Skip Navigation

Dysregulated Energy Expenditure in HIV-Infected Patients: A Mechanistic Review

  1. Evelyn Chang1,
  2. Rajagopal Sekhar1,2,
  3. Sanjeet Patel1, and
  4. Ashok Balasubramanyam1,2
  1. 1Translational Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas
  2. 2Endocrine Service, Ben Taub General Hospital, Houston, Texas
  1. Reprints or correspondence: Dr. Ashok Balasubramanyam, Translational Metabolism Unit, Div. of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Rm. 700B, One Baylor Plaza, Houston, TX 77030 (ashokb{at}bcm.tmc.edu).
 
Next Section

Abstract

Metabolic abnormalities are common in patients with human immunodeficiency virus (HIV) infection and range from protein catabolism to lipodystrophy and dyslipidemia associated with the use of highly active antiretroviral therapy. One abnormality is increased resting energy expenditure, which even occurs in clinically stable HIV-infected patients. Increased resting energy expenditure may aggravate the tendency towards weight loss and wasting, which are independent predictors of mortality. Despite much investigation, the factors associated with altered resting energy expenditure remain unclear; viral load, CD4 cell count, use of antiretroviral drugs, body composition, hormones, and proinflammatory cytokines have been imputed. Mechanisms that could explain increased resting energy expenditure include the HIV accessory protein viral protein R, antiretroviral drugs that affect mitochondrial function, and futile cycling within adipocytes. Other components of energy expenditure are also important to overall energy balance and may also be affected. Identifying unifying mechanisms will be an important step to finding effective treatments for HIV-related alterations in energy expenditure and to reversing metabolic risks in patients with HIV infection.

Metabolic abnormalities in patients with HIV infection range from accelerated protein catabolism (in the pre-HAART era) to lipodystrophy and dyslipidemia associated with HAART. One feature that was observed in the pre-HAART period and that has persisted since the advent of HAART is increased resting energy expenditure (REE). Increased REE, if unmatched by increased energy intake, may aggravate loss of both weight [1] and lean body mass, which are independent predictors of mortality in HIV-infected patients [2–6]. A similar phenomenon of increased REE has been observed in other chronic diseases, such as end-stage renal disease [7], rheumatoid arthritis [8], cancer [9], and chronic obstructive pulmonary disease [10]. Interventions, such as diet counseling [11, 12], nutritional supplementation [13–15], exercise [16, 17], and pharmacologic therapies (with megestrol acetate [18], dronabinol [19], thalidomide [20, 21], growth hormone [22–24], and testosterone [25, 26]) may prevent loss of lean body mass in HIV-infected patients. However, no intervention has proven to be effective for normalizing REE.

Previous SectionNext Section

Methods

We searched the PubMed database for articles published before 1 February 2006 and limited the search to articles published in the English language and involving adult human subjects. We used combinations of the terms “HIV,” “HAART,” “resting energy expenditure,” and “energy expenditure.” We only considered articles that reported outcomes of weight loss, REE, and REE per kg of fat-free mass (FFM).

We identified 85 articles with these search terms. Twenty-five articles were excluded: 5 did not include weight loss or REE as outcomes, 10 involved children, 3 lacked abstracts, and 7 had limited statistical analyses. Eighteen were review articles that provided us with additional references. We reviewed various types of literature, including case-control studies, textbooks, letters and/or editorials, and review articles about energy expenditure in other patient populations. Finally, 97 sources were selected, including 10 randomized, controlled trials; 18 cohort studies; 40 cross-sectional studies; 8 review articles; 2 letters; 2 meta-analyses; 12 laboratory reports; 1 textbook; 2 case-control studies; 1 case series; and 1 case report. The details of 5 cross-sectional and cohort studies are shown in the Appendix.

Previous SectionNext Section

Definition Of Ree

Total energy expenditure (TEE) can be divided into 4 measurable components: REE, physical activity, thermic effect of food, and adaptive thermogenesis. REE is the largest component, comprising 60%–65% of TEE [27]. REE is defined as the amount of energy consumed during metabolic activities to maintain homeostasis at rest. Voluntary physical activity fluctuates daily but generally comprises ∼30% of TEE in sedentary adults. Thermic effect of food is the energy consumed during digestion, absorption, and storage of food, comprising ∼10% of TEE [27]. Adaptive thermogenesis is a variable amount of energy expended in response to environmental changes, such as cold temperature, physical stress, trauma, and overfeeding. REE has been the focus of attention among HIV-infected patients.

There is generally a linear relationship between REE and FFM in healthy, nonobese adults [28, 29]. This relationship may be modeled using organ and tissue masses measured by MRI, assuming there to be stable, specific resting metabolic rates of individual organs and tissues [28, 30]. The most metabolically active organs are the liver, kidneys, heart, and brain, which together account for 5%–6% of body mass [28]. Skeletal muscle and adipose tissue, which constitute a large proportion of body mass, have some of the lowest metabolic rates [28]. FFM, particularly in the skeletal muscle and liver, explains 85% of the variance in REE [30].

Because FFM varies with age and sex, REE should be adjusted for FFM when comparing individuals. Body composition can be assessed by the following different methods to obtain a measure of FFM: bioelectrical impedance analysis, dual-energy X-ray absorptiometry, skinfold thickness, underwater weighing, and MRI or CT imaging. Bioelectrical impedance analysis and dual-energy X-ray absorptiometry are frequently used measurements and are highly correlated among control subjects with regard to FFM [48, 55], but bioelectrical impedance analysis does not adequately measure fat distribution. Because obesity is generally associated with increases in both fat mass and FFM, obese individuals have greater REE [31, 32] and TEE [32, 33] than nonobese patients.

Techniques to measure REE include indirect calorimetry, direct calorimetry, and double-labeled water analysis. Indirect calorimetry measures the rates of oxygen consumed (VO2) and carbon dioxide produced (VCO2) in a hood enclosing the head of an individual at rest and uses this information to calculate the respiratory quotient (RQ) according to the formula RQ = VCO2/VO2. REE can be calculated [29]:

where 4.686 is the caloric equivalent of a liter of oxygen when the RQ is 0.707, 0.707 is the RQ when fat is oxidized, 0.361 is the difference in the caloric equivalent of the liter of oxygen when the RQ is between 1.000 and 0.707, and 0.293 is the difference between the RQ for carbohydrate and fat oxidation.

Indirect calorimetry measures REE quite accurately and is easy to perform, but it requires the subject to remain still, awake, and undistracted while the measurements are obtained. Indirect calorimetry does not measure energy expenditure due to anaerobic processes or permit analysis of the specific type of fuel metabolized. Direct calorimetry uses the same principle, except the subject is placed completely within a sealed chamber. Direct calorimetry is very accurate and can track changing energy expenditure while a subject performs activities, but it is not widely available because of the expense of installing and maintaining a whole-body metabolic chamber. In the double-labeled water method, 2H218O is administered orally, and the loss of 2H2 and 18O is measured in saliva, urine, or blood over time by mass spectrometry. Oxygen and carbon dioxide exchange—and thus, energy expenditure—can be calculated from the changing isotope levels. This technique permits measurements of energy expenditure in a free-living subject, but it involves the expense of the stable isotopes and mass spectrometry. The majority of studies of REE in HIV-infected patients have used indirect calorimetry.

Previous SectionNext Section

Ree In Untreated Hiv-Infected Patients

Early research focused on REE, because it was thought to contribute to “AIDS wasting syndrome” [34]. Reports in the pre-HAART era [35–37] were conflicting with regard to whether REE per kg of FFM is elevated in HIV-infected patients. Importantly, REE per kg of FFM is increased even in asymptomatic HIV-infected patients [38, 39], suggesting that HIV infection, per se, is associated with increased REE. Viral load is correlated with REE per kg of FFM, and CD4 cell count may also be associated with changes in REE [40]. Patients with AIDS experience greater increases in REE per kg of FFM than patients with HIV infection who do not have AIDS; patients with AIDS and secondary or opportunistic infection experience even greater increases [41–44]. However, malabsorption [45] and cachexia [36] may be associated with a decrease in REE. Therefore, because of the varied complications of HIV infection, there is an extraordinarily wide range in REE, which could account for inconsistencies among the results of different metabolic studies [46].

Previous SectionNext Section

Ree In The Haart Era

Many studies, conducted both before and after the widespread use of HAART, have shown that REE per kg of FFM is indeed 9%–10% (630–663 kJ/day) higher in asymptomatic HIV-infected persons than it is in HIV-negative nonobese adults [47]. The factors associated with increased REE in asymptomatic HIV-infected patients remain unclear. Most investigations have focused on men; thus, it is difficult to ascertain if sex has an independent effect on REE. Two studies of asymptomatic HIV-infected women have shown that their REE is higher than that of HIV-uninfected women, even after adjusting for body composition [48, 49]. Furthermore, there are no reports of differences in REE among HIV-infected patients of different ethnicities. However, because ethnicity may contribute to differences in energy expenditure in HIV-uninfected persons [50, 51], this is a relationship worth investigating.

REE per kg of FFM is increased even in asymptomatic HIV-infected patients who are experiencing viral suppression while receiving HAART [52–54]. The specific contribution of HAART to REE has been difficult to quantify, because many early studies did not compare asymptomatic patients receiving HAART with those not receiving HAART. However, 1 study showed that viral load exerts a persistent effect on REE, despite HAART. Among a cohort of 372 HIV-infected patients, there was a significant increase in REE of 90 kJ/day per log10 copies/mL increase in HIV RNA load after adjusting for age, FFM, CD4 cell count, and HAART use [55]. Of note, viral load has not been correlated with REE in HIV-infected women [48] or in patients with lipodystrophy [56].

Some studies, as well as a recent meta-analysis, suggest that REE may not be significantly affected by HAART [47, 57], although others suggest that HAART exerts an independent effect on REE [55, 58]. An example of the latter is a longitudinal cohort study that examined the effects of initiating therapy with a protease inhibitor—based HAART regimen among asymptomatic, weight-stable, protease inhibitor—naive HIV-infected patients [59]. After the initiation of therapy, there was a significant decrease in viral load and an increase in CD4 cell count, followed by a decrease in REE per kg of FFM. After 24 weeks, there was no difference in REE between the HIV-infected patients and the HIV-uninfected control subjects, suggesting that HAART decreases REE by decreasing viral load. However, in another study, patients with HIV-associated wasting did not experience a significant change in REE after a median of 62 days of treatment with indinavir [60]. It is likely that these patients already had a lower REE than healthy persons because of malnutrition, although this was not assessed in the study. Another study demonstrated the independent effects of viral load and HAART on REE [55]. After adjusting for FFM and age, the mean REE (±SD) among HIV-infected patients receiving various HAART regimens was 250 ± 72 kJ/day greater than that among HAART-naive patients. This difference between the 2 groups was even greater after adjusting REE for CD4 cell count and viral load. The significance of this is uncertain, because it seems to contradict the findings of other studies. It is possible that various classes of drugs influence REE differently and that duration of HAART may affect REE.

HAART has been associated with body composition changes characterized by fat “redistribution” [61–65], a term commonly used to describe some combination of fat atrophy (usually peripheral) and fat accumulation (usually central). Although lipoatrophy and lipohypertrophy coexist, the 2 processes may be independent; lipoatrophy is a more specific consequence of HIV infection [66]. Scoring systems for lipodystrophy have been developed on the basis of body composition (trunk-to-limb fat ratio), waist-to-hip ratio, cholesterol level, and demographic characteristics [67]. However, classifying patients with variable degrees of lipodystrophy remains difficult. The question is whether clinically evident lipodystrophy—characterized by lipoatrophy of face, limbs, and buttocks; gynecomastia; lipomas; dorsocervical fat pad; increased visceral adipose tissue; insulin resistance; and dyslipidemia [54, 67]—exerts an effect on REE that exceeds that of HIV infection alone. Altered body composition certainly contributes to increased REE in HIV-infected patients with lipodystrophy; REE has been significantly correlated with waist-to-hip ratio [57], FFM [48, 53, 55, 56], and fat mass [53]. However, studies investigating the effects of fat redistribution have had varying results; some revealed that HIV-infected patients with lipodystrophy had greater REE per kg of FFM than those without lipodystrophy [57, 56], others found no difference [53, 61], and 1 study suggested that REE per kg of FFM is actually lower in HIV-infected patients with lipodystrophy [68]. A detailed meta-analysis revealed no significant difference in REE per kg of FFM between HIV-infected patients with and those without lipodystrophy [47]. However, in a recent study published since that meta-analysis, HIV-infected patients with lipodystrophy had increased REE, compared with HIV-infected patients without lipodystrophy; having lipodystrophy was associated with increased lipid oxidation and increased total energy and fat intake [69].

Previous SectionNext Section

Ree And Cytokines

Elevated levels of proinflammatory cytokines may contribute to cachexia and anorexia in patients with AIDS, as they do in patients with cancer [70] and rheumatoid arthritis [8]. Increased REE is correlated with serum levels of the catabolic cytokines IL-1β and TNFα in HIV-infected men [58]. In addition, TNFα is associated with a decrease in lean body mass [58], often in the context of acute parasitic infection [34]. However, the correlation between REE and TNFα is weak, particularly among asymptomatic HIV-infected women [49], who tend to have higher TNFα levels than HIV-infected men. The levels of soluble TNF receptor types I and II, which reflect TNF activity, increase with disease severity but do not correlate with REE in asymptomatic and symptomatic HIV-infected males [71]. Among patients with AIDS and secondary infections, increased REE per kg of FFM correlates with the inflammatory markers C-reactive protein level, erythrocyte sedimentation rate, ferritin level, IL-6 level, and soluble TNF receptor type I level [43]. Of these, C-reactive protein level is an independent predictor of REE per kg of FFM.

Elevated rates of lipolysis and protein turnover are also associated with increased REE due to unclear mechanisms [54, 72, 73]. Patients with congenital forms of lipodystrophy also have hyperglycemia, hypertriglyceridemia, and insulin resistance [74, 75], which are associated with increased lipolysis and protein turnover and elevated REE [76, 77]. The hypermetabolism of lipids and protein could be cytokine mediated. For instance, patients experiencing the early stages of cancer often have high circulating levels of cytokines, such as TNFα [70] and leukemia inhibitory factor [78], that are associated with increased lipolysis, insulin resistance, and elevated REE. Likewise, increased protein breakdown is correlated with elevated REE in HIV-infected patients and is associated with increased levels of TNFα and IL-6 [38].

Altered regulation of anabolic and adipocyte hormones has also been implicated in causing increased REE. Serum testosterone concentration [48, 58] has been positively correlated with REE, and serum leptin concentration [48] has been inversely correlated with REE, although neither has been correlated with REE per kg of FFM. However, the topic of dysregulated hormonal control of REE has not been systematically explored. Altered regulation of other hormonal axes involved in energy homeostasis, such as thyroid hormones, catecholamines, TNFα, IL-6, leptin, adiponectin, and resistin, could potentially result from chronic immune activation.

Previous SectionNext Section

Possible Mechanisms Underlying Increased Ree

Mitochondrial activity, through substrate oxidation and heat dissipation, is a key mechanism of energy expenditure in the basal state; thus, mitochondrial dysfunction is a likely cause of increased REE. Several factors could contribute to mitochondrial dysfunction in HIV-infected patients receiving and those not receiving HAART. First, there is a plausible role for a product of HIV itself. The HIV accessory protein viral protein R can reduce the mitochondrial membrane potential, inducing both a proton leak and apoptosis. By associating with the adenosine nucleotide translocator, viral protein R converts the mitochondrial permeability transition pore complex into a nonspecific channel, causing usually sequestered protons and mitochondrial cofactors to leak into the cytosol and inducing apoptosis by altering the ratio of the apoptosis-regulating regulatory proteins Bcl and Bax [79]. These effects could lead to altered energy regulation, adipocyte apoptosis, and lipotoxic insulin resistance.

Second, HAART drugs could affect mitochondrial function. Nucleoside reverse-transcriptase inhibitors inhibit DNA polymerase γ and, thus, mitochondrial transcriptional activity [80]. The action of nucleoside reverse-transcriptase inhibitors results in reduced amounts of mitochondrial DNA [80–84], which, when superimposed on abnormalities of mitochondrial ultrastructure [84, 85] and respiratory chain dysfunction [85–87], could reduce the efficiency of ATP production. Furthermore, mitochondrial DNA depletion in adipose tissue could cause apoptosis and lipoatrophy [83, 88, 89].

Finally, increased futile cycling could increase energy expenditure. Metabolic processes are regulated at several levels (e.g., gene transcription, protein translation, and posttranslational modifications), resulting in multiple mechanisms of substrate use to produce energy. These mechanisms can be envisioned as a set of cyclic events, generally occurring in series. Alterations in this system could induce redundancies, which would result in inefficient substrate use, generating heat rather than energy [90]. Patients with HIV-associated lipodystrophy have distinct metabolic abnormalities in lipid turnover. The rates of total and net lipolysis in the fasting state are markedly elevated, together with a marked increase in adipocyte reesterification [54]. These kinetic abnormalities indicate an increase in futile cycling within the adipocyte. Patients also have elevated plasma and whole-body lipid oxidation rates, as well as increased hepatic fatty acid reesterification [54]. Moreover, in the fed state, there is severe retardation of lipid clearance from chylomicrons, because the disposal of dietary fat is markedly prolonged by a defect in the entrapment function of lipoprotein lipase, leading to impaired fat storage [91]. Thus, the severe hypertriglyceridemia characteristic of HIV-associated lipodystrophy is a result of impaired clearance of triglyceride-rich lipoproteins in both fasting and fed states. These defects likely have a direct impact on energy expenditure. While fasting, increased futile cycling could elevate energy expenditure; while in the fed state, markedly delayed clearance of triglyceride-rich lipoproteins could contribute to increased diet-induced thermogenesis and further increase energy expenditure.

Previous SectionNext Section

Comparison Of Ree And Tee

REE is only a piece of the puzzle why HIV-infected patients tend to maintain a negative energy balance and lose weight. As some investigators have indicated, there does not seem to be a definite relationship between REE and weight change [44, 92]. In the absence of opportunistic infections, many patients are able to maintain a stable weight, even when not receiving HAART. TEE, which takes physical activity and diet-induced thermogenesis into account, is the true determinant of energy balance and weight change. To maintain weight, TEE must equal caloric intake.

Activity-related energy expenditure, TEE minus REE, contributes to most of the variance in TEE [93]. Physical activity, the largest component of activity-related energy expenditure, may be partially responsible for the negative energy balance that occurs during episodes of weight loss. However, studies have found that episodes of rapid weight loss associated with opportunistic infections are usually accompanied by fatigue and decreased physical activity, resulting in an overall decrease in TEE [44, 93]. This decrease in TEE may help to conserve lean body mass by counterbalancing increased REE. Diet-induced thermogenesis may not be as important quantitatively, although 1 study demonstrated that the level of diet-induced thermogenesis in HIV-infected patients was elevated, compared with that in HIV-uninfected control subjects [94].

When compared with a healthy HIV-uninfected control group, both asymptomatic HIV-infected patients [95, 96] and HIV-infected patients with secondary infections who were untreated with HAART [44] appeared to have decreased or normal TEE; this may represent an adaptive phenomenon, because many of these patients had decreased caloric intake. Decreased caloric intake, rather than increased REE, significantly correlates with the rate of weight loss [41, 44, 93]. Energy intake can be compromised by anorexia associated with opportunistic infections, adverse effects of antiretroviral drugs, upper gastrointestinal disease, malabsorption, or abnormal intermediary metabolism of carbohydrates, protein, and fat [44]. In weight-stable, asymptomatic HIV-infected patients untreated with HAART, increased caloric intake compensates for increased REE and accelerated protein turnover [38].

A subset of HIV-infected patients was found to have increased TEE. HIV-infected, men experiencing viral suppression with lipodystrophy had increased TEE, compared with that of both HIV-infected subjects without lipodystrophy and healthy control subjects—likely because of increased REE [56]. The factors underlying elevated REE and TEE in patients with lipodystrophy are poorly understood, but loss of body fat may be a contributor [56].

Previous SectionNext Section

Conclusions

Increased energy expenditure represents a persistent metabolic abnormality in HIV-infected patients. Increased REE contributes to nutritional imbalance and wasting. The causes of increased REE likely include viral factors, effects of secondary infections or complications, and effects of specific antiretroviral drugs. As part of the approach towards reducing metabolic risks in HIV-infected patients, it will be important to specify unifying mechanisms and find effective treatments for the alterations in energy expenditure.

Previous SectionNext Section

Acknowledgments

Financial support. National Institutes of Health (RO1 HL73696 to A.B.).

Potential conflicts of interest. All authors: no conflicts.

  • Received November 14, 2006.
  • Accepted February 12, 2007.
Previous SectionNext Section

Appendix

Selected cross-sectional and cohort studies

Previous Section
 

References

  1. ↵
    1. Mwamburi DM,
    2. Wilson IB,
    3. Jacobson DL,
    4. et al
    . Understanding the role of HIV load in determining weight change in the era of highly active antiretroviral therapy. Clin Infect Dis 2005;40:167-73.
    Abstract/FREE Full Text
  2. ↵
    1. Melchior JC,
    2. Niyongabo T,
    3. Henzel D,
    4. Durack-Bown I,
    5. Henri SC,
    6. Boulier A
    . Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition 1999;15:865-9.
    CrossRefMedlineWeb of Science
    1. Tang AM,
    2. Forrester J,
    3. Spiegelman D,
    4. Knox TA,
    5. Tchetgen E,
    6. Gorbach SL
    . Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002;31:230-6.
    MedlineWeb of Science
    1. Kotler DP,
    2. Tierney AR,
    3. Wang J,
    4. Pierson RN Jr
    . Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 1989;50:444-7.
    Abstract/FREE Full Text
    1. Wheeler DA,
    2. Gilbert CL,
    3. Launer CA,
    4. et al
    . Weight loss as a predictor of survival and disease progression in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:80-5.
    MedlineWeb of Science
  6. ↵
    1. Palenicek JP,
    2. Graham NM,
    3. He YD,
    4. et al
    . Weight loss prior to clinical AIDS as a predictor of survival. Multicenter AIDS Cohort Study Investigators. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10:366-73.
    MedlineWeb of Science
  7. ↵
    1. Neyra R,
    2. Chen KY,
    3. Sun M,
    4. Shyr Y,
    5. Hakim RM,
    6. Ikizler TA
    . Increased resting energy expenditure in patients with end-stage renal disease. JPEN J Parenter Enteral Nutr 2003;27:36-42.
    Abstract/FREE Full Text
  8. ↵
    1. Rall LC,
    2. Roubenoff R
    . Rheumatoid cachexia: metabolic abnormalities, mechanisms, and interventions. Rheumatology (Oxford) 2004;43:1219-23.
    Abstract/FREE Full Text
  9. ↵
    1. Lagman RL,
    2. Davis MP,
    3. LeGrand SB,
    4. Walsh D
    . Common symptoms in advanced cancer. Surg Clin N Am 2005;85:237-55.
    CrossRefMedline
  10. ↵
    1. Creutzberg EC,
    2. Schols AM,
    3. Bothmer-Quaedvlieg FC,
    4. Wouters EF
    . Prevalence of an elevated resting energy expenditure in patients with chronic obstructive pulmonary disease in relation to body composition and lung function. Eur J Clin Nutr 1998;52:396-401.
    CrossRefMedlineWeb of Science
  11. ↵
    1. McDermott AY,
    2. Shevitz A,
    3. Must A,
    4. Harris S,
    5. Roubenoff R,
    6. Gorbach S
    . Nutrition treatment for HIV wasting: a prescription for food as medicine. Nutr Clin Pract 2003;18:86-94.
    Abstract/FREE Full Text
  12. ↵
    1. Rabeneck L,
    2. Palmer A,
    3. Knowles JB,
    4. et al
    . A randomized controlled trial evaluating nutrition counseling with or without oral supplementation in malnourished HIV-infected patients. J Am Diet Assoc 1998;98:434-8.
    CrossRefMedlineWeb of Science
  13. ↵
    1. Williams SB,
    2. Bartsch G,
    3. Muurahaienen N,
    4. Collins G,
    5. Raghavan SS,
    6. Wheeler D
    . Protein intake is positively associated with body cell mass in weight-stable HIV-infected men. J Nutr 2003;133:1143-6.
    Abstract/FREE Full Text
    1. Berneis K,
    2. Battegay M,
    3. Bassetti S,
    4. et al
    . Nutrition supplements combined with dietary counseling diminish whole body protein catabolism in HIV-infected patients. Eur J Clin Invest 2000;30:87-94.
    MedlineWeb of Science
  15. ↵
    1. Suttmann U,
    2. Ockenga J,
    3. Schneider H,
    4. et al
    . Weight gain and increased concentrations of receptor proteins for tumor necrosis factor after patients with symptomatic HIV infection received fortified nutrition support. J Am Diet Assoc 1996;96:565-9.
    CrossRefMedlineWeb of Science
  16. ↵
    1. O'Brien K,
    2. Nixon S,
    3. Glazier RH,
    4. Tynan AM
    . Progressive resistive exercise interventions for adults living with HIV/AIDS. Cochrane Database Syst Rev 2004:4248.
  17. ↵
    1. Lox CL,
    2. McAuley E,
    3. Tucker RS
    . Aerobic and resistance exercise training effects on body composition, muscular strength, and cardiovascular fitness in an HIV-1 population. Int J Behav Med 1996;3:55-69.
    CrossRefMedlineWeb of Science
  18. ↵
    1. Von Roenn JH,
    2. Armstrong D,
    3. Kotler DP,
    4. et al
    . Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 1994;121:393-9.
    Abstract/FREE Full Text
  19. ↵
    1. Beal JE,
    2. Olson R,
    3. Laubenstein L,
    4. et al
    . Drobabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10:89-97.
    CrossRefMedlineWeb of Science
  20. ↵
    1. Reyes-Teran G,
    2. Sierra-Madero JG,
    3. Martinez del Cerro V,
    4. et al
    . Effects of thalidomide on HIV-associated wasting syndrome: a randomized, double-blind, placebo-controlled clinical trial. AIDS 1996;10:1501-7.
    MedlineWeb of Science
  21. ↵
    1. Haslett P,
    2. Hempstead M,
    3. Seidman C,
    4. et al
    . The metabolic and immunologic effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses 1997;13:1047-54.
    MedlineWeb of Science
  22. ↵
    1. Paton NI,
    2. Newton PJ,
    3. Sharpstone DR,
    4. et al
    . Short-term growth hormone administration at the time of opportunisitic infections in HIV-positive patients. AIDS 1999;13:1195-202.
    CrossRefMedlineWeb of Science
    1. Mulligan K,
    2. Tai VW,
    3. Schambelan M
    . Effects of chronic growth hormone treatment on energy intake and resting energy metabolism in patients with human immunodeficiency virus-associated wasting—a clinical research center study. J Clin Endocrinol Metab 1998;83:1542-7.
    Abstract/FREE Full Text
  24. ↵
    1. Mulligan K,
    2. Grunfeld C,
    3. Hellerstein MK,
    4. Neese RA,
    5. Schambelan M
    . Anabolic effects of recombinant human growth hormone in paitents with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 1993;77:956-62.
    Abstract
  25. ↵
    1. Grinspoon S,
    2. Corcoran C,
    3. Askari H,
    4. et al
    . Effects of androgen administration in men with the AIDS wasting syndrome. Ann Intern Med 1998;129:18-26.
    Abstract/FREE Full Text
  26. ↵
    1. Bhasin S,
    2. Storer TW,
    3. Asbel-Sethi N,
    4. et al
    . Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998;83:3155-62.
    Abstract/FREE Full Text
  27. ↵
    1. Whitney EN,
    2. Rolfes SR
    . Understanding nutrition. 8th ed. Belmont, CA: Wadsworth Publishing Company; 1999.
  28. ↵
    1. Wang Z,
    2. Heshka S,
    3. Gallagher D,
    4. Boozer CN,
    5. Kotler DP,
    6. Heymsfield SB
    . Resting energy expenditure-fat-free mass relationship: new insights provided by body composition modeling. Am J Physiol Endocrinol Metab 2000;270:539-45.
  29. ↵
    1. Ravussin E,
    2. Lillioja S,
    3. Anderson TE,
    4. Christin L,
    5. Bogardus C
    . Determinants of 24-hour energy expenditure in man: methods and results using a respiratory chamber. J Clin Invest 1986;78:1568-78.
    MedlineWeb of Science
  30. ↵
    1. Illner K,
    2. Brinkmann G,
    3. Heller M,
    4. Bosy-Westphal A,
    5. Muller MJ
    . Metabolically active components of fat free mass and resting energy expenditure in nonobese adults. Am J Physiol Endocrinol Metab 2000;278:308-15.
  31. ↵
    1. Pi-Sunyer FX
    . Overnutrition and undernutrition as modifiers of metabolic processes in disease states. Am J Clin Nutr 2000;72:533-7.
  32. ↵
    1. Leibel RL,
    2. Rosenbaum M,
    3. Hirsch J
    . Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995;332:621-8.
    CrossRefMedlineWeb of Science
  33. ↵
    1. Nair KS,
    2. Webster J,
    3. Garrow JS
    . Effect of impaired tolerance and type II diabetes on resting metabolic rate and thermic response to a glucose meal in obese women. Metabolism 1986;35:640-4.
    CrossRefMedlineWeb of Science
  34. ↵
    1. Grunfeld C,
    2. Feingold KR
    . Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992;327:329-37.
    MedlineWeb of Science
  35. ↵
    1. Hommes MJ,
    2. Romijn JA,
    3. Godfried MH,
    4. et al
    . Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism 1990;39:1186-90.
    CrossRefMedlineWeb of Science
  36. ↵
    1. Kotler DP,
    2. Tierney AR,
    3. Brenner SK,
    4. Couture S,
    5. Wang J,
    6. Pierson RN Jr
    . Preservation of short-term energy balance in clinically stable patients with AIDS. Am J Clin Nutr 1990;51:7-13.
    Abstract/FREE Full Text
  37. ↵
    1. Melchior JC,
    2. Salmon D,
    3. Rigaud D,
    4. et al
    . Resting energy expenditure is increased in stable, malnourished HIV-infected patients. Am J Clin Nutr 1991;53:437-41.
    Abstract/FREE Full Text
  38. ↵
    1. Crenn P,
    2. Rakotoanbinina B,
    3. Raynaud JJ,
    4. Thuillier F,
    5. Messing B,
    6. Melchior JC
    . Hyperphagia contributes to the normal body composition and protein-energy balance in HIV-infected asymptomatic men. J Nutr 2004;134:2301-6.
    Abstract/FREE Full Text
  39. ↵
    1. Hommes MJ,
    2. Romijn JA,
    3. Endert E,
    4. Sauerwein HP
    . Resting energy expenditure and substrate oxidation in human immunodefiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. Am J Clin Nutr 1991;54:311-5.
    Abstract/FREE Full Text
  40. ↵
    1. Mulligan K,
    2. Tai VW,
    3. Schambelan M
    . Energy expenditure in human immunodeficiency virus infection. New Engl J Med 1997;336:70-1.
    CrossRefMedlineWeb of Science
  41. ↵
    1. Grunfeld C,
    2. Pang M,
    3. Shimizu L,
    4. Shigenaga JK,
    5. Jensen P,
    6. Feingold KR
    . Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr 1992;55:455-60.
    Abstract/FREE Full Text
    1. Melchior JC,
    2. Raguin G,
    3. Boulier A,
    4. et al
    . Resting energy expenditure in human immunodeficiency virus-infected patients: comparison between patients with and without secondary infections. Am J Clin Nutr 1993;57:614-9.
    Abstract/FREE Full Text
  43. ↵
    1. Garcia-Lorda P,
    2. Serrano P,
    3. Jimenez-Exposito MJ,
    4. et al
    . Cytokine-driven inflammatory response is associated with the hypermetabolism of AIDS patients with opportunistic infections. JPEN J Parenter Enteral Nutr 2000;24:317-22.
    Abstract/FREE Full Text
  44. ↵
    1. Schwenk A,
    2. Hoffer-Belitz E,
    3. Jung B,
    4. et al
    . Resting energy expenditure, weight loss, and altered body composition in HIV infection. Nutrition 1996;12:595-601.
    CrossRefMedline
  45. ↵
    1. Jimenez-Exposito MJ,
    2. Garcia-Lorda P,
    3. Alonso-Villaverde C,
    4. et al
    . Effect of malabsorption on nutritional status and resting energy expenditure in HIV-infected patients. AIDS 1998;12:1965-72.
    MedlineWeb of Science
  46. ↵
    1. Macallan DC
    . Wasting in HIV infection and AIDS. J Nutr 1999;129(Suppl 1S):238-42.
  47. ↵
    1. Batterham MJ
    . Investigating heterogeneity in studies of resting energy expenditure in persons with HIV/AIDS: a meta-analysis. Am J Clin Nutr 2005;81:702-13.
    Abstract/FREE Full Text
  48. ↵
    1. Grinspoon S,
    2. Corcoran C,
    3. Miller K,
    4. et al
    . Determinants of increased energy expenditure in HIV-infected women. Am J Clin Nutr 1998;68:720-5.
    Abstract
  49. ↵
    1. Lane BJ,
    2. Provost-Craig MA
    . Resting energy expenditure in asymptomatic HIV-infected females. J Womens Health Gend Based Med 2000;9:321-7.
    CrossRefMedlineWeb of Science
  50. ↵
    1. Lovejoy JC,
    2. Champagne CM,
    3. Smith SM,
    4. de Jonge L,
    5. Xie H
    . Ethnic differences in dietary intakes, physical activity, and energy expenditure in middle-aged, premenopausal women: the Healthy Transitions Study. Am J Clin Nutr 2001;74:90-5.
    Abstract/FREE Full Text
  51. ↵
    1. Kaplan AS,
    2. Zemel BS,
    3. Stallings VA
    . Differences in resting energy expenditure in prepubertal black children and white children. J Pediatr 1996;129:643-7.
    CrossRefMedlineWeb of Science
  52. ↵
    1. Sharpstone DR,
    2. Murray CP,
    3. Ross HM,
    4. et al
    . Energy balance in asymptomatic HIV infection. AIDS 1996;10:1377-84.
    MedlineWeb of Science
  53. ↵
    1. Batterham MJ,
    2. Morgan-Jones J,
    3. Greenop P,
    4. Garsia R,
    5. Gold J,
    6. Caterson I
    . Calculating energy requirements for men with HIV/AIDS in the era of highly active antiretroviral therapy. Eur J Clin Nutr 2003;57:209-17.
    CrossRefMedlineWeb of Science
  54. ↵
    1. Sekhar RV,
    2. Jahoor F,
    3. White AC,
    4. et al
    . Metabolic basis of HIV-lipodystrophy syndrome. Am J Physiol Endocrinol Metab 2002;283:332-7.
    Medline
  55. ↵
    1. Shevitz AH,
    2. Knox TA,
    3. Spiegelman D,
    4. Roubenoff R,
    5. Gorbach SL,
    6. Skolnik PR
    . Elevated resting energy expenditures among HIV-seropositive persons receiving highly active antiretroviral therapy. AIDS 1999;13:1351-7.
    CrossRefMedlineWeb of Science
  56. ↵
    1. Kosmiski LA,
    2. Kuritzkes DR,
    3. Sharp TA,
    4. et al
    . Total energy expenditure and carbohydrate oxidation are increased in the human immunodeficiency virus lipodystrophy syndrome. Metabolism 2003;52:620-5.
    CrossRefMedlineWeb of Science
  57. ↵
    1. Kosmiski LA,
    2. Kuritzkes DR,
    3. Lichenstein KA,
    4. et al
    . Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 2001;15:1993-2000.
    CrossRefMedlineWeb of Science
  58. ↵
    1. Roubenoff R,
    2. Grinspoon S,
    3. Skilnik PR,
    4. et al
    . Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men. Am J Physiol Endocrinol Metab 2002;283:138-45.
  59. ↵
    1. Pernerstorfer-Schoen H,
    2. Schindler K,
    3. Parschalk B,
    4. et al
    . Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients. AIDS 1999;13:2389-96.
    CrossRefMedlineWeb of Science
  60. ↵
    1. Carbonnel F,
    2. Maslo C,
    3. Beaugerie L,
    4. et al
    . Effects of indinavir on HIV-related wasting. AIDS 1998;12:1777-84.
    MedlineWeb of Science
  61. ↵
    1. Renard E,
    2. Fabre J,
    3. Paris F,
    4. Reynes J,
    5. Bringer J
    . Syndrome of body fat redistribution in HIV-1-infected patients: relationships to cortisol and catecholamines. Clin Endocrinol (Oxf) 1999;51:223-30.
    CrossRefMedline
    1. Hengel RL,
    2. Watts NB,
    3. Lennox JL
    . Benign symmetric lipomatosis associated with protease inhibitors. Lancet 1997;350:1596.
    MedlineWeb of Science
    1. Lo JC,
    2. Mulligan K,
    3. Tai VW,
    4. Algren H,
    5. Schambelan M
    . “Buffalo hump” in men with HIV-1 infection. Lancet 1998;351:867-70.
    CrossRefMedlineWeb of Science
    1. Carr A,
    2. Samaras K,
    3. Thorisdottir A,
    4. Kauffman GR,
    5. Chisolm DJ,
    6. Cooper DA
    . Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093-9.
    CrossRefMedlineWeb of Science
  65. ↵
    1. Carr A,
    2. Samaras K,
    3. Burton S,
    4. et al
    . A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998;12:51-8.
    CrossRefWeb of Science
  66. ↵
    1. Bacchetti P,
    2. Gripshover B,
    3. Grunfeld C,
    4. et al
    . Fat distribution in men with HIV infection. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). J Acquir Immune Defic Syndr 2005;40:121-31.
    CrossRefMedlineWeb of Science
  67. ↵
    1. Carr A,
    2. Emery S,
    3. Law M,
    4. Puls R,
    5. Lundgren JD,
    6. Powderly WG
    . An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. HIV Lipodystrophy Case Definition Study Group. Lancet 2003;361:726-35.
    CrossRefMedlineWeb of Science
  68. ↵
    1. Van der Valk M,
    2. Reiss P,
    3. van Leth FC,
    4. et al
    . Highly active antiretroviral therapy-induced lipodystrophy has minor effects on human immunodeficiency virus-induced changes in lipolysis, but normalizes resting energy expenditure. J Clin Endocrinol Metab 2002;87:5066-71.
    Abstract/FREE Full Text
  69. ↵
    1. Sutinen J,
    2. Yki-Jarvinen H
    . Increased resting energy expenditure, fat oxidation and food intake in patients with highly active antiretroviral therapy-associated lipodystrophy. Am J Physiol Endocrinol Metab 2006;292:687-92.
    CrossRef
  70. ↵
    1. Tisdale MJ
    . Cancer cachexia: metabolic alterations and clinical manifestations. Nutrition 1997;13:1-7.
    CrossRefMedlineWeb of Science
  71. ↵
    1. Godfried MH,
    2. Romijn JA,
    3. van der Poll T,
    4. et al
    . Soluble receptors for tumor necrosis factor are markers for clinical course but not for major metabolic changes in human immunodeficiency virus infection. Metabolism 1995;44:1564-9.
    CrossRefMedlineWeb of Science
  72. ↵
    1. Hadigan C,
    2. Borgonha S,
    3. Rabe J,
    4. Young V,
    5. Grinspoon S
    . Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. Metabolism 2002;51:1143-7.
    CrossRefMedlineWeb of Science
  73. ↵
    1. Reeds DN,
    2. Mittendorfer B,
    3. Patterson BW,
    4. Powderly WG,
    5. Yarasheski KE,
    6. Klein S
    . Alterations in lipid kinetics in men with HIV-dyslipidemia. Am J Physiol Endocrinol Metab 2003;285:490-7.
  74. ↵
    1. Oral EA,
    2. Simha V,
    3. Ruiz E,
    4. et al
    . Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-8.
    CrossRefMedlineWeb of Science
  75. ↵
    1. Reitman ML,
    2. Arioglu E,
    3. Gavrilova O,
    4. Taylor SI
    . Lipodystrophy revisited. Trends Endocrinol Metab 2000;11:410-6.
    CrossRefMedlineWeb of Science
  76. ↵
    1. Klein S,
    2. Jahoor F,
    3. Wolfe RR,
    4. Stuart CA
    . Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics. Metabolism 1992;41:893-6.
    CrossRefMedlineWeb of Science
  77. ↵
    1. Cutler DL,
    2. Kaufmann S,
    3. Freidenberg GR
    . Insulin-resistant diabetes mellitus and hypermetabolism in mandibuloacral dysplasia: a newly recognized form of partial lipodystrophy. J Clin Endocrinol Metab 1991;73:1056-61.
    Abstract/FREE Full Text
  78. ↵
    1. Marshall MK,
    2. Doerrler W,
    3. Feingold KR,
    4. Grunfeld C
    . Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes. Endocrinology 1994;135:141-7.
    Abstract
  79. ↵
    1. Deniaud A,
    2. Brenner C,
    3. Kroemer G
    . Mitochondrial membrane permeabilization by HIV-1 Vpr. Mitochondrion 2004;4:223-33.
    CrossRefMedlineWeb of Science
  80. ↵
    1. Côté HC,
    2. Brumme ZL,
    3. Craib KJ,
    4. et al
    . Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811-20.
    CrossRefMedlineWeb of Science
    1. Pace CS,
    2. Martin AM,
    3. Hammond EL,
    4. Mamotte CD,
    5. Nolan DA,
    6. Mallal SA
    . Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther 2003;8:323-31.
    Medline
    1. Setzer B,
    2. Schlesier M,
    3. Walker UA
    . Effects of diadnosine-related depletion of mtDNA in human T lymphocytes. J Infect Dis 2005;191:848-55.
    Abstract/FREE Full Text
  83. ↵
    1. Walker UA,
    2. Bickel M,
    3. Lutke Volksbeck SI,
    4. et al
    . Evidence of nucleoside analogue reverse-transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002;29:117-21.
    MedlineWeb of Science
  84. ↵
    1. Walker UA,
    2. Brinkman K
    . An argument for mitochondrial toxicity in highly active antiretroviral therapy-induced lipoatrophy. AIDS 2001;15:1450-2.
    MedlineWeb of Science
  85. ↵
    1. Zaera MG,
    2. Miro O,
    3. Pedrol E,
    4. et al
    . Mitochondrial involvement in antiretroviral therapy-related lipodystrophy. AIDS 2001;15:1643-51.
    CrossRefMedlineWeb of Science
    1. Miro O,
    2. Lopez S,
    3. Martinez E,
    4. et al
    . Mitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV-infected patients who were never treated with antiretrovirals. Clin Infect Dis 2004;39:710-6.
    Abstract/FREE Full Text
  87. ↵
    1. McComsey GA,
    2. Paulsen DM,
    3. Lonergan JT,
    4. et al
    . Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005;19:15-23.
    MedlineWeb of Science
  88. ↵
    1. Shikuma CM,
    2. Hu N,
    3. Milne C,
    4. et al
    . Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy. AIDS 2001;15:1801-9.
    CrossRefMedlineWeb of Science
  89. ↵
    1. Lloreta J,
    2. Domingo P,
    3. Pujol RM,
    4. et al
    . Ultrastructural features of highly active antiretroviral therapy-associated partial lipodystrophy. Virchows Arch 2002;441:599-604.
    CrossRefMedlineWeb of Science
  90. ↵
    1. Newsholme EA
    . Substrate cycles: their metabolic, energetic and thermic consequences in man. Biochem Soc Symp 1978;43:183-205.
    Medline
  91. ↵
    1. Sekhar RV,
    2. Jahoor F,
    3. Pownall HJ,
    4. et al
    . Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome. Am J Clin Nutr 2005;81:1405-10.
    Abstract/FREE Full Text
  92. ↵
    1. Macallan DC,
    2. Noble C,
    3. Baldwin C,
    4. et al
    . Energy expenditure and wasting in human immunodeficiency virus infection. New Engl J Med 1995;333:83-8.
    CrossRefMedlineWeb of Science
  93. ↵
    1. Sheehan LA,
    2. Macallan DC
    . Determinants of energy intake and energy expenditure in HIV and AIDS. Nutrition 2000;16:101-6.
    CrossRefMedlineWeb of Science
  94. ↵
    1. Poizot-Martin I,
    2. Benourine K,
    3. Philibert P,
    4. et al
    . Diet-induced thermogenesis in HIV infection. AIDS 1994;8:501-4.
    MedlineWeb of Science
  95. ↵
    1. Heijligenberg R,
    2. Romijn JA,
    3. Westerterp KR,
    4. Jonkers CF,
    5. Prins JM,
    6. Sauerwein HP
    . Total energy expenditure in human immunodeficiency virus-infected men and healthy controls. Metabolism 1997;46:1324-6.
    CrossRefMedlineWeb of Science
  96. ↵
    1. Coors M,
    2. Suttmann U,
    3. Trimborn P,
    4. Ockenga J,
    5. Muller MJ,
    6. Selberg O
    . Acute phase response and energy balance in stable human immunodeficiency virus-infected patients: a doubly labeled water study. J Lab Clin Med 2001;138:94-100.
    CrossRefMedlineWeb of Science
| Table of Contents

This Article

  1. Clin Infect Dis. (2007) 44 (11): 1509-1517. doi: 10.1086/517501
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most