Effect of Exercise Training on Inflammation and Function in HIV Infected Veterans
Phase: NA
Conditions: HIV
Sponsor: VA Office of Research and Development

TITLE: 
Strength Training and Endurance Exercise for LIFE 
Trial # 
NCT02102060 
Registered 
3/27/2014 
Principal Investigators 
Krisann K. Oursler, MD, ScM,1,2 
Alice S. Ryan, PhD3,4
1 Salem Veterans Affairs Medical Center, Salem, Virginia 
2 Virginia Tech Carilion School of Medicine, Roanoke, Virginia 
3 Baltimore Veterans Affairs Medical Center Geriatric Research, Education, and Clinical Center 
at the Veterans Affairs Maryland Health Care System
4 University of Maryland School of Medicine, Baltimore, Maryland 
Funding 
The research described here was supported by the Department of Veterans Affairs Veterans 
Health Administration, Rehabilitation Research and Development Service, I01 RX000667 
Ethics approval and consent to participate 
The study was approved by the Institutional Review Boards at the Salem VAMC, Salem, VA and 
the University of Maryland IRB, Baltimore, MD.  
Written informed consent was obtained from each patient prior to participation. 
01/15/2021

Protocol Overview 
 
Hypothesis:  We hypothesize that high-intensity exercise training will increase cardiorespiratory 
fitness, which will be mediated by improved diastolic function and will correlate with decreased 
biomarkers of inflammation.  
 
Background: Adults with HIV on antiretroviral therapy have a life expectancy approaching that 
of the general population yet have impaired cardiorespiratory fitness and diastolic function that 
increase their risk for age-related disability. Chronic inflammation is a well-studied mediator of 
advanced aging with HIV, including cardiac dysfunction, yet the impact of exercise training is 
unclear.  The study objective is to develop an exercise program for older adults with HIV that 
targets pathophysiological processes of advanced aging and will prevent and improve disability. 
 
Design: The study is a randomized trial comparing 16-weeks of progressive aerobic and 
resistance training to usual care in sedentary older (50+ years) adults with HIV.  The center-
based exercise training is performed three times weekly under supervision. The end-target 
duration and intensity of aerobic exercise is 45 minutes at 70-80% of baseline heart rate 
reserve. Resistance training progresses from low-intensity to high-intensity based on initial one 
repetition maximum (1-RM) in the three upper body (chest press, seated row, pull-down) and 
three lower body exercises (leg press, knee extension, knee flexion).  Primary outcomes are 
cardiorespiratory fitness, cardiac function, and biomarkers of myocardial fibrosis and cardiac 
stress.  Secondary outcomes include muscle strength, body composition measured by Dual-
energy X-ray absorptiometry (DXA), and biomarkers of systemic Inflammation.  
 
 
Statistical Analysis Plan (SAP) 
 
Power Analyses  
 Power calculations were based on results from randomized exercise trials that included 
a sedentary control group. For outcomes of diastolic function1, cytokines 2, and biomarkers of 
myocardial fibrosis3 we used mean (SD) from exercise trials in older adults without HIV since 
results were not available for adults with HIV. Referenced values for VO2peak4 and strength5 
were obtained from trials in adults with HIV, but a younger population (mean age 30-45 years 
old). For these outcomes, a sample size of 22 participants per group provides at least 80% 
power to detect a between group difference with a two-sided alpha of 0.05. We acknowledge 
that older participants may have greater muscle soreness or fatigue as well as more medical 
problems. Therefore, our target enrollment number assumes a conservative attrition rate of 30% 
based on prior exercise interventions in adults with HIV.6,7  
 
Statistical Analyses 
ANOVA will be used to compare the change in the intervention group to the change in the 
control group for the following primary outcomes, AIM 1: (1) functional performance, (2) aerobic 
capacity, (3) diastolic function; AIM 2: (1) strength, (2) muscle mass. In the ANOVA models, the 
change from baseline to 16-weeks will be the dependent variable in models adjusted for the 
baseline value of the outcome measure and treatment group. Groups will be compared at 
baseline for differences in potential confounders such as age and comorbidity.  Additional 
adjustment will be made if the randomization produces groups that are not balanced on factors 
which are also associated with outcomes. We do not anticipate needing to adjust for sex, history  
of AIDS, or length of HIV infection (CD4 cell count) as our group assignment will be blocked on 
these factors. Similar analyses will be performed for secondary outcomes, intramuscular fat, 

percent body fat, plasma glucose, insulin, and lipids, blood pressure. All analyses will be two-
tailed. 
 
We will use regression analyses to test the following associations, Specific aim 1: change (16-
week value minus baseline value) in VO2peak with change in (1) diastolic function and (2) 
markers of systemic chronic inflammation, (3) change in diastolic function with change in 
myocardial fibrosis; Specific Aim 2 (1) change in strength with change in muscle mass, (2) 
change in muscle mass with change in markers of inflammation, change in intramuscular fat 
with change in (3) plasma lipid and (4) fasting glucose concentrations. These analyses will be 
adjusted as noted above, except they will not be adjusted for group as the analytic interest lies 
in the relation of change to change, not change to group. 
 
Analyses will include subjects who drop out before completion of the 16-week study period by 
way of multiple imputation. This intention to treat approach will investigate factors that may 
affect compliance and difficulty with exercise training, including pain/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 majority of 
the subjects will be recruited from the Salem VA HIV clinic, we will be able to obtain clinical data 
from subjects 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 48 training  sessions cannot be completed in 16 weeks, then total 
training time will be tracked, and incorporated into the data analysis.  
 
 
Data management 
A robust data management plan is in place to ensure the accuracy, completeness, 
legibility, and timeliness of the data collected across the two sites. The study data is managed 
carefully to ensure its integrity. Ongoing quality assurance activities include summary statistics 
to identify outliers that are then confirmed with source documents.  To maintain participant 
confidentiality, each participant is assigned a numerical ID which is used on all case report 
forms, data sheets and surveys. The keycode to link individuals with their assigned IDs are 
stored in locked cabinets and computer folders separate from study data. Data is entered 
directly from the source documents into data spreadsheets that are stored in limited access 
study folders on the VA server that can be accessed only through a password protected VA 
computer from either site.  
 
 
 
REFERENCES 
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