Whether patients who are infected with the human immunodeficiency virus(HIV+) should perform regular aerobic exercise and what dose should be prescribed for maximum benefit remains unknown. In patients without HIV infection, exercise has been demonstrated to have beneficial effects on aerobic fitness, mood, immune indices, and disease incidence. In diseases such as ischemic heart disease, diabetes, hypertension, cancer, and emphysema, exercise has been widely recommended(1,4,7,10,13,26). However, the effects of high intensity exercise over a long period of time(“overtraining”) have been well documented to increase infections and worsen immune indices in humans(6,12,18,20,25,28,37) and to increase mortality in laboratory animals(3,9,17). Although the levels of exercise in these studies were very high and likely would not be reproduced in the HIV+ population, HIV+ patients have still routinely received the recommendation from health care practitioners to exercise very little if at all. All of this based on surprisingly few studies that address the HIV+ population.
The utility of exercise training as a therapeutic measure to improve the aerobic fitness, immune indices, and mental outlook in HIV+ patients has not been clearly defined(8,21-24,32,33). Previous studies have suffered from substantial dropout rates, lack of measured aerobic fitness levels, widely disparate disease severity among patients (mixtures of asymptomatic and gravely immunocompromised patients), lack of gender and ethnic diversity, and small sample sizes. To overcome these problems, we studied an ethnically and gender diverse population of HIV+ subjects at an intermediate stage of HIV disease (between 100 and 500 CD4 lymphocyte count/mm3 and no evidence of opportunistic infections). This group of patients seemed very appropriate since this group comprises a growing segment of the HIV+ population and is especially targeted for treatment to prevent further immunologic deterioration. These subjects were randomly assigned to one of two different aerobic cycle ergometer exercise training intensities (three times per week), or to a control (nonexercising) group. Outcome measures included improved aerobic fitness, immune indices, and quality of life. These results help to establish a rational basis for exercise prescriptions in HIV+ patients.
All subjects were HIV+ with CD4 lymphocyte counts between 100 and 500 cells/mm3 on initial evaluation and were without signs of opportunistic infections as determined by health questionnaire, physical examination, chest radiographs, and exercise testing (no evidence of high or low VA/Q abnormalities, pulse oximeter desaturation, etc.). This study was approved by our institutional human investigation review board, and each subject gave written informed consent before participation. Potential study subjects were recruited from the HIV clinic at Harbor-UCLA Medical Center (an inner city county hospital) and randomized to one of three groups (Control, Moderate, and Heavy) by means of a computer-generated randomization process.
Exercise testing. Each subject performed a cardiopulmonary exercise test with gas exchange measurements at study entry and after 6 wk of study participation to accurately determine aerobic function as measured by the gas exchange lactic acidosis threshold (LAT) (5) and peak oxygen uptake (˙VO2max). The lactic acidosis threshold (LAT) was defined as the ˙VO2 above which the ˙VCO2 output(˙VCO2) increased more rapidly than the ˙VO2. This was determined from a plot of ˙VCO2 as a function of ˙VO2 (19,38). Peak ˙VO2 was defined as the maximally tolerated ˙VO2.
The exercise protocol was performed on an electronically braked stationary cycle ergometer (CardiO2 ergometer, Medical Graphics, Minneapolis, MN) and consisted of 3 min of rest, 3 min of unloaded cycling (0 W), and a continuous increase in work rate of 15-25 W·min-1 until exhaustion (marked by inability to maintain a pedaling cadence greater than 50/min despite verbal encouragement by the investigator). Heart rate and rhythm were monitored continuously with a single lead (modified MCL 1) electrocardiogram. Subjects respired through a mouthpiece and wore a noseclip; breath-by-breath gas exchange was measured by an integrated computerized system (CPX/D Cardiopulmonary Exercise System, Medical Graphics, Minneapolis, MN) using a disposable symmetrically disposed Pitot tube flowmeter(31). This system is well suited for the study of HIV+ patients since it allows accurate breath-by-breath flow measurements as well as the disposal of all equipment that comes in contact with the subject. Pulse oximeter estimation of arterial saturation was monitored continuously during each exercise test. All exercise tests were performed with the principal investigator present.
Immunologic indices. Each subject underwent three forms of immune evaluation at entry and after 6 wk of study participation: 1) Skin testing was performed with 0.1 mL of Candida albicans antigen (Berkeley Biologicals, Berkeley, CA, 1:500 m·v-1). The antigen was introduced intradermally with a 25-gauge needle and 1-mL syringe. The resulting induration was measured by the principal investigator on both axes (mm) and the resulting area (mm2) was calculated using the formula for an ellipse (area = π × length × width). 2) Blood was drawn before exercise testing (approximately 9 a.m. in each subject) from an arm vein for measurement of CD4 lymphocyte counts. These assays were all performed using standard laboratory protocol in the hospital Pathology Department at Harbor-UCLA Medical Center.
Virologic testing. Plasma was frozen (-70°C) from the same blood draw for HIV reverse transcriptase polymerase chain reaction (PCR) measurements at entry and after completion of the 6 wk study. All samples were paired, batched, and run at the same time after completion of the study. The number of copies of HIV RNA per mL was determined using the Amplicor commercial assay (27).
Quality of life evaluation. Each subject completed a Quality of Life (QOL) questionnaire at entry and after completion of the study. This self-administered instrument was a subset of the QOL questionnaire validated in prior HIV studies at Harbor-UCLA Medical Center(15).
Physical activity recall questionnaire. Each subject completed a physical activity recall questionnaire at entry and after completion of the study to determine whether significant changes in the amount of exercise performed outside the study had occurred.
Study intervention. Subjects were randomized to one of three groups: 1) The control group was advised to maintain their current level of activity without changes. 2) The moderate intensity exercise training group performed 1 h of exercise training three times per week for 6 wk at a work rate which was 80% of the LAT work rate (determined from the entrance cardiopulmonary exercise test). 3) The heavy intensity exercise training group performed exercise training three times per week for 6 wk at a work rate equal to 50% of the difference between their LAT and their ˙VO2max. This group performed a proportionally shorter amount of exercise while maintaining the total work per session identical to the moderate group. In this study, this resulted in training times of approximately 30-40 min.
All exercise training sessions were performed on a calibrated electronically braked cycle ergometer. Training work rates were not altered during the study, nor were pulse rates or perceived exertion recorded during training sessions.
Statistical analysis. Mean values are expressed as ± SE, unless otherwise specified. Subject demographics at study entry (including the group of subjects who did not complete the study) were compared using an unpaired t-test. Repeated measures ANOVA was used to compare the three groups who completed the study. Individual differences between groups were isolated with post hoc testing. The changes in aerobic fitness parameters (in a given subject group) were compared by pairedt-testing. Nonparametric responses to the QOL questionnaire, HIV PCR, and skin testing were evaluated using the Mann-Whitney Rank Sum Test(Kruskal-Wallis statistic). Significant differences were determined asP < 0.05.
Thirty four subjects were enrolled and 26 (77%) completed the study(Table 1). Patients who dropped out of the study were uniformly distributed among the three groups (three control, three moderate training, two heavy training). The reasons for not completing the study included a lack of regular transportation, conflicting work schedule, lack of motivation to exercise, and parole violation. However, no subject dropped out because of infection or illness. The study population included 11% females, 29% Hispanics, and 20% African-Americans.
The subjects had a mean age (mean ± SD) of 36 ± 9 yr and they had been HIV+ 39 ± 33 months. Of the subjects who entered the study, 27% were smokers. The average CD4 count at entry was 266 ± 128 cells/mm3. All but two patients were on recommended antiretroviral therapy during the study (zidovudine, zidovudine, and didanosine). No HIV or cardiopulmonary medications were altered during the study. The compliance rate with the exercise regimen for subjects who completed the study was 91% across all training periods. There were no significant extracurricular changes in exercise as reported on the pre/post study physical activity recall.
Changes in Aerobic Function with Exercise Training
At entrance, the aerobic parameters of the subjects (LAT and˙VO2max) did not differ significantly among the three groups(Table 1). The measured ˙VO2max for the entire study group was low normal at entry (85% of predicted(38)) and the LAT was 54% of the measured˙VO2max. An intensity related aerobic training effect was observed(Heavy > Moderate) in the exercising training groups relative to the control group. The LAT increased in a statistically significantly fashion in both exercising groups (P < 0.01). However, the˙VO2max and WRMax increased significantly only in the Heavy group (P < 0.01). After 6 wk of exercise training, the LAT, WRMax, and ˙VO2max changes (%, pre to post) in the three groups were (mean ± SE): Control -4% ± 6, -4% ± 4, and-7% ± 5, Moderate 10% ± 9, 3% ± 2, and -2% ± 4, and Heavy 23% ± 8, 11% ± 4, and 13% ± 4, respectively(see Fig. 1 and Table 2)).
Changes in Immune Indices with Exercise Training
CD4 counts. At study entry, the CD4 counts were highest in the Heavy training group and lowest in the Control group. However, this difference at study entry did not reach statistical significance. During the study, the CD4 counts in each of the three groups changes minimally in all three groups: 18 ± 25, 13 ± 14, -3 ± 15 (cells/mm3) for the control, moderate, and heavy exercise training groups, respectively(Fig. 2a and Table 2).
Candida albicans antigen skin testing. The skin test reactivity after 6 wk of study participation increased significantly in the moderate exercise training group (463 ± 401 m2) but not the heavy exercise training group (111 ± 158), while a nonsignificant fall in skin test reactivity was observed in the control group (-35 ± 36)(Fig. 2b and Table 2).
Changes in Viral Replication
Plasma HIV RNA. The number of plasma HIV RNA copies is inversely related to the HIV disease status; thus, a decrease in plasma HIV RNA copies is generally thought to indicate an improvement in immune function(30): At study entry the plasma HIV RNA levels were highest in the moderate group, with lower levels in the heavy and control groups, although these differences did not reach significance(Tables 1 and 2). Although the variability of the plasma HIV RNA was large before study entry, and from the pre- to the post-exercise test, the number of plasma HIV RNA copies decreased the most in the moderate exercise group (-10,403 ± 21,099 copies·mL-1), with smaller decreases observed in the heavy(-1,380 ± 6,331) and control groups (-9,053 ± 3,436)(Fig. 2c). These changes were also not statistically significant.
Changes in Quality of Life with Exercise Training
The results of the self-administered QOL questionnaire are detailed inTable 3. In brief, statistically significant improvements occurred in both exercise training groups relative to the control group for the questions related to quality of life, hope, and desire to continuing living. There were no significant differences between the results of the two exercise groups.
The current study attempts to determine whether regular aerobic exercise training should be recommended to patients who are HIV+, and if so, what training intensity would serve best for the maximum improvement in aerobic fitness, immune indices, and quality of life. Since heavy exercise training is felt by some investigators to be harmful to patients with damaged immune systems (2,8), we specifically designed our investigation to include a heavy exercise training group to determine whether heavy exercise causes adverse effects on immune indices. In addition, a variety of factors result in increased HIV replication in blood, e.g., influenza vaccination (29,35,36) and cytokine therapy (34); therefore, we included an assay of plasma HIV RNA to determine the effects of exercise training at various intensities on this important marker.
To answer these questions, 34 HIV+ subjects with CD4 lymphocyte counts between 100 and 500 (cells/mm3) were entered in the study (75% of the subjects completed the study). This study is unique when compared with prior studies involving exercise training in HIV+ individuals(14,22,23,33) since the population was drawn from an inner city population and included substantial numbers of Hispanics (29%), African-Americans (20%), and females (11%). In addition, this study did not suffer from the high dropout rates (25-50%)(22,23,33) observed in prior studies in HIV+ patients. The study completion rate was quite good (77%). Finally, the current study addressed poor or nonexistent control groups and/or lack of directly measure aerobic fitness by cardiopulmonary exercise testing (pre and post study), and incorporates more sophisticated outcome markers (e.g., plasma HIV RNA) in addition to CD4 counts (16).
The current study demonstrated clear improvements in aerobic function with aerobic exercise training, with the most marked improvement occurring at the highest training level (Fig. 1). The changes in CD4 count and plasma HIV RNA were small and did not reach statistical significance. Statistically significant improvements in immune indices (as measured by skin testing) was observed only in the moderate exercise group(Table 2). There were no episodes of immuno-compromized infections in any group and no participant quit the study for health reasons. Importantly, heavy exercise training resulted in a more marked improvement in aerobic performance and was not statistically different from moderate intensity exercise training in terms of immune indices (except skin testing). Therefore, there was no trend for immune indices to worsen with high intensity exercise training as had been previously postulated. Finally, quality of life improved in all questions for both exercise levels relative to the control group (Table 3).
Although the most rigorous outcome measure regarding aerobic exercise training would be a change in morbidity and mortality for the HIV+ subjects, the proxy outcome markers examined in this study were CD4 counts and plasma HIV RNA. Since short-term changes in CD4 lymphocyte counts may be an incomplete marker of immune response and clinical outcome(11,16,30), skin test reactivity and plasma HIV RNA were also examined. The largest decrease in plasma HIV RNA occurred in the moderate exercise training group although the control and heavy exercise groups also decreased. Therefore, although we failed to demonstrate that exercise training relative to the control group benefits HIV+ patients(as measured by enhanced control of HIV replication), there was no acute worsening related to heavy or moderate intensity exercise training.
In conclusion, aerobic exercise training in an HIV+ patient group is safe and effective in improving exercise tolerance. In addition, it appears that the most marked improvements in aerobic function and quality of life occur with high intensity exercise training relative to the control group, whereas the moderate exercise training yields the most beneficial effect on skin test reactivity. Aerobic exercise training should be promoted as a nonpharmacological therapy for the treatment of HIV+ patients in the intermediate stages of their disease. Expanded studies of longer duration appear warranted.
The authors would like to thank Cindy Sullivan, M.A. for her contributions in the formative stages of this project.
Funding was provided through a University Wide AIDS Task Force Grant.
Current address for W. A. O'Brien is Department of Medicine, UCLA School of Medicine and West Los Angeles Veterans, Affairs Medical Center, Los Angeles, CA.
Address for correspondence: William W. Stringer, M.D., 7 Plank House Road, Savanna, GA 31410.
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Keywords:©1998The American College of Sports Medicine
EXERCISE TRAINING; HIV+; AEROBIC FITNESS; SKIN TESTING; CD4 COUNTS; PLASMA HIV RNA; QUALITY OF LIFE