehabilitation, HIV, and aging and can be rapidly implemented using existing resources. 
Exercise-mediated changes to methylation provide a pre-clinical benchmark that demonstrate anti-aging 
effects of exercise. Epigenetic driven exercise strategies could play a valuable role in precision medicine. 
 
1.3 
Hypothesis and Study Aims 
The overarching hypothesis is that VTEL high-intensity functional circuit exercise in older HIV+ 
Veterans will improve the advanced aging phenotype and attenuate DNAm epigenetic processes 
underlying aging.  We will explore the use of DNAm Age as an innovative biomarker that can predict 
adaptation to exercise by testing its association with exercise outcomes. Our experimental approach 
includes a 12-week VTEL exercise intervention in 80 older HIV+ Veterans who are randomized to 
exercise or standard of care sedentary control groups with the specific aims: 
 
AIM 1. To determine the effect of VTEL exercise compared to control on:  
1.1 Cardiorespiratory fitness, anaerobic threshold, and O2pulse based on gas exchange at peak 
exercise 
1.2 Sarcopenia defined by the European Working Group on Sarcopenia44 
1.3 Frailty defined by the Fried Phenotype45 and the Veterans Aging Cohort Study (VACS) Index27 
 
AIM 2. To investigate the effect of VTEL exercise on DNAm Age20 as a biomarker of advanced aging 
 
AIM 3. To determine the effect of VTEL exercise on systemic inflammation by measure of: 
3.1 DNA methylation of genes encoding pro-inflammatory cytokines in leukocytes 
(transcriptional regulation) 
3.2 Corresponding systemic levels of pro-inflammatory cytokines IL-6 and IL-18  
(protein expression) 
 
2 
STUDY STRUCTURE AND GOVERNANCE 
 
2.1 
Overview 
The Salem VAMC (SVAMC) will function as the coordinating site under direction of the contact PI 
(Dr. Oursler) for the primary multi-PI Merit award (I01 RX002790, Oursler/Ryan/Marconi). Atlanta 
(AVAMC) and Baltimore (BVAMC) will function as the participant enrollment sites. SVAMC research staff 
will lead the exercise intervention which will be provided by VTEL broadcast to designated telehealth 
rooms located at Atlanta and Baltimore VAMCS which are supervised by local research staff. The study 
responsibilities and activities of each of the three medical centers is summarized in Table 1 below. 
Guidance for each research activity is provided in a single study Manual of Operations which is based on 
the Merit Award and written by the PIs (Oursler/Ryan/Marconi). The purpose of the Manual of 
Operations is to ensure scientific rigor and consistency of study activities across enrollment sites and 
thus attainment of study scientific aims.  The Manual of Operations will refer to a specific Standard 
Operating Procedure (SOP) for each research procedure.  The coordinating site will provide the template 
for each SOP to the enrollment sites. The enrollment sites are responsible for site-specific changes to 
SOPS, e.g., location and local oversight, and obtaining local regulatory approval (IRB and R&D) for 

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conduct of all research activities at their site. The coordinating site is responsible for all data 
management and analysis, and overall scientific integrity of the study.  
 
Table 1. Roles & Responsibilities by Site 
Salem 
Atlanta 
Baltimore 
Recruitment, Consent, and Enrollment 
 
X 
X 
Randomization 
X 
 
 
Baseline and follow-up testing 
 
X 
X 
Exercise intervention 
X 
 
 
Data collection 
 
X 
X 
Data management and analysis 
X 
 
 
Blood testing and banking for future testing  
 
X 
X 
 
2.2 
Communication Plan 
 
2.2.a 
Roles and Responsibilities 
Drs. Oursler, Ryan, and Marconi will provide overall scientific leadership for this study and are 
ultimately responsible for coordinating investigations and activities, for ensuring integrity of the 
scientific work, and for monitoring budgetary expenditures. They will share administrative 
responsibilities for the scientific management of this project and meeting the requirements of all 
regulatory boards (Institutional Review Boards and Research and Development Committees at Atlanta, 
Baltimore, and Salem VAMCs).  As the contact PI of the Merit Award, Dr. Oursler will be responsible for: 
a) meeting study benchmarks; b) coordination of data collection and quality assurance; c) interpretation 
of data and data analysis; and d) preparation of manuscripts, presentations, and progress reports.  Dr. 
Oursler will have a primary role in conduct of the VTEL exercise intervention, which will be broadcast 
from the Salem VAMC. She will supervise all Salem VAMC study staff. Dr. Marconi will be the site PI at 
the Atlanta VAMC (i.e., PI on the Atlanta VAMC IRB protocol). He will have the primary role of 
participant recruitment, retention, completion of planned testing, and data collection at the Atlanta 
VAMC.  He will supervise the study staff at the Atlanta VAMC. He will also facilitate collaboration with 
Atlanta VAMC co-investigators and oversee laboratory analyses conducted at the Atlanta VAMC, 
including sample collection, handling, processing, storage and assays. Dr. Ryan will be the site PI at the 
Baltimore VAMC (i.e., PI on the Baltimore VAMC IRB protocol). Dr. Ryan will have the primary role of 
participant recruitment, retention, completion of planned testing, and data collection at the Baltimore 
VAMC.  Of note, since Dr. Oursler’s move to the Salem VAMC, Dr. Ryan has been functioning in this 
capacity for their RR&D Merit Award (I01 RX000667, Oursler/Ryan), which includes Baltimore site 
participants in addition to those enrolled at the Salem VAMC.  She will supervise the study staff at the 
Baltimore VAMC. She will oversee laboratory analyses conducted at the Baltimore VAMC, including 
sample collection, handling, processing, storage and assay of biomarkers, and shipping of samples to the 
DNA methylation laboratory in Atlanta.   
 
2.2.b 
Investigators 
To ensure close communication, Drs. Oursler, Ryan, and Marconi will have standing scheduled 
conference calls which may also include each site’s research coordinator. During the initial study 
implementation period (first 3-6 months), calls will occur weekly and then as needed. Monthly 
teleconferences will occur using the VTEL research rooms throughout the 4- year study period and will 
include all PI’s and key staff. The purpose of the monthly VTEL meetings will be to monitor study 
benchmarks and for ongoing problem solving. The research team will review any important revisions to 
procedures and ensure that protocol fidelity is maintained across all sites. Drs. Oursler, Ryan, and 

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Marconi will have at least one in-person meeting annually to discuss plans for data analysis, 
presentations, publications, and future grant applications. Collaborators will be included. Support for 
this travel is included in the budget. Dr. Oursler already routinely travels to Baltimore to meet with Dr. 
Ryan and other collaborators.  Drs. Oursler and Marconi will continue to participate in monthly VACS-
related conference calls, including the steering committee and the Physical Function Working Group 
calls. In the unlikely event that conflict would arise related to the current proposal, Drs. Oursler, Ryan, 
and Marconi have several mutual resources and colleagues in the VACS and Gerofit networks. These 
individuals would help resolve any disputes related to this project.   
 
2.2.c 
Staff Coordination and Training 
Informal regular calls, emails and interactive Skype calls (shared computer screen) will occur 
among the research staff in addition to the formal monthly research team meetings. The program 
coordinator will be available daily for the research coordinators and will also facilitate communication 
with the exercise physiologist and data manager. As is currently routine for Dr. Oursler’s research team, 
the program coordinator will meet regularly with the data manager to discuss QA/QC issues.  Dr. Oursler 
will meet weekly with the exercise physiologist to ensure intervention fidelity and discuss any safety 
issues. Dr. Oursler and the program coordinator meet daily. Similarly, Drs. Marconi and Ryan have 
established research teams at each of their sites with coordinators located within the unit who can meet 
with them daily as needed.   
Coordination of study activities across the three sites will be ensured by using experienced 
research personnel with well-defined roles, as summarized in Table 2 below. All the research staff 
involved in the research will also fulfill the VA and NIH guidelines for ethical conduct of research and 
good clinical practice. Investigators and study staff will receive ongoing training in research ethics and 
good clinical practice to fulfill all requirements of the VA and local policy. A site visit will be performed 
by Dr. Oursler and the program coordinator during start-up, and as needed during the project, to 
provide training on the manual of operations and standard operation procedures.  These project-related 
documents as well as the case report forms (CRFs) will be located on the study’s network research folder 
and available at all time to all research staff. The program coordinator and data manager will provide 
ongoing education to the enrollment sites as part of their routine duties at Salem. 
 
Table 2. Research Staff for Project  
Title/role 
Location and effort 
Description 
Research coordinator 
Atlanta VAMC (100%) 
Responsible for the daily management of the 
study at the enrollment site which includes: 1) 
recruitment and screening of participants; 2) 
providing informed consent; 3) scheduling all 
testing and training visits; 4) completion of case 
report forms; 5) management of participant 
reimbursements; 6) maintenance of recruitment 
and retention statistics; 7) reporting and 
correspondence to regulatory and oversight 
committees; 8) maintenance of the regulatory 
study binder and participant research folders; 9) 
performing quality assurance of all study 
activities in coordination with the data manager. 
Research coordinator 
Baltimore VAMC (100%) 
Program coordinator 
Salem VAMC (50%) 
Responsible for overall oversight of the project 
which includes: 1) monitoring numbers for 
recruitment, enrollment, and completion; 2) 

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maintenance of current Manual of Operations; 
3) providing template SOPs and CRFs to 
enrollment sites; 4) coordinating calls and 
meetings; 5) conducting audits of CRFs and 
protocol deviations to assess and correct 
inconsistencies between sites and coordinators; 
6) reporting and correspondence to Salem 
VAMC regulatory committees; 7) maintenance 
of the Salem protocol regulatory study binder 
Exercise physiologist  
Salem VAMC (50%) 
1) conduct VTEL exercise per protocol; 2) 
instruct and supervise participants during all 
exercise sessions, including maintenance of 
exercise training logs and HR data; 3) coordinate 
VTEL classes with staff at AVAMC and BVAMC 
Data manager 
Salem VAMC (25%) 
1) oversee data collection and entry, including 
data QA/QC; 2) design and maintain databases 
located on Salem VAMC server and VINCI 
(REDCAP); 3) conduct data analysis and generate 
tables and figures  
 
2.3 
Data Handling and Analysis 
The project contact PI (Oursler) is responsible for the accuracy, completeness, and timeliness of 
all data management and analysis. At the enrollment sites, the Atlanta site PI (Marconi) and Baltimore 
site PI (Ryan) are responsible for their site’s data collection using the SOPs and CRFs provided by the 
Salem coordinating site.  Data will be access and stored on two VA computer servers: 1) the Salem 
VAMC network server (“p drive”), and 2) the national VHA server located in Austin, Texas called VA 
Informatics and Computing Infrastructure (VINCI). All of the data collected throughout the study will be 
stored in a secure and access-controlled database. The database will be housed and maintained by 
Salem VAMC. The Atlanta and Baltimore VAMCs will contribute to the database. 
 
2.3.a 
Data Management 
Paper forms for use as data collection will be derived from the case report forms (CRFs) to 
record and maintain data for each participant enrolled in the study. All data collection forms should be 
completed in a neat, legible manner to ensure accurate interpretation of data.  Data reported in the CRF 
derived from data collection forms or source documents should be consistent or any discrepancies 
should be explained.  Data from paper CRFs will be entered into VINCI using VA REDCap (detailed 
below). 
Source data that is generated directly as an electronic file or print out will be stored in a shared 
VA network folder with access only to authorized research staff. The shared folder will be located on a 
Salem VAMC network folder (P:\GeriatricResearchCollaboration) that is backed up, has limited access, 
and is protected by the VA firewall.  Individuals will be coded with study IDs in the research database. A 
separate file with PHI, PII, and the study key code will be kept in a different location in a password 
protected file. Paper copies with PHI (e.g., ICF, HIPAA) are stored in a locked drawer separately. Paper 
case report forms will be coded with the study ID. Any publications or presentations will not use PHI.  
Research records will be retained in accordance with the VA records control schedule.   Access to 
research study data will be removed for study personnel when they are no longer part of the research 
team.  Results will be presented and published in aggregate format unless separate permission is 
obtained by the Veteran. Publications will be reported per VHA policy.  PHI will not be shared with any 

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non-VA entity.  For any Information Security or Privacy incidents, suspected or actual, the ACOS for 
Research, Privacy Officer and Information Security Officer will be notified within 1 hour of discovery. 
 
2.3.b 
Data Entry 
Only authorized VA network users are permitted to use VA REDCap. For purposes of data entry, 
research personnel will log into the network-based application from a VA computer and create a 
username and profile. Once they are approved to use the application by REDCap, the study’s data 
manager will grant individual access to the project’s folder within REDCap. Research personnel will enter 
data into the REDCap study folder using the case report forms which will not include PII or PHI. REDCap 
(Research Electronic Data Capture) is a software toolset and workflow methodology for electronic 
collection and management of research data. REDCap projects rely on a thorough study-specific data 
dictionary defined in an iterative self-documenting process.  REDCap was developed specifically around 
HIPAA-Security guidelines. In addition to VAMCs, REDCap currently supports 240+ academic/non-profit 
consortium partners on six continents and over 26,000 research end-users (www.project-redcap.org).  
Specific for VA research, VA REDCap servers (where data are housed) reside on VA Informatics and 
Computing Infrastructure (VINCI) which is physically located at the VA Austin Information Technology 
Center (AITC) in Austin, Texas.  Thus, VA REDCap is accessible through the VA intranet only. 
 
2.3.c 
Data Storage and Access 
All data storage will be compliant with the guidelines set forth by Veterans Health 
Administration (VHA) Handbook 1200.12, Use of Data and Data Repositories in VHA Research, and all 
other applicable VA and VHA policies and regulations. Study data will be kept in accordance with the 
Department of Veterans Affairs Record Control Schedule 10-1 (RCS 10-1). Data will be stored on and 
accessed from study-specific folders located on two different VA computer servers: 1) the Salem VAMC 
network server (“p drive”), and 2) the national VHA server located in Austin, Texas called VA Informatics 
and Computing Infrastructure (VINCI). 
The following information was provided by VINCI Central at vaww.vinci.med.va.gov. The VA 
Informatics and Computing Infrastructure (VINCI) is a major informatics initiative of the Department of 
Veterans Affairs (VA) that provides a secure, central analytic platform for performing research and 
supporting clinical operations activities. It is a partnership between the VA Office of Information 
Technology (OI&T) and the Veterans Health Administration Office of Research and Development (VHA 
ORD). VINCI includes a cluster of servers for securely hosting suites of databases integrated from select 
national VA data sources (including CDW). VINCI servers for data, software applications, and virtual 
sessions are physically located at the VA Austin Information Technology Center (AITC), 1615 Woodward 
St., Austin, TX 78772-0001. This secure enclave with 105 high-performance servers and 1.5 petabytes of 
high-speed data storage has multiple layers of security and disaster recovery to prevent data loss. To 
ensure the protection of Veteran data, VINCI maintains compliance with the guidelines set forth by 
Veterans Health Administration (VHA) Handbook 1200.12, Use of Data and Data Repositories in VHA 
Research, and all other applicable VA and VHA policies and regulations. In addition, VINCI has undergone 
all security certification activities in support of obtaining an Authorization to Operate (ATO). Access to 
VINCI resources are approved in accordance with the requirements of National Data Systems (NDS), VHA 
Handbook 1200.12, Use of Data and Data Repositories in VHA Research, and all other applicable VA and 
VHA policies and regulations. All data transferred from VINCI may be audited for compliance. Only study 
team personnel explicitly authorized by the PI will have access to project data. VINCI data managers and 
VA OI&T personnel not under the purview of the study principal investigator control the servers, 
network, processors, firewall and software in the VINCI environment, including access rights granted to 
study personnel. The specific server where the data are stored within the VINCI environment will be 
chosen by VINCI personnel. The server name and location within the Austin Information Technology 

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Center may be changed at any time at the discretion of VINCI personnel. All software used to access 
sensitive patient data, whether provided by VINCI or developed by the study team, will run in virtual 
desktop sessions on VINCI servers within the Austin Information Technology Center. 
Analysis of the nutrition data collected using the 24-hour dietary recall questionnaire will occur 
using the a freely-available, web-based tool developed by NIH that called Automated Self-Administered 
24-hour Dietary Assessment tool (ASA24). Study staff will access the web-based ASA24 system from a VA 
computer and enter each participant’s dietary recall data using only a study ID number and date of the 
assessment.  No PHI will be stored in ASA24. ASA24 provides data analysis options that will produce a 
data output in Excel or SAS file format. The data output is downloaded directly onto the VA network 
drive. IP addresses are not stored or tracked by the ASA24 system. Data entered are secured at the 
hosting site using industry standard security controls, including firewalls and encryption. All data 
entered into the ASA24 system at the study staff’s computer is encrypted by the internet browser (e.g., 
Internet Explorer) using Secure Socket Layer (SSL) Technology. SSL allows for the authentication of data 
transfer to and from the ASA24 servers from VA computers. Only the research staff and the ASA24 
operations team can access the data for each study. Access is gained through usernames and strong 
passwords. Additional information is available by the National Cancer Institute at 
www.asa24.nci.nhi.gov. 
Only the following will have access to full participant records that include PHI and all research 
data collected: study PIs, Salem VAMC data manger and Salem VAMC program coordinator, 
representatives of the funding agency, and the Institutional Review Boards, or other regulatory 
agencies. If data is shared with other researchers, it will be done in such a way that participants will not 
be identified. Information gathered from this study may be published in abstract or article form in the 
medical literature. However, no participant will be identified by name in any publication. When study 
personnel are no longer part of the research team, we will amend the data access request to terminate 
that person’s access to all study data and notify the VA Information Security Officer of such action. No 
sensitive patient data will be shared with anyone who does not have a VA appointment. All study team 
personnel with access to sensitive patient data will stay current on required VA information security and 
privacy policy trainings. 
 
2.3.d 
Data Security and Confidentiality 
Beyond the data security measures of VINCI and REDCap discussed above, additional safeguards 
will be in place to allow secure and confidential data sharing between the Salem, Atlanta, and Baltimore 
VAMCs. An experienced data manager will have dedicated effort to ensure all collected data is 
maintained per VA regulations and will manage the data sharing research project folder which is located 
on the Salem VAMC network folder behind the VA firewall with limited access. This project folder will 
allow secure data sharing between the Salem and Atlanta VAMCs; a similar folder system is in place now 
between the Salem VAMC and Baltimore VAMC for conduct of an ongoing collaborative Merit Award 
project. The Salem VAMC network is compliant with FISMA (Federal Information Security Management 
Act) with appropriate security checks and backup systems.  
Protected healthcare information will be obtained during the course of this study. The collection 
of data will be HIPAA compliant under a Full Waiver of Authorization for Salem VAMC, where no 
participants will be enrolled. Atlanta and Baltimore VAMCs will have a partial HIPAA waiver for screening 
of the electronic medical record or local clinical database to identify potential participants. HIPAA and 
written informed consent will be obtained prior to any research procedures.  
Written records will be stored in locked research offices at the VA Medical Centers located in 
Salem, Atlanta, and Baltimore. Some of the results of the research tests performed may be stored in the 
VA electronic medical record (EMR), per local policy. These may include participant enrollment notes, 
documentation of the informed consent process, and electronic scanned copies of the consent forms, 

Page 10 of 31 
 
and DXA. The sensitive information collected will be maintained in accordance with the security 
requirements of 38 CFR Section 1.466, or more stringent requirements, the information will not be re-
disclosed except back to VA; and the information will not identify any individual patient in any report of 
the research, or otherwise disclose patient identities. 
Several provisions will be made to maintain data confidentiality. Unique identifiers will not be 
on any study related forms that contain data collected during the study. A unique study ID will be used 
on all study forms (case report forms (CRFs), test reports, and other study-related information). Only the 
informed consent form, HIPAA, and contact sheet will have protected health information (PHI) and will 
be stored in a separate folder from the research data in a different locked filing cabinet and VA 
computer folder. The list with linkage of study ID to name and SSN will be stored in a specific table, 
password protected and filed separately from the rest of the study data. Only select members of the 
research team will have a password and access to this table.  
Data entered from paper CRFs into the REDCap project folder by staff at enrollment sites is 
securely stored on the national VINCI server, as discussed above. However, it should be noted that this 
data will be identified by study ID and research visit dates only. No PHI will be stored on VINCI. Data that 
is not collected on VINCI will be stored on the Salem VAMC network shared folder. This source data will 
be uploaded as an excel or scanned file directly from computers located in the Baltimore and Atlanta 
VAMCs to the Salem network folder. This data includes: blood sample results, Polar and Garmin heart 
rate data, and printouts from the treadmill test and DXA scan. The linkage table of PHI to study ID or 
specimen ID will be maintained in a separate Salem VAMC network shared folder, and only select 
members of the research team will have the password and access to this table. 
Blood samples will be collected and assayed per the specific aims during the study period at 
laboratories located at the Baltimore and Atlanta VAMCs and Emory University. In addition, blood 
samples will be stored for future testing (banked) at laboratories located at the Baltimore and Atlanta 
VAMCs. All blood specimens will be stored with study ID and code numbers as the only identifiers.  
Results of laboratory assays from the study will be labeled only with study ID and code numbers.  Any 
specimen remaining after testing at the off-site laboratory will be destroyed per written a priori 
agreement with the laboratory director and PIs per VA regulations. Human research protection of all 
blood samples regardless of when blood samples assays are performed is under the prevue of the site 
performing the testing.  
Data from Polar heart rate monitors cannot be analyzed in aggregate without extraction of the 
data from the individual monitors. To do so, data from each individual monitor of participants in the 
VTEL exercise group will be uploaded to the Polar company commercial server using a VA approved USB 
interface and access to a confirmed secure non-VA internet server at each enrollment site. Data on the 
HR monitor has no PHI and is limited to heart rate, year of birth, and study ID number. This information 
will be temporarily stored on the Polar server.  The file with linkage of the study ID number to PHI will 
always remain behind the VA server at all times and is never released to Polar. Therefore, there is no PHI 
in the storage, extraction, and transfer of data from the Polar monitors.  Heart rate data is essential for 
exercise research and there is no available VA system that can perform this function.  
A Garmin Connect web account will be generated by research staff for the participants in the 
delayed entry exercise group. The account, including user ID and password, will not include any element 
of PHI or PII. Individual-level data is limited to heart rate, height, weight, sex and year of birth. For any 
individual over the age of 85, year of birth will be set at 1930. Data from the Garmin activity tracker 
device will be uploaded from the wrist tracker to the Garmin Connect web site via the app installed on 
each participant’s personal cell phone. Location tracking on the Garmin app will NOT be enabled on the 
phone. Data from the Garmin device will be temporarily stored on the Garmin commercial server 
(https://connect.garmin.com/en-US) (TLS 1.2, AES with 256-bit encryption (High); ECDH_P256 with 256 
bit exchange).  The file with linkage of the participant Garmin user ID to PHI will always remain behind 

Page 11 of 31 
 
the VA server at all times and is never released to Garmin. Therefore, there is no PHI/PII in the storage, 
extraction, and transfer of data from the Garmin device, phone app, or web site.  
The metabolic cart that collects gas exchange data and the DXA scan report are paper source 
documents. Participants are identified for both procedures by a study ID with no PHI. Scanned copies of 
these documents will be uploaded by the enrollment site to the Salem network folder. 
All data collection and storage procedures will be approved by each respective VAMC 
Information Security Officer (ISO) and Privacy Officer (PO). Salem VAMC already has procedures and 
approval in place for current exercise studies. 
 
2.3.e 
Statistical Plan 
Phenotypic Outcomes (AIM 1) and Biomarker DNAm Age (AIM 2): We hypothesize that the VTEL high-
intensity circuit exercise intervention will increase cardiorespiratory fitness and decrease sarcopenia and 
frailty (AIM 1) and decrease DNAm Age (AIM 2).  ANOVA models will be used with dependent variables of 
cardiorespiratory fitness (VO2peak, 2-minute step test) and DNAm Age (years). Logistic or multinomial 
models will be used with dependent variables of sarcopenia (present/not present) and frailty (robust/pre-
frail/frail). Secondary analyses will be performed that use the individual components of composite 
outcome as their own dependent variable (e.g., lean mass and strength from sarcopenia). ANCOVA will be 
used to test for between group difference by time (pre/post exercise). Baseline performance and 
demographic and clinical characteristics will be included in models to assess and adjust for known 
potential confounding factors based on our experience with older HIV+ adults. We do not expect 
significant variability or effect from HIV-related factors (e.g., antiretroviral therapy, viral load) since we will 
use our previous established eligibility criteria. We do not anticipate needing to adjust for sex or race since 
each individual will function as their own control. Nutritional analyses of macro and micronutrients will be 
performed to measure any change during the study, and if present, will be tested for within group and 
between group effects. A similar approach will be applied to smoking exposure, which will be quantitated 
at baseline and follow-up testing.  Treatment fidelity will be measured as percent of AEX time at target 
heart and entered in ANOVA models. For future planning, feasibility analyses will include calculation of 
rates for enrollment, retention, and attendance overall and by HIV group.  Aggregate data will be collected 
on adverse events and reasons for lost to follow-up.  
Analyses will include participants who drop out before completion of the 12-week intervention 
period by way of multiple imputation. This intention to treat approach will investigate factors that may 
affect compliance and difficulty with exercise training, including soreness and medical comorbidity. If the 
pattern of missing data is missing completely at random, or simply at random, our multiple imputation 
should eliminate bias due to loss to follow-up. Because the participants will be recruited from clinic-based 
VA cohorts, we will be able to obtain clinical data from participants who drop out of the study, but remain 
in clinical care, to determine if drop-out was related to medical conditions that may influence outcomes. 
Thus, we will be able to estimate bias introduced by loss to follow-up. If there is sufficient information, we 
may be able to model the drop-out process and adjust our analyses for loss to follow-up even if the 
missing data pattern is non-ignorable. If 36 training sessions cannot be completed in 12 weeks, then total 
training time will be tracked, and incorporated into the data analysis. 
 
DNA Methylation (AIM 3): We will examine the change of methylation levels after 12 weeks for each 
candidate marker using ANOVA models. To examine epigenetic association with each outcome, we will fit 
the linear regression model as follows: where Yi is the quantitative outcome measurement, Zi is the vector 
of covariates including age, race, smoking status and leukocyte proportions, and Ei is the candidate 
epigenetic marker. ANCOVA will be used to test for between group difference by time (pre/post exercise). 
The candidate epigenetic markers will involve individual CpG sites previously identified and discussed in 
detail section D4c. We will extend this linear regression model to account for batch/chip effects and 

Page 12 of 31 
 
longitudinal measures using a linear mixed model. We will adjust the significance threshold for multiple 
testing using Bonferroni correction (p<0.05/number of tests). 
 
Sample Size Estimates:  
AIM 1. Paired t-test was used to test for a mean change given a range of correlation between pre and post 
values with assumptions of α= 0.05 and 80% power. (Mean (SD) values for the VO2peak are from our current 
high-intensity AEX + RT trial in HIV+ Veterans (Table 3). Data for 2-minute step test are from our VTEL 
Gerofit exercise program (C3). Values for chair stands are results from a 10-week RT in older men.46 We will 
have 
adequate 
sample size even 
with attrition  
as high as 40% and 
a correlation of 
within 
person 
values as low as 
0.3.  
AIM 2:  Since 
change in DNAm 
Age with exercise training is unknown, we used values from our observational study of 19 male Veterans 
before and after antiretroviral therapy was started.23  We will have adequate sample size even with 
attrition of 28% and a correlation of within person values as low as 0.3. 
AIM 3:  As summarized by Tsai and Bell, epigenetic data generated by EWAS have two additional factors 
that affect power, stability of CpG sites and their variance within a biological sample.47 They performed 
power simulations based on micro-array based datasets (e.g., Illumina 450K) with the assumption that 
disease risk is affected by a single CpG site. Using Wilcoxon signed-rank test for paired study design (one 
sample), 80% power and α <0.05, they generated sample size estimates based on percent methylation 
difference (p.1437).47 Denham reported a 11.6% methylation difference after 4 weeks of AEX in a single 
CpG site in the EGF gene, which also showed decreased mRNA expression.48 On the basis of this 
literature, a sample size of 34 participants is sufficient to find an 11% difference in methylation of a 
relevant candidate gene with exercise.  
 
2.3.f 
Data Sharing and Publication 
Final data sets underlying all publications resulting from the proposed research will be shared 
outside the VA. A Limited Dataset (LDS) will be created and shared pursuant to a Data Use Agreement 
(DUA) appropriately limiting use of the dataset and prohibiting the recipient from identifying or re-
identifying (or taking steps to identify or re-identify) any individual whose data are included in the 
dataset. Data sharing and preservation will enable validation of results and advancing science by 
broadening the value of research data for intra and inter disciplinary developments ultimately benefiting 
the scientific community, industry, and the public at large. 
Publications from this research will be made available to the public through the National Library 
of Medicine PubMed Central website within one year after the date of publication (per guidance on the 
ORD website). 
 
2.3.g 
Data Safety Monitory Plan and Reporting 
  
VA regulatory requirements include a plan for data and safety monitoring (DSMP) for all studies 
greater than minimal risk. The DSMP for this study includes a biannual formal review by Drs. Oursler, 
Marconi, and Ryan of all adverse events and note to files reported by the study coordinators, data 
manager, and exercise physiologist. Additionally, an independent clinical monitor will act in an advisory 
Table 3. Sample Size Estimates by Outcome 
AIM 
Dependent 
Variable 
Pre/ Post Intervention 
Sample Size 
Pre- 
Mean (SD) 
Post- 
Mean (SD) 
correlation pre/post 
0.3 
0.5 
0.7 
1 
VO2peak, L/min 
2.17(0.13) 
2.46(0.14) 
4 
3 
2 
2-min. step test 
67 (18) 
86 (17) 
16 
14 
9 
Chair stands46 
17.8 (5.4) 
25.4 (5.6) 
8 
7 
5 
2 
DNAm Age,yrs23 
62(10.8) 
68.7(10) 
29 
21 
14 

Page 13 of 31 
 
capacity to the PIs to monitor participant safety, evaluate the study progress, and review adverse events 
and any safety issues. This review will include correspondence and logs maintained of all adverse events, 
protocol exceptions and deviations, which are reported to the respective IRB committee per local policy. 
Drs. Oursler, Marconi, and Ryan are readily available to research staff on a daily basis to manage any 
adverse event and are experienced with the target population of older patients with HIV. Dr. Marconi, 
an infectious diseases physician at the Atlanta VAMC, is an experienced clinician investigator who will be 
on site during study activities which occur at the Atlanta VAMC Rehabilitation R&D Center. Dr. Ryan, a 
Research Scientist at the Baltimore VAMC with a doctorate in Exercise Physiology, is experienced with 
conduct of exercise testing and training and will be on site during study activities which occur at the 
Baltimore VA GRECC. The major focus of the DSMP is safety, particularly on expected and unexpected 
adverse events directly attributable to participation in the research; i.e. muscle strain due to exercise. All 
protocols will adhere to good clinical practice guidelines. After review of the adverse events, the PIs will 
review policies and procedures and make recommendations accordingly. If there is a serious unexpected 
adverse event that brings into question the safety of a procedure or of the protocol, the PIs will 
temporarily suspend new enrollment into the protocol and work in concert with the VA Research Office 
and IRB to further evaluate the situation and determine if additional steps are necessary. 
 
On a weekly basis, each site PI is responsible for conducting safety reviews with staff and will be 
available by phone for urgent issues. When unavailable to staff, a designee is indicated. During exercise 
training, ongoing monitoring by the research coordinator is conducted prior to each exercise training 
session that includes vital signs and an established panel of safety questions and is documented on the 
exercise log CRF. The exercise physiologist will also monitor participant’s heart rate and rating of 
perceived exertion (RPE) during the exercise training. If there is an issue, the participant will not 
exercise, and the site PI will be contacted and will evaluate the participant. A participant will be 
discontinued from the study and referred for medical care if any adverse event (AE), inter-current 
illness, or other medical condition or situation occurs such that continued participation in the study 
would not be in the best interest of the participant. Emergency procedures are in place should a 
participant need immediate medical attention during exercise training or testing.  
 
Discontinuation Criteria: 
x 
Lost to follow-up: Missing study visits and cannot be contacted 
x 
Requested withdrawal: Participant requests to discontinue participation 
x 
Death: Also an SAE that is reported to IRB 
x 
Excluded: After study enrollment, development of a medical problem that meets exclusion criteria 
x 
Completed: All study procedures have been performed after the exercise intervention  
 
Minimal reporting requirements for the study are as follows: 
AE/SAEs: All AEs must be graded for severity and relationship to the research procedure or intervention 
(see below) by a licensed clinician (i.e., physician, nurse, nurse practitioner, physician’s assistant) but the 
relationship to the study can only be assessed by a clinician investigator familiar with the protocol.  All 
SAEs will be reported to the site’s local IRB as per VHA Handbook 1058.01 and local policy. 
 
Severity of Event:  All AEs will be assessed by the clinician using the following defined grading system:  
x 
Mild: events require minimal or no treatment and do not interfere with the patient’s daily activities. 
x 
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 

Page 14 of 31 
 
x 
Severe: events interrupt a patient’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating. 
x 
Life-threatening: any adverse drug experience that places the patient or participant, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include 
a reaction that had it occurred in a more severe form, might have caused death. 
 
Serious Adverse Event (SAE)is defined as an AE meeting one of the following conditions, per the 
International Conference on Harmonization (ICH) definitions: 
x 
Results in death during the period of protocol defined surveillance. 
x 
Is life-threatening (defined as a participant at immediate risk of death at the time of the event). 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization during the period of 
protocol defined surveillance. 
x 
Results in congenital anomaly or birth defect. 
x 
Results in a persistent or significant disability/incapacity. 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event 
may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.   
 
Relationship to Study Intervention: The clinician investigator’s assessment of the relationship of an AE to 
study interventions is part of the documentation process, but it is not a factor in determining what is or 
is not reported in the study.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported.  All AEs must have their possible relationship to study intervention assessed using 
the following terms: associated or not associated.  To help assess, the following guidelines are use: 
x 
Associated – The event is temporally related to the participation of the study procedure and no 
other etiology explains the event. 
x 
Not Associated – The event is temporally independent of study procedure and/or the event 
appears to be explained by another etiology. 
 
New Abnormal Clinical Findings from Research Testing: Any medical condition that is present at 
screening will be considered a baseline condition and will not be reported as an AE.  If the severity of 
any pre-existing medical condition increases to a new level of diagnosis during the study period, then it 
will be recorded as an AE. 
 
Unanticipated and Unexpected Events: The terms "unanticipated" and "unexpected" refer to an adverse 
event or problem that is new or greater than previously known in terms of nature, severity, or 
frequency, given the procedures described in protocol-related documents and the characteristics of the 
study population and affects rights, safety or welfare of participants. 
Serious adverse events and serious problems which are UN-anticipated (regardless of relatedness to the 
research) will be reported to the IRB Chair or designee within 5 business days. 
 
Protocol deviation (PD): A PD is any noncompliance with the clinical trial protocol or Good Clinical 
Practice (GCP).  The noncompliance may be either on the part of the participant, the investigator, or the 
study site staff.  As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  It is the responsibility of all sites to use continuous vigilance to identify and 
report deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity.  All deviations must be promptly reported to each site’s 

Page 15 of 31 
 
corresponding IRB. All deviations from the protocol must be addressed in study participant data 
collection forms.  A completed copy of the Protocol Deviation (PD) Form must be maintained in the 
Regulatory File, as well as in the participant’s data collection forms folder/binder.  Protocol deviations 
must be sent to the local IRB per their guidelines.  All research personnel are responsible for knowing 
and adhering to their IRB requirements.  
 
3 
STUDY METHODS 
 
3.1 
Study Design 
This study is a multi-site exercise intervention for Veterans receiving care at the Atlanta and 
Baltimore VAMCs that will randomize approximately 80 participants (40 per site) at these VAMCS, 
herein referred as enrollment sites. The intervention is 12-weeks of high-intensity functional circuit 
exercise performed 3 times weekly in a supervised group setting. Exercise training will be led by an 
exercise physiologist at the Salem VAMC (coordinating site) and broadcast to the enrollment sites. HIV-
infected Veterans 50 years of age and older will be enrolled at the Atlanta and Baltimore VAMCs. Eligible 
participants will be randomized to exercise training (N=40) or control (N=40) groups. All participants will 
undergo baseline testing and follow up testing after 12 weeks at their respective enrollment site. 
Participants in the Control Group will be instructed to maintain their baseline sedentary lifestyle (as 
defined in eligibility criteria) during the 12-week intervention period. After follow-up testing is complete, 
participants in the control group will have the option of completing 12-week exercise training (delayed 
entry exercise) which will be a combined home and center-based exercise program. Pre-post exercise 
testing will be conducted in these participants to gauge individual progress and provide individual 
feedback that is a benefit of study participation, but these results will not be part of the randomized trial 
analyses. 
 
3.2 
Coordinating Center at the Salem VAMC (Research Activities Conducted at SVAMC) 
 
3.2.a 
Exercise Intervention: VTEL Exercise Training 
Exercise Training Description  
The exercise physiologist located at the SVAMC will be responsible for conduct of all exercise training 
under the supervision of the PI.  Exercise training will be delivered by VTEL broadcast from the Salem 
VAMC to participants at the Atlanta VAMC and Baltimore VAMC. In the event that the Salem EP is not 
available to deliver the training, the exercise training can be delivered by another experienced EP 
through a telehealth platform. Research staff at the Atlanta and Baltimore VAMCs will be in the room 
with the participant to help with heart rate monitors and portable exercise equipment, and in the event 
of an emergency.  Rooms will be equipped with steps, hand and ankle weights, dumbbells, chairs, and 
bands. No stationary exercise equipment will be used in either aerobic (AEX) or resistance training (RT).  
The intervention consists of high-intensity circuit exercise training performed 3 times weekly for 12 
weeks in a group setting. Circuit training is an exercise modality consisting of a series of exercises at 
different stations.  
 

Page 16 of 31 
 
Functional Circuit Training Details:   The group exercise training sessions will be performed 3 times 
weekly and last approximately an hour, including warm up (8-10 min.), functional circuit training (48 
min.), and cool-down/stretching (8-10 min.). Our clinical program, Tele-Gerofit, supports the feasibility 
of this design in a small area where each station is not defined necessarily by an area but by available 
equipment.49 Each exercise circuit will consist of one AEX station and three RT stations with minimal rest 
between stations. The AEX will be performed for three minutes. Each RT station will include 1-3 sets of a 
strength exercise that is completed within 3 minutes (min). The total exercise time per circuit is 12 
minutes (3 min. AEX + 9 min. RT (3 x 3 min.)). Heart rate is monitored during the entire circuit with 
targets set for AEX and RT that is analogous to high-intensity interval training. Details are provided 
under exercise intensity. Specific exercises to be used for AEX and RT for each circuit are summarized in 
Table 4. Progression of intensity is performed by increasing the size of the steps (AEX) and number of 
repetitions and weight of dumbbells or hand/ankle weights (RT). In the first week, only 1-2 RT exercise 
set will be performed as the participant becomes acclimated to the exercises for a total of 24-36 
minutes (6-9 mins/circuit). Then participants will advance to three sets per RT exercise for a total of 48 
minutes of high-intensity circuit training.  
Exercise Intensity: To ensure that AEX intensity is met, participants will wear Polar HR monitors (Polar, 
Lake Success NY) with alarm limits set by the exercise physiologist and programmed into the watch by 
enrollment site staff. The AEX protocol will follow exercise interventions protocols that have been 
successful in older HIV+ Veterans. Participants will initially train at 50% heart rate reserve (HRR), 
increasing target HR by 5-10% weekly until 70-80% HRR is reached. Based on our work to date, three 
minutes of AEX per circuit is feasible.  Resistance training (RT) progression will also be based on our prior 
experience with center-based progressive high-intensity RT in HIV+ adults.  This protocol involves initial 
weight lifting of 50-60% 1-RM in two sets of 8 repetitions with progression to 12 repetitions. Then 
training weight is increased by an amount (~10%) that causes the muscle group to fatigue/fail after eight 
repetitions. However, functional RT exercises utilize multiple muscle groups, unlike traditional RT. 
Therefore, we will use the number of repetitions for specific functional RT exercises as the target, based 
on thresholds set by Rikli and Jones. The use of hand and ankle weights and multiple muscle 
engagement will help provide higher 
intensity RT.  Strength exercises will be 
performed until muscle fatigue at three 
stations of the circuit with each strength 
exercise performed quickly.   
 
Treatment Fidelity: The exercise 
physiologist will maintain a training log for 
each exercise session for each participant. 
The log includes the type of each RT 
exercise and number of sets, the type and 
duration of each AEX exercise, and any 
special participant feedback or concern. 
The heart rate will be measured and 
recorded continuously using a chest-strap 
heart rate monitor (Polar Electro Inc., Lake 
Success, NY) and downloaded by the 
enrollment site staff at their site. The exercise physiologist will compile and review weekly HR data on 
the Salem VAMC shared folder to document AEX duration and intensity.  The exercise physiologist will 
meet weekly with Dr. Oursler to ensure interim training targets are met for each participant. In addition, 
Table 4. Circuit Exercises by Modality 
Circuit 
AEX (Target HR) 
RT (8-12 reps) 
1 
Step Ups 
Bicep curls 
Chest Press 
Lateral Shoulder Raise 
2 
Shadow Boxing 
Romanian Dead Lift 
Side Bends 
Calf Raises 
3 
Step Ups 
Squat 
Reverse Wood Chop 
Bent Over Row 
4 
Lateral Side Steps 
Lateral Band Walk 
Triceps Extension 
Wide Pull 
AEX, aerobic exercise; RT, resistance training 

Page 17 of 31 
 
progress and any issues will be discussed on the monthly VTEL conferences with Drs. Oursler (Salem), 
Ryan (Baltimore), and Marconi (Atlanta).   
 
Adherence to Exercise Training Sessions: The intervention is designed as 12-weeks of exercise training 
performed 3 times weekly on Monday, Wednesday, and Friday for a total of 36 sessions. However, due 
to federal holidays, 36 sessions may not be feasible within 12 weeks and so time allowance will be made 
for 36 consecutive sessions to be performed with 100% adherence. Given that occasional missed 
exercise sessions will occur (usually due to travel in our experience), up to 3 additional exercise sessions 
will be offered to allow participants to reach 36 exercise training sessions. This provision minimizes the 
risk of muscle strain and exercise intolerance by allowing sufficient time to reestablish training 
progression and is a standard approach in progressive exercise training trials.  
 
3.2.b 
Randomization 
After baseline testing is complete, eligible participants will be randomized 1:1 to VTEL exercise or 
standard of care control groups.  Randomization will occur in blocks of 2-10 participants at each site. An 
independent statistician will provide an allocation list for each site that will be managed by an individual 
without access to study data or contact with participants. The size of the block may vary by site and 
COVID safety practices.  Block randomization is routinely used in smaller trials to ensure equal 
distribution between groups. In this application, it also serves to adjust the cohort size of each exercise 
group from a minimum of one participant to a maximum of five participants. 
 
3.2.c 
Delayed Entry Exercise for Control Group 
 
Since the start of the study, participants randomized to the standard of care control group have 
had the option of entering an exercise training program after completion of 12-week follow-up testing, 
extending their participation time. This delayed entry exercise program, beyond the RCT design, has 
been provided so that the potential benefits of exercise are available to all participants despite initial 
randomization allocation. In the interest of ensuring that all participants may receive exercise toward 
the end of the award, the delayed entry exercise program will be changed from an identical one in the 
VTEL intervention arm to a hybrid home and center-based program. Since this may affect willingness to 
participate, the change in protocol will be implemented at the initial screening and recruitment of a 
cohort, not active participants.  
 
 
The new delayed entry exercise program leverages advances in commercial physical activity 
trackers which now accurately measure wrist-based heart rate and are validated in older 
adults.50Delayed entry exercise will consist of 12-weeks of home-based exercise that is an individualized 
exercise prescription based on maximum heart rate, like the VTEL exercise group. However, a Garmin 
wrist device (Garmin Vivosmart 5, Garmin International, Inc. Olathe, KS, USA) will be used rather than a 
Polar heart rate band for heart rate monitoring. A Garmin Connect account will be generated by study 
staff which will include a “dummy” email that is not accessible to the participant and has no PHI/PII. The 
participant’s heart rate data from treadmill testing will be entered into each Garmin Connect account to 
define moderate intensity and vigorous intensity based on the same heart rate zones as used by the 
Polar monitors. Participants will be asked to wear the Garmin device continuously during waking hours, 
placing it on the charger each night at bedtime. Wear-time adherence will be assessed by a participant 
Garmin paper log which will include non-wear time and technical issues.  This Garmin-based exercise 
program will include phone feedback at least weekly and in-person support group sessions at least 
monthly. These sessions will be conducted by an exercise physiologist who will adjust and progress the 
participant’s exercise prescription based on individualized weekly targets and personal tolerance.  
 

Page 18 of 31 
 
Research coordinators at the Atlanta and Baltimore sites will conduct an initial orientation visit for each 
participant to setup the Garmin device and link it with the Garmin Connect app on their personal cell 
phone. One device will be given to each participant as an incentive for participation in the delayed entry 
exercise group. Coordinators will help install the Garmin Connect app on the participant’s personal 
phone to ensure location tracking is off and no PII (e.g., personal email) is used. Education with written 
material will be provided on specific exercise (e.g., walking, jumping jacks) and activities (e.g., mowing 
lawn) which do not require specialized equipment and are classified as either moderate intensity or 
vigorous intensity.51 For the first 4 weeks participants only moderate intensity exercise/activity will be 
provided. Target duration will begin with 15 minutes of daily moderate intensity activity and will be 
progressed 10-15% weekly or as tolerated by the participant with a 1-month goal of 150 minutes of 
moderate physical activity per week ACSM Physical activity Guidelines for Americans.8 After 4 weeks, 
participants will be instructed to increase intensity to include vigorous exercise/physical activity with the 
12-week goal of at least 75 minutes of vigorous intensity activity per week.  The participant will be 
instructed to synch the Garmin wrist device with the phone app prior to the weekly call with the 
exercise physiologist, who will then review minutes in each intensity level on the Garmin Connect web 
site. This weekly call will last 30-60 minutes and will be used to assess tolerance, provide motivational 
feedback based on behavioral change techniques and make adjustments to progression of exercise in 
duration and intensity. This combination of activity trackers and feedback sessions has been effective in 
sedentary older adults.52–55 A monthly in-person group session will be held at each site which includes 
participants in the delayed entry control group from the same enrollment cohort. An exercise 
physiologist will lead a group discussion on challenges and incentives of exercising for the purpose of 
encouraging peer-support, which has been observed in the VTEL sessions. These sessions will occur after 
weeks 4, 8, and 12 of the exercise training period. At the 12-week in-person session participants will 
meet with the local site research coordinator who will uninstall the Garmin Connect app on the 
participant’s phone and reset the Garmin device. Participants will be provided instructions on how to 
establish a personal Garmin Connect account which cannot be accessed by research staff for use after 
the end of the study.  
3.3 Enrollment Sites: Atlanta VAMC (AVAMC) and Baltimore VAMC (BVAMC) 
Overview: Details on the research activity conducted at the enrollment site are provided here in the 
Salem VAMC protocol for the purpose of demonstrating the project’s scientific rigor (robust and 
unbiased experimental design and methodology) and likelihood of achieving scientific aims.  As the 
coordinating site, the Salem VAMC PI and research team is responsible for creating the manual of 
operations and standard operating procedures that will be implemented by enrollment sites. This will 
ensure consistency of tests and procedures among all the sites. All research activity conducted at the 
enrollment sites is under the FWA of each site’s respective IRB. Salem VAMC research team members 
who have access to PHI will be included as approved collaborators in the IRB protocol at each 
enrollment site.  
 
3.3.a 
Participant Enrollment: Recruitment, Informed Consent, and Eligibility  
Pool of Potential Participants 
Together these sites have established a well-defined pool of HIV+ Veterans in the Veterans Aging Cohort 
Study (VACS) by recruiting from their Infectious Disease (ID) Clinics. 
Atlanta VAMC: Potential participants will be recruited from the 1,900 HIV+ Veterans at the Atlanta 
VAMC ID Clinic, where approximately 1,000 patients are 50+ years of age and 93% of whom are 
receiving antiretroviral therapy.  
Baltimore VAMC: Potential participants will be recruited from the 950 HIV+ Veterans at the Baltimore 
VAMC ID Clinic, where approximately 700 patients are 50+ years of age and 85% of whom are receiving 
antiretroviral therapy.  

Page 19 of 31 
 
 
Recruitment and Screening 
Veterans receiving care at the Atlanta and Baltimore VAMCs will be recruited using techniques proven 
effective in our previous studies, including flyers and brochures. In addition, databases linked to the VA 
electronic medical record will be used to identify potential participants based on HIV status, age and 
current medication list. Local clinical registries (i.e. HAVACS and HIV Clinical Case Registry (CCR)), 
appointment systems (i.e. VISTA) and national data warehouses (i.e. VINCI/CDW) can be used for this 
purpose. Patients who are identified as potentially eligible will be mailed an introductory letter 
informing them that a research study is taking place and they might be eligible. The letter will inform 
them that someone from the study team will be calling them to tell them more about the study. The 
letter will provide phone numbers and/or a return post-card that allows them to opt-out of further 
contact. Additionally, providers can request permission to give a patient’s name to study staff, or 
provide study information to patients in order for the patient to contact the study staff directly. 
Providers will be invited to refer patients they feel might be eligible for the study. 
 
Informed Consent  
Written informed consent will be obtained from each participant in a private setting at the enrollment 
sites prior to any research activity that is not part of the partial HIPAA waiver. Staff will explain the 
purpose, risks, and benefits of the study during the consenting process. Participants will be given the 
opportunity to read the consent form or to have it read to them and to ask questions before signing. All 
sections of the consent will be reviewed with any questions answered. A timeframe will be given to 
complete the consent and provide an opportunity to ask questions and validate the participant’s 
understanding of the information included in the informed consent document.  
Copies of signed consent forms will be kept in a locked filing cabinet within a locked office in the study's 
research offices at the Atlanta or Baltimore VA Medical Centers.  Per VA guidelines, a list of participants 
who sign an informed consent form will be maintained. HIPAA form will be reviewed and signed at the 
time of the informed consent. HIPAA forms will be stored with the informed consent form.  
 
Enrollment and Completion Targets 
Feasibility of the project is supported by investigators with a track record of collaboration and the 
existing infrastructure including experience staff, well-defined population, and available exercise, VTEL, 
and lab equipment. Based on prior exercise trials we have conducted in this population, we expect a 
33% eligibility failure rate and a 30% attrition rate. Due to the COVID hold in 2019-2000, first study year, 
no participant activity occurred and a 1-year cost-extension has been awarded which will allow for 
completion of 40 participants per site to complete the exercise trial within the project period (Table 5). 
 
Table 5 
Y  2 
Y  3 
Y  4 
Y  5 
total 
Quarter 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
 
Completers 
2 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
4 
2 
 
80 
         AVAMC 
1 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
2 
1 
 
40 
         BVAMC 
1 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
2 
1 
 
40 
 
Eligibility  
HIV+ adult men and women of all races and ethnicities who are 50 years of age and older will be eligible. 
Eligibility criteria are based on our exercise research in older HIV+ adults and American College of Sports 
Medicine guidelines and are designed to minimize attrition, maximize safety, and limit confounding 

Page 20 of 31 
 
factors. Of note, smoking is not an exclusion criterion since approximately 70% of the otherwise eligible 
HIV+ Veterans are smokers, and if excluded would decrease the study’s generalizability.  
Inclusion Criteria: Participants will be on antiretroviral therapy with HIV viral suppression because HIV 
viremia affects DNA methylation and DNAm age. Only sedentary adults will be eligible (not engaging in 
structured activity for exercise (≥1/week). 
Exclusion Criteria: Specific eligibility criteria are listed in Table 6 below and include objective cut-off 
limits designed to maximize safety and minimize attrition but not prohibitively limit enrollment and 
maintain generalizability. Eligibility will be determined by information collected by a clinician study 
investigator during the eligibility visit which occurs after informed consent is obtained. The eligibility 
visit includes history and physical exam (H&P), review of the electronic medical record, and resting ECG. 
The following eligibility checklist was used for IRB submission at the enrollment sites: 
 
Table 6. Eligibility Checklist 
*based on date of H&P 
Inclusion Criteria 
Yes 
No 
 
 
 
Veteran living with HIV and under care at VAMC 
 
 
50 years of age and older 
 
 
Stable antiretroviral therapy (ART) (same ARV medications within 3 months)  
 
 
At least one HIV-1 PCR < 20 c/ml (viral load) within prior 6 months 
 
Exclusion Criteria 
Yes 
No 
 
  
  
History of AIDS defining illnesses (within 6 months; CDC Criteria) 
 
 
Myocardial infarction (within 3 months)  
 
 
Exertional or unstable angina (current chest pain that limits activity)  
 
 
Severe congestive heart failure (EF < 20% in last year or NYHA Classification III or IV)  
  
  
Uncontrolled hypertension (SBP >180 &/or DBP > 110 mm Hg)  
 
 
Therapy with beta blockers or non-dihydropyridine calcium channel blocker (within 1 month) 
 
 
Screening EKG with ischemia, complex arrhythmia, or high-grade block (per Minnesota Code)  
  
  
Poorly controlled DM within prior 1 month (FBS>180 mg/dl, RBS > 299 mg/dl, or HbA1C > 10) 
  
  
Receiving treatment for cancer except skin cancer (within 3 months)  
  
  
Peripheral vascular disease with claudication 
  
  
Severe arthritis limiting ambulation  
  
  
Neurologic disease limiting ambulation (requiring assist device) 
  
  
End stage liver disease (decompensated liver disease)  
  
  
Chronic renal failure (requiring dialysis)  
 
  
Severe pulmonary disease (home O2, admission for dyspnea or pneumonia within 1 month)  
  
 
Use of systemic steroids (testosterone or glucocorticoids) or growth hormone (within 6 months)  
 
  
Dementia (based on Evaluation to Consent) 
 
 
Signs or symptoms of any medical comorbidity that would preclude exercise testing or training 
 
 
Exercise on routine basis (structured resistance or aerobic exercise > 1 time per week) 
 
 
Past medical history of COPD or emphysema AND mMRC score =4  
 
 
January 2020 
 
 
Withdrawal 
Participants are free to withdraw from participating in the study at any time upon their request. 
Participants who elect to withdraw from the study will not perform additional research portions of the 

Page 21 of 31 
 
study (i.e., research blood draws).  Data that has been already collected prior to withdrawal will be used 
in analysis, unless the participants request otherwise in writing.  
 
3.3.b 
Testing Procedures at Enrollment Sites 
Summary of the research procedures to be performed at each timepoint are summarized in Table 7 
below. All testing will be conducted in participants located at Atlanta and Baltimore VAMCs within 5 
weeks of the eligibility visit (baseline) or end of a 12-week intervention phase. For delayed entry 
controls, follow-up testing will occur at ~12-weeks and ~ 24-weeks.  
 
Table 7. Summary of study procedures and outcome measures 
Procedure  
Outcome  
Measures 
Treadmill Test 
Exercise Capacity 
Aerobic capacity (VO2peak)  
O2 pulse 
Anaerobic Threshold (AT) 
DXA 
Body Composition 
Body fat 
Appendicular skeletal mass index 
(ASMI): 
Bone density 
Functional 
performance 
Strength and endurance 
Chair stand 
Arm curve 
2-minute step test 
Frailty 
 
Fried Frailty Phenotype 
VACS Index 
Blood Sample 
Biomarker of Aging 
DNAm Age20 
DNA Methylation (DNAm) 
of Candidate Genes 
Inflammation-related genes: 
NFKB256; ASC57; 5 CpG sites in 
genes related to CRP37,58 
Exercise-related genes: GHRH and 
FGF143; Epidermal growth factor 
(EGF) 48 
Biomarkers of 
Inflammation 
e.g., IL-6, IL-18, high-sensitivity 
CRP38–41,43  
Survey 
Health-related QoL 
WHOQOL-HIV 59 
Social Support 
Exercise Social Provisions Scale 60   
Exercise Barriers 
Barriers-Specific Efficacy 
Questionnaire 61  
System Usability 
System Usability Scale (SUS) 62 
Garmin Tracker* 
Physical Activity 
Step counts  
MVPA minutes  
Sedentary time  
*Delayed exercise group only; MVPA, moderate vigorous physical activity 
 
Treadmill Testing: Participants will be asked to exercise to voluntary exhaustion during a graded treadmill 
test using a modified Bruce protocol.63 After a resting 12-lead electrocardiogram is completed and 
reviewed by the study physician, participants will be asked to exercise to voluntary exhaustion during a 
treadmill test using a modified Bruce protocol. A final report on the test results will be made by a 

Page 22 of 31 
 
cardiologist. If abnormal findings are seen on the test, the participant will be referred to their primary 
care physician. The visit for the exercise treadmill test will take about 45-60 minutes and will take place 
in the Baltimore and Atlanta VAMCs. 
 
Oxygen (O2) consumption, CO2 production, and minute ventilation will be measured breath-by-breath 
using a metabolic cart and the following data will be collected:  
VO2peak. Rationale: O2 consumption at peak exercise effort, VO2peak, is used as the standard measure of 
aerobic capacity in sedentary adults since the majority are not able to reach maximal aerobic capacity 
defined as a plateau in O2 consumption.64 Method: VO2peak will be the average of the final 30 second 
values of O2 consumption at peak exercise.  
O2 Pulse. Rationale: Oxygen pulse is a measure of the efficiency of O2 delivered or consumed. Method: O2 
pulse will be calculated as the milliliters of O2 consumed per heartbeat (VO2/HR).  
Ventilator Threshold. Rationale: The onset of anaerobic metabolism or anaerobic threshold (AT) is an 
estimate of submaximal exercise capacity and can be measured in several ways. We will use ventilatory 
threshold (VT) as a well-described clinical estimate of AT that has a high test-retest reliability in adults 
with chronic disease.65  Method: VT will be derived from two different plots including using V-slope 
method and ventilatory equivalents. O2 consumption at VT and the percentage of VTO2/VO2peak will be 
determined.  
 
Dual-energy X-ray absorptiometry (DXA): Participants will undergo a DXA after an overnight fast. Total 
and regional lean tissue mass and bone density will be measured. Change in muscle mass and adiposity 
will be calculated and tested for between group differences. 
Appendicular skeletal mass index (ASMI): ASMI will be calculated as lean appendicular mass/height2. 
Established cut-offs for ASMI measured by dual-energy X-ray absorptiometry (DXA) will be used to 
define low muscle mass.66,67 ASMI predicts clinical outcomes in diverse patient populations.68,69  
Adiposity: total, truncal, and appendicular fat mass and percent body fat 
 
Functional Performance Testing Battery: Function tests will include standard measures of functional 
performance. Body circumferences (waist, hip), weight, and height will be measured using the protocol 
established in the Third National Health and Nutrition Examination Survey. We have performed this set 
of physical function tests on over a hundred HIV-infected adults and expect it to take 20-30 minutes to 
complete. Function testing will take place in the Baltimore and Atlanta VAMCs with VTEL supervision by 
the Salem VAMC exercise physiologist to ensure testing accuracy.  
 
Lower extremity strength by timed chair stands: Rationale: The 30-second chair stand correlates with 1-
RM leg-press performance in older men (r = .78)70 and predicts mobility disability71 and mortality.15 The 
test-retest reliability is 0.89.71 Method: The number of times is counted within 30 seconds that a 
participant can rise to a full stand from a seated position without arm assistance. 
Upper extremity strength by timed arm curl: Rationale: The 30-second arm curl test correlates with 1-RM 
biceps strength (r= 0.62)71 and improves with RT.46 Method: The number of times a hand weight can be 
curled through a full range of motion in 30 seconds is measured. The test-retest reliability is 0.80.72 
Two-minute step test (2-MST): Rationale: Cardiopulmonary exercise testing will not readily be available 
when the VTEL exercise program is translated to clinical care. The 2-MST correlates with VO2peak in 
older patients (r=0.33; p<0.01)73 and is advocated as a surrogate measure of aerobic capacity in space 
limited settings72 Method: The test will be performed according to the Rikli and Jones protocol in which 
the number of times the right knee reaches a pre-determined height is counted in 2 minutes.71 The test-
retest reliability is 0.88.72 As a secondary analysis, we will correlate the 2-MST with VO2peak, not 
previously reported in HIV+ adults.  

Page 23 of 31 
 
 
Frailty: 
Frailty phenotype:  The frailty phenotype by Fried et al. will be used to measure frailty phenotype.74 
Rationale: The Fried frailty phenotype has been widely studied in HIV+ adults.75 Method: The five 
domains of the phenotype (slowness, weakness, low activity, weight loss, and exhaustion) will be 
measured and scored as previously described.74   
VACS Index:  Based on our research  in the Veterans Aging Cohort Study (VACS)76 and recent epigenetics 
literature,77 the VACS Index will be calculated27 and used as a secondary measure of frailty. The VACS 
Index will be calculated based on clinically available lab values, such as kidney and renal function, age, 
and CD4 cell count and HIV-1 RNA level (viral load).27 
 
Blood Sampling:  Blood collection, storage, and testing will be performed in the Baltimore and Atlanta 
VAMC laboratories. The samples will be collected across multiple draws. One of the blood draws will be 
conducted after an overnight fast. Staff will attempt to phlebotomize the patient during the approved 
fasting DXA visit to minimize discomfort and inconvenience to the patient. Blood samples will be 
collected in appropriate tubes using established protocols per the planned assays. Plasma will be 
immediately separated by centrifugation at 4°C, aliquoted, then frozen at -80°C and stored until further 
processing and analysis. Pre/post intervention samples from the same participant will be analyzed in the 
same assay.  
Inflammatory Biomarkers: Testing of inflammatory biomarkers will occur at each respective enrollment 
site using the same kits since procedures are very standardized. We appreciate that change in plasma 
levels of cytokines can vary greatly between and within individuals. Our analysis plan takes this point 
into consideration by including change in cytokines as an independent variable in models of the primary 
and secondary outcomes. Changes in plasma levels will be calculated pre/post intervention and will be 
tested for association with changes in outcomes as well as between group differences.  
DNA Methylation Assay: Samples will be tested for DNA methylation in the laboratory of Dr. Yan Sun in 
Atlanta using established methods as previously described. 23,58,78  Samples from Baltimore participants 
will be shipped directly to Dr. Sun’s lab. In sum, Dr. Sun will conduct a comprehensive interrogation of 
epigenome-wide CpG sites using the Illumina Infinium Methylation EPIC (850K) BeadChip. The 850K chip 
covers 99% of the NCBI Reference Sequence (RefSeq) genes, with sites covering the promoter, 
untranslated regions, and gene body, >95% of CpG islands, enhancer regions from FANTOM5 and 
ENCODE, as well as differentially methylated sites across tissue types. The EZ DNA Methylation Kit (Zymo 
Research, Orange CA) will be used to bisulfite-convert 0.5 μg of gDNA per sample. Bisulfite-converted 
DNA samples will be whole-genome amplified, enzymatically fragmented, and purified. Samples will be 
hybridized to the array. The array will then be fluorescently stained, scanned, and assessed for 
fluorescence intensities to quantify the methylation levels of each DNAm site. 
Blood Banking: Blood sampling will include additional volume for future testing related to 
cardiometabolic disease and aging. These samples will be stored at the Atlanta and Baltimore VAMCs. 
 
Clinical Data: Medical history and clinical laboratory values will be collected at the eligibility visit by a 
research clinician. Data will include comorbid conditions, medication use, CD4 cell count and HIV-1 PCR 
level, and other clinical labs included in the VACS Index.  Both the participant and review of medical 
records will be used as source of the data. 
 
Smoking: Smoking history is part of the baseline medical assessment and will be repeated as part of follow-
up testing due to its effect on DNA methylation. Smoking exposure will be quantitated as current, prior, or 
never use, as well as pack-year use, which has been used to measure effects on DNA methylation.79 
 

Page 24 of 31 
 
Alcohol and Illicit Drug Use: Alcohol and illicit drug use will be assessed due to their potential effect on 
adherence. The AUDIT-C will be used to measure alcohol use. Illicit drug use will be quantitated as 
current, prior, or never use by drug class. 
 
Diet and Nutrition Assessment: All participants will be interviewed three separate times during baseline 
and follow-up periods to allow for comprehensive and unbiased assessment of diet. Interviews will be 
performed at unannounced times by a Baltimore or Atlanta VAMC research team member who has 
been trained in the interview method for a 24-hour dietary recall questionnaire.  All participants will be 
counseled in the principles of a weight stable American Heart Association diet80 prior to baseline testing 
to minimize dietary influences on the metabolic tests. Members of the research team will monitor diets 
and body weight throughout the study to ensure stability and counsel participants as necessary to 
maintain diet intake and weight. This will minimize confounding effects of weight loss and dietary 
heterogeneity. 
 
Surveys: A total of 4 surveys will be completed by participants on paper during the study to cover the 
domains of health-related quality of life (QoL), social support from group exercise, barriers to exercise, 
and system usability (Table 7). QoL will be considered a secondary outcome and will be assessed with 
other outcomes before and after the intervention period. The remaining surveys will be used for 
program evaluation and will be collected after 4 weeks of exercise training.  
  
VTEL Feasibility: Rates will be calculated for enrollment, attendance, and retention. Participant 
satisfaction with VTEL system will be assessed with the System Usability Scale (SUS) . The relationship of 
social support and self-reported exercise barriers will be tested with attendance and retention rates. 
The same four surveys will be collected from participants in the delayed exercise home-based pilot with 
the SUS adapted for the Garmin device. 
 
Garmin Wrist Device: The Garmin Vivosmart v5 will be used to collected from each participant the 
following data: minutes of moderate intensity and vigorous intensity exercise/activity, number of 
exercise bouts, step-counts, and sedentary time. No GPS (location) data will be collected. Data from the 
wrist device will be uploaded to the Garmin Connect website via the Garmin Connect phone app. 
Research staff will access the website to extract daily and weekly mean values and record them on a 
case report form before entering into the study database. A report for each participant will be 
generated for the weekly feedback session.  
 
3.3.c 
Risks and Benefits of Procedures at Enrollment Sites 
 
There are potential risks associated with some of the procedures included in this study. 
However, the procedures have been planned by the investigators to minimize the danger of any major 
complication. All medical procedures will be supervised by qualified medical personnel who will carefully 
monitor the participant. If new medical problems are discovered or encountered during this protocol, 
participants will be referred to their physicians for further evaluation and management. Risks associated 
with specific procedures are discussed below: 
 
1. Exercise testing and training. The acute risk for a cardiac event during exercise testing and training is 
small. The AHA consensus statement on exercise standards estimates that the acute risk of sudden 
cardiac arrest during exercise training in adults with known cardiac disease is approximately 1 event per 
60,000 hours of aerobic exercise. The primary risk is muscle soreness and injury, which will be minimized 
by close supervision and appropriate warm-ups. 
2. Blood sampling:  There is a minimal risk of bruising and infection from blood drawing. 

Page 25 of 31 
 
3. Radiation exposure: For the DXA, the total amount of exposure is 20 mR (whole body = 1 mR, lumbar 
spine = 7 mR, hip = 7 mR, forearm = 5 mR).  
4. Tests of functional performance:  These tests involve a variety of timed walks and getting up from a 
chair. There is a small risk that adults will fall, get chest pain, become short of breath or become dizzy 
during these tests. Adults will be instructed to stop the test if there are any untoward symptoms such as 
chest pain. We have performed >100 tests of functional performance without complication.  
5. Nutrition: There are minimal risks associated with the administration of the 24-hour diet recall. It is 
possible that some participants may feel uncomfortable discussing their diet.  
6. Surveys:  There are minimal risks associated with participants completing the surveys.  
 
3.3.d 
Measures to Minimize Risk 
The exclusion criteria have been developed for older HIV+ adults to minimize risk of adverse 
events.  Exercise training will take place in rooms located within the Atlanta and Baltimore VAMCs near 
clinical areas and with specific safety procedures developed for VTEL exercise. A research staff member 
at the enrollment site will measure blood pressure before every exercise session and will remain in the 
room during the exercise class.   
1. Exercise testing and training: Exercise testing will only be conducted after the participant is examined 
by a physician and the resting ECG and vital signs are obtained. A clinician (MD/NP) and exercise 
physiologist are present in the room with a defibrillator, emergency medications and resuscitation 
equipment during all testing. Exercise testing will be performed as per the guidelines of the American 
College of Sports Medicine. The ECG is continuously monitored. Specifically, a full 12-lead ECG, BP, and 
breathing are monitored during every minute of the test by personnel who are trained in 
cardiopulmonary resuscitation, exercise testing and emergency treatment of cardiac arrhythmias. The 
test will be stopped if electrocardiographic, heart rate, or BP abnormalities occur or if the participant 
has any symptoms of cardiovascular decompensation (e.g., chest pain, extreme dyspnea, dizziness or 
faintness, fatigue, pallor or cyanosis, cardiac arrhythmias including atrial fibrillation or flutter, frequent 
PVC's, second or third degree AV block or other intraventricular conduction defects, significant ST 
segment elevation or depression (> 2mm), SBP > 240 mmHg, DBP > 120 mmHg, or a decrease in SBP 
from the previous stage > 20 mmHg). Emergency medications are available should the participant need 
treatment. ECG, BP, and breathing are monitored for at least 6 minutes post exercise, or until the 
participant's heart rate and BP have returned to their pretest values. Disqualified participants will be 
referred to their physician for further evaluation. The clinician (MD/NP) and exercise physiologist are 
responsible for safety monitoring. 
2. Blood sampling:  Risk associated with blood sampling is minimized by use of aseptic technique and an 
experience and certified phlebotomist. The research coordinator is responsible for safety monitoring of 
this procedure. 
3. Radiation exposure: Exposure is minimal for the DXA scans. participants will be instructed, verbally 
and in writing in the informed consent, to notify research staff of any additional radiologic tests outside 
of the study. We do not expect women over 50 years of age to be childbearing, but menopause will be 
confirmed by history and a serum pregnancy test performed, if needed.  The PI is responsible for safety 
monitoring. 
4. Tests of functional performance:  These tests involve a variety of timed walks, getting up from a chair, 
and tests of balance. No tests will be performed before the participant is examined by a physician. An 
exercise technician who is trained in CPR will be administering these tests. A crash cart and emergency 
medications are available in the area where these tests are performed. The exercise physiologist is 
responsible for safety monitoring. 
5. Nutrition:  The 24-hour recall allows participants to discuss their diet with research staff in a private 
setting and in a non-judgmental manner. The research coordinator is responsible for safety monitoring. 

Page 26 of 31 
 
6. Surveys:  Confidentiality will be protected by using only study ID number on the surveys and having 
participants complete them in a private setting. 
 
7. Garmin wrist device: This brand and style of commercial physical activity device was chosen based on 
prior work with older veterans which showed it was preferred compared to other commercially 
available devices based on ease of use and comfort. 81 The risk of minimal wrist discomfort will be 
minimized by appropriate sizing of the device band and the option for participants to remove the device 
at bedtime.   
 
Confidentiality of data:  Confidentiality of data is of concern, particularly when information includes HIV 
status. The investigative team has taken extensive steps to ensure the confidentiality of the data as 
discussed above in Data Management section. All members of the research team are responsible for 
minimizing loss of confidentiality of participant records, and the PI is ultimately responsible for all 
aspects of study conduct.  
 
3.3.e 
Benefits 
The participants may not benefit from taking part in the study. However, participants will 
receive a thorough assessment of their functional performance and risk factors for cardiovascular 
disease and bone disorders, which are common in HIV-infected adults but not routinely considered by 
their providers. They will be told of abnormal findings and with their written permission, results will be 
forwarded to their health care providers for appropriate medical follow-up. In prior studies, these types 
of assessment have detected previously undiagnosed problems (e.g., osteoporosis). Participants 
enrolled in the intervention study, and delay entry controls will benefit from a training intervention, 
which should improve their level of functioning and potentially decrease their risk for future cardiac 
events. Some participants may embrace the new behavior of exercise after exercise training during the 
study and incorporate the activity into their routine. Any of these changes in the future will give them an 
opportunity to improve their quality of their life. Comparing the two exercise interventions, the VTEL  
exercise may have greater, more immediate increase in aerobic capacity but the delayed entry control 
group may have more durable benefits for all outcomes. We believe that the benefits associated with 
this study will exceed the risks, thereby resulting in a low risk: benefit ratio for any participant. 
 
3.3.f 
Costs/Compensation 
Compensation will be allocated directly at each site, per their local policies and procedures. Each 
site has the same target completion rate and annual participation reimbursement budget, but will be 
allowed to adjust reimbursement per study procedure as deemed appropriate per local standards. 
Participant name, address, social security number, and amount of payment will be submitted to the 
Internal Revenue Service for tax reporting purposes for any financial compensation they receive per 
calendar year as a result of participation in this research study. The Salem VAMC team will not have 
access to this information. All participants are reimbursed for baseline and follow-up testing. For 
performance of VTEL exercise training, reimbursement is provided per exercise session for travel cost 
and a completion bonus at end of 36 sessions (VTEL intervention group). The delayed exercise control 
group will complete follow-up testing at 24-weeks in addition to 12-weeks, and therefore total study 
reimbursement will be greater. During the delayed exercise period, the control group will be reimbursed 
for the weekly phone calls and monthly in-person group visits. 
 
Use of research samples may lead to inventions or discoveries that could become commercially 
valuable. In the event of scientific discoveries made using participant samples, study participants will not 
receive compensation or profits from any inventions, discoveries, or products.  

Page 27 of 31 
 
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