Updated March 2004 — Currently Under Revision
Key to Abbreviated Terms Within Guidelines
ATP adenosine triphosphate
BCM body cell mass
BIA bioelectric impedance analysisBUN blood urea nitrogen
BW body weight
CI caloric intake
CMV cytomegalovirusCPK creatine phosphokinase
DEXA dual energy x-ray absorptiometry
DT dietary thermogenesis
EEA energy expenditure of activityEM extracellular material
Fat fat compartment
gastroesophageal reflux disease
HAART highly active antiretroviral therapyIL interleukin
LBM lean body mass
PRE progressive resistance exercise
rhGH recombinant human growth hormoneREE resting energy expenditure
TBW total body weight
TEE total energy expenditure
TNF tumor necrosis factorTPN total parenteral nutrition
UBW usual body weight
VAT visceral adipose tissue
VLDL very low density lipoprotein
The clinician should ensure that patients with HIV-associated weight loss are receiving effective ARV therapy (see Guidelines for the Use of Antiretroviral Therapy).
Significant weight loss negatively impacts a patient’s quality of life and self-image. Despite advances in the treatment of HIV/AIDS, the majority of HIV-infected patients experience weight loss at some time during the course of the disease.
The Nutrition for Healthy Living study has been longitudinally following HIV-infected participants to examine the causes and consequences of malnutrition.1 Between 1995 and 2000, there were 552 evaluable patients, and weight loss was the strongest independent predictor of mortality despite the availability of HAART. A 4- to 6-fold increase in mortality was seen in patients with ≥10% weight loss from baseline or the previous visit.
For patients experiencing weight loss, the clinician’s tasks include documenting the character and circumstances of the weight loss, estimating the major alteration of body composition, attempting to understand the mechanisms contributing to the weight loss, and treating both the underlying metabolic derangement as well as any confounding conditions present. The expectation of treatment for the weight loss should be an improved quality of life and performance status.
Although much remains to be understood about the relationship between losses of body mass and HIV infection, the following principles are essential to the effective management of weight loss and nutrition in HIV-infected patients:
- Rapid loss of weight (more than 5% of usual body weight over a 2- to 3-month period) and lean body mass are highly associated with impending hospitalization and mortality.2
- Therapeutic attention to reversing weight loss without addressing the etiology has never been convincingly proven to improve overall prognosis.3
- Although new HAART regimens have reduced the prevalence of wasting syndrome, they have at the same time been associated with previously unrecognized variations to body composition.4
- The mechanisms that cause weight loss are myriad and usually multifactorial.
Weight loss is a symptom that warrants a carefully executed diagnostic evaluation for correctable or treatable confounding conditions.
As further research uncovers the pathophysiologic mechanisms of weight loss in HIV infection, more effective therapies can be anticipated.
II. ASSESSMENT OF BODY COMPOSITION
The clinician should measure and record the weight of HIV-infected patients at each visit.
For the purposes of this chapter, the following definitions concerning body composition will be used:
- Body weight (BW) is the total mass constituting all cellular and non-cellular components and can be simply measured by an office scale.
- The body cell mass (BCM) includes all non-adipose cells as well as the aqueous compartments of the fat cells.
- The fat compartment (Fat) represents the non-aqueous component of adipocytes.
- The lean body mass (LBM) represents the BCM and extracellular material (EM) exclusive of fat.
BW = BCM + EM + Fat
LBM = BCM + EM
Accurate assessment of body composition can be accomplished by one of three methods. Sophisticated isotope dilution studies and dual energy x-ray absorptiometry (DEXA) scans are research techniques that may not be generally available to most physicians in their day-to-day management of patients. Bioelectric impedance analysis (BIA) is practical and relatively inexpensive and should be used, if possible. However, BIA can lead to misinterpretation of body composition when there are significant volume shifts or regions of active inflammation. Measurement of skin folds is an inexpensive method of assessing body fat; however, to obtain reproducible results, an experienced healthcare provider should obtain the measurements.
The clinician should be vigilant for HIV-associated malnutrition, even in patients who appear to be maintaining their usual body weight. Weighing the patient should not be the sole method used to detect nutritional deficiencies.
Loss of BW in HIV-infected adults usually signifies a perturbation of more than a single compartment (see Table 1). Generally, it will be possible to identify the compartment that is most significantly decreased, although a marked decrease in one compartment may be counterbalanced by increases in another, with little net change in the measured BW. For example, a patient with marked reduction in BCM due to severe deconditioning may have no net change in BW because of increases in fat. Therefore, depending solely on the examining room scale to detect nutritional deficiencies can be misleading.
Studies have confirmed that malnutrition with alterations in BCM and fat occurs at all stages of HIV infection.5 For individual patients, such body composition changes may not correlate with a decline in CD4 cell counts or a history of opportunistic diseases. However, certain alterations in body composition are directly linked to prognosis and even time to death. Regression analysis studies have linked time of death to a point in time when the BCM and BW reach 54% and 66% of ideal values, respectively.2 Significant unintentional loss of body mass is usually considered to be >5% of the usual BW over 1 to 2 months. A ≥10% decrease in the usual BW is one criterion for wasting syndrome6 (see Section VI: The Wasting Syndrome). Although many presume that delay or reversal of lost BW could improve life expectancy, this has never been confirmed by controlled clinical studies. Hence, simply supplementing caloric intake without addressing reversible causes of weight loss is not generally beneficial.
|Table 1: Clinical Determination of Changes in Body Composition|
III. ASSESSING NUTRITIONAL STATUS
A careful nutritional assessment should be conducted by a registered dietitian for any patient who has involuntary weight loss of at least 5% of the UBW, demonstrates clinical evidence of LBM loss, or follows a restrictive diet involving major food groups.
Poor nutrition may be one of many co-factors encountered in HIV-infected patients. In the United States, poor socioeconomic status and other factors, such as dietary restrictions mandated by HAART, co-existent gastrointestinal disease, alternative therapy diets, psychiatric disorders, active drug and alcohol use, and/or hospitalization for opportunistic diseases, may result in inadequate caloric consumption or assimilation.7
A thorough medical history and a focused physical examination are the most valuable tools in assessing nutritional status.
A careful nutritional assessment is an important part of the management of HIV-infected patients. Food diaries that are maintained by the patient are often incomplete but can be useful to the clinician for estimating the frequency, quality, and size of meals. It is especially useful to enlist the help of a registered dietitian when attempting to assess the adequacy of a patient’s nutritional intake. A thorough medical history is the most valuable tool in assessing nutritional status. Emphasis on the review of systems will occasionally uncover symptoms indicative of a co-morbid condition that influences the nutritional state. A focused physical examination is similarly important.
IV. ENERGY EXPENDITURE
Energy expenditure needs to be met by caloric intake to avoid catabolism and weight loss. Total energy expenditure (TEE) equals resting energy expenditure (REE) plus dietary thermogenesis (DT) plus the energy expenditure of activity (EEA). When weight is stable, the TEE needs to equal the caloric intake (CI). Therefore, it follows that weight loss might occur because of decreases in the caloric intake or because of increases in energy expenditure.
Decreased caloric intake can occur for a variety of reasons in HIV-infected patients. For the TEE to decrease in this setting, there needs to be a decrease in the EEA. It is postulated that the lethargy and fatigue that often accompany the malnutrition of AIDS are compensatory in nature.5
Resting energy expenditure in all stages of HIV/AIDS may be increased by >10% when compared with non-HIV-infected individuals.5
The REE in the HIV-infected patient is typically increased by >10%, which is similar in degree to severe thyrotoxicosis. The pathogenic reasons for this observation are discussed in Section V: Weight Loss.
Lipid abnormalities, such as hypertriglyceridemia, elevation of the serum very low density lipoprotein (VLDL), and hypocholesterolemia, are frequently observed in patients with symptomatic HIV/AIDS. These lipid aberrations are contributed to by substrate futile cycling. Futile cycling of free fatty acids between the liver and the peripheral fat cells requires adenosine triphosphate (ATP) energy expenditure that is not replenished because the free fatty acids are not oxidized in this process.
V. WEIGHT LOSS
The pathophysiology of weight loss in HIV/AIDS is not completely understood. However, many features of catabolism in HIV infection are similar to other chronic illnesses. The mechanisms can be divided into three categories:
- Decreased nutrient intake
- Decreased nutrient absorption
- Disturbances of metabolism
1. Decreased Nutrient Intake
When patients present with dysphagia or odynophagia, the clinician should evaluate for causes of neoplasms, stomatitis, and/or esophagitis, especially when the patient’s CD4 count is <200 cells/mm3.
After active opportunistic diseases have been excluded in patients with voluntary restricted caloric intake, clinicians should consult with or refer the patient to a dietitian, psychiatrist/psychologist, or social worker.
There are myriad causes of inadequate oral intake of caloric substrate for patients with HIV/AIDS. Anorexia is prevalent, and in patients receiving HAART, it is most often related to medication toxicity. Less frequently, anorexia may result from opportunistic conditions of the oral cavity, upper gastrointestinal tract, endocrine, or central nervous system, especially in patients with CD4 cell counts <200 cells/mm3. Endogenous cytokines and interferons also may precipitate a significant loss of appetite.8 Active substance use and depression are also causes of decreased nutrient intake.
Dietary restrictions for some HAART regimens pose significant barriers to adequate caloric intake and good nutrition. It may be necessary to consider a change in HAART under these circumstances (see Table 2).
Dysphagia and odynophagia are barriers to adequate nutrition. Examples of conditions causing dysphagia include aphthous and chemotherapy-induced stomatitis; herpes simplex and CMV infections; candidal esophagitis; or neoplasms of the oral cavity, posterior pharynx, or esophagus.
In patients with CD4 cell counts >200 cells/mm3, the most common cause of voluntary decrease in oral intake is anorexia as a result of medications that cause nausea, alteration in taste, and/or gastroesophageal reflux disease (GERD). Voluntary restriction of caloric intake may occur because of difficulty with complex medical regimens; economic barriers to good nutrition; avoidance due to holistic or alternative therapy restrictive diets; psychiatric disorders, including depression and bipolar disease; and physician-recommended restrictive diets for medical reasons, such as pancreatitis, renal disease, or HAART.
|Table 2: Manufacturers’ Guidelines Combining Antiretroviral Medication and Food|
|Data are from manufacturers’ information and Fields-Gardner C, Salomon S, Davis M. Living Well With HIV and AIDS: A Guide to Nutrition. Chicago, IL: The American Dietetic Association, 2003.* TDF + ddI EC can be taken on an empty stomach or with a light meal; TDF + ddI buffered tablets should be taken on an emptystomach.|
2. Decreased Nutrient Absorption
For all patients with chronic diarrhea, the clinician should examine for and treat gastrointestinal opportunistic infections (Mycobacterium avium complex, bacterial pathogens such as Salmonella, Cryptosporidium, microsporidia, Isospora, Giardia, Entamoeba, Clostridium difficile), as well as assess for ARV-induced diarrhea.
The clinician should evaluate patients with chronic diarrhea in the setting of weight loss for malabsorption by 3-day fecal fat measurement, D-xylose absorption studies, and jejunal and/or colon biopsy.
Chronic diarrhea can be defined as at least two watery stools per day lasting for more than 3 weeks. When malnutrition and weight loss are caused by chronic diarrhea, malabsorption of essential nutrients is usually associated. Despite an adequate or even supranormal nutrient consumption, these patients suffer malnutrition because of intestinal malabsorption caused by chronic intestinal microbial colonization with such pathogens as M. avium complex, Cryptosporidium, Isospora, or microsporidia. An in-depth discussion of gastrointestinal pathogens can be found in Chapter 9: Gastrointestinal Complications of HIV. Molecular hybridization studies have confirmed the presence of HIV in the bowel walls of patients with AIDS enteropathy.9 Although there is no definitive evidence that HIV enteropathy results in malabsorption, it is a theoretical contributory factor after other etiologies have been excluded.
Common features of the malabsorptive syndromes are steatorrhea, villous atrophy, and diminished absorptive surface area, along with functional defects in pathogen-injured cells and poor differentiation of villous epithelial cells due to rapid cell turnover. Patients with nutrient malabsorption generally report several episodes of diarrhea daily, occasionally with steatorrhea, and they may have an associated vitamin B12 deficiency.
Evaluation of patients with chronic diarrhea may include stool studies for enteric pathogens, ova and parasites, Clostridium difficile toxin, acid-fast bacilli stain, and modified acid fast stain for organisms such as cryptosporidium. Antigen testing of stool is available in some laboratories for infections such as cryptosporidiosis and giardiasis. If this evaluation is non-diagnostic, colonoscopy with biopsy may be indicated to look for certain infections such as CMV, or non-infectious processes such as inflammatory bowel disease. Chronic malabsorption from pathogens such as M. avium complex requires upper endoscopy with small bowel biopsy for diagnosis.
Several studies indicate that selenium deficiency correlates with HIV progression and mortality. More studies are required to determine whether the selenium deficiency is a cause or an effect of clinical disease progression. Serum carotene levels may be reduced in patients with the wasting syndrome. It is likely that patients who have limited access to micronutrients would benefit from supplementation.
3. Disturbances of Metabolism
The clinician should perform a comprehensive medical evaluation when rapid unintentional weight loss (≥10% of the UBW) occurs over weeks to months because it is frequently associated with a life-threatening opportunistic infection or neoplasm.
Clinicians should consider measuring total and free testosterone levels in all HIV-infected men with changes in libido, loss of LBM, or fatigue.
Because women lose a disproportionate amount of body fat at all stages of HIV infection, malnutrition should be suspected in women demonstrating fat loss.
Deranged metabolism may induce weight loss either through ineffective or excessive utilization of energy substrate (see Table 3). Abnormal energy expenditure at rest has been described in the setting of HIV infection.10 Certain opportunistic infections, such as disseminated M. avium complex, may induce extraordinary consumption of energy substrate. Although REE may be elevated during the course of HIV infection, in patients with rapid weight loss despite adequate caloric consumption, an evaluation for an opportunistic infection or neoplasm should be performed. The mechanisms by which HIV infection triggers an increase in REE are not fully understood.
|Table 3: Metabolic Abnormalities Associated With Weight Loss in HIV/AIDS|
After early reports of elevated levels of tumor necrosis factor (TNF) in HIV/AIDS, this cachexin was implicated as a cause of wasting.11 However, subsequent studies failed to document consistent elevation of TNF levels. Other cytokines, including interleukin-1, IL-2, IL-6, and α-interferon, also have been measured at elevated levels compared with non-HIV-infected persons. Some animal models have implicated cytokines as a cause of weight loss. It is plausible that, for some patients, synergy between one or more cytokines contributes to observed catabolism and weight loss. Cytokines have many physiologic effects including the induction of other catabolic agents, such as cortisol, catecholamines, adrenocorticotropin hormone (ACTH), and glucagon.
Futile cycling refers to the inappropriate mobilization of peripheral free fatty acids, which are then re-esterified into triglycerides rather than being oxidized by the liver. Thus, cytokines redirect energy away from the periphery and toward the liver to fuel an acute phase response. This results in an increased VLDL level with a net consumption of energy in the form of ATP. Animal models have implicated TNF in futile cycling, although its quantitative impact in humans with HIV infection has not been established.5,12
Under circumstances of starvation, the body can regulate the catabolism of muscle and fat separately. In prolonged fasting states, there is generally protein sparing relative to the loss of fat. In contrast, in HIV/AIDS and other conditions (e.g., septicemia), protein wasting seems to occur at an increased rate. It has been postulated that this proteolysis adaptation is cytokine mediated.
Serum testosterone levels have a circadian rhythm and are standardized to morning samplings. Studies of endocrine function in men with AIDS have documented low serum testosterone levels.13 Testosterone is an anabolic steroid that, if deficient, could contribute to protein wasting. Elevated prolactin levels also have been documented, especially in patients with CD4 counts ≤200 cells/mm3. The observed elevations of prolactin raise the probability of a hypothalamic hypogonadism. Interestingly, certain cytokines, including IL-1, can reduce the responsiveness of the testicular Leydig cells, which sets the stage for primary hypogonadism as well. Body composition studies have defined differences in the patterns of weight loss between men and women.14,15 Men generally demonstrate a disproportionate decrease in LBM relative to fat loss. In contrast, women lose a disproportionate amount of body fat relative to LBM at all stages of HIV infection. Testosterone is difficult to accurately measure in women because levels are normally low in women. Free testosterone levels are thought to give a more accurate representation of available testosterone in both HIV-infected men and women. Less is understood about the impact of low testosterone levels in women, although in one study, HIV-infected women either of low weight or losing significant weight had a greater likelihood of hypoandrogenemia compared with non-HIV-infected controls.16 Further studies to demonstrate whether HIV-infected women with hypoandrogenemia might benefit from testosterone replacement are needed.
When weight loss is associated with profound fatigue, postural hypotension, hyperkalemia and/or hyponatremia, clinicians should consider adrenal insufficiency, especially in cases of disseminated M. avium complex and CMV infection.
Cortisol is generally elevated in patients with opportunistic infections, most notably M. avium complex. Cytokines may contribute to the induction of cortisol. Adrenal insufficiency also may be seen in patients with HIV/AIDS. Generally, this is in the setting of advanced disease complicated by multiple opportunistic infections. One mechanism for adrenal failure may be the infiltration and ablation of adrenal tissue by CMV or other pathogens.
The euthyroid sick state has been well described in many chronic illnesses. This condition is associated with an increase in reverse T3 and results in a reduction of energy consumption. Patients with AIDS were studied and found to have normal levels of reverse T3. It has been postulated that preservation of normal thyroid function in the setting of AIDS might lead to an inappropriately high basal metabolic rate and contribute to weight loss.5
Myopathy has been described as a complication of HIV infection, as well as of NRTIs. The pathogenesis of the myopathic changes has been attributed to mitochondrial toxicity. In its full expression, the myopathy may be severe with marked muscle atrophy and weakness predominantly involving the proximal muscle groups, myalgias, elevated serum creatine phosphokinase (CPK), abnormal electromyograms with irritative features, and abnormal muscle biopsies.
B. Management of Gradual HIV-Associated Weight Loss
(see Figure 1)
1. Nutritional Supplementation
Although nutritional supplementation is indicated for all patients with weight loss, the clinician should not supplement caloric intake without first addressing reversible causes of weight loss.
Clinicians should recommend the use of “once daily” multivitamin supplements containing selenium (20-40 mcg) for all HIV-infected patients experiencing weight loss.
Clinicians should not recommend high-dose vitamin therapy because this might exacerbate pre-existing gastrointestinal dysfunction and/or anorexia.
Clinicians should consider medical conditions, such as pancreatitis, diabetes mellitus, or renal insufficiency, in planning macronutrient balances.
In general, a good target for daily caloric intake should be 1.3 times the caloric demands needed to maintain a basal metabolic rate. A simple estimate of basal metabolic requirements is 25 to 30 Kcal/kg. Hence, for a healthy 70-kg patient, 1750 to 2100 Kcal are required to maintain the basal metabolic rate. For the same patient infected with HIV, 2730 to 3640 Kcal would be needed. To achieve anabolic effects, an additional 5 to 10 Kcal/kg is required.17 The proportion of macronutrients should approximate 50% to 55% carbohydrates, 15% to 20% protein, and 30% fat. However, medical conditions such as pancreatitis, diabetes mellitus, or renal insufficiency need to be considered in planning the macronutrient balances.
Consultation with a registered dietitian is a valuable resource for the patient and the clinician. The dietitian is often able to determine the causes of eating difficulties through use of food diaries, food models, or direct measurement of ingested food products.
Gastric hyperacidity, early satiety, irritable bowel, and lactose intolerance frequently confound the management of HIV-infected patients. Frequently spaced, small-volume meals may be better tolerated. Liquid nutritional supplements are useful for patients who have limited access to prepared meals or for those who require complex medication regimens requiring fasting at odd times throughout the day. A list of some of the available oral nutritional supplements can be found in Table 4. In general, patients who have severe wasting (≥10% of the UBW) should receive supplements with higher caloric content, such as EnsurePlus or Perative. The latter product is a semi-elemental formulation that is better tolerated when intestinal malabsorption is present. The higher osmolarity products, such as EnsurePlus, Criticare, and Peptomen, may be more likely to induce diarrhea and often require dilution. Juven is a nutritional mixture of β-hydroxy β-methylbutyrate, glutamine, and arginine. Studies of Juven have demonstrated enhancement of LBM in patients with AIDS.18 Prescribed micronutrients and vitamin supplementation are especially advisable for indigent patients or for those with possible malabsorption. A multivitamin with minerals is generally adequate. The use of high-dose vitamin “therapy” should be discouraged as this might exacerbate preexisting gastrointestinal dysfunction and/or anorexia. Selenium supplementation in HIV/AIDS has been the subject of a number of studies.19,20 Serum selenium deficiency has been correlated with a higher risk of AIDS mortality, and in vitro studies suggest that selenium may suppress TNF -induced HIV replication. The use of daily multivitamin supplements containing selenium (20-40 mcg) is advisable, especially in patients experiencing weight loss. In patients with evidence of severe, long-standing malnutrition, measurement of serum selenium levels may be indicated.
|Figure 1: Management of Gradual Weight Loss in the HIV-Infected Patient|
|Table 4: Selected Commercially Available Liquid Nutritional Supplements*|
|* The products listed above do not represent a complete listing of the commercially available supplements.|
2. Treatment of Anorexia
When patients present with anorexia, clinicians should perform a careful review of the medication list to determine whether the anorexia is medication-induced.
Anorexia is an obstacle to adequate nutrition and needs to be addressed when present. Careful and frequent review of medications should be undertaken to determine whether any of them are implicated. Neuropsychiatric testing is often helpful in the evaluation of anorexia when the cause cannot be determined by clinical evaluation.8 Appetite stimulants should be considered when the cause of anorexia cannot be determined or reversed (see Appendix A). Periactin may be an effective appetite stimulant for some patients. Megestrol acetate and dronabinol result in modest increases in appetite. Many patients do not tolerate the CNS effects of dronabinol, even at low doses. Dronabinol, despite improving appetite, has not been convincingly shown to increase TBW. Megestrol does result in slow and modest increases in TBW, but this is usually associated with increases in fat and little change in the BCM. Megestrol can lower the serum testosterone levels. This raises the possibility that a eugonadal male patient receiving megestrol may become hypogonadal. In addition, there is a potential for adrenal insufficiency when long-term use of megestrol is discontinued.7 Clinicians should screen for hypogonadism and adrenal insufficiency in patients receiving megestrol for prolonged periods.
3. Treatment of Noninfectious Diarrhea
When recalcitrant diarrhea occurs as a complication of HAART, clinicians should consider a change in therapy if suitable alternatives with a high likelihood of successful viral suppression are available (based on HIV resistance testing).
HIV-infected patients experience diarrhea for a variety of reasons. Several reports have underscored the usefulness of calcium supplements for patients experiencing nelfinavir-induced diarrhea. Other modalities, such as pancreatic enzymes and psyllium fiber supplements have been useful for PI-induced diarrhea. Many patients note an increase in symptoms following meals and will voluntarily avoid adequate alimentation to reduce bowel frequency. When pancreatic insufficiency is present, supplemental pancreatic enzymes may be helpful in reducing diarrhea and post-prandial bloating. As previously noted, avoidance of lactose-containing foods and the use of lactase supplements may be useful. Cautious use of antimotility agents such as loperamide or diphenoxylate hydrochloride is sometimes helpful. For severe cases, octreotide and tincture of opium have also been used.
4. The Role of Exercise
Clinicians should advise patients to participate in a fitness program that uses progressive resistance exercise.
The benefits of an adequate fitness program cannot be overemphasized. Progressive resistance exercise (PRE) increases LBM in conjunction with adequate caloric intake.21 The effects of resistance exercise are potentiated by anabolic steroids and are diminished in the hypogonadal male (see Section 5: Anabolic Steroids).
Aerobic exercise results in little or no increase in BCM as compared to PRE. Aerobic exercise may increase CD4 counts, but such exercise has no definite effect on T-cell function. In addition, aerobic activity without sufficient energy substrate may induce further weight loss. Reported effects of aerobic exercise on CD4 cell function have been variable.22 Aerobic fitness programs do, however, improve performance status and quality-of-life measures.
5. Anabolic Steroids
Clinicians should exclude specific endocrine abnormalities, such as hypothalamic hypogonadism and hyperthyroidism, before prescribing oxandrolone.
Clinicians should monitor for hypogonadism in eugonadal men who are receiving long-term nandrolone or oxandrolone.
Anabolic steroids are the most effective long-term means of restoring BCM (see Appendix A). Nandrolone has a high anabolic/low androgenic profile. It must be administered parenterally. Oxandrolone is probably the most effective oral agent for restoring BCM. It is moderately expensive, although it is now being reimbursed by most third-party payers. It is likely that nandrolone and oxandrolone are safe for use in women. There is a potential for these agents to “turn off” endogenous testosterone production in eugonadal men; therefore, long-term use requires monitoring for hypogonadism.23 Both oxandrolone and nandrolone have a relatively low potential to cause hepatic toxicity when compared with oral androgenic anabolic steroids.23 These agents are non-narcotic Schedule III drugs under the Anabolic Steroids Control Act of 1990. Although the use of oxandrolone is indicated by the FDA to promote weight gain following surgery or trauma, it is not specifically approved for HIV-associated weight loss. Polycythemia, injection site infection, or local nerve trauma are unusual complications of nandrolone use.
6. Androgenic Anabolic Steroids
Clinicians should consider short-term (several months) testosterone therapy with supraphysiologic doses, in conjunction with PRE, to achieve BCM increase in selected male patients demonstrating a rapid rate of muscle loss.
Because androgenic anabolic steroids cause virilization, a general recommendation for their use in women cannot be made until further studies have been completed.
Because androgen enhances libido, clinicians should strongly reinforce safer sexual practices for patients receiving androgenic anabolic steroids.
The androgenic anabolic steroids include testosterone. As noted previously, hypogonadism can be associated with HIV infection in men. The attendant decrease in libido, depression, and loss of muscle mass may be reversed to some degree by replacement therapy. Although not FDA-approved, supraphysiologic doses of testosterone in conjunction with PRE result in significant increase in the BCM.24 Unwanted side effects include acne, accelerated hair loss, and behavioral changes. Virilization makes use of such available agents unsuitable for use in women; however, new studies of experimental low-dose testosterone patches in women are underway.
There is a strong association between Kaposi’s sarcoma (KS) and the human herpes virus type 8. However, the male preponderance in cases of KS has led to studies linking serum testosterone levels and KS occurrence. There is epidemiologic evidence implicating androgenic steroids as a promoter of KS in the setting of AIDS.25 Although there is no firm evidence that androgenic steroids promote KS, many HIV Specialists suggest caution in prescribing androgenic steroids for patients with preexisting KS.
Testosterone can also cause prostate cancer and hepatic toxicity, including cholestasis, peliosis hepatitis, and primary hepatic carcinoma. A natural consequence of exogenous testosterone replacement is testicular atrophy, if not already present. Increases in libido mandate the reinforcement of safer sexual practices for all patients receiving this form of therapy. The transdermal testosterone preparations seem to have the safest therapeutic profiles. Local irritation of the adhesive/accelerant is common, and patients complain about the cosmetic and emotional impact of wearing a transdermal patch throughout the day. Androgel, a transdermal testosterone gel preparation, has been approved by the FDA for the treatment of hypogonadism. This topical preparation is applied directly onto the skin without a patch; transfer of drug from patient to others by direct contact with the skin application site is a potential problem. A newer form of testosterone replacement with buccal absorption (applied under the upper lip) has also become available. All of the androgenic anabolic agents are non-narcotic Schedule III drugs under the Anabolic Steroids Control Act of 1990. They are approved for the treatment of male hypogonadism. With the improvement of immune function and overall well-being, hypogonadism may improve, and exogenous testosterone can be discontinued with careful monitoring of testosterone levels. Clinicians should be aware of the potential for steroid abuse.
7. Recombinant Human Growth Hormone
Clinicians should consider prescribing a 12-week course of recombinant human growth hormone (rhGH) after hypogonadism and active opportunistic diseases have been excluded.
Clinicians should discontinue rhGH treatment if no weight gain is observed after the initial 3 to 4 weeks of therapy.
If weight loss continues despite several weeks of rhGH therapy, the clinician should re-evaluate for coexistent opportunistic infections.
rhGH (Serostim) is the only drug that is FDA-approved for treatment of HIV/AIDS-associated weight loss and seems to be a highly effective agent for improving both TBW and BCM (see Appendix A).26 It should be considered only when hypogonadism has been excluded and after treatment of conditions leading to malabsorption or anorexia are addressed. A wide array of side effects is associated with its use. These include muscle and joint pain, carpal tunnel syndrome, peripheral neuropathy, peripheral edema, hyperglycemia, and pancreatitis. Some of these symptoms and signs may improve with dose reduction. Reduced doses of 3 to 4 mg/day have been better tolerated by some, without necessarily compromising efficacy. rhGH is expensive, thus many third-party payers will not cover its cost. The duration of therapy is unclear, but a number of studies have shown prolonged maintenance of BCM after a 12-week course.27 The patient’s response should be monitored closely. If weight loss continues despite several weeks of rhGH therapy, an investigation for coexistent opportunistic infection is warranted.
Growth hormone has also been studied in syndromes of fat accumulation. In one study, there was a significant reduction in visceral adipose tissue (VAT) among 30 patients after 6 months of treatment with recombinant human growth hormone, but VAT re-accumulated 12 weeks after discontinuation.28 A large clinical trial showed a significant decrease in visceral fat content when 4 mg/day rhGH was injected subcutaneously and a trend toward significance when 4 mg every other day was used.29 rhGH is not FDA-approved for the treatment of lipodystrophy.
8. Experimental Cytokine Mediators
Interest in using agents that modify circulating levels of cytokines, especially TNF, was reflected by a number of uncontrolled clinical studies in the early 1990s.30 The use of cytokine modifiers as a treatment for HIV/AIDS-associated wasting is of unproven efficacy. As discussed in Section V-A: Weight Loss: Pathophysiology, although TNF levels may be elevated in some patients with wasting, this observation is not uniform, and elevated levels are unlikely to be the primary cause of weight loss in most patients. Furthermore, technical difficulties in performing assays for TNF make it impossible to compare studies using different methodology. The effectiveness of agents such as pentoxifylline and thalidomide are modest at best. Thalidomide has shown some promise in Africa in promoting weight gain in persons with AIDS and mycobacterial disease. In this country, increases in LBM have been demonstrated with thalidomide.31 Thalidomide is available on a restricted basis for the treatment of HIV-associated aphthous stomatitis or wasting syndrome. Registration with the manufacturer Celgene (phone: 888-423-5436) is required.
VI. THE WASTING SYNDROME
Clinicians should perform a detailed evaluation for opportunistic infections or malignancies in all patients with wasting syndrome.
Wasting syndrome was added to the AIDS surveillance case definition in 1987. Not surprisingly, because of the non-specific nature of wasting syndrome, there was a high concordance with other opportunistic conditions, including cryptosporidiosis, M. avium complex, and CMV infection. In the era of HAART, the incidence of reported cases of wasting syndrome has decreased dramatically, nearly paralleling the decreases in incidence of AIDS and AIDS-associated mortality.
Wasting syndrome, as defined by the Centers for Disease Control and Prevention (CDC), is an involuntary loss of ≥10% of the baseline (usual) body weight plus either chronic diarrhea, weakness, or documented fever, in the absence of a concurrent illness or condition.6,32 Wasting syndrome is predictive of the onset of opportunistic infections and neoplasms. An aggressive diagnostic program is indicated with the appearance of the wasting syndrome (see Figure 2).
|Figure 2: Management of Wasting Syndrome|
|* See Section V: Weight Loss.|
B. Nutritional Intervention in the Wasting Syndrome
The clinician should perform an immediate evaluation to determine the cause of the wasting syndrome.
For patients with conditions that prevent enteral feeding, total parenteral nutrition (TPN) may be indicated for short-term management.
The clinician should monitor supplementation with micronutrients by frequently assessing serum electrolytes and blood glucose in the first several weeks of re-feeding.
The goals of therapy are three-fold:
- To undertake nutritional triage and to supplement nutrition in patients for whom urgent nutritional support might be life-saving.
- To treat and control all complicating conditions that are contributory to malnutrition.
- To attempt to intervene with therapies matched to the metabolic derangement(s) most likely to be operative.
Emergency treatment of patients who have lost excessive body weight (≥10%), especially over a brief period of time, can prove to be lifesaving (see Figure 2). Such persons usually have a poor performance status with Karnofsky scores of ≤60, suffer inanition, and may require acute hospitalization.7 An immediate evaluation needs to be performed to determine the cause of the wasting syndrome. Enteral alimentation should be considered when gastrointestinal function is adequate. In some patients with partial malabsorption, an elemental or semi-elemental caloric supplement is well tolerated. However, for patients with conditions that prevent enteral feeding, TPN is indicated for short-term management. Close attention should be given to supplementation with micronutrients, and frequent assessments of the electrolytes and blood glucose are necessary in the first several weeks of re-feeding. As discussed earlier, the long-term prognosis of AIDS is not affected by hyperalimentation. The goals should be to acutely stop the catabolic reduction of BCM while secondary opportunistic conditions are identified and treated. Except in rare instances of intractable and massive diarrhea with malabsorption, TPN nutrition is generally not needed for more than 1 or 2 months.
VII. FAT REDISTRIBUTION (LIPODYSTROPHY) SYNDROMES
Although HAART has resulted in a dramatic decrease in AIDS-associated morbidity, it is estimated that as many as 60% to 80% of patients receiving HAART for more than 1 year will demonstrate changes in body composition and/or blood lipids.33 Two new syndromes of abnormal body morphology or lipodystrophy have been described that seem to be associated with the newer treatment modalities34: 1) fat accumulation/redistribution syndrome, and 2) lipoatrophy syndrome. A more thorough discussion of these syndromes is covered in Long-Term Complications of Antiretroviral Therapy.
PIs were the first to be implicated in the fat redistribution syndrome, and the NRTIs have been proposed as triggers for the lipoatrophy syndrome. Of note, patients may also present with a mixed picture of morphological changes. Definitive etiologies of these abnormal body morphology syndromes remain unknown.
The fat redistribution syndrome is important in the discussion of body composition and weight loss. The total body weight of patients exhibiting the fat redistribution syndrome usually varies little from their usual body weight. In addition to the somatic changes, a number of metabolic disturbances have been described. Insulin resistance with hyperglycemia, hyperlipidemia (with elevated triglycerides, elevated LDL cholesterol, and decreased HDL cholesterol), and decreased hemostasis in patients with hemophilia have been reported.26 These metabolic abnormalities may also occur independently of the fat redistribution syndromes. Initially termed lipodystrophy, this syndrome is best described as fat accumulation or redistribution syndrome. The most prominent signs are somatic and dysmorphic changes, including facial and limb fat wasting, central and/or localized adiposity, and visceral fat accumulation. Localized fat accumulation may take the form of an enlarged dorsocervical fat pad, multiple lipomata, or breast enlargement in both women and men. The proportionate involvement of the involved sites varies dramatically among patients. The mechanism of these abnormalities remains unclear. Although these complications have historically been attributed to PIs, they can also be seen in patients receiving non-PI-based HAART.
There is concern for increased cardiovascular risk among patients with these dyslipidemias, with some studies suggesting increased risk, and others finding no increased risk.35 Regardless, it is important to address any lipid abnormalities found, based on the current National Cholesterol Education Program (NCEP) guidelines and the Adult AIDS Clinical Trials Group (AACTG) Cardiovascular Focus Group recommendations.
The lipoatrophy syndrome, the other pattern of abnormal body morphology, is marked by predominant loss of subcutaneous fat resulting in severe peripheral fat wasting without localized fat accumulation. HAART is expected to generally improve overall nutritional status with increases in total body weight and intracellular (relative to extracellular) water.4 Thus, loss of body weight should not be interpreted as an acceptable side effect of HAART. The major aberrations in body composition changes are in the fat compartment with significant decrease in fat content. Severe instances of lipoatrophy can result in a 5- to 10-kg decrease in body weight.
Clinicians should consider the possibility of concurrent lactic acidosis and/or hepatic dysfunction in patients with lipoatrophy.
These morphologic changes are sometimes associated with lactic acidosis, abnormal liver chemistries, fatigue, hypoalbuminemia, and elevated triglycerides and total cholesterol. The current theory regarding lactic acidosis is that it may be caused by nucleoside analogue-associated mitochondrial toxicity. Although rare, lactic acidosis may be intractable and fatal; pregnant women are particularly vulnerable. When lactic acidosis syndrome occurs, it is usually in association with constitutional symptoms of fatigue, abdominal pain, anorexia, nausea and vomiting, myalgias, shortness of breath with tachypnea, and abnormal liver chemistries.34 In this setting, it is important to measure serum CO2 and lactic acid levels. ARV therapy should be interrupted for symptomatic lactic acidosis. Routine monitoring of lactic acid is not recommended. However, in patients with prior lactic acidosis in whom nucleoside analogue therapy is being resumed, monitoring lactic acid levels for the first 3 to 6 months after reinstitution should be considered.
1. Tang AM, Forrester J, Spiegelman D, et al. Weight loss and survival in HIV-positive patients in the era of HAART. J Acquir Immune Defic Syndr 2002:31:230-236.
2. Kotler DP, Tierney AR, Wang J, et al. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 1989;50:444-447.
3. Kotler DP. Management of nutritional alterations and issues concerning quality of life. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16(Suppl 1):S30-S35.
4. Carbonel F, Maslo C, Beaugerie L, et al. Effect of indinavir on HIV-related wasting. AIDS 1998;12:1777-1784.
5. Grunfeld C, Kotler DP. Pathophysiology of the AIDS wasting syndrome. AIDS Clin Rev 1992;224:191-224.
6. Nemechek PM, Polsky B, Gottlieb MS. Treatment guidelines for HIV-associated wasting. Mayo Clin Proc 2000;75:386-394.
7. Coodley GO, Loveless MO, Merrill TM. The HIV wasting syndrome: A review. J Acquir Immune Defic Syndr 1994;7:681-694.
8. Greene JB. Clinical approach to weight loss in the patient with HIV infection. Gastroenterol Clin North Am 1988;17:573-586.
9. Fox CH, Kotler DP, Tierney AR, et al. Detection of HIV-1 RNA in intestinal lamina propria of patients with AIDS and gastrointestinal disease. J Infect Dis 1989;159:467-471.
10. Hommes M, Romijn JA, Godfried MH, et al. Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism 1990;39:1186-1190.
11. Grunfeld C, Pang M, Shimizu L, et al. 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;55:455-460.
12. Feingold KR, Adi S, Staprans I, et al. Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production. Am J Physiol 1990;259:E177-E184.
13. Coodley GO, Loveless MO, Nelson HD, et al. Endocrine function in the HIV wasting syndrome. J Acquir Immune Defic Syndr 1994;7:46-51.
14. Grinspoon S, Corcoran C, Miller K, et al. Determinants of increased energy expenditure in HIV-infected women. Am J Clin Nutr 1998;68:720-725.
15. Kotler DP, Thea DM, Heo M, et al. Relative influences of sex, race, environment, and HIV infection on body composition in adults. Am J Clin Nutr 1999;69:432-439.
16. Huang JS, Wilkie SJ, Dolan S, et al. Reduced testosterone levels in human immunodeficiency virus-infected women with weight loss and low weight. Clin Infect Dis 2003:36;499-506.
17. Macallan DC, Noble C, Baldwin C, et al. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 1995;333:83-88.
18. Clark R, Feleke G, Din M, et al. Effects of Juven on muscle wasting. Presented at the 12th International Conference on AIDS; July 1, 1998; Geneva, Switzerland.
19. Hori K, Hatfield D, Maldarelli F, et al. Selenium supplementation suppresses tumor necrosis factor alpha-induced human immunodeficiency virus type 1 replication in vitro. AIDS Res Hum Retroviruses 1997;13:1323-1332.
20. Look MP, Rockstroh JK, Rao GS, et al. Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection. Biol Trace Elem Res 1997;56:31-41.
21. Roubenoff R, McDermott A, Weiss L, et al. Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus. AIDS 1999;13:231-239.
22. Perna FM, LaPerriere A, Klimas N, et al. Cardiopulmonary and CD4 cell changes in response to exercise training in early symptomatic HIV infection. Med Sci Sports Exerc 1999;31:973-979.
23. Grinspoon S, Corcoran C, Askari D, et al. Effects of androgen administration in men with the AIDS wasting syndrome: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129:18-26.
24. Strawford A, Barbieri T, Van Loan M, et al. Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: A randomized controlled trial. JAMA 1999;281:1282-1290.
25. Christeff N, Winter C, Gharakhanian S, et al. Differences in androgens of HIV positive patients with and without Kaposi’s sarcoma. J Clin Pathol 1995;48:513-518.
26. Mulligan K, Grunfeld C, Hellerstein MK, et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with HIV infection. J Clin Endocrinol Metab 1993;77:956-962.
27. Krentz AJ, Koster FT, Crist DM, et al. Anthropomorphic, metabolic and immunologic effects of recombinant human growth hormone in AIDS and AIDS-related complex. J AIDS 1993;6:245-251.
28. Engelson ES, Glesby MJ, Mendez D, et al. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. J Acquir Immune Defic Syndr 2002:30:379-391.
29. Kotler DP et al. Growth hormone (Serostimreg) effectively reduces visceral adipose tissue (VAT) accumulation and non-HDL cholesterol. In: Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract #LbOr18.
30. Grunfeld C, Feingold KR. The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy 1991;3:143-158.
31. Kaplan G. Thalidomide promotes weight gain and increase in fat-free mass in HIV-associated wasting. Presented at the 5th Conference on Retroviruses and Opportunistic Infections; 1998 (Abstract #476); Chicago, Illinois.
32. Nwanyanwu OC, Nahlen BL, Stehr-Green JK, et al. AIDS cases with wasting syndrome who meet the CDC surveillance criteria. J Acquir Immune Defic Syndr 1993;6:966-967.
33. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidemia, and diabetes mellitus: A cohort study. Lancet 1999;353:2093-2099.
34. Carr A, Miller J, Law M, et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: Contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000;14:F25-F32.
35. Dube M, Fenton M. Lipid abnormalities. Clin Infect Dis 2003;36(Suppl 2):S79-S83.
Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:370-374.
Berger JR, Pall L, Hall CD, et al. Oxandrolone in AIDS-wasting myopathy. AIDS 1996;10:1657-1662.
Christeff N, Winter C, Gharakhanian S, et al. Differences in androgens of HIV positive patients with and without Kaposi’s sarcoma. J Clin Pathol 1995;48:513-518.
Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS 1997;11:1347-1352.
Grinspoon S, Corcoran C, Miller K, et al. Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 1997;82:1332-1337.
Hayes CR, ed. Integrating nutrition therapy into medical management of human immunodeficiency virus. Clin Infect Dis 2003;36(Suppl 2):S51-S109.
Mitchell JB, Paquet AJ, Pizza FX, et al. The effect of moderate aerobic training on lymphocyte proliferation. Int J Sports Med 1996;17:384-389.
Mulligan K. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition with HIV infection. J Acquir Immune Defic Syndr 2000;23:35-43.
Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society – USA panel. J Acquir Immune Defic Syndr 2002;31:257-275.
|TABLE A-1 THERAPY FOR GRADUAL HIV-ASSOCIATED WEIGHT LOSS|
|* Because a central role of TNF in wasting has not been established, this treatment approach should be considered speculative and of unproven effectiveness.|