Abstract
Fatigue and depressive symptoms are prevalent and associated with poor clinical outcomes, though the underlying physiological mechanisms of fatigue and depression are poorly understood. We examined the impact of cardiorespiratory fitness (CRF) on fatigue and depressive symptoms in one-hundred and nine PLHIV. CRF was examined by maximal cardiorespiratory stress test and determined by peak oxygen uptake. Patient-reported fatigue was examined utilizing the HIV-Related Fatigue Scale. Depressive symptoms were examined with the PROMIS 29 and Beck Depression Inventory. Data was collected at baseline and six months. Generalized estimating equations were used to determine the effect of CRF on fatigue and depressive symptoms over time. Participants were approximately 53 years old, 86% African American (n=93), and 65% male (n=70). After controlling for age and sex, fatigue was inversely associated with CRF (ß= −0.163; p=0.005). Depressive symptoms were not associated with CRF as measured by the Beck Depression Inventory (p=0.587) nor PROMIS 29 (p=0.290), but over time, depressive symptoms decreased (p=0.051). Increased CRF was associated with decreased fatigue levels, but was not associated with depressive symptoms. These results should guide future research aimed at how CRF might inform interventions to improve fatigue in PLHIV.
Keywords: cardiorespiratory fitness, fatigue, depressive symptoms, HIV, symptom management
Introduction
People living with HIV (PLHIV) have a high burden of physical and mental health symptoms (Webel et al., 2018a). Symptoms experienced by PLHIV, including fatigue and depressive symptoms can dramatically affect their quality of life. Fatigue and depressive symptoms are among the most prevalent and burdensome symptoms experienced by PLHIV (Webel et al., 2018b) and are associated with poor clinical outcomes such as decreased medication adherence and engagement with care in PLHIV; yet less is known about the relationship of these symptoms to physiological mechanisms that impact the health of this population. Healthy behaviors, including regular physical activity, may prevent or mitigate these detrimental symptoms in PLHIV.
Cardiorespiratory fitness denoted as the maximal oxygen consumption (VO2 max), measures an individual’s ability to transport inhaled oxygen to the mitochondria, and in turn, carry out physical activity. CRF can be accurately measured using maximal cardiorespiratory exercise tests. PLHIV have among the lowest levels of CRF (26.4 ml/min/kg) of those living with chronic illnesses (Vancampfort et at., 2019). Major factors contributing to the variance of CRF include genetics, sex, physiological factors such as inflammation and percent body fat (Chou, Holzemer, Portillo, & Slaughter, 2004), and lifestyle behaviors such as smoking and levels of daily physical activity (Chou, Holzemer, Portillo, & Slaughter, 2004; Zeller, Swanson, & Cohen, 1993).
The purpose of this analysis is to explore the underlying impact of CRF on the burdensome symptoms of fatigue and depression in PLHIV. We hypothesized increased CRF would be associated with decreased fatigue and depression based on the literature in other comorbidities (Carek, Laibstain, & Carek, 2011; O’Dwyer, Durcan, & Wilson, 2017). The secondary purpose is to examine the modifying impact of age and sex on cardiorespiratory fitness in PLHIV. We hypothesized that CRF would be lower as age increased and women would have less CRF compared to men based on the literature in other comorbidities (Vancampfort et at., 2019).
Methods
Design and Sample
We conducted a secondary analysis of baseline and six-month data from BOosting health By Changing AcTivity, (BOBCAT) a randomized clinical trial, which aimed to improve physical activity and cardiometabolic outcomes in a sample of sedentary PLHIV. One-hundred and nine (n=109) virally suppressed PLHIV were included in the analysis. Study procedures were approved by the Institutional Review Board at University Hospitals, Cleveland Medical Center. This six-month clinical trial with two group randomization tested the effect of a self-management intervention on lifestyle exercise and cardiorespiratory fitness ( NCT02553291).
Procedures
Written informed consent was obtained from all participants, prior to any study procedures. Survey data of demographic, health, and physical activity characteristics were collected. Maximal cardiorespiratory testing was performed. After baseline data were collected, participants were randomized 1:1, stratified on sex and race, to either a control condition or BOBCAT self-management intervention which educated participants on behavior change techniques and healthy lifestyle choices. At the six month visit all participants repeated the maximal cardiorespiratory testing.
Measures
Fatigue was examined utilizing the HIV-Related Fatigue questionnaire (Pence, Barroso, Leserman, Harmon, & Salahuddin, 2008). Depressive symptoms were examined with the PROMIS 29 (Cella et al., 2010) and Beck Depression Inventory (Beck, Steer, & Brown, 1996). Data were collected at baseline and six months and analyzed as described per protocol.
Cardiorespiratory Fitness
Cardiorespiratory exercise tests were completed at baseline and six months using a computer-controlled Lodi bicycle ergometer (Groninger, Netherlands) with a MGC Diagnostics Cardiopulmonary Express system (MGC Diagnostics, St. Paul, MN). All tests utilized a 20-watt ramp protocol. Cardiorespiratory fitness was measured by peak oxygen uptake, which is maximal value of oxygen uptake in the final 30 seconds of exercise. Percent of predicted peak oxygen uptake was determined by the Wasserman-Hansen equation (Hansen, Sue, & Wasserman, 1984). The linear regression slope of the minute ventilation (VE) and VCO2 was used to determine ventilatory efficiency (VE/VCO2 slope) (Sun, Hansen, Garatachea, Storer, & Wasserman, 2002).
Analysis
Statistical analyses were performed using Stata version 14.0 (College Station, Texas). Data were cleaned for statistical analysis and descriptive statistics were run. Variable distributions were examined through analysis of frequencies and inspection of graphs. We examined bivariate relationships over time. We analyzed CRF by decade of age and sex. Generalized estimating equations (GEE) with an unstructured covariance matrix and an identity link function were used to examine the effect of fatigue and depression symptoms in cardiorespiratory fitness over six months.
Results
One hundred and nine PLHIV enrolled in this study with 101 (93%) participants retained at 6 months. Participants were approximately 53 years old, 86% African American (n=93), and 67% male (n=73). Participants had been living with HIV for an average of 15.8 (±7.6) years. Demographic and medical characteristics are summarized in Table 1.
Table 1.
Demographic and Medical Characteristics
| Demographic/Medical Characteristic | Subjects (n = 109) |
|---|---|
| Age (31–71 years) | 52.8 |
| Gender | |
| Male (%) | 73 (67) |
| Transgender (%) | 3 (2.8) |
| Race (%) | |
| African American | 93 (86) |
| White | 13 (12) |
| Other | 2 (2) |
| Marital Status | |
| Married or Domestic partnership (%) | 9 (8) |
| Single/separated/divorced (%) | 93 (86) |
| Current smoker (%) | 65 (60) |
| Chronic kidney disease (%) | 6 (6) |
| Diabetes Mellitus (%) | 12 (13) |
| Heart Failure (%) | 5 (5) |
| Asthma (%) | 20 (21) |
Cardiorespiratory Fitness
We examined CRF stratified by age in decades (Table 2 A.), which demonstrated that CRF did not vary between age groups. We examined CRF by sex (Table 2 B.), which demonstrated that women had significantly worse CRF compared to men, but there are no significant differences by decade.
Table 2 A.
Stratification by Age in Decades
| Age in Decades | 30–40 years | 41–50 years | 51–60 years | 61–70 years | p-value |
|---|---|---|---|---|---|
| N | 6 | 31 | 57 | 12 | |
| VO2 peak ml/kg/min (mean (sd)) | 17.48 (4.85) | 18.03 (5.90) | 16.21 (5.18) | 16.13 (3.68) | 0.461 |
| VE/VC02 (mean (sd)) | 28.33 (2.07) | 33.24 (5.77) | 33.31 (5.92) | 34.50 (5.16) | 0.173 |
| VO2 at Anaerobic Threshold (mean (sd)) | 11.37 (3.70) | 11.06 (5.15) | 9.75 (3.49) | 10.30 (3.99) | 0.509 |
Table 2 B.
Stratification by Gender
| Male | Female | p-value | |
|---|---|---|---|
| N | 73 | 33 | |
| VO2 peak ml/kg/min (mean (sd)) | 18.60 (4.57) | 12.32 (3.93) | <0.001 |
| VE/VC02 (mean (sd)) | 32.94 (4.94) | 33.62 (7.37) | 0.593 |
| VO2 at Anaerobic Threshold (mean (sd)) | 11.22 (4.23) | 8.04 (2.69) | <0.001 |
Fatigue and CRF
After controlling for age and sex, fatigue was negatively associated with CRF (ß= −0.163; p<=0.01) (Table 3). We also found as Ve/VCO2 increases, fatigue increases and that over the six-month study period, fatigue increased in this patient population.
Table 3.
Generalized Estimating Equations
| Predictor | HIV Fatigue Scale | HIV Fatigue Scale | Beck Depression Inventory | PROMIS |
|---|---|---|---|---|
| Estimate; Std. Err; p-value | Estimate; Std. Err; p-value | Estimate; Std. Err; p-value | Estimate; Std. Err; p-value | |
| VO2 peak ml/kg/min (mean (sd)) | −0.565; 0.265; 0.033* | −0.16308; 0.058; 0.005* | −0.119; 0.219; 0.587 | −0.333; 0.315; 0.29 |
| Time point | −2.171; 1.937; 0.262 | −0.538; 0.462; 0.244 | −2.962; 1.189; 0.013* | −6.458; 3.513; 0.066* |
| VO2max time interaction | 0.118; 0.114; 0.303 | 0.029; 0.027; 0.291 | 0.144; 0.06; 0.017* | 0.475; 0.243; 0.051* |
| VE/VC02 (mean (sd)) | 0.41; 0.203; 0.044* | 0.08; 0.043; 0.063 | 0.077; 0.12; 0.525 | 0.192; 0.171; 0.262 |
| Time point | 3.803; 2.421; 0.116 | 0.179; 0.58; 0.756 | −1.51; 1.767; 0.393 | 10.844; 5.646; 0.055* |
| VE/VC02 time interaction | −0.12; 0.068; 0.079 | −0.007; 0.017; 0.671 | 0.029; 0.055; 0.585 | −0.294; 0.161; 0.067* |
| VO2 at Anaerobic Threshold (mean (sd)) | −0.589; 0.304; 0.053* | −0.155; 0.068; 0.022* | −0.176; 0.199; 0.377 | −0.615; 0.246; 0.012* |
| Time point | −2.239; 1.89; 0.236 | −0.559; 0.445; 0.209 | −1.501; 1.102; 0.173 | −4.741; 2.343; 0.043* |
| VO2 at Anaerobic Threshold x time interaction | 0.199; 0.171; 0.246 | 0.049; 0.039; 0.211 | 0.097; 0.096; 0.311 | 0.567; 0.258; 0.028* |
significant, p-value ≤ 0.05
Depressive Symptoms and CRF
After controlling for age and sex, depressive symptoms were not associated with CRF as measured by the Beck Depression Inventory (p=0.59) nor PROMIS 29 (p=0.29) (Table 3). Over the six-month study period, depressive symptoms decreased significantly (p=0.05).
Discussion
Our study is among the first to examine cardiorespiratory mechanisms associated with symptoms in PLHIV over time. We observed several novel findings in PLHIV including: patient-reported fatigue was associated with CRF, but not depressive symptoms; depressive symptoms improved over time, and contrary to our hypothesis, CRF did not vary by age groups.
Our main findings demonstrate increased CRF was associated with decreased fatigue levels, but was not associated with depressive symptoms. The inverse relationship between CRF and fatigue demonstrated in our results show promise for decreasing the burden of fatigue through interventions aimed at increasing CRF such as higher intensity physical activity.
These data are consistent with previously reported data demonstrating improvement of CRF are associated with a reduction of fatigue with exercise in individuals with systemic lupus erythematosus (O’Dwyer et al., 2017). Yet diverge from data observing an improvement of CRF with reduction of depression associated with exercise in individuals with systemic lupus erythematosus (O’Dwyer et al., 2017). The inconsistencies between studies may be attributed to differing patient populations or lack of consistency of measures. This, in turn, demonstrates the need for further investigation regarding the association of CRF with fatigue and depression symptoms.
Depressive symptoms decreased over the six-month study period. In general, rates of depressive disorders decrease significantly with age (Rabkin, 2008). Physical activity is associated with decreased depression symptoms in individuals with experiencing mild to moderate depression (Carek et al., 2011). Factors that may explain our results include: participants may have derived some symptom benefit from participation in the study, the depression measures may have introduced social desirability or repeat test bias over time, and it is possible that our study time frame is insufficient to draw conclusions about long-term depressive symptoms. Further research is needed to determine the relationship between depressive symptoms and CRF.
Finally, we observed that CRF did not vary between age groups. Stability of CRF over age groups varies from existing literature and may be due to the very low CRF values we observed. Existing literature demonstrates that aging is associated with decline in CRF (Kohler, Rorato, Braga, Velho, & Krause, 2016). Factors that may explain our results include that our sample consisted of a relatively older population with minimal younger participants, leading to a lack of variance in age as a variable. Further investigation of CRF in a more diversified age sample is needed in addition to a sample with increased CRF.
Based on our results, further investigation should examine the relationship between CRF, fatigue and depressive symptoms, in order to confirm our results. These data should be compared to individuals with chronic conditions other than HIV, to examine the generalizability of these results across comorbidities.
Limitations
The strengths of our study include a longitudinal study design and objective measure of CRF. However, this study has several limitations. All participants came from a single study site, and were demographically homogenous, with the majority of participants being African American and of similar socioeconomic status, decreasing the generalizability of the results. A multi-site study would provide more diverse and representative data. Additionally, the low CRF levels observed may be related to the age of the adults that comprised this study.
Conclusions
It is essential to address the burdensome symptoms of fatigue and depressive symptoms in PLHIV, since these symptoms are consistently associated with poor clinical outcomes. Our data has demonstrated that CRF was inversely related to fatigue levels, but was not associated with depressive symptoms. Therefore, these results should guide future research aimed at how CRF might inform interventions to improve fatigue in PLHIV.
Acknowledgments
Funding: This work was supported by the American Heart Association under grant 14CRP20380259; a developmental grant from the University Hospitals/Case Western Reserve University Center for AIDS Research (National Institutes of Health Grant # P30 AI036219); and National Institute of Nursing Research under grant R01NR018391
Footnotes
Disclosure/Conflict of Interest: The authors have no conflicts of interest to report.
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