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Exercise Treatment for HIV–Associated Metabolic and Anthropomorphic Complications

Yarasheski, Kevin E.1; Roubenoff, Ronenn2

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Exercise and Sport Sciences Reviews: October 2001 - Volume 29 - Issue 4 - p 170-174
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Abstract

INTRODUCTION

The metabolic and anthropomorphic complications associated with human immunodeficiency virus (HIV) infection and its treatment include muscle wasting, peripheral insulin resistance, hypertriglyceridemia, hypercholesterolemia, central adiposity, peripheral lipoatrophy, lactic acidosis, and osteopenia (3,5,6,12). The pathogenesis is unclear, but several mechanisms have been proposed (Table 1). Evidence suggests that the pathogenesis is multifactorial, rather than a distinct phenotype caused by a single syndrome or agent. These complications may be associated with increased morbidity, mortality, disability, and cardiovascular disease risks in people infected with HIV. Despite this, highly active antiretroviral medication regimens (HAARTs) used to manage HIV and the acquired immunodeficiency syndrome (AIDS) have effectively lowered plasma viremia, increased CD4+ T-lymphocyte counts, decreased the incidence of opportunistic infections (OIs), and increased survival in most patients.

Table 1
Table 1:
Hypothesized mechanisms for HIV-associated metabolic complications

Because the pathogenesis is unclear, treatments for these complications have been experimental and nonselective. Tested treatments include diet, exercise, pharmacologic agents (insulin secretagogues, insulin sensitizers, HMG-CoA reductase inhibitors, niacin, fibrates), endocrine agents (insulin, androgens, anticytokine agents, anticatabolic/proteolytic agents, growth hormone, growth factors), nutritional supplements (vitamins, minerals, antioxidants, whey protein, glutamine, carnitine, conjugated linoleic acid, creatine, β-hydroxy-β-methylglutarate), and surgery (liposuction).

Weight-lifting and aerobic/endurance exercise training are established and efficacious interventions for the management of several of these complications in HIV-seronegative people (see ACSM Position Statements). Several recent studies suggest that exercise training is an effective nonpharmacologic treatment for HIV-related metabolic and anthropomorphic complications. This review summarizes some of these findings.

HIGHLY ACTIVE ANTIRETROVIRAL REGIMENS USED TO MANAGE HIV/AIDS.

Food and Drug Administration–approved antiviral medications are designed to inhibit reverse transcription of viral DNA in the nucleus of the infected T-lymphocyte (CD4+) or to inhibit the proteolytic processing of proviral particles to minimize the formation of infective HIV viral particles in the T cells (Table 2). Several new inhibitors of viral fusion and entry into CD4+ T cells are in clinical trials.

Table 2
Table 2:
Generic and brand names for the three classes of Food and Drug Administration—approved antiretroviral medications

The nucleoside analog reverse transcriptase inhibitors (NRTIs) were the first medications available to manage HIV infection, followed by the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Patients were typically treated with two-drug combinations (one NRTI plus one NNRTI). Toxicities noted in patients using dual therapy included mitochondrial toxicity, neuropathy, myopathy, muscle wasting, hypertriglyceridemia with low total cholesterol, dorsocervical adipose tissue deposition, peripheral lipoatrophy, nausea, and anemia. In 1996 to 1997, the HIV-aspartyl protease inhibitors (PIs) became available. They are typically used in combination with NRTIs and NNRTIs, and triple therapy is considered the most potent anti-HIV regimen. It is also the most cumbersome, most expensive, and potentially most toxic treatment regimen.

The use of PI-based HAARTs has substantially reduced the high rates of morbidity and mortality associated with HIV infection. Quality of life and survival times have improved. Severe muscle protein wasting and weight loss appear less frequently. However, the introduction of PIs and the development of insulin resistance, hyperlipidemia, central adiposity, peripheral lipoatrophy, lactic acidosis, and osteopenia are temporally related. Some have concluded that PIs cause the metabolic and anthropomorphic complications in HIV, but substantial evidence in opposition to this presumption has appeared. Regardless, we propose that well-designed, monitored, progressive-resistance and aerobic exercise training programs are effective nonpharmacologic treatments for managing the metabolic and anthropomorphic complications in HIV/AIDS.

AIDS WASTING

Before PI-based HAARTs, weight loss was frequently observed in patients in the developed world, and it remains a cardinal feature of AIDS in Africa and Asia (3,5,14). In some, weight loss was rapid, profound, and characterized by muscle wasting, debilitating fatigue, chronic diarrhea, and anorexia. Some of the wasting was attributed to malnutrition, malabsorption, reduced appetite, or the presence of other OIs. Definitions of AIDS wasting include ≥ 10% weight loss at anytime in the prior year or ≥ 5% weight loss in the prior 4 to 6 months (14), or the inability to reestablish premorbid weight (normal or ideal) after weight loss (3). AIDS wasting differs from starvation, where lipids are preferentially utilized and proteins are spared. AIDS wasting is associated with increased morbidity and mortality rates and further compromises immune function (5,14). Death typically ensues when body weight declines to 66% of typical weight or body cell mass declines to 54% of normal (5).

Unexplained, involuntary, persistent weight loss was also observed and remains common today, even with PI-based HAARTs. For example, between 1995 and 1999, 18% of 633 HIV-infected adults lost ≥ 10% of their body weight, and 21% lost 5% to 9% of their body weight over 6 months and sustained this weight loss for ≥ 1 y (13). This is believed to be a form of metabolic dysregulation characterized by negative energy balance, increased rates of whole-body protein synthesis and breakdown, a disproportionately low rate of muscle protein synthesis, activation of proteolytic pathways in muscle, an accelerated plasma glutamine rate of appearance, failure to preserve muscle protein mass at the expense of adipose tissue, and failure to gain lean weight when energy and macronutrient intakes were increased (see reviews [(3,6,13,14]).

The fundamental mechanism for this metabolic dysregulation has not been identified. Initially, overproduction of proinflammatory cytokines (especially tumor necrosis factor-α) was implicated (reviewed in Corcoran and Grinspoon [(3]) in AIDS muscle wasting. However, direct evidence in support of this was not demonstrated. Cytokine-mediated muscle protein wasting cannot be ruled out until intramuscular cytokine levels are measured in AIDS wasting.

In the PI-based HAART era, when weight loss appears to be less, another subtle, unrecognized form of muscle wasting might occur. Body weight may be stable or increasing, but it may include more adipose and less lean, bone mineral, and muscle tissue (12,13). Resistance exercise training might best be targeted to prevent weight loss, maintain or protect a desirable muscle/adipose ratio, or restore body weight and muscle mass to “normal or desirable” levels after a period of weight loss. Treatment strategies range from eradicating acute illness, increasing nutrient and energy intake, weight-lifting exercise training, and pharmacologic and endocrine therapies (anabolic or anticatabolic). Exercise training is contraindicated during rapid weight loss associated with an acute illness or active OI.

RESISTANCE EXERCISE TRAINING FOR AIDS WASTING

Reports indicate that supervised weight-lifting and aerobic exercise are not contraindicated in people infected with HIV (1,2,4,7–11,15). An acute bout of stepping exercise did not increase circulating HIV RNA (viremia), and 8 wk of progressive resistance exercise training (3 d/wk, 1 h/d, 80% one-repetition maximum) increased maximum voluntary muscle strength and physical function in people infected with HIV (7). The exercise program increased fat-free mass (FFM) in AIDS wasting (2.8 kg) and HIV-infected asymptomatic subjects (1.4 kg), and the increments persisted after 8 additional wk of usual activity (Figure 1). Resistance exercise training increased lean mass in HIV-infected men and women and may have been more effective at restoring lean mass in AIDS-wasting patients than in asymptomatic HIV-infected patients.

Figure 1
Figure 1:
Change in lean and fat mass in response to 8 wk of resistance training and after an additional 8 wk of usual activity in adults with or without AIDS wasting. +P < 0.09, **P < 0.002 wasted vs not wasted. (Reprinted from Roubenoff, R., A. McDermott, L. Weiss, J. Suri, M. Wood, R. Bloch, and S. Gorbach. Short-term progressive resistance training increases strength and lean body mass in adults infected with human immuno-deficiency virus. AIDS 13:231–239, 1999. Copyright © 1999 Lippincott Williams & Wilkins. Used with permission.)

Progressive resistance exercise training has been reported to increase lean and reduce adipose tissue mass in HIV-infected women. Agin et al. (1) examined the separate and combined effects of 14 wk of resistance exercise training and whey protein supplementation (high-glutamine, high-quality protein) on lean, adipose tissue mass and maximum voluntary muscle strength in 30 underweight HIV-infected women. Similar increases in FFM (1.4 to 1.6 kg) and body cell mass (0.5 to 0.7 kg) were observed in all three groups. Whole-body adipose mass was reduced most in the exercise group (−1.8 kg). Improvements in maximum voluntary muscle strength were greatest in the women assigned to exercise training(≈ 80%), intermediate in the exercise-plus–whey protein group (≈ 55%), and least in the women who received whey protein without exercise (≈ 10%). Progressive resistance exercise training increased FFM and muscle strength in women with AIDS wasting. The findings did not support whey protein supplementation alone or in combination with resistance exercise training to increase muscle strength or FFM.

COMBINED RESISTANCE AND AEROBIC EXERCISE TRAINING FOR WASTING AND METABOLIC COMPLICATIONS ASSOCIATED WITH HIV/AIDS

We propose that resistance and aerobic exercise training should comprise an effective training program for people living with HIV/AIDS and experiencing metabolic and anthropomorphic alterations. In support of this, Roubenoff et al. (8) reported that 16 wk of combined weight lifting and aerobic exercise training increased upper- and lower-body muscle strength by 7% to 19% and reduced trunk adipose tissue mass by 1.1 kg but did not increase lean mass or bone mineral density in 10 HIV-infected men receiving PI-based HAARTs.

Two studies support the notion that progressive resistance exercise training attenuates AIDS muscle wasting and provides a cardioprotective effect to oppose the metabolic complications associated with HIV/AIDS. Yarasheski et al. (15) found that an individualized, supervised progressive resistance exercise training program (three upper- and four lower-body exercises, 1 to 1.5 h/d, 4 d/wk, 16 wk) increased FFM by 1.4 kg, increased thigh muscle cross-sectional area by 5 to 7 cm2, and did not reduce adipose tissue mass. Maximum voluntary muscle strength increased by 23% to 38%. Fasting serum triglycerides declined after training, especially in subjects with baseline hypertriglyceridemia (15). Resistance exercise training increased muscle mass and muscle strength and may have promoted serum triglyceride clearance in hypertriglyceridemic HIV-infected men treated with antiviral therapy.

In a 24-wk study, 43 eugonadal men with AIDS wasting were randomly assigned to a progressive resistance exercise training (3 times/wk) or no–exercise training groups and further randomized to receive 200 mg/wk testosterone enanthate (TE) or placebo in a double-blind, placebo-controlled manner (4). Equivalent increments in muscle strength (9% to 28%), arm and thigh muscle cross-sectional areas, and lean body mass (4% to 9%) were noted in the three treatment groups. Exercise training without TE increased serum high-density lipoprotein cholesterol levels, whereas they tended to decrease in the TE/no exercise group. Progressive resistance exercise training induced muscle hypertrophy and a cardioprotective effect in men with AIDS wasting.

Combined Resistance Exercise Training and Anabolic-Androgenic Agents

This appears justified because 20% to 50% of men with AIDS are hypogonadal and replacement androgens correct this deficiency (3). These studies indicate that progressive resistance exercise training improves lean and muscle mass, increases maximum voluntary muscle strength, and improves quality of life and well-being in AIDS wasting (2,9,10). Whether these improvements are amplified by combining exercise with anabolic-androgenic agents (TE, oxandrolone, nandrolone decanoate, oxymetholone) in HIV/AIDS is controversial. The distinction is important because the use of anabolic-androgenic therapies has been associated with additional risks for dyslipidemia, hepatotoxicity, prostate hypertrophy, increased libido, and acne (3,4,10) in HIV/AIDS. They may not necessarily add to the exercise-induced muscle hypertrophy or increased muscle strength. In general, physiologic replacement of anabolic-androgenic agents plus resistance exercise training was no more effective at increasing muscle mass and strength than was exercise alone (2,4), whereas supraphysiologic doses of TE, oxandrolone, and nandrolone decanoate plus resistance exercise training were more effective than exercise alone (9,10). High-dose anabolic-androgenic therapy may be required to amplify exercise-induced muscle hypertrophy in HIV/AIDS, but the long-term tolerability of high-dose anabolic-androgenic therapy and the effects on adipose tissue distribution, lipid profiles, and liver function need to be examined in HIV/AIDS.

Cardiovascular Exercise Training and HIV/AIDS

In HIV-seronegative men and women, aerobic exercise training is effective for reducing adiposity, serum triglycerides, total and low-density lipoprotein cholesterol levels, and cardiovascular disease risk and for increasing peripheral insulin sensitivity and high-density lipoprotein cholesterol levels (see ACSM Position Statements). The benefits of aerobic exercise training would appear ideal to oppose the metabolic and anthropomorphic alterations associated with HIV/AIDS. However, a large clinical trial of aerobic exercise training has not been performed in the current era of metabolic and anthropomorphic complications in HIV/AIDS.

In studies conducted before the appreciation of the HIV/AIDS-associated metabolic and anthropomorphic complications, aerobic exercise training improved aerobic capacity, work output, indexes of immune function, mental attitude, and quality of life in small heterogeneous groups of people living with HIV/AIDS (reviewed in Stringer [(11]). Other studies (reviewed in Stringer [(11]) reported similar exercise-induced improvements in aerobic capacity and power but only in participants who attended ≈ 50% to 75% of the prescribed exercise training sessions. Supervised, monitored, and progressive exercise training programs may be required to motivate and improve exercise compliance and effectiveness in people living with HIV/AIDS. Evidence is lacking, but it appears likely that aerobic and resistance exercise training trials will be beneficial for HIV/AIDS patients with anthropomorphic and metabolic complications.

SUMMARY

Progressive resistance exercise training interventions are particularly useful to manage AIDS wasting. Combined aerobic and resistance exercise training regimens should be further evaluated for their effectiveness in treating muscle wasting, muscle fatigue and weakness, central adiposity, peripheral insulin resistance, dyslipidemias, and osteopenia in HIV/AIDS. Exercise training programs can be less expensive and equally effective and may avoid drug toxicities common to pharmacologic or hormonal therapies. The use of exercise training to modulate muscle substrate metabolism in HIV/AIDS may be more appealing than treatment with anabolic, anticatabolic, glucose-, or lipid-lowering agents in HIV/AIDS. Some of these agents add to the excessive pill burden associated with HAARTs and have been associated with hepatotoxicity and other adverse events. Combined exercise training with low-dose oral glucose- and lipid-lowering agents may provide added benefits but need to be tested. Strategies that promote long-term adherence to a prescribed progressive exercise regimen will be most effective in HIV/AIDS.

Acknowledgments

K.E.Y. is supported by National Institutes of Health grants DK-49393, DK-54163, DK-59531, DK-56341, RR-00036, RR-00954, and AI-20593. R.R. is supported by USDA Cooperative Agreement 58-1950-9-001 and National Institutes of Health grants AG-15797, DK-45734, and RR-00054. Barbara Stanerson, PT, Jill Schulte, MS, Michael Wood, BS, and Jennifer Layne, MS, provided exercise training expertise.

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Keywords:

muscle protein wasting; hyperglycemia; dyslipidemia; central adiposity; HIV-protease inhibitors

© 2001 Lippincott Williams & Wilkins, Inc.