Approximately 1.2 million people living in the United States are infected with the human immunodeficiency virus (HIV), and in 2015 alone, 39,513 new cases of HIV were diagnosed (7). The introduction of highly active antiretroviral therapies has substantially delayed the progression from HIV to acquired immunodeficiency syndrome and has markedly increased life expectancy of people living with HIV (PLWH). When diagnosed early and treated appropriately, the life expectancy of an individual diagnosed with HIV is now nearing that of an individual without HIV (19). Thus, current medical care for PLWH has expanded from primarily focusing on acute treatment of HIV to include long-term management of the disease and associated comorbidities.
Substance (drug or alcohol) abuse is a common comorbid condition found in individuals infected with HIV and often consists of mixed abuse of several substances. In a recent survey, 64% of PLWH reported having used an illicit drug, and of those people, 1 in 4 reported use of illicit drugs or alcohol at a level that warranted treatment (20). Loss of skeletal muscle mass (myopathy) and function are strong predictors of increased mortality among PLWH (32). Human immunodeficiency virus infection (13,34,35) and substance abuse, especially alcohol abuse (23,34), can independently lead to consequences for skeletal muscle, and when both are present, the myopathic effects can be exacerbated (8).
Skeletal muscle health and recovery from muscle damaging events, such as exercise, are mediated in part through an immune system response (33), and HIV-associated muscle wasting has been linked to an increase in circulating inflammatory cytokine concentrations (28). The immune system is compromised in PLWH, and in addition, common substances of abuse including alcohol, marijuana, cocaine, methamphetamines, and heroin can further suppress the immune system, decrease antitumor activity of natural killer cells, and decrease lymphocyte numbers (21). Thus, in PLWH, substance abuse might further compromise the immune system, and thus, play an especially important role in impaired muscle health.
For PLWH without a history of substance abuse, exercise training can improve health, prevent or reverse muscle wasting, and induce muscle hypertrophy and increases in strength (13,16,17,22). A potential mechanism involved in such musculoskeletal health benefits from exercise in PLWH is a reduction in systemic inflammation, which would be evidenced by changes in the circulating cytokine profile. In healthy individuals, long-term (e.g., 12 weeks) resistance exercise training can improve the circulating cytokine profile (14). Although this does not seem to have been examined with PLWH, exercise training can improve the cytokine profile of individuals with immune disease (10,37). Specifically, in patients with the autoimmune disease multiple sclerosis, 8 weeks of resistance exercise training reduced resting interferon (IFN)γ, interleukin (IL)-10, and IL-4 concentrations (37). Similarly, combined aerobic and resistance training (RT) reduced IFNγ and IL-17 (10). The results suggest an anti-inflammatory effect of training programs involving resistance exercise and indicate that RT could be a useful intervention for PLWH to increase muscle mass and improve the cytokine profile.
Human immunodeficiency virus and substance abuse both negatively affect the muscular and immune systems and the combined effects are, at least in part, additive. No study seems to have investigated the effect of RT on muscle health or cytokine concentrations for PLWH recovering from substance abuse. Given that in the absence of substance abuse, RT can increase the muscle mass and strength of PLWH and improve the HIV-relevant cytokine profile in both healthy individuals and individuals with immune disease, it is possible that RT might have the same effects for PLWH recovering from substance abuse. Therefore, the purpose of this study was to determine the effect of RT on muscle health markers (mass, strength, and power) and basal circulating biomarkers for men living with HIV undergoing substance abuse treatment.
Experimental Approach to the Problem
Men infected with HIV and recently admitted to an inpatient substance abuse treatment facility were recruited and assigned to 1 of the 2 experimental conditions for 6 weeks: progressive overload resistance exercise training 3 times per week (RT group) or no exercise (control group). All participants received the treatment facility's standard of care for substance abuse and HIV infection throughout the study period; this care does not include any exercise prescription. Before (PRE) and after (POST) the 6-week intervention period, muscle mass, upper-body and lower-body muscle strength, maximal lower-body power, and resting and fasted concentrations of a panel of circulating cytokines, vascular cellular adhesion molecule–1 (VCAM-1), and cortisol were measured.
Sixteen men (Mean ± SD: 42 ± 11 years, 180 ± 9 cm, and 90 ± 21 kg) infected with HIV and recently admitted to an intensive 60-day inpatient substance abuse/addiction treatment program for PLWH in Dallas, TX volunteered for this study. Participants were informed of the procedures and risks of the study and subsequently provided written informed consent to participate and to have their medical records access by the primary investigator. The study and all procedures were approved by the University of North Texas Institutional Review Board for Use of Humans in Research and complied with the Declaration of Helsinki. To be eligible for the study, volunteers could not have engaged in regular RT for at least 6 months before the study or have any medical or orthotic limitations (e.g., herniated discs) that would put them at increased risk during the exercise sessions or prevent them from performing the exercises involved in the study. All participants were cleared for participation in the study by a physician. Because of the controlled nature of the treatment facility in which the participants live, the sleep pattern, diet, and involvement in nonstudy-related substance abuse treatment activities (e.g., counseling and community service) were similar for all participants. Similarly, adherence to individual medication plans was tightly monitored and enforced by the facility medical staff. Drug use history and most recent CD4+ cell count were obtained from the review of the facility intake forms at the conclusion of the study. Drug use information was not available for 1 participant and recent CD4+ cell count data were not available for 4 participants. The choice of drugs abused (Table 1) were similar between the 2 groups and in general indicated a mixed drug abuse. The most recent CD4+ cell count ranged from 64 to 848 cells·mm−3 and did not differ (p > 0.05) between the RT group (362 ± 188 cells·mm−3) and the control group (619 ± 326 cells·mm−3).
Exercise Test Familiarization Session
Participants were familiarized with the exercise tests (machine bench press, seated knee extension, and standing isometric squat) at least 3 days before the first experimental session (PRE). These tests were selected because they are not technically demanding, and thus, require fewer familiarization sessions than traditional multijoint free weight exercise (e.g., squat). Because participants lived at the treatment facility for only 60 days, the selection of these tests allowed time for familiarization, PRE testing, a 6-week intervention, and POST testing to be performed. After a standardized dynamic warm-up (lunges, high knees, heel kicks, high kicks, and body weight squats), the exercise equipment was fitted to the participant, and device settings (e.g., seatback height) were recorded for use during testing. Participants were then instructed in the proper technique for the exercise tests and subsequently practiced the tests with a light resistance. After participants demonstrated proper technique, the resistance was increased and a few repetitions were performed to determine the proper resistance (weight) to be used during testing.
Experimental Sessions (PRE and POST)
Fasted (12 hours, overnight) resting blood samples were collected using venipuncture of an antecubital vein in the morning at 0700–0800 hours. After blood collection, anthropometric measurements were obtained (body mass, height, skinfolds, and body segment circumferences) and used for subsequent determination of muscle mass using the method of Martin et al. (18). Upper-arm circumference was measured at the midpoint between the acromion process and the lateral epicondyle of the humerus; forearm circumference was measured at the widest point of the forearm. Skinfold thickness was measured at the front of the thigh and medial calf. Participants then consumed the breakfast provided by the treatment facility cafeteria to all of their residents.
After breakfast, participants performed the standardized dynamic warm-up followed by assessment of maximal strength in the machine bench press and standing isometric squat as well as maximal vertical jump performance. Maximal strength (1 repetition maximum [1RM]) in the machine bench press was estimated by the indirect method of Epley (9). Briefly, each participant completed as many repetitions as possible at a resistance load estimated to allow for 2–20 repetitions, and then, the following equation was used to determine maximal strength:
. To determine maximal isometric squat strength, participants stood on a force place (AMTI, Watertown, MA) and, in a quarter squat position, pressed against a fixed barbell for 10 seconds. Peak force generated during the isometric squat was recorded. To determine maximal vertical jump, participants stood on a force plate (AMTI), with hands placed on their hips, and then performed 3 consecutive maximal vertical jumps; the results from the jump that generated the greatest vertical jump height were used for subsequent analysis of power. The POST testing was separated from the last training session by at least 72 hours to avoid short-term, carry-over effects from the last exercise bout.
Resistance Training Program
After the PRE testing was completed, participants were assigned using randomization to 1 of 2 experimental conditions for 6 weeks: RT or control. For the RT group, resistance exercise training was performed 3 times per week (Monday-Wednesday-Friday) for 6 weeks under the supervision of an experienced trainer. Each resistance exercise session involved 3–5 sets of 5–12 repetitions of standard resistance exercises designed to target all major muscle groups. Sessions included free weight exercises (bench press, incline bench press, back squat, calf raise, shoulder press, weighted lunge, upright row, and weighted sit-up) and cable machine exercises (lateral pull down, seated row, bench press, knee extension, and knee flexion). Different loads and exercises were used on different days to provide variation in the exercise stress after progressive overload format modeling. The load used by each participant was determined by the trainer and was increased when participants were able to perform the prescribed repetitions using proper technique. Table 2 illustrates the overload training and resistance exercise prescription for this study.
Whole blood obtained at the PRE and POST testing sessions was allowed to clot and was then centrifuged (1,500g, 15 minutes, 4° C). The resultant serum was stored (−80° C) in multiple aliquots until analysis. Serum cytokine concentrations were determined (in duplicate) by a commercially available multiplex bead-based assay kit (EMD Millipore, Billerica, MA) using a charge coupled device–based Luminex MAGPIX (Luminex, Austin, TX) system. This kit measured the following panel of cytokines: IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF)-α. Vascular cell adhesion molecule–1 and cortisol were measured using commercially available enzyme-linked immunosorbent assays from Abcam (Cambridge, MA) and Alpco (Salem, NH), respectively.
Data were examined for the assumptions of parametric statistics. For the cytokine data, the assumptions of normality and equality of variances were violated; thus, the data were log-transformed before analysis. Data for each variable were analyzed using a 2 (time) × 2 (condition) analysis of variance with repeated measures on time using SPSS version 22 (IBM Corporation, Chicago, IL). Fisher's least significant difference post hoc analysis was used where appropriate to determine pairwise differences. The alpha level of significance was set at 0.05. Data are presented as mean ± SD and as raw, not log-transformed, values.
The results for muscle mass, strength, and power, as well as upper-arm and lower-arm circumferences are presented in Table 3. As expected, the measures of strength (estimated machine bench press 1RM and isometric squat peak force) and the measure of lower-body power (vertical jump power) increased significantly (p ≤ 0.05) from PRE to POST in the RT group but were unchanged in the control group. Similarly, muscle mass and arm circumferences increased significantly in the RT group but were unchanged in the control group. Participants tolerated the exercise testing and RT program well, and no adverse effects of the exercise testing or the RT program were observed. Individual results for bench press and muscle mass are presented in Figures 1 and 2, respectively.
The results for serum cytokines, VCAM-1, and cortisol are presented in Table 4. There were no changes from PRE to POST or time × condition interaction effects observed for IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, VCAM-1, or cortisol. The reported cortisol concentrations were at the high end of the normal range for morning measurements at PRE and POST.
The aim of this study was to determine the effect of RT on muscle mass, muscle strength, and basal concentrations of circulating cytokines for men living with HIV and undergoing treatment for substance abuse. No previous study seems to have investigated or characterized the effect of RT in this clinical population. The major findings of this study were that 6 weeks of RT increased muscle mass, muscle strength, and muscle power. The training intervention had no significant effect on the basal circulating concentrations of the measured biomarkers (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, VCAM-1, or cortisol). It should be noted that, consistent with previous literature (39), there were large individual variations in circulating cytokine concentrations and large individual variations in changes in concentrations over the duration of study for these biomarkers. Overall, the results show that RT can improve the health of men living with HIV who are undergoing treatment for substance abuse and that this improvement does not seem to be associated with a reduction in systemic inflammation as indicated by the circulating cytokine profile.
As expected, the resistance exercise regimen used in this study was successful in improving muscle mass and physical performance measures (muscle strength and power) in this unique population of PLWH undergoing substance abuse treatment. Appreciable work has been completed to investigate the effect of RT in PLWH, and it has been shown that RT can improve muscle mass and strength (22,27). The improvements in those studies were similar to those in this study. The increases in muscle mass and performance in this study are also similar to those previously found for 6 weeks of combined resistance and endurance training in overweight middle-aged men using a RT program that was almost identical to the one used in this study (15). This indicates that the men in this study improved similarly to men without HIV or a substance abuse history. Muscle strength is a key health indicator because it is significantly associated with reduced morbidity and mortality across a range of populations and medical conditions (1,12,38). Therefore, the strength increases found in the current study might have important health implications, especially if these improvements can be maintained or further increased after the 6-week program. Similarly, the increase in muscle mass observed after 6 weeks of RT could aid in combating myopathy (muscle wasting), a condition often comorbid with substance abuse and HIV. Substance abuse and HIV can independently induce myopathy, and when combined, these effects are additive (8). The improvements in muscle mass from RT observed in this study are greater than the improvements in lean body mass observed in men living with HIV after 24 weeks of testosterone replacement therapy (3). Thus, although not directly investigated in this study, the findings suggest that RT could be a more potent tool than hormone therapy to improve skeletal muscle health and counteract myopathy from HIV and substance abuse (2,3). The findings of this study support and expand on the previous findings for PLWH and extend them to PLWH and with substance abuse by demonstrating that RT added to substance abuse treatment can increase muscle mass, strength, and power in this population.
In addition to causing changes in anthropometry, strength, and power, resistance exercise can acutely and chronically alter the circulating cytokine profile. Acutely, resistance exercise potently stimulates cytokine production in men and women with multiple sclerosis (10,37) and in healthy individuals (6,29,30), whereas RT can (25,26), but does not always (11,24), induce a reduction in resting serum proinflammatory cytokine concentrations in healthy individuals. In this study, the 6-week RT intervention did not affect resting cytokine concentrations for PLWH recovering from substance abuse. It is possible that the duration of the training intervention was not sufficient to observe changes in resting cytokine concentrations. Furthermore, because HIV infection is associated with immunosuppression, increased immune cell activation, and a concomitant elevation in the concentrations of proinflammatory cytokines at rest (4,36), it is possible that the HIV status of the participants precluded the intervention from altering resting cytokine concentrations. In addition, participants were recovering from substance abuse. The 4 substances cited as primary and secondary drugs of abuse (methamphetamine, alcohol, cocaine, and marijuana) can impair immune function (5,31), and these effects can synergize with the immunosuppressive effects of HIV infection (5). Thus, the participants' history of substance abuse and HIV status could, at least in part, help explain in the lack of detectable change in resting cytokine concentrations from the exercise intervention.
Although the 6-week RT intervention did not alter the circulating cytokine profile, participants improved muscle mass, strength, and power, which are associated with positive health benefits. These outcomes are especially important for persons affected by myopathy associated with HIV and substance abuse because it seems that the training program targeted specific myopathy-related symptoms (muscle mass, strength, and power). Furthermore, all participants tolerated the exercise testing well and all participants in the RT group tolerated the RT well with no adverse effects. Thus, a supervised resistance exercise program during substance abuse treatment for PLWH could be a valuable addition to the standard of care. Future research should investigate longer durations of training and different exercise protocols (e.g., adding aerobic exercise) in this population.
Based on the findings of this study, RT is a valuable addition to substance abuse treatment for men living with HIV. Patients tolerated the nonlinear periodized resistance exercise intervention 3 times per week with no adverse effects; this suggests that other traditional RT programs previously used successfully by practitioners with other untrained populations are likely to also be efficacious in this population. Because RT is not currently included in the standard of care, men living with HIV undergoing treatment for substance use represent a potential new clientele. Therefore, practitioners should begin to implement such programs in this population and could use the findings of this study to support the efficacy of such interventions in improving health.
This study was funded by an internal grant (ROP) from the University of North Texas to JLV. The authors have no conflicts of interest to disclose. The results of this study do not constitute endorsement by the National Strength and Conditioning Association.
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