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Wasting
HIV-Associated Wasting
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Introduction
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Pathophysiology
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transparent imageMetabolic Alterations
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transparent imageAnorexia
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transparent imageHypogonadism
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transparent imageGastrointestinal Disorders
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transparent imageVirologic and Immunologic Factors
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Evaluation of Wasting
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transparent imageWeight Loss
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transparent imageBody Composition
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transparent imageBioimpedance Analysis
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transparent imageAnthropometry
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transparent imageOther Techniques
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transparent imageGastrointestinal Evaluation
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transparent imageEndocrine Evaluation
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transparent imageNutritional Assessment
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Interventions for Wasting
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transparent imageManagement of Primary and Secondary Infections
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transparent imageNutritional Interventions
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transparent imageOral Nutritional Supplementation
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transparent imageNonvolitional Feeding
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transparent imageEnteral Feeding
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transparent imageParenteral Nutrition
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Pharmacologic Treatments
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transparent imageAppetite Stimulants
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transparent imageMegestrol Acetate
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transparent imageDronabinol
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transparent imageOther Drugs Used to Stimulate Appetite
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transparent imageProtein Anabolic Agents
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transparent imageRecombinant Human Growth Hormone
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transparent imageShort-Term Growth Hormone for Acute Wasting
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transparent imageAnabolic/Androgenic Steroids
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transparent imageTestosterone
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transparent imageNandrolone Decanoate
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transparent imageOxandrolone
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transparent imageOxymetholone
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transparent imageCytokine Modulation
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transparent imageThalidomide
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transparent imageOther Cytokine Suppressors
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Exercise
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Summary and Recommendations
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References
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Related Resources
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Introduction
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The U.S. Centers for Disease Control and Prevention (CDC) recognized wasting as an AIDS-defining condition in 1987. The "wasting syndrome" is defined as a weight loss of at least 10% in the presence of diarrhea or chronic weakness and documented fever for at least 30 days that is not attributable to a concurrent condition other than HIV infection itself.(1) In practice, any involuntary weight loss of that magnitude is typically considered wasting.

A significant relationship between weight loss and mortality, disease progression, or both has been demonstrated in numerous prospective and retrospective studies both before the advent of effective antiretroviral therapy (ART) (2-11) and in the current era of treatment, in regions where such therapy is available.(12,13) In addition to weight loss, depleted levels of body cell mass, which contains the metabolically active tissue, have been associated with increased risk of mortality in patients with HIV infection.(2,5,6) It is important to note that death from malnutrition in patients with AIDS occurred at the same degree of depletion of weight and body cell mass (66% and 54% of normal, respectively) (2) as was seen in historical reports of death from starvation.(14,15) Body mass index (BMI; see www.cdc.gov/nccdphp/dnpa/bmi/index.htm), calculated by dividing an individual's weight in kilograms by the square of his or her height in meters, also has predictive value. Evaluation of data from a large French cohort studied between 1985 and 1997 found hazards ratios for death of 2.2 and 4.4 for BMIs of 16.0-18.4 and <16.0 kg/m2, respectively, after adjusting for other factors that affect mortality (p < .0001 in each case).(11) In this same study, weight losses of <5%, 5-10%, and >10% were associated with hazards ratios for death of 1.9, 3.3, and 6.7, respectively (p < .0001 in each case).

The prevalence of wasting as an initial AIDS-defining diagnosis was estimated to range up to 37% in surveys performed before the advent of effective ART.(16-22) Some reports suggest that the incidence of wasting has declined since the introduction of effective ART,(22,23) but data from other studies indicate that wasting remains a significant complication, even in populations with widespread access to effective ART.(24-26) A recent report from a large cohort study suggested that although weight loss is an infrequent occurrence, a more gradual, progressive loss of lean tissue continues in many subjects.(27) Moreover, although weight gain (28-30) and increased muscle protein synthesis (31) may occur with initiation of ART, lean tissue is not consistently restored.(28)

Weight loss in HIV infection is characterized by depletion of both fat and lean tissue.(32-39) Rapid weight loss has been associated with acute infections,(40,41) whereas more gradual weight loss has been associated with malabsorptive disorders.(41) Patients with HIV infection have also been shown to experience periods of weight stability and weight gain.(41)

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Pathophysiology
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Factors that have been demonstrated or hypothesized to contribute to wasting include metabolic alterations, anorexia, malabsorptive disorders, hypogonadism, and excessive cytokine production. Because wasting in most cases results from a combination of factors or failed compensatory responses, the diagnostic process must recognize the possibility of multiple etiologies.

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Metabolic Alterations
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Increased resting energy expenditure (REE) is a common finding in patients with HIV infection,(40,42-49) particularly in those with systemic secondary infections.(40,43,50) However, hypermetabolism is not a universal finding,(33,50,51) and there is no convincing causal relationship between REE and wasting. Instead, decreased energy intake has been found to be the primary contributor to wasting, particularly during periods of rapid weight loss.(40,46) Elevated REE may serve as a cofactor in accelerating weight loss and provides evidence of a failure to compensate for decreased energy intake. Studies using stable isotope techniques have demonstrated that total energy expenditure (TEE) is not significantly elevated in weight-stable patients with HIV infection, when compared with estimates of TEE in other studies of healthy adults.(46,48,52) Patients losing weight have been found to have decreased levels of TEE, despite elevated rates of REE, reflecting a decrease in physical activity levels.(46)

A variety of other metabolic alterations have also been described in HIV-infected individuals, including: increased (47,53) and decreased (54) rates of protein turnover; decreased rates of muscle protein synthesis (53); and increased rates of de novo hepatic lipogenesis,(55) lipid flux, and oxidative and nonoxidative lipid disposal.(45) As of yet, no mechanistic relationship has been demonstrated between these or other metabolic alterations and wasting. In fact, it has been shown that the reversal of wasting is not contingent upon a reversal of elevated REE.(56)

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Anorexia
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As discussed above, decreased energy intake, coupled with inappropriately elevated REE, is a major factor in negative energy balance that results in weight loss. Anorexia can result from a variety of factors caused by HIV infection itself, secondary infection, and treatments for either. Painful oral and esophageal complications such as candidiasis and aphthous ulcers can reduce voluntary food intake. Nausea is a frequent adverse effect of medications. Depression, fatigue, altered taste perception, and social isolation can also contribute to anorexia or loss of interest in eating. Moreover, dosing regimens for some antiretroviral medications impose restrictions on feeding schedules that can limit the opportunities for eating.

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Hypogonadism
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Impotence and low testosterone levels have been reported in men with AIDS, even in the absence of weight loss.(57-63) Decreased testosterone levels may be the result of a functional disorder of the hypothalamus,(58) primary testicular failure,(57) or both. HIV-infected men with wasting have been reported to have significantly lower total and free testosterone levels than weight-stable men.(63) In hypogonadal men with wasting, muscle mass and total body potassium (an index of body cell mass) were found to be positively and significantly correlated with serum free testosterone levels, and exercise capacity correlated with total testosterone levels.(62) It is not yet clear whether decreased testosterone levels are a cause or consequence of wasting. A case-control study found that declines in serum bioavailable testosterone levels occurred concurrently with wasting.(64) More recently, however, data from a cohort study suggested that hypogonadism was not a factor in gradual loss of lean body mass (LBM) in men receiving effective ART.(27) In addition to malnutrition, a variety of commonly used medications, including ketoconazole, cimetidine, ganciclovir, and megestrol acetate have been associated with low testosterone levels.(60) Decreased free testosterone levels have also been found in HIV-infected women with wasting (65). The endocrine complications of HIV infection are discussed in detail in the chapter "Endocrine Manifestations of HIV."

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Gastrointestinal Disorders
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Chronic diarrhea and malabsorption remain common findings in HIV-infected patients. Where ART is available, diarrhea associated with intestinal pathogens such as microsporidia, Cryptosporidium, Giardia lamblia, cytomegalovirus (CMV), and Mycobacterium avium has decreased, whereas ART-associated diarrhea has increased. Thus, the overall incidence rate of diarrhea has remained constant.(66) In addition to a loss of calories associated with malabsorption, diarrhea can secondarily contribute to weight loss by discouraging food intake. The quantitative contribution of diarrhea and malabsorption to wasting has not been described. The gastrointestinal complications of HIV infection are discussed in detail in the chapter "Gastrointestinal Manifestations of HIV."

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Virologic and Immunologic Factors
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Cytokine disturbances have long been implicated in the metabolic disorders and wasting that accompany HIV infection.(27,67-73) For example, alterations in triglyceride (TG) metabolism, such as hypertriglyceridemia, slowed TG clearance, and increased de novo hepatic lipogenesis, correlate with elevated circulating levels of interferon alfa (IFN-alfa).(55,74) Moreover, initiation of ART in previously untreated subjects with advanced HIV infection leads to parallel reductions in IFN-alfa and TG levels.(75) Tumor necrosis factor alpha (TNF-alpha) has been variably reported to be increased or normal in patients with AIDS.(76) Increases in levels of soluble TNF receptors,(69) interleukin 1 (IL-1) receptor antagonist,(70) and IFN-alfa (71) have been observed in HIV-infected patients with weight loss. One longitudinal study linked lean tissue loss to TNF-alpha and IL-1 beta (production by circulating mononuclear white blood cells in men with HIV infection.(27) However, it cannot be determined from these studies whether the increases in cytokine levels are a cause of wasting or a concurrent manifestation of advancing HIV disease, which might accelerate lean tissue loss by some other mechanism. For example, several studies have also suggested an independent association between HIV viral load and weight loss.(77-79) Overall, the specific roles of cytokines and HIV viral load in the mechanism(s) of wasting require further study.

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Evaluation of Wasting
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Weight Loss
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Although weight is measured during most routine medical assessments, its utility as a diagnostic tool has been underrecognized. The usefulness of this easily obtained measurement can be improved if serial weights are measured under standardized conditions.(80) Ideally, weights should be recorded on the same scale; shoes, heavy clothing, and jewelry should be removed; and patients should void before weighing. Weight data obtained in this way can be used in both the diagnosis and monitoring of wasting.

Calculation of the BMI is a simple means of comparing a patient's current weight with population norms. Tables of weight for height, such as the Metropolitan Life Insurance tables,(81) can provide another means of comparing an individual's weight with population standards. The following formulas provide a simple approximation of ideal weight for height in adults: for men, 106 lbs. for the first 5 feet plus 6 lbs. for each additional inch; for women, 100 lbs. for the first 5 feet plus 5 lbs. for each additional inch.

Weight trends can be a valuable tool for monitoring a patient's nutritional status. As described earlier, rapid weight loss (>4 kg in <4 months) has been associated with episodes of acute infection (41); in fact, because weight loss may precede other clinical symptoms, it may be the first indication of infection.(40,80) In contrast, chronic or more gradual weight loss (>4 kg in >4 months) tends to reflect gastrointestinal complications.(41)

Additional factors must be considered in the evaluation of wasting in the current treatment era. For example, it is important to distinguish between voluntary and involuntary weight loss. Moreover, it is critical to be able to distinguish between classic wasting (which is more likely to occur in the context of virologic or immunologic failure, a secondary infection, or anorexia) and changes in regional fat distribution that are commonly referred to as "lipodystrophy." In addition, symptomatic hyperlactatemia has been described in patients on nucleoside analogue reverse transcriptase inhibitor (NRTI)-containing regimens and is associated with nonspecific symptoms such as rapid weight loss, abdominal pain, and fatigue,(82) and therefore might be misclassified as wasting. Metabolic complications of ART are discussed in more detail in the chapter "Metabolic Complications of HIV Therapy."

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Body Composition
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Because weight loss typically consists of both fat and lean tissue, measurement of body composition for diagnostic purposes, although potentially useful, is not essential. Although several early studies demonstrated that mortality is related not just to loss of weight but also to depletion of lean tissue, a recent study performed in patients on ART suggested that weight loss was a better predictor of mortality than lean or fat tissue measured by bioelectric impedance.(13) Nonetheless, there has been considerable interest in the measurement of body composition in patients with HIV infection, and such measurements can be useful in conjunction with well-maintained weight records to characterize an individual's response to various medical or nutritional interventions.

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Bioimpedance Analysis
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This technique is based on the differential resistance to a low-intensity electrical current by the fat and lean compartments of the body. Measured values of resistance and reactance obtained by bioimpedance analysis (BIA) can be used in regression equations (eg, see Kotler et al [83]) to estimate fat, LBM, and total body water. There is less consensus regarding the ability of BIA to estimate body cell mass and intracellular and extracellular water with accuracy. The equipment is relatively inexpensive and portable. A measurement takes only approximately 10 minutes and involves no pain or discomfort for the patient. However, accurate estimation of body composition using this technique depends to a large extent on accurate measurement of weight and height, as well as correct and consistent positioning of electrodes. Because there are no population standards for fat or lean tissue, BIA cannot be used to diagnose wasting. However, careful and consistent measurements with BIA can be useful for monitoring changes over time.

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Anthropometry
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Sequential measurements of midarm circumference, using a tape measure, and triceps skinfold, using calipers, can be used as surrogate indicators of change in arm muscle circumference, which has been shown to predict survival in other catabolic illnesses.(84) Although these and other anthropometric measurements can also be used to estimate whole-body composition, the equations used in such calculations have not been validated in patients with HIV-associated wasting. Anthropometric measurements are highly technique dependent. Duplicate or triplicate measurements should be obtained by a trained clinician, and serial measurements should be performed by the same individual whenever possible.

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Other Techniques
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There are a variety of other research methods for measuring whole body composition, including dual-energy x-ray absorptiometry (DEXA), dilution techniques, underwater weighing, magnetic resonance imaging (MRI), computed tomography (CT), total body electrical conductivity (TOBEC), and whole-body counting of potassium, nitrogen, and other elements. Regional body composition analysis can be performed using DEXA, MRI, or CT. All of the techniques listed provide more accurate estimates of body composition than BIA or anthropometry but generally involve more costly equipment and a require a greater degree of patient cooperation and time. Although useful in research, they are not considered to be necessary for standard nutritional assessment.

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Gastrointestinal Evaluation
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As discussed earlier, a slow weight loss pattern has been typically associated with malabsorptive disorders, and a gastrointestinal evaluation might be indicated in such individuals if no other explanation for wasting is evident. Malabsorption can occur in the absence of diarrhea, so the presence of gastrointestinal disorders should not be excluded on the basis of normal bowel patterns alone. The evaluation of gastrointestinal symptoms associated with HIV infection are discussed in detail in the chapter "Gastrointestinal Manifestations of HIV."

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Endocrine Evaluation
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Although a variety of endocrine disturbances have been documented in patients with HIV infection, hypogonadism is of primary concern in patients with wasting. In men with wasting, serum testosterone levels should be measured. Some clinicians believe that free or bioavailable testosterone levels are a more accurate diagnostic tool than total testosterone levels. In the absence of specific evidence of impairment of other hormone systems, additional endocrine evaluations for wasting are not warranted.

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Nutritional Assessment
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Patients with wasting should undergo a comprehensive dietary assessment including diet history, estimation of current energy intake, and identification of factors that might interfere with food intake. Quantitative estimation of daily energy intake, along with macro- and micronutrients, should be obtained by a trained dietitian, using techniques such as diet history, 24-hour recall, or prospective food intake diaries. Food frequency questionnaires are not considered reliable for estimating an individual's energy intake. Because there is wide interindividual variability in the accuracy of self-reported food intake, this information should be considered in conjunction with an individual's weight history and current disease state.

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Interventions for Wasting
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Management of Primary and Secondary Infections
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It has long been recognized that treatment of the underlying primary or secondary infection can result in weight gain in patients with HIV infection.(28,29,85,86) Obtaining meaningful prospective weight data from controlled trials of ART has been complicated by the occurrence of lipoatrophy (regional fat loss) in many patients. Although the full impact of long-term ART on wasting is not known, aggressive management of primary HIV infection remains an important component of the treatment and prevention of wasting.

Treatment of secondary infections and other complications of HIV infection is also an important factor in the management of wasting, as first evidenced by an increase in weight and body cell mass in patients with disseminated CMV infection treated with ganciclovir.(87) Opportunistic infections that interfere with swallowing (such as candidal, herpes, or CMV esophagitis) render patients particularly susceptible to wasting. In addition to secondary infections, aphthous ulcers, chronic diarrhea, or malabsorption of any etiology; depression; and other contributors to anorexia should be treated.

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Nutritional Interventions
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Nutritional strategies to forestall or reverse wasting must work to maintain or increase energy intake. Patients with HIV infection can increase protein synthesis rates during periods of increased dietary intake.(47,88) However, nutritional supplementation alone is unlikely to fully restore weight or lean tissue in patients with HIV infection.

Dietary counseling by a registered dietitian can help individuals identify target energy intake and food choices to suit individual tastes, practices, and tolerances; should emphasize the importance of maintaining energy intake, even during periods when eating is not pleasurable; and can give patients techniques for managing HIV- or medication-related symptoms such as anorexia, early satiety, nausea, vomiting, diarrhea, food intolerances, and oral or esophageal ulcers. Because HIV-infected persons are at increased risk for food-borne infections, food safety is also an important component of dietary counseling. Patients who have received nutrition education can also make more informed evaluations of claims by faddists who put forth expensive and potentially harmful nutritional regimens.

At present, there are no universally accepted HIV-specific recommendations for intake of energy or macronutrients. TEE in weight-stable HIV-infected individuals is comparable to that seen in healthy subjects,(46,48,52) so the target ranges for energy intake derived from the Recommended Dietary Allowances for adults could be applied (33-44 and 29-44 kcal/kg in men and women, respectively).(89) However, individual requirements vary more widely in persons with HIV infection, owing to the variable presence of increased rates of REE or reduced activity levels. The recommended level of protein intake in healthy adults is 0.8 g/kg, and although no specific protein requirements have been determined for HIV-infected patients, it is frequently recommended that they consume 1.5 g/kg per day. However, there are currently no empiric data to support this recommendation.

Decreased serum levels of micronutrients are a frequent finding in HIV-infected patients and most likely reflect poor nutritional intake (eg, see Coodley et al [90]). Although decreased serum concentrations of selected vitamins and minerals have been associated with increased rates of disease progression and mortality in patients with HIV infection, there have been no controlled prospective studies demonstrating that supplementation with any vitamin or mineral reverses wasting. Thus, unless a patient has evidence of specific nutrient deficiencies, a generic, low-cost daily multivitamin and mineral supplement should suffice.

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Oral Nutritional Supplementation
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Increases in net daily energy intake can be achieved with the use of oral supplements, despite some compensatory decrease in self-selected food consumption. Such supplements can be very useful in individuals for whom an inability or unwillingness to prepare or consume meals becomes an impediment to oral intake. A variety of liquid and solid oral supplements are available, including conventional preparations and specialized formulas for patients with specific intolerances (eg, fat malabsorption or lactose intolerance). Elemental formulas provide another option for individuals with malabsorptive disorders. Some small studies suggest an increased benefit from special oral preparations containing specific amino acids and proprietary agents for people with HIV infection.(91-95) However, until further data become available, the primary criteria for selection of a specific supplement should be tolerability and cost.

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Nonvolitional Feeding
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In the short term, repletion or maintenance of weight by enteral or parenteral routes might be considered in individuals who are unable to meet nutritional goals with oral intake because of profound anorexia, nausea, oral or esophageal lesions, diarrhea, or neurologic disorders, but in whom there is potential for stabilization or improvement. Although it may be common for patients receiving enteral or parenteral feeding to gain weight,(96-103) increases in LBM are a less consistent finding.(96,97,99,100) Two studies suggest that survival may be increased in patients receiving enteral or parenteral nutritional support, when compared with those receiving standard nutritional counseling (104) or those who decline supplemental feeding.(98) A major factor in choosing a specific nonvolitional feeding technique is the importance of using the gastrointestinal tract to the greatest extent possible.

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Enteral Feeding
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Individuals with full or mildly impaired gut function might be candidates for short-term nasogastric tube feeding or, for longer periods, percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ). In some cases these approaches can use standard or elemental enteral formulas, so the cost of the nutrition itself is considerably less than for parenteral feeding. Placement of the PEG tube is a relatively simple procedure, and routine care and maintenance can be performed by the patients at home. The most common complication is superficial skin infection; other potential complications include aspiration, necrotizing fasciitis, and colocutaneous fistulas.

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Parenteral Nutrition
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Provision of central or peripheral parenteral nutrition may nutritionally stabilize and maintain hydration in patients who experience a loss of gastrointestinal function. The costs and risks of this therapeutic maneuver are greater than for enteral approaches, and there is no widespread consensus regarding the appropriate use of this technique in individuals with advanced HIV infection.

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Pharmacologic Treatments
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Appetite Stimulants
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Megestrol Acetate
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A synthetic progestational agent, megestrol acetate, has been shown to be a potent appetite stimulant and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-associated anorexia. In two randomized, double-blind, placebo-controlled trials of patients with HIV-associated weight loss who were studied before the availability of effective ART, treatment with megestrol acetate significantly increased food intake, weight, self-reported appetite, and sense of well-being.(105,106) In one of these trials, doses of 100, 400, and 800 mg/day were compared, and energy intake, weight, and sense of well-being increased in a dose-dependent manner.(105) In both trials, the majority of weight gained was fat. For example, patients treated with 800 mg megestrol acetate per day for 12 weeks gained an average of 3.5 kg, but only 1.1 kg was LBM.(105) In another trial, treatment with the same dose of megestrol acetate resulted in a 4.5-kg increase in fat with no change in LBM over a comparable treatment period.(106 Weight gain of an even greater magnitude was reported in an open-label pharmacokinetic study of megestrol acetate, but body composition was not measured.(107) It should be noted that healthy, HIV-negative subjects who lose weight due to voluntary or involuntary restriction of energy intake also tend to regain a disproportionate amount of fat during the early stages of weight recovery.(108) However, the failure of HIV-infected patients treated with megestrol acetate to gain LBM may also derive from the hypogonadism that has been shown to occur in men treated with this agent.(60,109) To determine whether testosterone replacement could improve the proportion of weight gained as LBM in patients receiving megestrol acetate, a multicenter study was performed in which men with wasting were treated with megestrol acetate (800 mg/day) and randomly assigned to receive a replacement dose of testosterone enanthate (200 mg every other week by intramuscular injection) or placebo.(110) Most of the participants in this study received effective ART. Preliminary data suggest that, consistent with earlier studies, there was significant weight gain with megestrol acetate, but, in contrast to previous studies, approximately half of the weight gained was lean tissue. Coadministration of testosterone in replacement doses was not associated with this increase in lean tissue accrual. However, sexual functioning was retained in those who received testosterone and diminished significantly in those on placebo during megestrol acetate treatment.

In addition to hypogonadism, adrenal suppression,(110,111) deep venous thrombosis,(112) and avascular necrosis (113) have been reported in patients receiving megestrol acetate.

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Dronabinol
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A synthetic form of delta-9 tetrahydrocannabinol (an active ingredient in marijuana), dronabinol is approved by the FDA for treatment of HIV-associated anorexia. Although open-label studies of dronabinol in patients with cancer (114,115) and HIV infection (116) demonstrated a consistent improvement in self-reported appetite, weight did not increase consistently. A double-blind, placebo-controlled, crossover study of dronabinol in a small number of HIV-infected men with weight loss produced no significant increases in weight or self-reported appetite or energy intake.(117) There was also no significant increase in weight in a larger, randomized, double-blind, placebo-controlled, multicenter trial of dronabinol in patients with HIV-associated weight loss.(118) Average weight change in patients randomized to receive dronabinol (2.5 mg two times per day; n = 50) was +0.1 kg over the 6-week treatment period, as compared with -0.4 kg in those who received placebo (n = 38; p = .14). Although there was no change in weight, self-reported appetite, nausea, and mood improved significantly over the treatment period. In a pharmacokinetic study, patients treated with dronabinol alone failed to gain weight, and those who received dronabinol in combination with megestrol acetate experienced no greater weight gain than those who received megestrol acetate alone.(107)

Some patients have suggested that smoked marijuana may be more effective than dronabinol because the dose can be more effectively titrated to the desired effect. Recently, the effects of smoked marijuana, oral dronabinol, and oral placebo on virologic and immunologic parameters were evaluated in a 3-week, randomized, partially blinded, metabolic ward study.(119) Subjects were allowed to eat ad libitum during the study. Significant weight gain occurred in all three groups, with greater weight gain seen in the two groups randomized to treatment with cannabinoids. However, in all three groups, the composition of the weight gained was predominantly (~80%) fat, and there was a tendency toward greater fat accrual in the central, rather than peripheral regions.(120) The most frequently reported adverse effects of dronabinol are euphoria, dizziness, and thinking abnormalities.(118)

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Other Drugs Used to Stimulate Appetite
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The antihistamine cyproheptadine increased energy intake and weight in a small open-label study in patients with HIV-associated weight loss.(121) Glucocorticoids have also been used to stimulate appetite, but these agents have specific protein catabolic effects and are therefore not recommended as a therapy for HIV-associated wasting.

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Protein Anabolic Agents
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Recombinant Human Growth Hormone
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Administered in pharmacologic doses, recombinant human growth hormone (GH) caused significant weight gain and retention of nitrogen and potassium during a short-term metabolic ward study,(45) and increases in weight and LBM in a 3-month open-label study.(122) In a randomized, double-blind, placebo-controlled trial in 178 patients with HIV-associated wasting, treatment with GH (0.1 mg/kg/day) for 3 months produced sustained and significant (p < .001 vs placebo) increases in weight (+1.6 kg) and LBM (+3.0 kg) that were accompanied by a decrease in fat (-1.7 kg).(123) Treadmill work output at volitional exhaustion increased significantly in patients treated with GH, and changes in work output and time to exhaustion were significantly and positively correlated with changes in LBM. Adverse effects included arthralgias, myalgia, puffiness, and diarrhea, which generally responded to dose reduction. All patients were required to be maintained on ART throughout the study, and there was no acceleration of viral replication with GH. Preliminary results from a recently completed study in 757 HIV-infected patients with 10% weight loss indicate that GH (6 mg daily or every other day) increased LBM, decreased fat, and improved performance on a cycle ergometer in patients in the current treatment era,(124) thus confirming the results of prior studies treatment.

In two separate placebo-controlled trials, combinations of pharmacologic doses of insulinlike growth factor-1 (total 10 mg/day) with smaller doses of GH (total 1.4 mg/day [125] or 0.7 mg/day[126,127]) produced increases in LBM that were comparable to or less than those obtained with GH alone.

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Short-Term Growth Hormone for Acute Wasting
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Because weight loss in patients with HIV infection occurs most rapidly during episodes of acute secondary infection, it has been hypothesized that treatment during these periods might prevent or mitigate this weight loss.(41) Two randomized, double-blind, placebo-controlled studies of short-term treatment with GH in HIV-infected subjects with newly diagnosed opportunistic infections have shown that treatment with GH can induce weight gain and accrual of LBM.(128,129) However, it is unclear whether there is any long-term advantage to such short-term treatment. Because treatment with GH in non-HIV-infected patients hospitalized in an intensive care unit has been associated with greater mortality rates,(130) GH treatment is contraindicated in HIV-infected patients during critical illness. However, it should be noted that no such deleterious effects were observed in the two aforementioned studies of GH treatment in HIV-infected patients with mild to moderately severe secondary infections.

The FDA granted accelerated approval for GH in HIV-associated wasting at a dose of 6 mg/day for patients with weight >55 kg and lower doses for weight <55 kg. The cost of this recombinant agent limits its accessibility, and the optimal therapeutic and maintenance dosing regimens have not yet been identified. Data are limited regarding whether weight is maintained following discontinuation of GH treatment.

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Anabolic/Androgenic Steroids
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Several injectable, oral, and transdermal anabolic/androgenic steroids, varying in the extent of their anabolic and androgenic properties and their potential for toxicity, are being used to treat wasting and symptoms of hypogonadism in patients with HIV infection. Testosterone is approved for treatment of hypogonadism. Nandrolone decanoate and oxymetholone have FDA approval for treatment of anemia. However, it should be emphasized that currently, apart from low doses of oxandrolone, wasting is not an approved indication for use of any of these agents.

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Testosterone
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In HIV-negative hypogonadal men, testosterone replacement produced striking increases in weight and LBM.(131,132) In randomized, double-blind, placebo-controlled studies of HIV-positive men with reduced serum testosterone levels, weight and LBM have also increased after testosterone treatment, but to a more modest extent than in hypogonadal HIV-negative men.(133-136) These less robust responses may be a result of the fact that in all of the studies in men with HIV infection, the average baseline serum testosterone levels were not as low as those in the seronegative men.

Two randomized, placebo-controlled studies of injectable testosterone, alone or in combination with resistance exercise, have also been performed in HIV-infected men with wasting, one using a replacement dose (100 mg/week) in men with low serum testosterone levels (137) and the other using a supraphysiologic dose (200 mg/week) in eugonadal men.(138) In both studies, significant increases in LBM occurred with either testosterone or exercise, and in the latter study these effects tended to be additive. Taken together, these studies suggest that testosterone can increase LBM, muscle mass, and function in men with wasting and low serum testosterone levels, and a pharmacologic dose can similarly improve lean tissue in eugonadal men with wasting. In some cases, these changes have been associated with improvements in self-assessed quality of life and indices of depression.(139)

Based on evidence suggesting that HIV-infected women with wasting may have lower free testosterone levels than seronegative controls,(65) a randomized, double-blind, placebo-controlled study was performed in 53 women with HIV-associated wasting.(140) A specially prepared transdermal system was developed to deliver 0, 150, or 300 (µg/day in the three study groups. A significant increase in weight (+1.9 kg [4%]) was seen in the women receiving physiologic testosterone (150 (µg/day), but the weight gain was primarily fat.

Physiologic testosterone replacement has not been associated with significant adverse effects in any of the aforementioned studies in men. However, testosterone in pharmacologic doses decreases high-density lipoprotein (HDL) cholesterol levels, and thus might increase risk of cardiovascular disease. In addition, the effects of pharmacologic testosterone on the risk of prostate cancer in the setting of HIV infection are unknown. Testosterone enanthate or cypionate is administered by intramuscular injection. Transdermal preparations (both by patch or gel) for men are also commercially available.

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Nandrolone Decanoate
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An injectable derivative of 19-nortestosterone, nandrolone decanoate has a relatively long half-life. Although nandrolone is approved only for the treatment of anemia associated with chronic renal failure, there has been considerable off-label use of this agent in patients with HIV infection. Significant increases in weight and LBM (generally 3-4 kg) have been seen in open-label studies in men using doses ranging from 100 mg every 2 weeks to 600 mg/week for treatment periods of 12-16 weeks.(141-144) Studies using higher doses have not produced proportionally greater increases in LBM. In one study, subjects who were randomly assigned to undergo supervised progressive resistance exercise during nandrolone treatment had greater increases in weight, LBM, and strength than those receiving nandrolone with no exercise, demonstrating that the protein anabolic effects of nandrolone can be augmented by concurrent resistance exercise.(144)

In preliminary reports from separate randomized, double-blind, placebo-controlled studies in men (145) and women (146) with a documented weight loss of >=5%, treatment with nandrolone (200 mg/week in men and 100 mg every other week in women) for 12 weeks was associated with significant increases in LBM with no changes in fat. Men who were randomized to nandrolone had significant decreases in total testosterone, sex hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, and HDL cholesterol levels, and increases in hemoglobin and hematocrit. In women, some hoarseness and hirsutism were reported. Nandrolone had no significant effect on liver enzymes in either study.

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Oxandrolone
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An oral testosterone derivative, oxandrolone is approved by the FDA as a short-term treatment for weight loss incurred in conjunction with surgery, chronic infection, trauma, or prolonged use of corticosteroids. There is no HIV-specific indication for this agent. At the approved dosing level (5-20 mg/day), there appears to be less potential for virilizing effects and hepatic toxicity than has been seen with other oral agents. In a placebo-controlled study in 63 HIV-infected men with >10% weight loss, those randomized to receive oxandrolone in a dose of 15 mg/day gained an average of 0.6 kg at the end of the 16-week study period; weight was unchanged in those who received 5 mg/day and decreased in those on placebo (-1.1 kg).(147) The composition of the weight change was not measured. Oxandrolone treatment was associated with improvements in self-reported appetite and activity, and there were no reported toxicities. In HIV-infected men with weight loss, a 20-mg/day dose of oxandrolone in combination with resistance exercise and testosterone replacement produced striking increases in LBM (+6.9 kg) and indices of strength.(148) As with pharmacologic testosterone and nandrolone, oxandrolone treatment in this latter study produced significant decreases in HDL cholesterol. Higher doses of oxandrolone have been studied in HIV-associated wasting, but no data are available on either safety or efficacy.

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Oxymetholone
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Another oral agent, oxymetholone, was reported to produce weight gain (mean 5.7 kg) and improvements in Karnofsky score in an early open-label study in patients with HIV-associated weight loss.(149) More recently, a double-blind, placebo-controlled study was performed in which 92 men and women with wasting received oxymetholone in total daily doses of 100 or 150 mg or placebo.(150) Preliminary data indicate that both dosing levels of oxymetholone produced significant increases in weight and LBM (+3.7 and +2.7 kg for weight and LBM, respectively, in the group that received 100 mg/day). However, elevations in liver enzymes occurred in 14% of patients receiving oxymetholone. Compared to the 150-mg/day dose of oxymetholone, 100 mg/day appeared to have equivalent efficacy with less toxicity. Oxymetholone is currently approved as a treatment for anemia, but not for wasting.

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Cytokine Modulation
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Because excessive generation of cytokines in response to infection has been associated with metabolic disturbances, anorexia, and wasting, several investigators have studied the effects of relatively weak suppressors of cytokine production in patients with HIV-associated wasting. Agents studied to date include three putative suppressors of TNF-alpha: thalidomide, pentoxifylline, and ketotifen, as well as dietary omega-3 fatty acids, which reduce IL-1 and TNF-alpha production by white blood cells.(151)

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Thalidomide
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The effects of thalidomide in patients with HIV-associated weight loss have been evaluated in three randomized, double-blind, placebo-controlled studies.(152-154) In the largest study of the three, 100 patients were randomized to receive thalidomide in doses of either 100 or 200 mg (nightly) or placebo for 8 weeks.(154) Patients randomized to either dosing level of thalidomide experienced modest but significant increases in weight (~4%). Treatment with a higher dose (200 mg) did not result in a better rate of weight gain and was associated with increased frequency of adverse effects and higher dropout rate. Other studies of thalidomide in patients with HIV infection have shown dramatic reversal of oral aphthous ulcers in a placebo-controlled clinical trial,(155) and reductions in stool frequency in patients with chronic diarrhea.(156) In each case, increases in weight accompanied improvement in symptoms. The most prevalent adverse effects of thalidomide in patients with HIV infection have been somnolence, peripheral neuropathy, hypersensitivity, and neutropenia.

Despite evidence that thalidomide decreases HIV replication and TNF-alpha production in vitro, plasma levels of HIV RNA and TNF-alpha were found to increase modestly (0.3-0.4 log for HIV RNA) in two recent clinical trials of this agent.(154,155) Although the durability and clinical significance of these increases are not known at this time, they have created uncertainty about the potential role for thalidomide in the treatment of wasting in patients with HIV infection.

Thalidomide is available as a treatment for erythema nodosum leprosum. Because of the well-documented and tragic teratogenic effects in infants whose mothers used this drug during pregnancy, thalidomide can be obtained only through specially licensed prescribers and pharmacists, and patients treated with this agent must adhere to strict guidelines for prevention of conception.

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Other Cytokine Suppressors
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Small studies of a variety of other weak cytokine suppressors, including pentoxifylline,(157-159) omega-3 fatty acids (fish oil [160,161], and ketotifen [either alone (162) or in combination with oxymetholone (149)]) have produced results that are modest at best and provide no compelling rationale to pursue these agents as treatments for HIV-associated wasting.

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Exercise
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Exercise (both aerobic and resistance) is an excellent nonpharmacologic means of maintaining or restoring fitness level and LBM in patients with HIV infection. In an early study, progressive resistance training was reported to increase upper and lower body strength and weight in individuals recovering from acute Pneumocystis pneumonia.(163) More recently, increases in weight, LBM, strength, and functional performance have been noted in HIV-positive patients undergoing progressive resistance training, alone or in combination with anabolic steroids.(137,138,148,164-166) Studies have shown that moderate exercise is safe in patients with HIV infection, with no apparent deleterious effects on immune function (167,168) or viral load.(169)

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Summary and Recommendations
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Wasting continues to contribute to increased mortality and morbidity in patients with HIV infection, even in populations with access to effective ART. Thus, it remains important to monitor weight, minimize the impact of disease factors that can contribute to wasting, and intervene to mitigate or reverse weight loss when necessary. Maintenance of adequate food intake is essential in this effort, and dietary measures should be the foundation upon which other interventions are built. Patients should be encouraged to maintain or increase activity levels and to engage in moderate resistance exercise training when possible. A variety of pharmacologic measures including appetite stimulation and the use of protein anabolic therapies have been shown to be effective in promoting weight gain and lean tissue accrual. Such interventions have been demonstrated to improve functional capacity and quality of life, although further research is required to determine whether reversal of wasting improves survival.

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