Malnutrition in Patients with AIDS Lonny M. Hecker, M.D., and Donald P. Kotler, M.D. Malnutrition is a frequent problem in persons infected with the human immunodeficiency virus. The origin of malnutrition in patients with AIDS may be multifactorial. The primary mechanisms include disorders of food intake, alterations in intermediary metabolism, and nutrient malabsorption. Attention to the problems of malnutrition in patients with AIDS is of paramount importance because the timing of death in these patients may be more closely related to degree of body cell mass depletion than to any specific underlying infection. Nutritional support can improve nutritional status in selected patients, and repletion of body cell mass may be associated with functional improvement. Early assessment, attention to nutritional requirements, and prompt intervention can minimize wasting and replete body cell mass. This article examines the evidence for malnutrition in patients with AIDS, reviews the studies of nutritional support, and presents an approach to the management of malnutrition in AIDS.

The acquired immunodeficiency syndrome (AIDS) has become a major world health problem. In the United States alone it is estimated that more than 1.5 million people are infected with the human immunodeficiency virus (HIV).’ Globally, it is estimated several times that number are infected. HIV produces profound defects in systemic and mucosal immunity that are associated with a variety of opportunistic infections and ma1ignancies. Protein-energy malnutrition (PEM) is common in patients with AIDS and may precede all overt manifestations of the disease. Since 1987 HIV seropositivity with wasting (weight loss of >lo% over two months) has been classified as AIDS by the Centers for Disease Control.2 Several factors confound the ability to study PEM in persons with AIDS. PEM may occur at any stage of the disease. Its development is multifactorial and includes conditions that lead to diminished food intake, Dr. Hecker is a Fellow in Gastroenterology, and Dr. Kotler is Associate Professor of Clinical Medicine, St. Luke‘s- Roosevelt Hospital Center, Columbia University College of Physicians & Surgeons, New York, NY 10025.

alterations in intermediary metabolism, and nutrient malabsorption. More than one complication may be present simultaneously. The factors affecting nutritional status change over the course of the disease. The study of malnutrition and the utility of nutrition support is further confounded because many AIDS-related infections are untreatable. The goals of nutritional assessment and intervention are i mproved n ut rit io nal status, prolonged survival, and enhanced quality of life. Several published case reports claim that nutritional support has a positive effect upon quality of life issues but comprehensive studies are still lacking. Our aim is to review the current state of knowledge concerning PEM in AIDS. Studies of nutritional support will be presented. The concepts elucidated by these studies will be synthesized into an approach to the management of PEM in AIDS.

Body Composition Studies in AIDS Weight loss is a prominent feature of AIDS. In Africa the syndrome is known as “slim” d i ~ e a s eO’Sullivan .~ et al.4 reviewed the medical records of 50 patients with AIDS in various New York City hospitals. NUTRITION REVIEWSIVOL 48, NO 11INOVEMBER 1990 393

Despite pre-illness weights that were higher than ideal, 59% of the patients were classified as moderately depleted and 62% had lost >lo% of their pre-illness weight. Another study of 22 patients referred for gastrointestinal complaints showed that 96% lost a mean of 34 k 19 lb.5 An early case-control study compared 12 persons with AIDS to 1 1 homosexual controls.6 Those with AIDS weighed significantly less than controls (80% vs. 101% of ideal). Measurements of somatic protein depletion (midarm muscle circumference) and visceral protein depletion (serum albumin, retinol-binding protein, and iron-binding capacity) were also reduced in HIV-infected person^.^-^ The prevalence and severity of malnutrition were later examined in a cross-sectional study of body composition in 32 patients with AIDS.* Whole-body counting of endogenous 40K was used as an indicator of body cell mass. This measurement was possible because >97% of all potassium in the body is found in the nonadipose cellular c ~ r n p a r t m e n t .The ~ group with AIDS weighed significantly less than controls (82% vs. 103% of ideal body weight). Body cell mass was reduced out of proportion to weight loss (68% of normal). Body fat content, determined anthropometrically, was depleted to a lesser degree. This pattern of depletion resembles a stressed or injured state rather than semistarvation, which is associated with nitrogen sparing and increased fat utilization. A subsequent study examined the role of depletion of body cell mass in survival. Data on 28 patients who underwent nutritional assessments within 100 days of death from a wasting illness were analyzed retrospectively.1° Clinical iIlnesses associated with wasting included disseminated cytomegalovirus infection, pneumonia due to Pneumocystis carinii, infection with Mycobacterium avium intracellulare, cryptosporidiosis, microsporidiosis, toxoplasmosis, Kaposi’s sarcoma, lymphoma, and dementia. Total body potassium was analyzed as a function of time before death, and the relationship was found to be linear. 394 NUTRITION REVlEWSlVOL 48, NO 11INOVEMBER 1990

Body weight, expressed as a percentage of ideal, obeyed the same relationship. Body cell mass was depleted by -50% at death, while body weight decreased by -33%. The level of body fat depletion, however, did not correlate with the timing of death. Thus the timing of death in patients with AIDS who have wasting illnesses may be more closely related to the degree of depletion of body cell mass than to its underlying cause. In the same study the average weight on day 100 before death was 91% of ideal, while total body potassium was 71% of normal.Io Thus, approximately three months before death, these patients were of normal weight with significant depletion of body cell mass. These data illustrate the subtlety with which PEM may develop. Further investigation regarding the origin of PEM in patients with AIDS includes a prospective study of energy balance in five clinically stable patients with AIDS who were followed for six weeks.” Over the course of the study the patients had stable measurements of body cell mass, a fact indicating that progressive wasting is not an essential feature of AIDS. On the contrary, wasting results from specific complications of the disease. Consequently, it is helpful to approach the study of PEM in AIDS by examining the underlying pathophysiologic mechanisms that include eating disorders, disturbances in intermediary metabolism, and nutrient malabsorption.

Pathophysiologic Mechanisms of PEM in AIDS Food intake may be inadequate because of mechanical difficulties with eating or loss of appetite. Patients may have problems chewing or swallowing due to diseases localized to the oral cavity, pharynx, or esophagus. The most common presenting complaint is odynophagia due to esophagitis caused by Candida albicans, a fungus. Esophageal ulcers of viral, mycobacterial, and neoplastic varieties also affect food intake. Anorexia may be a side effect of various medications. Neurologic disease may im-

pair appetitive function or produce swallowing disorders.l2 There is also evidence suggesting that unabsorbed micronutrients in the lower bowel (ileum and colon) are associated with signals that decrease appetit ive behavior.’, Anorexia is a common feature of systemic illnesses and is thought to be a direct effect of increased release of cytokines, such as tumor necrosis factor (TNF), interleukin-1, interferon, and others.14 Studies have shown elevated concentrations of TNF and a-interferon in sera of patients with AIDS.1Sr16Administration of TNF to animals causes acute anorexia and weight 10ss.l~ No cytokine is able to account for all the metabolic changes in sepsis, and cytokine-interferon interactions may act to produce the changes seen. Studies of resting metabolic rates in patients with AIDS have yielded conflicting results. In one such study clinically stable patients with AIDS had lower resting metabolic rates than did controls and were hypometabolic when compared to predictions made by the Harris-Benedict equation.” Hypometabolism appeared to be related to the presence of malabsorption, which would be an appropriate metabolic r e ~ p 0 n s e .Conflicting l~ results by Hommes et a1.l8 demonstrated increased resting metabolic rates in persons with AIDS-related complex. As one would expect, patients with AIDS who have acute or chronic infections and fever have metabolic rates that are 20-60% above predicted levels (authors’ personal observation, 1988). Additional evidence for altered metabolism was found in a prospective study of thyroid hormone indexes of patients with Al DS.l9 Chronic debi Iitati ng iIIness typically lowers levels of thyroxine and triiodothyronine (T3) in serum and raises the level of reverse T,. Serum values from patients with AIDS, however, revealed significantly increased serum thyroxine, normal T, and a paradoxical decrease in reverse T., The persistence of normal T, levels, despite progressive illness and malnutrition, may contribute to the wasting syndrome of AIDS.

Supporting evidence for the changes in intermediary metabolism includes the finding of elevated fasting triglyceride levels in people with AIDS.20 Hyperlipidemia, with accumulation of very-low-density lipoproteins (VLDL), has been observed in various acute and chronic infections, while starvation decreases fasting serum triglyceride levels. Hypertriglyceridemia results from decreased lipoprotein lipase activity, increased fatty-acid synthesis and esterification, and increased lipoprotein synthesis in the liver. A follow-up study showed that hypertriglyceridemia in AIDS was associated with increased serum concentrations of ainterferon.16 The third principal mechanism of AIDSrelated malnutrition is intestinal dysfunction. A diarrheal illness occurs in >50% of people with AIDS.21 Several studies have shown that an appropriate diagnostic work-up can identify one or more enteric pathogens in ~ 8 5 % of the cases.22 Patients with diseases of the small intestine develop a malabsorption syndrome that clinically resembles celiac sprue or short-bowel syndrome. Such patients usually exhibit slow, progressive weight loss that may stabilize at a low level. A recent study of jejunal biopsy specimens showed that 62% of patients with AIDS, chronic diarrhea, and weight loss had partial villous atrophy with or without crypt hyp e r p l a ~ i a .Many ~ ~ of these patients had protozoal infections (e.g., Cryptosporidiurn parvurn, lsospora beli, and the microsporidian Enterocytozoon bieneusi). Microspora species was recently recognized as an intestinal pathogen in AIDS, and microsporidiosis has been documented by transmission electron microscopy in 20 AIDS patients with chronic diarrhea and weight loss.24 Many studies have documented xylose and fat malabsorption in HIV-infected persons, even in the absence of Lactase deficiency is very Jejunal structure and function were examined in a series of biopsies from AIDS patients with and without intestinal pathogens as determined by electron microsNUTRITION REVIEWSIVOL 48, NO 1 IINOVEMBER 1990 395

copy.27 Cryptosporidiosis and microsporidiosis were associated with decreased jejunal disaccharidase activity and xylose malabsorption. Ratios of sucrase to lactase and maltase to lactase were increased in the patients with intestinal coccidioses, an observation consistent with rapid turnover and functional immaturity of villous enterocytes. This pattern of intestinal injury is similar to that seen in tropical and nontropical sprue. It is also possible that HIV alone may affect the structure and function of the small intestine. HIV has been demonstrated in cells of the intestinal mucosa by molecularhybrid izatio n tech n iq ues.25,28s29 Thus PEM in patients with AIDS is multifactorial in origin and is a result of identifiable processes similar to those found in other diseases. Deficiencies of both micronutrients and macron utrients can affect patients with AIDS. Micronutrients are involved in immune function, and their deficiencies may exacerbate the clinical immune deficiency. Evidence of pyridoxine (vitamin Bs) deficiency in asymptomatic HIV-seropositive individuals has been found.30 Herbert et a 1 . 3 ’ ~ reported ~~ that approximately onethird of patients with AIDS are in negative vitamin 6 1 2 balance, one-third are in negative folate balance, and one-tenth are in negative balance for both. Other studies in different populations have shown normal or elevated folate levels and decreased concentrations of vitamin B,,.33 Harriman et al.34 evaluated absorption of vitamin B, in 11 patients with AIDS who did not have diarrhea or weight 1 0 ~ s Only . ~ three patients had low serum 612 levels, but eight had abnormal Schilling tests. All patients with abnormal Schilling tests had histologic evidence of chronic inflammation on duodenal biopsy, and five of the 11 had HIV, detectable by in-situ hybridization, in the mononuclear cells of the lamina propria. The authors speculated that longstanding vitamin B, malabsorption may begin early in the course of HIV infection and may be related to localization of HIV in cellular reservoirs in the terminal ileum. 396 NUTRITION R€V/€WSIVOL 48, NO 11INOVEMBER 1990

Other investigators found that levels of selenium in plasma were significantly reduced independent of m a l a b ~ o r p t i o n . ~ ~ Several studies have demonstrated reduced levels of zinc in sera from HIV-infected person^.^^^^^ However, a reliable method for identifying zinc depletion has not been established, and confounding factors such as hypoalbuminemia and tissue sequestration due to increased cytokine activity may be important.

Studies of Nutritional Support Several recent articles have presented the hypothesis that malnutrition is the underlying cause for full clinical expression of Al DS in HIV-seroposit ive indi v i d ~ a l s . ~ ~ , ~ Although normal immune function clearly is dependent on good nutritional status,39 there are no scientific data indicating that ma1n utrition itself predisposes HIV-infected persons to AIDS. In addition, several patients in the cross-sectional study discussed previously developed AIDS despite normal body composition.8 The actual impact of malnutrition and its treatment upon the ultimate clinical course of AIDS is still poorly understood. Until recently, nutritional support for the person with AIDS was not a popular topic for scientific study. Letters to the editor and several case reports suggested that nutritional intervention in this group was effective in improving nutritional s t a t ~ s . ~Several ~ , ~ ’ recent scientific studies have examined the efficacy of nutritional support in persons with AIDS. One such study looked at AIDS patients with serious cytomegalovirus (CMV) infections who were treated with ganciclovir, a drug that suppresses DNA synthesis by herpes viruses.42When untreated, the disease was associated with progressive weight loss, depletion of body cell mass, loss of body fat, and a decreased concentration of albumin in serum. Untreated patients lost an average of 132 g (1554 kJ)/ day, with 12% of the energy loss coming from body cell mass and the rest from fat. Patients treated with ganciclovir gained 49

g (1075 kJ)/day, with 9% being distributed to the body cell mass compartment and the rest to fat. The serum albumin level increased by an average of 0.1 g/L per day, implying visceral protein repletion. This study demonstrates the complex interaction between illness and nutritional status and emphasizes the paramount importance of treating underlying infections. The ability to promote weight gain and replete body cell mass with antiviral therapy, in the absence of specific nutritional support, was also demonstrated in an early study that included subsequent clinical observations of patients treated with a ~ i d o t h y m i d i n eThe .~~ study of the effects of ganciclovir also suggests that n ut rit ional su pport may have very significant limitations. Despite therapy with ganciclovir, and in some cases total parenteral nutrition, several patients, later found to have coexisting mycobacterial infections, failed to replete body cell mass. Aggressive nutritional support may be ineffective in patients with serious systemic illnesses. In the pediatric population with AIDS, malnutrition may lead to growth failure. It was demonstrated that, in a subpopulation of severely ill, HIV-seropositive infants with lymphocytic interstitial pneumonitis and failure to thrive, careful monitoring of food intake, frequent feeding, hypercaloric formulas, and in some cases nocturnal nasogastric feeds, resulted in intake of the recommended amount of calories and adequate rate of weight gain.44This study suggests that early attention to nutritional status and adequate intake of protein, calories, and micronutrients are beneficial in chi Idren with AIDS. A study of the adult population with AIDS indicated that specialized diets may be effective. Fifteen persons with chronic diarrhea consumed a low-fat, low-residue elemental diet for 10 days in a prospective, nonrandomized multicenter Several of these patients were shown to have microsporidiosis. Diarrhea was alleviated, and all subjects completing the study maintained their weight over a short follow-up. Thus attention to dietary intake and

use of low-fat elemental diets may be useful for some patients. As noted earlier, anorexia is a common problem in patients with AIDS. Therefore, Von Roenn et al.46tested the effectiveness of the appetite stimulant megestrol acetate, a synthetic progesterone. Fourteen HIVseropositive patients without diarrheal illness who had lost >lo% of their pre-illness body weight were treated with 80 mg of megestrol acetate orally four times daily for four All treated patients reported increased appetite and weight gain. The long-term effects of this medication on weight gain, repletion of body cell mass, and quality of life are not yet known. In many cases, adequate intake of calories and protein cannot be achieved volitionally, and enteral alimentation is indicated. This statement is particularly applicable to patients who have a poor appetite or who have difficulty chewing or swallowing because of oral, esophageal, or neurologic complications. Enteral alimentation may even benefit patients with syndromes of malabsorption. In one study enteral nutrition was provided to eight malnourished patients with AIDS who had severe eating disorders and systemic infections but who were free of intestinal disease.47 Enteral feedings were administered via a percutaneously placed, endoscopically directed gastrostomy (PEG) tube. A formula with relatively low osmolarity, partially hydrolyzed protein, and 50% of the lipid as medium-chain triglycerides was selected. Patients were fed enough formula via the PEG tube to provide 500 kcal/day above estimated requirements. At the onset of the study, all patients were bedridden and severely malnourished, with evidence of somatic and visceral protein depletion. Two months of enteral nutritional support resulted in an average 3-kg weight gain and statistically significant increases in total body potassium, body fat content, and serum albumin level. Total iron-binding capacity of serum proteins and total lymphocyte count also rose, indicating repletion of somatic and visceral proteins. Most patients showed marked functional improveNUTRITION REVlEWSlVOL 48, NO 1llNOVEMBER 1990 397

ment, and all but one were able to be discharged from the hospital. The results of this study indicate that nutritional repletion can be achieved with enteral support in some patients with AIDS despite systemic infection. For certain patients, however, enteral nutrition is not feasible. In such cases, particularly those patients with severe malabsorption, total parenteral nutrition (TPN) may be the only alternative. The feasibility of long-term TPN at home and its effect upon body composition were evaluated in a recent prospective, longitudinal study involving 12 patients with AIDS and PEM.48 The patients were followed for an average of 14 weeks. The response varied with the underlying illness. Repletion of body cell mass and body fat was achieved in patients with eating disorders or nutrient malabsorption. Patients with disseminated systemic infections, however, accumulated fat but did not replete body cell mass. The results of this investigation demonstrate that the effectiveness of TPN is ultimately related to the patients’ overall clinical situation. The studies reviewed above allow several important conclusions to be drawn. First, the origin of malnutrition in AIDS may be multifactorial. The presence of coexisting systemic infections and the availability of specific antimicrobial treatment may have profound effects upon the ability to replete body cell mass. Nutritional support can be used to improve nutritional status in selected patients with AIDS, and repletion of body cell mass may be associated with functional improvement. An understanding of the pathophysiologic mechanisms involved in creating and perpetuating PEM in a particular person is crucial because the success of nutritional intervention depends on careful adaptation of the mode of therapy to the precise clinical circumstances.

Suggested Approach to Nutritional Management Nutritional management may be conceptualized as a mathematical equation 398 NUTRITION REVIEWSIVOL 48, NO 111NOVEMBER 1990

wherein nutritional status is a function of intake, absorption, and metabolism. As discussed previously, disturbances in any of the components of this equation can result in PEM. The prevention and treatment of PEM in patients with AIDS depends on an approach specifically targeted to avoid, and when necessary to correct, these disturbances. These goals may be efficiently accomplished via a three-pronged approach that includes nutritional counseling and assessment as well as appropriate nutritional intervention. The type of counseling, complexity of the assessment, and the degree of intervention must vary with the individual’s stage of disease. The three stages useful to consider in this regard are as follows: HIV seropositive but asymptomatic, underweight but stable, and actively wasting. Special considerations must be given to growing infants and children and pregnant or lactating women.49 Nutritional counseling is of great importance for the individual who is HIV seropositive but remains asymptomatic. Topics that should be addressed include creation of a well-balanced diet with particular attention to both macro- and micronut rients,34,50-52avo idance of si ng le-nut rient diets, megadosing and unproved nutritional t h e r a p i e ~ , ~food ~ . ~ ~safety,55 and drug-nutrient i n t e r a ~ t i o n .The ~ ~ ultimate goal must be to avoid the development of PEM. The patient who is underweight but stable must also undergo nutritional assessment. The assessment must include a careful dietary history, calculation of nutrient intake, some form of body composition analysis to evaluate somatic protein status, and laboratory tests to evaluate visceral protein d e p l e t i ~ n . ~Suspected ’ nutrient malabsorption may be further evaluated with specific tests that assess carbohydrate and fat absorption (i.e., D-xylose, 14C-triolein58).Disturbances in metabolism may be documented by monitoring daily fever curves. In some cases measurement of basal metabolic rate may be helpful. Medical evaluation is undertaken as clinical I y indicated.

When the cause can be found for a disturbance in intake, absorption, or metabolism, treatment, if available, should be instituted promptly. Changes in diet, calorie-dense nutritional supplements, and appetite stimulants are appropriate for those with anorexia of unknown or untreatable e t i ~ l o g y .When ~ ~ , ~specific ~ treatment is unavailable, patients with malabsorption may likewise respond favorably to dietary changes, nutritional supplements, and appetite stimulants. Patients who are hypermetabolic during early treatment and those without an identifiable or treatable opportunistic infection may be nutritionally supplemented and treated with nonspecific anti-inflammatory drugs to reduce fever and metabolic rate. Patients with active wasting should be approached in the same manner as those who are underweight and stable; however, a greater sense of urgency is required. Infectious complications should be treated expediently. Whenever possible, nutritional requirements should be met by use of the gastrointestinal tract. The indications and limitations of enteral alimentation in patients with AIDS are similar to those for persons not infected with HIV.60Diarrhea is not an inevitable consequence of tube feedings, and attention to choice of formula, mode of delivery, and other contributing factors will minimize the incidence of this problem.6is62 Percutaneous endoscopic gastrostomies can be utilized when long-term enteral alimentation is anticipated. Total parenteral nutrition should be reserved for cases where nutritional requirements cannot be met using the gastrointestinal tract. Published guidelines for the use of TPN nutrition in the non-HIV-infected population are a p p l i ~ a b l e Ethical .~~ issues for the use of TPN in terminal patients who are in the final stages of their disease should be considered.M Strict attention to sterile technique is required to prevent catheter-related infection^.^^ Longterm nutritional support with home TPN is feasible in selected cases and can eliminate the need for long-term hospitalizati o n.66

Conclusion Protein-calorie malnutrition is common in patients with AIDS. Its origins are multifactorial. Early assessment, attention to nutritional requirements, and prompt intervention can minimize wasting and replete body cell mass. Ultimately this therapeutic strategy should result in improved and possibly prolonged survival for persons with AIDS. Acknowledgments: Dr. Hecker was supported by training grant no. AGO0124 and Dr. Kotler was supported by grant no. A121414 from the National Institutes of Health.

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