Weight Loss and Wasting

Weight Loss and Wasting

in HIV Patients

Christine A. Wanke, M.D., Kristy M. Hendricks, Sc D, R.D.

INTRODUCTION

As has been true with so many infectious diseases, it has been hoped that improvement in the therapy of HIV will eliminate weight loss and wasting as complications of HIV. In this chapter, we hope to convince the reader that even in the era of successful highly active antiretroviral therapy (HAART), weight loss and wasting remain significant clinical problems.

Initial reports evaluating the nutritional status of HIV infected subjects reported a strong association between body weight and mortality, with death occurring at 66% of ideal body weight (8, 26, 35, 72). Body cell mass or lean body mass comprises the body’s active cellular components and is of primary importance for quality of life, functional capacity and survival. These initial reports showed a greater loss of lean body mass than fat stores, with values 54% of normal at death (35, 36).

Current evidence indicates that overall body composition may be more important than weight in effecting outcome and that weight alone is not a reliable marker of nutritional status (19, 21, 33, 48, 55). Both body fat and lean body mass are depleted in HIV and it appears the pattern of loss may vary with body composition at baseline and disease course (19, 49). Subjects having a higher percent body fat (>15%) at baseline lost more fat than lean body mass and those with <15% baseline fat lost more lean body mass than fat mass (24). Although decreases in lean body mass have been shown to be greater in all patients during secondary infections, those patients with greater fat reserves were able to depend on stored fat to a greater degree (33). Some studies have shown a similar pattern of greater reliance on fat stores in HIV infected women (21). Whether this is secondary to increased fat stores at baseline or hormonal control is unknown. Only in the late stages of HIV wasting did women show significant loss of lean body mass, amenorrhea and decreased muscle mass. However, a recent publication by Tang, et al (62) suggests that weight loss was the best predictor of death in an HIV infected cohort, and was more sensitive than lean body mass.

EPIDEMIOLOGY

Data from the Adult and Adolescent HIV Disease Project, a National Surveillance Project with a large and demographically diverse study population (N= 46, 678), found the incidence of wasting syndrome as defined by Center for Disease Control (CDC) AIDS Surveillance case definition (see Table 1) declined between 1992 through 1999 (11). The incidence of opportunistic infections was high at or after a diagnosis of wasting syndrome occurred. The Multicenter AIDS Cohort Study examined the incidence and predictors of wasting syndrome over calendar time also using the CDC definition case definition (58). Characteristics of persons diagnosed with wasting changed over time, with all symptoms (anemia, fever, fatigue, thrush) still reported in the HAART era, but at a lower rate. Diarrhea was found to be reported at a similar rate as prior to HAART suggesting it continues to play a major role in current wasting syndrome.

The incidence and prevalence of weight loss and wasting were examined in a prospective, longitudinal cohort of HIV infected adults (69). These study participants make study visits every six months for measurement of height, weight, body composition, and Resting Energy Expenditure (REE). For the purposes of this study, wasting was defined in three ways; first, as a measured 10 % decrease in body weight from the time of study entry, second, as a loss of 5% of measured body weight between any 2 six months visits that persists for at least one year, or a fall in the body mass index to below 20 kg/m². Eighty-eight (13.9%) of 633 enrolled participants met one of the definitions of wasting at the time they enrolled in the study and were excluded from the analysis; a total of 469 participants had sufficient data to determine these wasting outcomes. A total of 139 participants (29.5%) of the cohort met one or more of the definitions of wasting after study entry. Sixty eight patients (14.5 %) met a definition of wasting by experiencing a weight loss of 10% of body weight since study entry; 36 patients (7.7%) had a body mass index that fell below 20 kg/m²; and 75 patients (15.9%) of the cohort met a definition of wasting by losing more than 5% of body weight within a 6 month period that was sustained for more than 1 year. Of these patients, 320 (68%) used HAART; 64 participants began HAART while they were followed by the study, 31 (48%) of these met one of the definitions of wasting after they began HAART. One hundred (31%) of the remaining participants who have used HAART also met a definition of wasting. Twenty-six percent of the individual participants who had never used HAART also met a definition of wasting, a percentage slightly less than that seen in the participants who did use HAART or who developed wasting after beginning HAART. The incidence of wasting is very high in this cohort; the cumulative prevalence of wasting is even higher at 35.8% (69). An additional analysis from this same cohort suggested that the frequency of weight loss has not changed over time. When rates of weight loss were assessed yearly from 1995 to 2003, rates of loss of 5% of body weight per year increased over the time period studied, even after the introduction of HAART (63).

A total of 58% (289/633) of this same cohort lost a mean of 4 kg between any two study visits; 1.3 kg of this loss was lean body mass; 2/3 or 2.7 kg was fat mass. A further cross-sectional analysis of data from the same cohort demonstrated that weights of patients in the study were a mean of 1.9 kg lower for each 100 cell decrement in CD₄ cells (17). Sixty-eight percent of decrease in weight in these patients was fat mass, whereas only thirty-two percent was lean body mass. These data suggest that while weight loss and wasting are extremely common, both may be predominantly loss of fat rather than lean, as some studies early in the HIV epidemic have suggested. Another publication from this cohort, using the same definitions of wasting, found that while weight loss and wasting remained common, the number of AIDS defining conditions (ADCs) is decreasing. The contribution of ADCs to the development of wasting was relatively small (70).

Studying this same cohort, Tang, et al found weight loss of ≥ 10% from baseline or previous visit was significantly associated with a four-to-six fold increase in mortality in the era of HAART (62). This underscores the concept that weight loss in HIV associated individuals continues to be associated with death. Therefore, the diagnosis and appropriate treatment of wasting syndrome is essential. It has recently been recommended that the current CDC definition of wasting (see Table 1) be expanded (23). Predictors of wasting pre HAART may no longer be reliable as exclusively predicting wasting (23). Defining levels of risk for nutritional complications is essential for identification of individuals requiring nutrition intervention to prevent wasting.

DIFFERENTIAL DIAGNOSIS

The other major nutritional /metabolic issue in HIV, the lipodystrophy syndrome, may be confused with or confuse the recognition of weight loss and wasting. As patients with lipodystrophy may lose weight, gain weight, or remain weight stable, it may be difficult to accurately differentiate weight loss/wasting from the fat atrophy seen with lipodystrophy. While a standard case definition does not exist and the distinctions may truly be obscure in some patients, appropriate categorization will be possible in most patients. It is important to distinguish between voluntary nutritional weight loss and involuntary or intentional weight loss. Those patients with wasting/ weight loss will have progressive unintentional decrease in weight, a decrease in lean and/or fat mass by bioelectrical impedance, and a decrease in mid-arm circumference. Patients with fat atrophy or mixed fat atrophy/ fat accumulation may have no consistent alteration in weight. These individuals may have fat atrophy in the face, extremities, and buttocks, with or without central fat accumulation. Therefore patients with fat atrophy will likely have decreases in mid arm circumference with no change or increase in waist circumference. Unlike patients without body fat redistribution, in whom bioelectrical impedance provides an easy and reliable means to determine body composition, in those patients with fat redistribution, bioelectrical impedance does not provide an accurate measure of body composition (16, 21).

CLINICAL MANIFESTATIONS

It appears that malnutrition frequently develops gradually during the course of HIV and may be detected prior to weight loss by evaluating changes in body composition. Wasting/weight loss may occur more rapidly in the context of significant diarrhea, anorexia, secondary infection, or virologic failure. Both magnitude and pattern of weight loss appear to be predictive of changes in body composition and two primary patterns have been described (40, 73). The first is the patient who presents with rapid, severe weight loss most often associated with non-gastrointestinal infections. These patients are acutely catabolic and frequently regain weight quickly once the infection resolves. However, these patients may not return to their ideal or premorbid weight. The second pattern is the patient with chronic relentless weight loss, which is generally associated with gastrointestinal manifestation and a state of semi starvation. Response to nutrition therapy in these patients depends on the ability to provide adequate calories while limiting gastrointestinal symptoms. The magnitude of loss is considerable with each and the mechanisms, which are discussed in detail below, may occur simultaneously in an individual. In addition, the conflicting outcomes of studies evaluating nutrition and HIV reflect the diverse clinical spectrum of the disease.

RISK FACTORS/ PATHOGENESIS

The wasting seen in HIV infected individuals is multifactorial and heterogeneous (25, 30, 55, 61). Decreased dietary intake, gastrointestinal malabsorption and abnormal metabolism of nutrients are seen to varying degrees of severity, independently or in combination and are summarized in Table 2. HIV associated comorbid conditions emphasize the state of compromised health and vulnerability in patients. Patients may have multiple independent, but related complications (such as mouth sores, nausea, fever, diarrhea, fatigue) that pose a high degree of nutritional risk in this population. The diverse clinical spectrum of the disease and its effects on nutritional status underscore the need for individualized medical nutrition therapy for wasting. It is crucial to identify the mechanism of weight loss associated with each patient so that treatment may be appropriately targeted.

Decreased dietary intake has been documented in all stages of HIV infection and may be secondary to anorexia, mouth sores, pain with swallowing, nausea, abdominal pain, vomiting, diarrhea, medication side effects, depression, dementia or fatigue (3, 41).

It has been theorized that high levels of cytokines circulating in HIV may be associated with anorexia but many medications that patients with HIV take may also cause anorexia or nausea. Studies attempting to quanitate calorie intake in HIV infected individuals show a wide range of intakes consistent with a heterogeneous disease (3, 5, 41). The most negative effects, or lowest dietary intakes, being seen in patients with AIDS or more advanced disease.

Studies evaluating diet in otherwise healthy populations have documented marginal nutrient intakes in underprivileged segments of the population and this is likely to be true in HIV infected individuals as well. Access to adequate and appropriate nutrition may be an issue. Thus, the patients’ socioeconomic situation needs consideration in the overall risk assessment and treatment formulation. Use of alcohol or drugs may also negatively impact nutrient intake and dietary quality. As with many chronic diseases, when the patient becomes more debilitated, the ability to perform activities of daily living such as food shopping and preparation may be effected. Patients may also experience financial difficulties in the ability to obtain food. In some instances patients may be eating inappropriately because of lack of knowledge of appropriate nutritional intake.

The micronutrient status of HIV positive individuals has been evaluated in several studies and intakes close to the RDA reported for most nutrients, despite inadequate serum levels in many instances (4). However, many of these studies were done pre-HAART and may not apply in the current era, when patients are much more likely to be on effective suppressive antiviral therapy. This topic has been recently reviewed and many questions remain about the role of micronutrients in HIV infection and treatment in the era of HAART (64). Serum levels of many nutrients are difficult to interpret in inflammation; this concept will be discussed in greater detail under nutritional assessment. A progressive decline in serum micronutrient status has been associated with disease progression, and increased oxidative stress reported in HIV has been suggested as a potential cause of increased antioxidant requirements (2,4,15). Studies to date do indicate a correlation between dietary intake and serum levels of many nutrients, and HIV infected individuals probably have increased micronutrient needs, although the exact requirements for individual nutrients has not been determined (74).

Malabsorption of nutrients may be secondary to intestinal infection with enteric pathogens, enteropathy, chronic antibiotic use or the effects of HIV on the intestinal epithelial cell (5, 28). Malabsorption as assessed by intestinal biopsies documented villous atrophy in sixty two percent of HIV infected individuals studied. Malabsorption has been reported in all stages of the disorder, and while malabsorption is common in diarrhea, studies have documented abnormal d-xylose tests and fat malabsorption in the absence of diarrhea (7, 31). In addition, there is still the strong suggestion that HIV enteropathy continues to occur. The gut is the largest lymphoid organ in the body and the persistence of virus in this reservoir may have a direct or indirect (via cytokine dysregulation) impact on gut function. Diarrheal illness can be acute or chronic in individuals with HIV and occurs in an estimated 20-50% of infected individuals in the pre-HAART era (71). Currently diarrhea in HIV infection is more likely to be associated with medications than with opportunistic pathogens. Studies have found a low calorie intake and high stool frequency, but not malabsorption, predictive of the severity of weight loss. Determination of the underlying intestinal defects is essential in defining appropriate nutrition therapy for the patient (68).

Abnormal nutrient metabolism has been documented at varying stages of the disease and may be the result of multiple mechanisms including secondary infections or the cytokine mediated acute phase response to HIV infection (43). Altered assimilation of nutrients secondary to HIV infection or as a result of the medications used to decrease viral replication is also being evaluated and their role in the metabolic profile seen in some patients is under investigation. Resting Energy Expenditure (REE) has been evaluated in multiple studies of HIV infected individuals, including those with wasting. Reports have been inconsistent, finding both hypo and hypermetabolism (22, 34, 42, 56). One study reported normal Total Energy Expenditure (TEE) despite an increase in REE and theorized this was secondary to a decrease in physical activity (39).

The two primary patterns of HIV associated malnutrition of acute versus chronic weight loss previously described are thought to be due to distinctly different mechanisms (24). Determination of which primary mechanism has lead to wasting may aid in developing more appropriate therapy. It should be noted that because of the complexity of the disorder, these groups are not mutually exclusive nor are they the only causes of wasting.

As discussed, patients with primarily gastrointestinal infections most frequently report a slow steady weight loss. These patients appear to have a normal metabolic response to malnutrition, including decreased basal metabolic rate. The primary underlying mechanism is inadequate dietary intake. The effects of starvation on otherwise healthy individuals have been well studied and are outlined in Table 3. Briefly, in the early stages (first 3-4 days), protein breakdown occurs as needed for gluconeogenesis. If the semistarvation state continues, long term adaptation of metabolism converts to reliance on fat as a primary fuel source, yielding ketones and sparing protein as much as possible. Basal metabolic rate decreases about 10% in an attempt to conserve energy; in children calories are shunted away from growth and toward body homeostasis. Therapy in these patients should be directed at providing adequate nutrients within the limitations of gastrointestinal function and repletion of body weight and lean body mass.

It is thought that in patients with acute weight loss secondary to non-gastrointestinal infections the underlying mechanism is a cytokine driven increase in energy expenditure and preferential catabolism of lean body mass, thus both calorie and protein needs are significantly elevated in these patients. Most studies document an increase in BMR of 10% or greater. The majority of studies have found fat free mass to be the best predictor of REE. Although patients demonstrate accelerated protein synthesis, particularly of acute phase proteins, protein breakdown is even more significantly elevated. Other effects on intermediary metabolism include alterations in carbohydrate and lipid metabolism with elevated serum triglycerides. These alterations in substrate utilization are thought to be responsible for the less than optimal response many patients have to refeeding, which includes significant gains in fat stores but limited deposition of lean body mass.

DIAGNOSTIC EVALUATION

The overall goals of nutritional assessment are identification of patients at risk of nutrition deficiency or excess, design of individualized nutrition therapy, and the evaluation of nutrition interventions on health, complications, quality of life and survival. Because the areas of nutrition assessment each evaluate different aspects of nutritional status and can be relatively insensitive, evaluation of the patient is based on a combination of dietary, biochemical, clinical and anthropometric or body composition methods. Nutrition information must be integrated with the information from the medical history and physical examination (73).

Dietary assessment is essential in evaluating current intake and determining barriers to adequacy. A number of methods exist for evaluating dietary intake; all have advantages and disadvantages and many clinicians use a combination of methods (24-hour recall followed by food records) to more accurately determine intake (38). The 24-hour recall asks the patient to describe all the food and beverages a person has consumed in the previous day or 24 hours. Information is obtained by interviewing the subject and/or family member about the type of food, amount, time and place where food is eaten. It requires about 20 minutes and literacy is not required. However, in an ill population food intake in the 24 hours prior to an interview may not be typical and recall skills vary. Food records require that the subject record all beverages and food consumed over a specific period of time, usually 1 to 7 days, including one weekend day. Subjects must be literate and cooperative, but recall is not a bias and the information obtained is detailed. The diet history method attempts to establish usual intake of a person over several months to a year. Detailed background information relevant to diet such as income, allergies etc., is obtained along with a 24-hour recall and food frequency information. While it provides a more complete and detailed intake and accounts for variation, it is time consuming, dependent on memory and requires a highly skilled interviewer. All of these methods have the problem of accuracy in patient reporting and errors in nutrient analysis, but are recommended for use in clinical practice in the assessment of individual intakes. From the information obtained the clinician can formulate an intervention that is individualized to optimize the patient's nutritional status.

The importance of changes in body composition in HIV infected individuals has been discussed and increasingly sophisticated methods of assessment are being developed. A general overview of methods available, basic assumptions, technical difficulty, accuracy and cost are summarized in the following references (38, 48). Many methods are used exclusively for research. Most assume normal body water distribution, use various equations to determine body compartments (generally fat free and fat mass) and not all have been validated in subjects with HIV infection. Anthropometry is the assessment of body size and its’ proportions by measuring limb circumferences and skin fold thickness at various locations. In general it is a very good indicator of overall nutritional status and should be routinely assessed in any population with a chronic disease. Although simple, inexpensive, and accurate in many populations, it is an indirect measure of body fat and lean body mass and has the disadvantages of not separating out fluid shifts between body compartments. Weight, height, skinfold thicknesses, and arm circumference are the primary measures. Waist and hip circumference are also useful in following fat redistribution. Weight is expressed as percent ideal body weight, percent usual body weight, and body mass index in weight in kg/ height in m². Although weight alone may not be sensitive, pattern of weight loss is important to evaluate and routinely graphing weight data is useful in following nutritional status over time. Bioelectrical impedance though practical, may not be accurate in people with regional changes in fat. Dual Energy X-ray Absorptiometry (DEXA), while accurate, is currently less available and relatively expensive except in research settings for assessment of body composition.

Laboratory or biochemical assessment of nutritional status generally measures a nutrient or its metabolite in blood, urine or feces and is frequently used to confirm deficiencies or excesses suspected on dietary clinical, or anthopometric evaluation (38). Biochemical measurements usually detect changes before clinical or anthropometric measures of assessment and provide objective data on nutritional status. Laboratory evaluation of protein status, a metabolic profile for lipid and carbohydrate utilization and primary micronutrients of issue in HIV infected individuals should be assessed on routine nutrition screening (see Table 4). A more in-depth biochemical assessment will depend on the clinical risk factors of the individual patient, any abnormalities determined on screening, and may include more sensitive measures of protein status, metabolism and micronutrient status. Micronutrient status of HIV infected individuals is particularly difficult to assess by standard laboratory tests as patients have depressed serum levels of many micronutrients secondary to inflammatory mediator shifts and are not truly deficiency. Assessment of enzymes or functional parameters dependent on the specific nutrient may be a more valid measure of nutritional status in these cases.

Subjective global assessment (SGA) of nutritional status has also been effectively applied in HIV infected subjects showing good correlation with body composition and deteriorating nutritional status. SGA also correlated well with the CDC case definition of wasting and identified malnourished patients but did not detect early wasting (48).

MANAGEMENT

Prevention of wasting/weight loss by frequent weight monitoring and risk assessment with education on nutrition and exercise goals is essential. Similarily, assessment of comorbidities and treatment side effects which may impact weight loss is important. Treatment of associated infections and achieving optimal HAART therapy is a primary medical goal in conjunction with appropriate medical nutrition therapy. Assessment of level of risk for wasting reflects consideration of the complex factors discussed above which may lend to nutritional compromise.

Medical nutrition therapy aims to prevent and/or treat HIV associated nutrition complications (1). In HIV related wasting, the primary goal is an increase in lean body mass proportion of weight gain and as previously discussed; devising effective treatment strategies depends on understanding the underlying causes of wasting in each patient (46, 47, 50). Energy and protein needs should be estimated, with additional calorie sources broadly following the Dietary Guidelines. Micronutrient supplementation may be required during treatment of wasting, as intake may have been inadequate for some time.

How to best achieve optimal nutrient intake is then determined. This is best achieved in conjunction with a registered dietitian experienced with HIV. If it is possible for the patient to meet caloric goals through a regular diet, nutrition counseling should focus on how to best achieve this. Oral supplements help many patients whose intake is difficult to increase, and should be the first step in nutrition support of the patient. Enteral or parenteral nutrition support are important therapies but are less physiologic, more invasive and costly and should be used appropriately as determined by either gastrointestinal limitations or other medical indication (32). Goals should be set for restoration of a healthy, lean body mass and micronutrient repletion. Nutrition recommendations should be modified, as needed based on follow up assessment of nutritional status.

Exercise has also been shown to improve body composition and may also stimulate appetite. More specifically, progressive resistance exercise training (PRT) has been associated with increased weight and lean body mass in HIV associated wasting and in conjunction with individualized nutrition counseling (57).

While consultation with a dietitian or nutritionist is the cornerstone of therapy for wasting and weight loss there are situations in which pharmacological interventions for these conditions will be of great benefit to patients (9).

For patients who have anorexia, treatment with an appetite stimulant can result in a significant increase in nutrient intake. Both megestrol acetate and dronabinol have been shown to increase caloric intake (63, 66). The composition of accrued weight with megestrol acetetate has been determined; the majority of the increase in body weight is fat mass (2/3 fat and 1/3 lean) (66). The majority of side effects with megestrol acetate are related to its hormonal characteristics; it may lead to menstrual irregularities in women and sexual dysfunction in men; it may also lead to fluid accumulation and has been associated with venous thrombosis and adrenal suppression (12). The side effects of dronabinol are more limited; the most common side effect is a dysphoria which can be debilitating in some patients.

For patients who have suffered a loss in lean body mass but have adequate nutrient intake the use of anabolic agents may be considered. Anabolic agents may be androgens (testosterone) or androgenic analogues (nandrolone, oxandrolone, oxymethalone) or more purely anabolic (growth hormone) (6, 13, 18, 20, 27, 37, 44, 45, 54, 59, 60). All of these agents have been shown to be effective in increasing lean body mass, although the amount of increase has not returned lean body mass in most patients to their pre-morbid weight or body composition. Evidence is accruing that combination therapy (appetite stimulant plus androgenic agent and/or exercise) may be superior to single agent therapy in treating HIV associated weight loss and wasting (53, 67). Each of the anabolic agents has a distinctive side effect profile and each has a different route of administration. Testosterone may given by injection, by transdermal patch or in a gel formulation; nandrolone is an injection and both oxandrolone and oxymethalone are oral agents. All have been shown to be safe and effective in women as well as men. Growth hormone was able to promote a substantial increase in lean body mass in patients with HIV and is the only agent to result in an increase in lean mass and a commensurate decrease in fat mass. However, growth hormone is also an injection and has a side effect profile that includes arthralgias, myalgias, fluid retention and rarely, the development of hyperglycemia. It must be noted that intensive progressive resistance training has been able to result in equal increases in lean body mass as growth hormone and for the patients who are able to adhere to a rigorous exercise program, avoids all of the potential side effects of the pharmacologic interventions (14, 52).

Attempts to revert cytokine status to normal by blocking TNF with pentoxyfylline have not been successful in treating HIV weight loss (10). The precise mechanism by which thalidomide works is not clear, but thalidomide has been successful in increasing lean body mass in patients infected with HIV (29, 51). The side effect profile of thalidomide has limited its usefulness, as up to 50% of patients in some trials have requested that the drug be discontinued.

CONCLUSION

The use of highly active antiretroviral therapy has significantly reduced the morbidity and mortality associated with HIV; at the present time it is feasible to consider HIV as a chronic manageable disease. However, wasting and weight loss remain common and are associated with increased mortality. Attention must be paid to the nutritional status and needs of HIV infected patients to allow quality of life to be maximized for these patients.

TABLES AND FIGURES

Table 1. Definitions of Wasting

Table 2. Causes of Malnutrition in HIV

Table 3. Alterations in Metabolism due to Starvation Versus Inflammation

Table 4. Nutritional Assessment

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