General nutrition, weight loss, and wasting syndrome pdf

GENERAL NUTRITION, WEIGHT LOSS, AND WASTING SYNDROME
KEY TO ABBREVIATED TERMS WITHIN GUIDELINES
INTRODUCTION
RECOMMENDATION:
The clinician should ensure that patients with HIV-associated weight loss are receiving
effective ARV therapy (see Chapter 4: Guidelines for the Use of Antiretroviral Therapy).
Significant weight loss negatively impacts a patient’s quality of life and self-image. Despite advancesin the treatment of HIV/AIDS, the majority of HIV-infected patients experience weight loss at sometime during the course of the disease.
The Nutrition for Healthy Living study has been longitudinally following HIV-infected participantsto examine the causes and consequences of malnutrition.1 Between 1995 and 2000, there were 552evaluable patients, and weight loss was the strongest independent predictor of mortality despitethe 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 andcircumstances of the weight loss, estimating the major alteration of body composition, attempting tounderstand the mechanisms contributing to the weight loss, and treating both the underlying meta-bolic derangement as well as any confounding conditions present. The expectation of treatment forthe 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 andHIV infection, the following principles are essential to the effective management of weight loss andnutrition 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 com-position.4 • The mechanisms that cause weight loss are myriad and usually multifactorial.
Key Point:
Weight loss is a symptom that warrants a carefully executed diagnostic evaluation for cor-rectable or treatable confounding conditions.
As further research uncovers the pathophysiologic mechanisms of weight loss in HIV infection,more effective therapies can be anticipated.
ASSESSMENT OF BODY COMPOSITION
RECOMMENDATION:
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 compart- • 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.
The body composition compartments relate as shown below: 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 areresearch techniques that may not be generally available to most physicians in their day-to-daymanagement of patients. Bioelectric impedance analysis (BIA) is practical and relatively inexpen-sive and should be used, if possible. However, BIA can lead to misinterpretation of body com-position when there are significant volume shifts or regions of active inflammation. Measurementof skin folds is an inexpensive method of assessing body fat; however, to obtain reproducibleresults, an experienced healthcare provider should obtain the measurements.
Key Point:
The clinician should be vigilant for HIV-associated malnutrition, even in patients whoappear to be maintaining their usual body weight. Weighing the patient should not be thesole method used to detect nutritional deficiencies.
Loss of BW in HIV-infected adults usually signifies a perturbation of more than a single compart-ment (see Table 1). Generally, it will be possible to identify the compartment that is most signifi-cantly decreased, although a marked decrease in one compartment may be counterbalanced byincreases in another, with little net change in the measured BW. For example, a patient withmarked reduction in BCM due to severe deconditioning may have no net change in BW because ofincreases in fat. Therefore, depending solely on the examining room scale to detect nutritional defi-ciencies can be misleading.
Studies have confirmed that malnutrition with alterations in BCM and fat occurs at all stages ofHIV infection.5 For individual patients, such body composition changes may not correlate with adecline in CD4 cell counts or a history of opportunistic diseases. However, certain alterations inbody composition are directly linked to prognosis and even time to death. Regression analysisstudies 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 tobe >5% of the usual BW over 1 to 2 months. A ≥10% decrease in the usual BW is one criterion forwasting syndrome6 (see Section VI: The Wasting Syndrome). Although many presume that delay orreversal of lost BW could improve life expectancy, this has never been confirmed by controlledclinical studies. Hence, simply supplementing caloric intake without addressing reversible causesof weight loss is not generally beneficial.
CLINICAL DETERMINATION OF CHANGES IN BODY COMPOSITION
Change in Body
Physical
Laboratory
Composition
Examinations
◗Body Cell Mass
Proximal muscle wasting, ▼CPK (if myopathy present) decreased exercise tolerance weakness of deltoids/ ◗Extracellular/
◗Intravascular
ASSESSING NUTRITIONAL STATUS
RECOMMENDATION:
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 UnitedStates, poor socioeconomic status and other factors, such as dietary restrictions mandated byHAART, co-existent gastrointestinal disease, alternative therapy diets, psychiatric disorders, activedrug and alcohol use, and/or hospitalization for opportunistic diseases, may result in inadequatecaloric consumption or assimilation.7 Key Point:
A thorough medical history and a focused physical examination are the most valuable toolsin 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 clini-cian for estimating the frequency, quality, and size of meals. It is especially useful to enlist the helpof a registered dietitian when attempting to assess the adequacy of a patient’s nutritional intake. Athorough medical history is the most valuable tool in assessing nutritional status. Emphasis on thereview of systems will occasionally uncover symptoms indicative of a co-morbid condition thatinfluences the nutritional state. A focused physical examination is similarly important.
ENERGY EXPENDITURE
Energy expenditure needs to be met by caloric intake to avoid catabolism and weight loss. Totalenergy 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 thecaloric intake (CI). Therefore, it follows that weight loss might occur because of decreases in thecaloric intake or because of increases in energy expenditure.
In Steady State: CI = TEE = REE + DT + EEA
Decreased caloric intake can occur for a variety of reasons in HIV-infected patients. For the TEE todecrease in this setting, there needs to be a decrease in the EEA. It is postulated that the lethargyand fatigue that often accompany the malnutrition of AIDS are compensatory in nature.5 Key Point:
Resting energy expenditure in all stages of HIV/AIDS may be increased by >10% whencompared with non-HIV-infected individuals.5 The REE in the HIV-infected patient is typically increased by >10%, which is similar in degree tosevere 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 densitylipoprotein (VLDL), and hypocholesterolemia, are frequently observed in patients with sympto-matic HIV/AIDS. These lipid aberrations are contributed to by substrate futile cycling. Futilecycling of free fatty acids between the liver and the peripheral fat cells requires adenosinetriphosphate (ATP) energy expenditure that is not replenished because the free fatty acids arenot oxidized in this process.
WEIGHT LOSS
A. Pathophysiology
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. Themechanisms can be divided into three categories: 1. Decreased Nutrient Intake
RECOMMENDATIONS:
When patients present with dysphagia or odynophagia, the clinician should eval-
uate 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 withHIV/AIDS. Anorexia is prevalent, and in patients receiving HAART, it is most often relat-ed to medication toxicity. Less frequently, anorexia may result from opportunistic condi-tions of the oral cavity, upper gastrointestinal tract, endocrine, or central nervous system,especially in patients with CD4 cell counts <200 cells/mm3. Endogenous cytokines andinterferons also may precipitate a significant loss of appetite.8 Active substance use anddepression are also causes of decreased nutrient intake.
Key Point:
Dietary restrictions for some HAART regimens pose significant barriers to adequatecaloric intake and good nutrition. It may be necessary to consider a change in HAARTunder these circumstances (see Table 2).
Dysphagia and odynophagia are barriers to adequate nutrition. Examples of conditionscausing dysphagia include aphthous and chemotherapy-induced stomatitis; herpes sim-plex and CMV infections; candidal esophagitis; or neoplasms of the oral cavity, posteriorpharynx, or esophagus.
In patients with CD4 cell counts >200 cells/mm3, the most common cause of voluntarydecrease in oral intake is anorexia as a result of medications that cause nausea, alter-ation in taste, and/or gastroesophageal reflux disease (GERD). Voluntary restriction ofcaloric intake may occur because of difficulty with complex medical regimens; eco-nomic barriers to good nutrition; avoidance due to holistic or alternative therapyrestrictive diets; psychiatric disorders, including depression and bipolar disease; andphysician-recommended restrictive diets for medical reasons, such as pancreatitis,renal disease, or HAART.
MANUFACTURERS’ GUIDELINES COMBINING ANTIRETROVIRAL MEDICATION AND FOOD
To be taken
Can be taken
Comments
with or with-
with food
Avoid meals with >50 g fat. Avoid vitamin E supple- ments. Do not take antacids 1 hour before or aftertaking APV.
Light meal increases AUC 70%, Cmax 57%.
Take with acidic beverage. Do not take antacids or magnesium supplements 1 hour before or after tak-ing DLV.
Take 1 hour before or 2 hours after meals. Alcohol may exacerbate toxicity. Avoid acidic beverages. Do not take aluminum- or magnesium-containingantacids.
Take 1 hour before or 2 hours after meals. Drinkplenty of fluids (8-10 cups/day). Grapefruit juice mayaffect absorption.
Although absorption is decreased with food, systemicavailability is not affected.
To increase absorption by 50-80%, take with meal To increase absorption, take with meal containing500-1000 kcal (20-50% fat).
Take with food that contains both protein and fat. To increase absorption, take with a meal containing>15 g fat.
Take within 2 hours of high-fat meal or snack.
Grapefruit juice may increase retention.
Fatty meal increases TDF AUC by 40%.
Fatty food may decrease bioavailablility (clinical sig- Data are from manufacturers’ information and Fields-Gardner C, Salomon S, Davis M. Living Well With HIV and AIDS: A Guideto 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 2. Decreased Nutrient Absorption
RECOMMENDATIONS:
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 morethan 3 weeks. When malnutrition and weight loss are caused by chronic diarrhea, malab-sorption of essential nutrients is usually associated. Despite an adequate or even supra-normal nutrient consumption, these patients suffer malnutrition because of intestinal mal-absorption caused by chronic intestinal microbial colonization with such pathogens as M. avium complex, Cryptosporidium, Isospora, or microsporidia. An in-depth discussionof gastrointestinal pathogens can be found in Chapter 9: Gastrointestinal Complicationsof HIV. Molecular hybridization studies have confirmed the presence of HIV in the bowelwalls of patients with AIDS enteropathy.9 Although there is no definitive evidence thatHIV enteropathy results in malabsorption, it is a theoretical contributory factor after otheretiologies have been excluded.
Common features of the malabsorptive syndromes are steatorrhea, villous atrophy, anddiminished absorptive surface area, along with functional defects in pathogen-injuredcells and poor differentiation of villous epithelial cells due to rapid cell turnover. Patientswith nutrient malabsorption generally report several episodes of diarrhea daily, occasionallywith steatorrhea, and they may have an associated vitamin B12 deficiency.
Evaluation of patients with chronic diarrhea may include stool studies for entericpathogens, ova and parasites, Clostridium difficile toxin, acid-fast bacilli stain, and modi-fied acid fast stain for organisms such as cryptosporidium. Antigen testing of stool isavailable in some laboratories for infections such as cryptosporidiosis and giardiasis. Ifthis evaluation is non-diagnostic, colonoscopy with biopsy may be indicated to look forcertain infections such as CMV, or non-infectious processes such as inflammatory boweldisease. Chronic malabsorption from pathogens such as M. avium complex requiresupper endoscopy with small bowel biopsy for diagnosis.
Several studies indicate that selenium deficiency correlates with HIV progression andmortality. More studies are required to determine whether the selenium deficiency is acause or an effect of clinical disease progression. Serum carotene levels may be reducedin patients with the wasting syndrome. It is likely that patients who have limited accessto micronutrients would benefit from supplementation.
3. Disturbances of Metabolism
RECOMMENDATIONS:
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.
Key Point:
Because women lose a disproportionate amount of body fat at all stages of HIVinfection, malnutrition should be suspected in women demonstrating fat loss.
Deranged metabolism may induce weight loss either through ineffective or excessiveutilization of energy substrate (see Table 3). Abnormal energy expenditure at rest hasbeen described in the setting of HIV infection.10 Certain opportunistic infections, suchas disseminated M. avium complex, may induce extraordinary consumption of energysubstrate. Although REE may be elevated during the course of HIV infection, inpatients with rapid weight loss despite adequate caloric consumption, an evaluationfor an opportunistic infection or neoplasm should be performed. The mechanisms bywhich HIV infection triggers an increase in REE are not fully understood.
METABOLIC ABNORMALITIES ASSOCIATED WITH WEIGHT LOSS IN HIV/AIDS
• Abnormal energy expenditure/hypermetabolism • Cytokine induction of other catabolic agents • Fat redistribution/“lipodystrophy” • HAART-associated hypercholesterolemia, hypertriglyceridemia, and insulin • Myopathy due to HIV and/or nucleoside mitochondrial toxicity After early reports of elevated levels of tumor necrosis factor (TNF) in HIV/AIDS, thiscachexin was implicated as a cause of wasting.11 However, subsequent studies failed todocument consistent elevation of TNF levels. Other cytokines, including interleukin-1, IL-2, IL-6, and ␣-interferon, also have been measured at elevated levels compared withnon-HIV-infected persons. Some animal models have implicated cytokines as a cause ofweight loss. It is plausible that, for some patients, synergy between one or morecytokines contributes to observed catabolism and weight loss. Cytokines have manyphysiologic effects including the induction of other catabolic agents, such as cortisol, cat-echolamines, adrenocorticotropin hormone (ACTH), and glucagon.
Futile cycling refers to the inappropriate mobilization of peripheral free fatty acids, whichare 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 acutephase response. This results in an increased VLDL level with a net consumption of energyin the form of ATP. Animal models have implicated TNF in futile cycling, although itsquantitative impact in humans with HIV infection has not been established.5,12 Under circumstances of starvation, the body can regulate the catabolism of muscle andfat separately. In prolonged fasting states, there is generally protein sparing relative tothe loss of fat. In contrast, in HIV/AIDS and other conditions (e.g., septicemia), proteinwasting seems to occur at an increased rate. It has been postulated that this proteolysisadaptation is cytokine mediated.
Endocrine Factors
Serum testosterone levels have a circadian rhythm and are standardized to morning sam-plings. Studies of endocrine function in men with AIDS have documented low serumtestosterone levels.13 Testosterone is an anabolic steroid that, if deficient, could contributeto protein wasting. Elevated prolactin levels also have been documented, especially inpatients with CD4 counts ≤200 cells/mm3. The observed elevations of prolactin raise theprobability of a hypothalamic hypogonadism. Interestingly, certain cytokines, includingIL-1, can reduce the responsiveness of the testicular Leydig cells, which sets the stage forprimary hypogonadism as well. Body composition studies have defined differences inthe patterns of weight loss between men and women.14,15 Men generally demonstrate adisproportionate decrease in LBM relative to fat loss. In contrast, women lose a dispro-portionate amount of body fat relative to LBM at all stages of HIV infection. Testosteroneis 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 availabletestosterone in both HIV-infected men and women. Less is understood about the impactof low testosterone levels in women, although in one study, HIV-infected women eitherof low weight or losing significant weight had a greater likelihood of hypoandrogenemiacompared with non-HIV-infected controls.16 Further studies to demonstrate whether HIV-infected women with hypoandrogenemia might benefit from testosterone replacementare needed.
Key Point:
When weight loss is associated with profound fatigue, postural hypotension, hyper-kalemia and/or hyponatremia, clinicians should consider adrenal insufficiency, espe-cially 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 insuf-ficiency also may be seen in patients with HIV/AIDS. Generally, this is in the setting ofadvanced disease complicated by multiple opportunistic infections. One mechanism foradrenal failure may be the infiltration and ablation of adrenal tissue by CMV or otherpathogens.
The euthyroid sick state has been well described in many chronic illnesses. This condi-tion is associated with an increase in reverse T3 and results in a reduction of energyconsumption. Patients with AIDS were studied and found to have normal levels ofreverse T3. It has been postulated that preservation of normal thyroid function in the set-ting of AIDS might lead to an inappropriately high basal metabolic rate and contribute toweight loss.5 Myopathy
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 andweakness predominantly involving the proximal muscle groups, myalgias, elevatedserum 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
RECOMMENDATIONS:
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 con-
taining selenium (20-40 mg) 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 mel-
litus, or renal insufficiency, in planning macronutrient balances.
In general, a good target for daily caloric intake should be 1.3 times the caloric demandsneeded to maintain a basal metabolic rate. A simple estimate of basal metabolic require-ments is 25 to 30 Kcal/kg. Hence, for a healthy 70-kg patient, 1750 to 2100 Kcal arerequired 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 10Kcal/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 aspancreatitis, diabetes mellitus, or renal insufficiency need to be considered in planningthe macronutrient balances. Consultation with a registered dietitian is a valuable resource for the patient and the cli-nician. The dietitian is often able to determine the causes of eating difficulties throughuse of food diaries, food models, or direct measurement of ingested food products.
Gastric hyperacidity, early satiety, irritable bowel, and lactose intolerance frequently con-found the management of HIV-infected patients. Frequently spaced, small-volume mealsmay be better tolerated. Liquid nutritional supplements are useful for patients who havelimited access to prepared meals or for those who require complex medication regimensrequiring fasting at odd times throughout the day. A list of some of the available oral nutri-tional 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 asEnsurePlus or Perative. The latter product is a semi-elemental formulation that is better tol-erated when intestinal malabsorption is present. The higher osmolarity products, such asEnsurePlus, Criticare, and Peptomen, may be more likely to induce diarrhea and oftenrequire dilution. Juven is a nutritional mixture of ␤-hydroxy ␤-methylbutyrate, glutamine,and arginine. Studies of Juven have demonstrated enhancement of LBM in patients withAIDS.18 Prescribed micronutrients and vitamin supplementation are especially advisable forindigent patients or for those with possible malabsorption. A multivitamin with minerals isgenerally adequate. The use of high-dose vitamin “therapy” should be discouraged as thismight exacerbate pre-existing gastrointestinal dysfunction and/or anorexia. Selenium sup-plementation in HIV/AIDS has been the subject of a number of studies.19,20 Serum seleniumdeficiency has been correlated with a higher risk of AIDS mortality, and in vitro studiessuggest that selenium may suppress TNF ␣-induced HIV replication. The use of daily multi-vitamin supplements containing selenium (20-40 mg) is advisable, especially in patientsexperiencing weight loss. In patients with evidence of severe, long-standing malnutrition,measurement of serum selenium levels may be indicated.
MANAGEMENT OF GRADUAL WEIGHT LOSS IN THE HIV-INFECTED PATIENT
>5% loss of total body weight in 2 to 3 months ≥10% loss of total body weight in >3 months Treat AND add nutritional supplements, begin progressive resistance exercise Consider options for:• appetite stimulants• anabolic steroids• androgenic anabolic steroids• HGH SELECTED COMMERCIALLY AVAILABLE LIQUID NUTRITIONAL SUPPLEMENTS*
Products
Calories/cc % Carbo
% Protein % Fat Osmols
Features
Peptides and free aminoacids semi-elemental formalabsorption Designed for patients withESRD and liver failure. Lowin protein, adjusted mineralcontent.
* The products listed above do not represent a complete listing of the commercially available supplements.
2. Treatment of Anorexia
RECOMMENDATION:
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 whetherany of them are implicated. Neuropsychiatric testing is often helpful in the evaluation ofanorexia when the cause cannot be determined by clinical evaluation.8 Appetite stimulantsshould 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 patientsdo not tolerate the CNS effects of dronabinol, even at low doses. Dronabinol, despiteimproving appetite, has not been convincingly shown to increase TBW. Megestrol doesresult in slow and modest increases in TBW, but this is usually associated with increasesin 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-termuse of megestrol is discontinued.7 Clinicians should screen for hypogonadism and adrenalinsufficiency in patients receiving megestrol for prolonged periods. 3. Treatment of Non-Infectious Diarrhea
RECOMMENDATION:
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 haveunderscored the usefulness of calcium supplements for patients experiencing nelfinavir-induced diarrhea. Other modalities, such as pancreatic enzymes and psyllium fiber sup-plements have been useful for PI-induced diarrhea. Many patients note an increase insymptoms following meals and will voluntarily avoid adequate alimentation to reducebowel frequency. When pancreatic insufficiency is present, supplemental pancreaticenzymes may be helpful in reducing diarrhea and post-prandial bloating. As previouslynoted, avoidance of lactose-containing foods and the use of lactase supplements may beuseful. Cautious use of antimotility agents such as loperamide or diphenoxylatehydrochloride is sometimes helpful. For severe cases, octreotide and tincture of opiumhave also been used.
4. The Role of Exercise
RECOMMENDATION:
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. Progressiveresistance exercise (PRE) increases LBM in conjunction with adequate caloric intake.21The effects of resistance exercise are potentiated by anabolic steroids and are diminishedin the hypogonadal male (see Section 5: Anabolic Steroids).
Aerobic exercise results in little or no increase in BCM as compared to PRE. Aerobicexercise may increase CD4 counts, but such exercise has no definite effect on T-cellfunction. In addition, aerobic activity without sufficient energy substrate may induce fur-ther weight loss. Reported effects of aerobic exercise on CD4 cell function have beenvariable.22 Aerobic fitness programs do, however, improve performance status and quality-of-life measures.
5. Anabolic Steroids
RECOMMENDATIONS:
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 (seeAppendix A). Nandrolone has a high anabolic/low androgenic profile. It must be admin-istered parenterally. Oxandrolone is probably the most effective oral agent for restoringBCM. 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 ineugonadal men; therefore, long-term use requires monitoring for hypogonadism.23 Bothoxandrolone and nandrolone have a relatively low potential to cause hepatic toxicity when compared with oral androgenic anabolic steroids.23 These agents are non-narcoticSchedule III drugs under the Anabolic Steroids Control Act of 1990. Although the use ofoxandrolone 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 siteinfection, or local nerve trauma are unusual complications of nandrolone use.
6. Androgenic Anabolic Steroids
RECOMMENDATIONS:
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 sex-
ual practices for patients receiving androgenic anabolic steroids.
The androgenic anabolic steroids include testosterone. As noted previously, hypogonadismcan 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 withPRE result in significant increase in the BCM.24 Unwanted side effects include acne, accel-erated hair loss, and behavioral changes. Virilization makes use of such available agentsunsuitable for use in women; however, new studies of experimental low-dose testosteronepatches in women are underway.
There is a strong association between Kaposi’s sarcoma (KS) and the human herpes virustype 8. However, the male preponderance in cases of KS has led to studies linkingserum testosterone levels and KS occurrence. There is epidemiologic evidence implicat-ing androgenic steroids as a promoter of KS in the setting of AIDS.25 Although there is nofirm evidence that androgenic steroids promote KS, many HIV Specialists suggest cautionin prescribing androgenic steroids for patients with pre-existing KS.
Testosterone can also cause prostate cancer and hepatic toxicity, including cholestasis,peliosis hepatitis, and primary hepatic carcinoma. A natural consequence of exogenoustestosterone replacement is testicular atrophy, if not already present. Increases in libidomandate the reinforcement of safer sexual practices for all patients receiving this form oftherapy. The transdermal testosterone preparations seem to have the safest therapeuticprofiles. Local irritation of the adhesive/accelerant is common, and patients complainabout the cosmetic and emotional impact of wearing a transdermal patch throughout theday. Androgel, a transdermal testosterone gel preparation, has been approved by theFDA for the treatment of hypogonadism. This topical preparation is applied directly ontothe skin without a patch; transfer of drug from patient to others by direct contact withthe skin application site is a potential problem. A newer form of testosterone replace-ment 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 theAnabolic Steroids Control Act of 1990. They are approved for the treatment of malehypogonadism. With the improvement of immune function and overall well-being,hypogonadism may improve, and exogenous testosterone can be discontinued with care-ful monitoring of testosterone levels. Clinicians should be aware of the potential forsteroid abuse.
7. Recombinant Human Growth Hormone
RECOMMENDATIONS:
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 co-existent opportunistic infections.
rhGH (Serostim) is the only drug that is FDA-approved for treatment of HIV/AIDS-associatedweight 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 excludedand after treatment of conditions leading to malabsorption or anorexia are addressed. Awide array of side effects is associated with its use. These include muscle and joint pain,carpal tunnel syndrome, peripheral neuropathy, peripheral edema, hyperglycemia, andpancreatitis. 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 necessarilycompromising efficacy. rhGH is expensive, thus many third-party payers will not cover itscost. The duration of therapy is unclear, but a number of studies have shown prolongedmaintenance of BCM after a 12-week course.27 The patient’s response should be monitoredclosely. If weight loss continues despite several weeks of rhGH therapy, an investigationfor co-existent 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 after6 months of treatment with recombinant human growth hormone, but VAT re-accumulated12 weeks after discontinuation.28 A large clinical trial showed a significant decrease invisceral fat content when 4 mg/day rhGH was injected subcutaneously and a trendtoward significance when 4 mg every other day was used.29 rhGH is not FDA-approvedfor the treatment of lipodystrophy.
8. Experimental Cytokine Mediators
Interest in using agents that modify circulating levels of cytokines, especially TNF, wasreflected by a number of uncontrolled clinical studies in the early 1990s.30 The use ofcytokine 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 beelevated in some patients with wasting, this observation is not uniform, and elevated lev-els 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 studiesusing different methodology. The effectiveness of agents such as pentoxifylline andthalidomide are modest at best. Thalidomide has shown some promise in Africa in pro-moting weight gain in persons with AIDS and mycobacterial disease. In this country,increases in LBM have been demonstrated with thalidomide.31 Thalidomide is availableon a restricted basis for the treatment of HIV-associated aphthous stomatitis or wastingsyndrome. Registration with the manufacturer Celgene (phone: 888-423-5436) is required.
THE WASTING SYNDROME
RECOMMENDATION:
Clinicians should perform a detailed evaluation for opportunistic infections or malignan-
cies 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 otheropportunistic conditions, including cryptosporidiosis, M. avium complex, and CMV infection. In theera 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.
A. Diagnosis
Wasting syndrome, as defined by the Centers for Disease Control and Prevention (CDC), isan 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.6,32Wasting syndrome is predictive of the onset of opportunistic infections and neoplasms. Anaggressive diagnostic program is indicated with the appearance of the wasting syndrome(see Figure 2).
MANAGEMENT OF WASTING SYNDROME
(≥10% loss of total body weight in 1 to 2 months) B. Nutritional Intervention in the Wasting Syndrome
RECOMMENDATIONS:
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.
1) To undertake nutritional triage and to supplement nutrition in patients for whom urgent nutritional support might be life-saving.
2) To treat and control all complicating conditions that are contributory to malnutrition.
3) To attempt to intervene with therapies matched to the metabolic derangement(s) most Emergency treatment of patients who have lost excessive body weight (≥10%), especially overa brief period of time, can prove to be life-saving (see Figure 2). Such persons usually have apoor performance status with Karnofsky scores of ≤60, suffer inanition, and may require acutehospitalization.7 An immediate evaluation needs to be performed to determine the cause ofthe wasting syndrome. Enteral alimentation should be considered when gastrointestinal functionis adequate. In some patients with partial malabsorption, an elemental or semi-elementalcaloric supplement is well tolerated. However, for patients with conditions that prevent enteralfeeding, TPN is indicated for short-term management. Close attention should be given to supplementation with micronutrients, and frequent assessments of the electrolytes and bloodglucose 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 acutelystop the catabolic reduction of BCM while secondary opportunistic conditions are identifiedand 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.
FAT REDISTRIBUTION (LIPODYSTROPHY) SYNDROMES
Although HAART has resulted in a dramatic decrease in AIDS-associated morbidity, it is estimatedthat as many as 60% to 80% of patients receiving HAART for more than 1 year will demonstratechanges in body composition and/or blood lipids.33 Two new syndromes of abnormal body mor-phology or lipodystrophy have been described that seem to be associated with the newer treatmentmodalities34: 1) fat accumulation/redistribution syndrome, and 2) lipoatrophy syndrome. A morethorough discussion of these syndromes is covered in Chapter 4B: Long-Term Complications ofAntiretroviral Therapy.
PIs were the first to be implicated in the fat redistribution syndrome, and the NRTIs have been pro-posed as triggers for the lipoatrophy syndrome. Of note, patients may also present with a mixedpicture of morphological changes. Definitive etiologies of these abnormal body morphology syn-dromes remain unknown.
The fat redistribution syndrome is important in the discussion of body composition and weightloss. The total body weight of patients exhibiting the fat redistribution syndrome usually varies lit-tle from their usual body weight. In addition to the somatic changes, a number of metabolic dis-turbances have been described. Insulin resistance with hyperglycemia, hyperlipidemia (with ele-vated triglycerides, elevated LDL cholesterol, and decreased HDL cholesterol), and decreasedhemostasis in patients with hemophilia have been reported.26 These metabolic abnormalities mayalso occur independently of the fat redistribution syndromes. Initially termed lipodystrophy, thissyndrome is best described as fat accumulation or redistribution syndrome. The most prominentsigns are somatic and dysmorphic changes, including facial and limb fat wasting, central and/orlocalized adiposity, and visceral fat accumulation. Localized fat accumulation may take the formof an enlarged dorsocervical fat pad, multiple lipomata, or breast enlargement in both womenand men. The proportionate involvement of the involved sites varies dramatically among patients.
The mechanism of these abnormalities remains unclear. Although these complications have his-torically 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 predom-inant loss of subcutaneous fat resulting in severe peripheral fat wasting without localized fat accu-mulation. HAART is expected to generally improve overall nutritional status with increases in totalbody weight and intracellular (relative to extracellular) water.4 Thus, loss of body weight should notbe interpreted as an acceptable side effect of HAART. The major aberrations in body compositionchanges are in the fat compartment with significant decrease in fat content. Severe instances oflipoatrophy can result in a 5- to 10-kg decrease in body weight.
Key Point:
Clinicians should consider the possibility of concurrent lactic acidosis and/or hepatic dys-function in patients with lipoatrophy.
These morphologic changes are sometimes associated with lactic acidosis, abnormal liverchemistries, fatigue, hypoalbuminemia, and elevated triglycerides and total cholesterol. The currenttheory regarding lactic acidosis is that it may be caused by nucleoside analogue-associated mito-chondrial toxicity. Although rare, lactic acidosis may be intractable and fatal; pregnant women areparticularly vulnerable. When lactic acidosis syndrome occurs, it is usually in association with con-stitutional symptoms of fatigue, abdominal pain, anorexia, nausea and vomiting, myalgias, shortnessof breath with tachypnea, and abnormal liver chemistries.34 In this setting, it is important to measureserum 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 acido-sis in whom nucleoside analogue therapy is being resumed, monitoring lactic acid levels for thefirst 3 to 6 months after reinstitution should be considered.
REFERENCES
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 5. Grunfeld C, Kotler DP. Pathophysiology of the AIDS wasting syndrome. AIDS Clin Rev 6. Nemechek PM, Polsky B, Gottlieb MS. Treatment guidelines for HIV-associated wasting. Mayo 7. Coodley GO, Loveless MO, Merrill TM. The HIV wasting syndrome: A review. J Acquir Immune 8. Greene JB. Clinical approach to weight loss in the patient with HIV infection. Gastroenterol Clin 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 immunodeficiencysyndrome. 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 infec- tion 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 immunode- ficiency 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 HumRetroviruses 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 infec-tion. 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. AIDS1999;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 Med1998;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. JAMA1999;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 Metab1993;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 Syndr2002:30:379-391.
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 AIDSConference; July 7-12, 2002; Barcelona, Spain. Abstract #LbOr18.
30. Grunfeld C, Feingold KR. The metabolic effects of tumor necrosis factor and other cytokines.
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 cohortstudy. 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-relatedlipodystrophy syndrome. AIDS 2000;14:F25-F32.
35. Dube M, Fenton M. Lipid abnormalities. Clin Infect Dis 2003;36(Suppl 2):S79-S83.
FURTHER READING
Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with seleniumdeficiency. 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 withand 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. AIDS1997;11:1347-1352.
Grinspoon S, Corcoran C, Miller K, et al. Body composition and endocrine function in women withacquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 1997;82:1332-1337.
Hayes CR, ed. Integrating nutrition therapy into medical management of human immunodeficiencyvirus. 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 prolif-eration. Int J Sports Med 1996;17:384-389.
Mulligan K. Hyperlipidemia and insulin resistance are induced by protease inhibitors independentof 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 withantiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society - USApanel. J Acquir Immune Defic Syndr 2002;31:257-275.
A P P E N D I X A
T H E R A P Y F O R G R A D U A L H I V - A S S O C I AT E D W E I G H T L O S S
TABLE A-1
THERAPY FOR GRADUAL HIV-ASSOCIATED WEIGHT LOSS
Anticipated Effects
Daily Dose Range
Comments
Appetite Stimulants
▼appetite, ▼BM, 400-800 mg/day with meals cause impotence; risk of throm-boembolism, adrenal insufficiency Anabolic Steroids
▼performance status, 1 gel-pak daily, or 1 patch/ patch, buccal mucoad- ▼BM, ▼mood/libido vigilant for peliosis hepatitisAndrogenic << Anabolic vigilant for peliosis hepatitisAndrogenic << Anabolic vigilant for peliosis hepatitisAndrogenic << Anabolic Growth Hormone
Cytokine Inhibitors*
Available to registered prescribersfor oral aphthae and wasting.
Lowers serum TNF. Efficacy forwasting not established.
* Because a central role of TNF in wasting has not been established, this treatment approach should be considered speculative

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