Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com)

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Review Article [1] | July 01, 1996 By Jamie Hayden Von Roenn, MD [2] and Kevin Knopf, MD [3] Early intervention and attention to nutritional status are essential in patients with cachexia. Identification of reversible causes of decreased energy intake and/or weight loss is the first step in treatment. When such factors

Introduction Anorexia and cachexia are frequent complications of both HIV infection and cancer. Involuntary weight loss and associated malnutrition result in physical and psychological consequences that affect both morbidity and mortality. Numerous investigators have reported on the relationship between involuntary weight loss and adverse outcome in the setting of HIV infection or cancer. Malnutrition adversely affects immune function, increases the risk of infection, and diminishes tolerance to radiation therapy, response to chemotherapy, and overall survival [1]. Whether nutritional status is evaluated using simple clinical nutritional markers, such as serum albumin and percentage of usual body weight, or by sophisticated research techniques, the deleterious effects of malnutrition on the clinical course of HIV infection are well documented. Indeed, malnutrition is a predictor of both risk of hospitalization and survival [2]. Regardless of the clinical setting, death from wasting is directly related to the magnitude of tissue depletion, suggesting that the preservation and/or restoration of body cell mass may enhance survival [3].

Pathogenesis of Wasting The pathogenesis of wasting is incompletely defined. However, it appears to result from complex interactions among decreased energy intake, altered energy expenditure, malabsorption, and hormonal/cytokine and metabolic abnormalities. The respective roles of individual factors, such as altered insulin sensitivity, hypertriglyceridemia, futile cycling of glucose and/or free fatty acids, hypermetabolism or hypometabolism, and alterations in the cytokine milieu, are difficult to identify. Ultimately, weight loss is determined by the balance between energy intake and energy expenditure. Increasingly, data suggest reduced energy intake as the major determinant of involuntary weight loss in patients with HIV infection, and, to a less degree, in those with cancer [1,4,5]. Anorexia is a frequent clinical complaint of patients with malignant disease or HIV infection. Bruera, in a review of 275 consecutive cancer patients admitted to a palliative care unit, noted anorexia to be present in 85% of patients, second in frequency only to the complaint of asthenia and more common than complaints of cancer-related pain [1]. Similarly, anorexia is a highly prevalent symptom in the setting of HIV infection, although its exact prevalence is unknown. In a review of clinical risk factors for malnutrition in 104 HIV-infected patients (including asymptomatic patients, as well as those with AIDS or AIDS-related complex [ARC]), anorexia was identified as the predominant risk factor in 60% of patients [6]. Furthermore, Burger et al reported the benefit of intensified oral nutritional intervention in malnourished HIV-infected outpatients, suggesting that poor spontaneous nutrient intake is an important pathogenetic factor in the development of HIV-related malnutrition [7]. In patients with HIV infection, the degree of weight loss has been closely associated with reduced energy intake. McCorkindale et al noted a correlation between weight loss and decreased oral intake over a 16-month period in asymptomatic patients with HIV infection or early ARC [8]. In an evaluation by Grunfeld et al comparing metabolic parameters and oral intake in HIV-seropositive subjects, seronegative controls, and AIDS patients with and without active secondary infections, a highly significant correlation between 28-day weight loss and caloric intake was identified, while no correlation was seen between resting energy expenditure and weight loss [5]. Similarly, Macallan et al found reduced energy intake, not elevated energy expenditure, to be the primary determinant of Page 1 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) weight loss in 27 HIV-seropositive men at different stages of the disease [4]. Although weight loss appears to be progressive over the course of HIV infection, it does not occur continuously. Rather, weight is more often lost in a stepwise fashion in association with opportunistic complications of the underlying immunosuppression. This episodic weight loss is associated with decreased oral intake, which, during its early stages, may be amenable to therapeutic intervention. Although not all investigators agree, a number of studies suggest that attention to oral intake by clinicians results in an improvement in overall nutritional status. McKinley et al demonstrated improved nutritional status in adult outpatients who received nutritional assessment, counseling, and follow-up, compared with outpatients who received no nutritional intervention [9]. In contrast, Chleblowski et al reported progressive weight loss in HIV-infected individuals despite dietary counseling, suggesting the need for earlier intervention and consideration of increased target levels for energy intake [10].

Etiology of Anorexia The etiology of anorexia is incompletely understood. Cytokine Production The endogenous production of cytokines contributes to the development of anorexia and cachexia in both HIV infection and advanced cancer. Experimental therapy in vitro and in vivo with cytokines, such as interferon, tumor necrosis factor (TNF), and interleukin-1 (IL-1), can produce striking anorexia [11-13]. Tumor necrosis factor, although frequently cited as a major cause of anorexia, is not consistently elevated in the serum of patients with cancer cachexia or HIV-related wasting [11-14]. Although individual cytokines can result in significant anorexia when given as single factors in the experimental setting, tolerance to their anorexic effects generally develops and normal food intake resumes [11]. Synergism between cytokines (eg, IL-1 plus interferon-alfa or TNF) may result in irreversible anorexia, metabolic abnormalities, and progressive weight loss. Reversible Causes Food intake may be further decreased by readily identifiable, often reversible causes. Nausea and Vomiting--Chronic nausea is a frequent complaint in patients with HIV infection or cancer. Nausea and vomiting can occur as a result of mechanical obstruction, infectious complications, or as a side effect of medications (see Tables 1 and 2). In the setting of HIV infection, numerous medications are prescribed both for prophylaxis and treatment of opportunistic infections that, alone or in combination, may cause nausea and vomiting; examples include sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia or clarithromycin (Biaxin) as therapy or prophylaxis for Mycobacterium avium complex. Nausea and vomiting occur as both an immediate and late effect of treatment with chemotherapeutic drugs such as cisplatin (Platinol). Radiation therapy, particularly when the treatment field includes the gastrointestinal tract, may also cause significant nausea. In patients with advanced disease, whether cancer or HIV infection, a not infrequent cause of nausea and vomiting is a rapid increase in the dose of narcotic analgesics. In patients receiving high doses of narcotics, nausea may be severe, chronic, and accompanied by other gastrointestinal symptoms, including abdominal pain, constipation, and large bowel distention. Psychosocial or Financial Factors--Decreased oral intake may result from psychosocial or financial factors. Patients have identified anxiety, depression, and/or a sense of isolation as factors interfering with oral intake. Neuropsychiatric symptoms associated with HIV infection and opportunistic pathogens of the central nervous system or central nervous system metastases, including dementia, sensory and motor abnormalities, and psychosis, also may result in decreased caloric intake. Mechanical impediments to food intake secondary to strictures and/or progressive malignant disease further impair nutritional status. Oral and esophageal conditions that result in dysphasia and food aversions, such as esophageal candidiasis, aphthous stomatitis, and therapy-induced mucositis, occur in patients with both cancer and HIV infection. Cytomegaloviral or herpetic esophagitis are most frequently seen in the severely immunocompromised host. Bulky oropharyngeal Kaposi's sarcoma or other aerodigestive tract malignancies may also make eating painful or unpleasant. Early satiety may further compromise oral intake. Early satiety may be secondary to ascites, hepatomegaly, or massive splenomegaly (due to progressive malignancy or organ infiltration by opportunistic infections [eg, cytomegalovirus or M avium complex]). Abdominal fullness, regardless of the cause, has been identified as one of the most important symptoms influencing weight loss in Page 2 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) patients with unresectable malignancy [15]. Diarrhea is the most common gastrointestinal tract symptom in patients with HIV infection. It is often difficult to treat and may become a major debilitating aspect of a patient's illness. Not infrequently, diarrhea is associated with decreased oral intake, perhaps because patients attempt to reduce fecal output by restricting food intake, or because unabsorbed nutrients in the gastrointestinal tract suppress appetite. Similarly, diarrhea is a prominent symptom in patients with certain tumors, such as metastatic islet-cell cancers.

Appetite Stimulants Anorexia interferes with quality of life and social interaction; the enjoyment of meals with family and friends; and overall performance status. Although weight maintenance and/or improvement in nutritional status have not been proven to enhance survival, there is little doubt that an improvement in appetite favorably affects quality of life. In patients with an intact gastrointestinal tract and the functional ability to swallow, anorexia has been identified as an important target for therapeutic interventions. Because decreased oral intake is a major contributor to the weight loss associated with HIV infection and advanced cancer, pharmacologic interventions, until recently, have focused on appetite stimulation. Corticosteroids Numerous uncontrolled studies have advocated the use of corticosteroids for the treatment of cancer-related anorexia. Prospective, double-blind placebo-controlled trials in patients with cancer-associated anorexia have demonstrated that corticosteroid treatment enhances appetite but does not significantly improve body weight. Moertel et al randomized 116 patients with advanced gastrointestinal malignancies to receive placebo or dexamethasone (0.75 or 1.5 mg orally four times daily) [16]. Although the objective of the trial was to evaluate the antineoplastic effect of dexamethasone, the patients randomized to dexamethasone noted significant improvement in appetite after 2 weeks of therapy. Unfortunately, the appetite improvement disappeared after 4 weeks of treatment and was not associated with weight gain or a survival benefit. A randomized, double-blind, placebo-controlled trial of prednisolone (5 mg orally three times daily) in a similar patient population also reported improved appetite with steroid therapy that failed to translate into weight gain [17]. Bruera et al described the results of a 14-day, randomized, double-blind placebo-controlled, crossover trial of oral methylprednisolone (16 mg twice daily) in patients with cancer anorexia and cachexia. Patients received their initial drug assignment for 5 days, followed, after a 2-day washout period, by treatment with the other medication for 5 additional days [18]. At the completion of the double-blind phase on day 13 of the trial, all patients were placed on 32 mg/d of methylprednisolone, on an open basis, for another 20 days. A statistically significant enhancement of appetite was noted during steroid therapy, but the benefits were short lived. At the completion of the 20-day open phase trial, all of the nutritional parameters had returned to baseline levels. Two randomized prospective trials have evaluated the efficacy of intravenous methylprednisolone for cancer cachexia. Robustelli et al randomized 403 patients to 8 weeks of treatment with methylprednisolone (125 mg IV daily) or placebo [19]. Compared with placebo, methylprednisolone was associated with a significantly greater improvement in patient-reported quality of life and appetite without significant weight gain. An 8-week placebo-controlled trial of methylprednisolone (125 mg IV daily) vs placebo in 173 female patients with terminal cancer also noted significant appetite improvement with corticosteroid treatment [20]. The short-term positive impact of corticosteroids on appetite, coupled with their lack of effect on body weight and potential for serious side effects, has limited the use of these agents as a primary treatment for cancer-associated anorexia and cachexia. Prolonged corticosteroid treatment has been associated with immunosuppression, proximal muscle weakness, delirium, osteoporosis, electrolyte imbalance, hyperglycemia, and fluid retention, to name a few of the long-term effects. To date, corticosteroids have not been well evaluated as a treatment for anorexia in the setting of HIV infection. Cyproheptadine Cyproheptadine is an antihistamine with antiserotonergic properties that is approved in the United States for the treatment of allergic disorders. In early clinical trials with this agent, improvements in appetite and weight gain were noted in geriatric patients, adults with essential anorexia, and Page 3 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) adolescents with anorexia nervosa. Because of the suggested appetite enhancement with this agent, a randomized, double-blind, placebo-controlled trial was performed in which 295 patients with advanced cancer were randomized to receive either placebo or oral cyproheptadine (8 mg three times daily) [21]. The median time on the study was slightly over 1 month. Only 25% of the subjects completed the planned 3 months of therapy; the remaining 75% had to discontinue treatment due to clinical deterioration. For treated patients, cyproheptadine led to minimal appetite enhancement without an increase in body weight. Cyproheptadine has not been tested in patients with HIV-associated anorexia. Hydrazine Sulfate Hydrazine sulfate is a metabolic inhibitor that has been evaluated as an antineoplastic agent and as a potential therapy for the amelioration of cancer-associated cachexia and anorexia. Clinical trials failed to show any antineoplastic activity of this agent [22]. However, the purported mechanism of hydrazine sulfate, ie, inhibition of gluconeogenesis, and in vitro data indicating that the drug inhibits the cytolytic activity of TNF in cell culture, suggested hydrazine sulfate as a potential treatment for cancer cachexia [23]. Multiple clinical trials in the 1970s and early '80s arrived at conflicting results regarding the utility of this agent for the treatment of cachexia [22]. Because of the unsettled controversy surrounding hydrazine sulfate, three large randomized clinical trials have recently been performed. Two of the trials randomized patients to hydrazine sulfate or placebo in addition to standard therapy for non-small-cell lung cancer [24,25]. The third trial randomized patients with colorectal carcinoma to receive hydrazine sulfate or placebo without concurrent systemic antineoplastic treatment [26]. All three trials failed to demonstrate benefit from hydrazine sulfate use, either as an antineoplastic agent or for the amelioration of cancer-associated anorexia. These data have dampened enthusiasm for further evaluation of hydrazine sulfate for the treatment of HIV-associated anorexia. Cannabinoid Derivatives The appetite-enhancing effects of marijuana and its derivatives have been well documented. At least one randomized study found dronabinol (delta-9-tetrahydrocannabinol [Marinol]), the primary psychoactive component of marijuana, to be a more effective antiemetic than the phenothiazines and more frequently associated with increased oral intake [27]. Dronabinol has been evaluated in phase II studies for its effect as an appetite stimulant in patients with cancer anorexia. In a 6-week dose-ranging study, 30 patients with unresectable cancer received 2.5 mg of dronabinol daily, 2.5 mg twice daily, or 5 mg once daily [28]. Patients in all treatment groups continued to lose weight, although the rate of weight loss decreased. In the two higher-dose arms, both mood and appetite improved. Five patients discontinued treatment because of adverse effects. A phase II study reported on the effect of 4 weeks of higher-dose dronabinol (2.5 mg orally three times daily) on appetite in patients with advanced cancer and anorexia [29]. Of 18 evaluable patients, 13 reported an improvement in appetite. In contrast to prior studies, only 4 of the 13 patients had significant side effects, including only one case of neuropsychologic toxicity (slurred speech). There were no reports of somnolence or dysphoria. This study suggests that in well-selected patients with advanced cancer, dronabinol may be an effective intervention to stimulate appetite. More recent studies have focused on the appetite-enhancing effect of dronabinol in patients with HIV infection. Gorter et al reported on 10 AIDS patients treated with dronabinol (2.5 mg orally three times daily) in a noncomparative unblinded study. Patients remained on the study from 4 to 20 weeks [30]. Dronabinol resulted in a median weight change of +0.54 kg/mo, and 7 of the 10 patients gained weight. The appetite-enhancing effect of dronabinol in HIV-infected patients was further evaluated in a multicenter, randomized, double-blind, placebo-controlled study [31]. Patients were randomized to receive placebo or dronabinol (2.5 mg orally twice daily 1 hour before lunch and 1 hour before supper). The primary study end points were changes in appetite, mood, and weight. Of 139 patients enrolled in the trial, 89 were evaluable for response. As compared with placebo, dronabinol resulted in an improvement in appetite, as measured by a visual analog scale (P = .01); a trend toward weight gain after 6 weeks (-.4 vs +.1 kg; P = .21); and an improvement in mood (P = .005), as assessed by a visual analog scale. The dronabinol dose had to be reduced to 2.5 mg once daily in 18% of patients due to neurologic toxicity. After completion of the 6-week randomized study, patients could continue on dronabinol, unblinded, for up to 1 year. Of the 90 patients for whom data are available from the unblinded study extension, appetite stimulation was maintained for at least 6 months and an increase in body weight of equal to or more than 2kg was reported in 38% of patients. Page 4 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) Megestrol Acetate Megestrol acetate, a synthetic orally active progestational agent used widely for the treatment of metastatic breast cancer and endometrial cancer, has been reported to stimulate appetite and weight gain. When treated with conventional doses (160 mg/d) of this agent, approximately 30% of breast cancer patients gain weight. A phase I-II study of high-dose megestrol acetate (480 to 1,600 mg/d) for the treatment of advanced breast cancer reported marked appetite stimulation and weight gain of more than 2 kg in 81% of patients [32]. Several controlled randomized studies have subsequently demonstrated the beneficial effect of megestrol acetate on cancer cachexia [33,34]. Across the studies, megestrol acetate-treated patients reported improved appetite and caloric intake, increased body weight, and improved sense of well-being. The observed weight gain appeared to be nonfluid weight, primarily adipose tissue, based on the lack of clinically evident edema or ascites and on body composition studies [35]. Because of the perceived appetite-enhancing effect and excellent tolerability of megestrol acetate, two double-blind randomized placebo-controlled trials of the drug were performed in patients with AIDS-associated weight loss [36,37]. In the four-arm trial, patients were randomly assigned to receive placebo or megestrol acetate oral suspension (100, 400, or 800 mg daily) for 12 weeks. Patients enrolled in the two-arm trial received either placebo or megestrol (800 mg/d) for 12 weeks. Patients in both trials were evaluated at 4-week intervals for changes in weight and body composition, caloric intake, sense of well-being, toxicity, and appetite. Among the 195 patients evaluable for efficacy in the four-arm trial, a weight gain of equal to or more than 2.3 kg was noted in 64.2% of the patients treated with 800 mg/d of megestrol acetate, as compared with 21.4% of patients given placebo (P less than .001). An intention-to-treat analysis showed a statistically significant difference between the placebo group and the 800-mg megestrol acetate group with regard to the number of patients who gained equal to or more than 2.3 kg (8/32 [25%] vs 38/61 [62.3%]; P = .002). Compared with placebo-treated patients, evaluable patients given 800 mg/d of megestrol acetate reported a significant improvement in overall well-being and showed significant increases in mean weight gain (-.7 vs +3.5 kg; P less than .001), lean body mass (-.7 vs + 1.1 kg; P less than .001), appetite grade (P less than .001), and caloric intake (-107 vs +645 kcal/d; P = .001). In the two-arm trial, there was no statistically significant difference between the percentage of actively treated patients and placebo recipients who gained equal to or more than 5 lb at any time during the 12 weeks. The number of patients evaluated was quite small, however (29 patients in the megestrol acetate group and 36 in the placebo group). Mean weight change, maximum weight change, and percentage maximum weight change were significantly greater with 800 mg of megestrol acetate than with placebo. Mean maximum weight decreased by 0.7 lb in the placebo group but increased by 5.6 lb in the 800-mg megestrol group in the 2 arm trial (P = .027). This represented a statistically significant percentage maximal weight change (P = .017). Similar to the four-arm trial, the megestrol-treated group in the two-arm trial experienced an improvement in appetite and perception of overall well-being, as compared with the placebo group. No statistically significant differences between treatment groups were noted in either study with respect to serious adverse events. The number of patients developing opportunistic infections did not vary between treatment groups. There were no differences in survival based on treatment. These studies concluded that in patients with AIDS-related weight loss, megestrol acetate can stimulate significant weight gain, which is associated with a patient-reported improvement in overall sense of well-being. Possible Mechanism of Weight Gain--Although patients treated with 800 mg/d of megestrol acetate showed an increase in weight, a significant proportion of the observed weight gain was fat mass [36,37]. Megestrol acetate, despite its minimal intrinsic androgenic effects, results in erectile impotence in a dose-dependent fashion [37]. Since androgens have a significant influence on lean body mass, a potential explanation for the excess fat accrual in male patients treated with megestrol acetate is a reduction in serum testosterone levels. Recently published data support this hypothesis [38]. A retrospective analysis of circulating total testosterone concentrations and body composition measurements in 12 patients enrolled in the four-arm megestrol acetate trial demonstrated a significant decrease in serum testosterone levels by week 4. These data suggest that the addition of testosterone replacement to megestrol acetate may enhance the accrual of lean tissue. This hypothesis is currently being tested by the AIDS Clinical Trials Group.

A Role for Exercise? Page 5 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) The wasting associated with AIDS is characterized primarily by a loss of muscle mass, strength, and endurance. Because the prognosis for patients with AIDS worsens with loss of fat-free mass, therapies that increase both weight and muscle mass may be of particular value. Exercise is one such potential intervention. It is widely accepted that regular exercise contributes to health maintenance. An 8-year prospective study of the general US population indicated that poor physical fitness has an adverse effect on longevity, while higher levels of physical fitness are associated with improved survival for both men and women [39]. Furthermore, long-term AIDS survivors have identified exercise as a factor contributing to their prolonged survival [40]. Potential Benefits of Exercise in HIV-Infected Patients Exercise may affect an HIV-infected individual in a variety of ways. Several investigators have noted improvements in immunologic and psychological parameters with exercise across all stages of HIV infection [41,42]. Keyes et al reported on the effects of cardiovascular conditioning in a 16-week crossover trial, which included 6 persons with AIDS, 18 with ARC, and 4 with HIV-associated lymphadenopathy [41]. Exercise resulted in statistically significant improvements in CD4 count (mean increase, 68 cells/mm³), helper/suppressor cell ratios (mean increase, .072), and resting and recovery pulses. While on an exercise program, subjects reported improved exercise tolerance and appetite, as well as decreased fatigue and depressive symptoms. Schlenzig et al published the results of a randomized controlled trial of exercise vs observation in a group of 49 HIV-seropositive subjects stratified by CD4 count [42]. Of the 49 patients, 23 participated in a 6-month exercise program. After 3 months, maximum aerobic power increased significantly in patients who took part in the exercise program but decreased in the control group. Maximum volume of oxygen consumption was significantly higher in the exercise group than in controls. CD4 counts were stable in both arms. The effects of progressive resistance exercise on muscle function and body composition in patients with HIV infections have also been evaluated. MacArthur et al studied the impact of a 24-week program of exercise training in 32 HIV-seropositive subjects with a mean CD4 count of 144 cells/mm³ (range, 7 to 392 cells/mm³) [43]. Unfortunately, only six patients completed the training program. For the six compliant subjects, there was evidence of a training effect after 24 weeks, as indicated by improvements in maximum oxygen consumption, oxygen pulse, and minute ventilation. No adverse immunologic effects (CD4 count measurements) were noted. The large dropout rate, however, raises concern that exercise may represent an increased stress for HIV-infected patients. Although no data were collected on energy expenditure or intake, it may be that an unstimulated appetite may be unable to keep pace with the energy demands of exercise. Risks vs Benefits of Exercise in HIV-Infected Patients Although moderate exercise is associated with increased health in control subjects, the balance between the risks and benefits of exercise in HIV seropositive patients is not as well defined. The dropout rate in some of the exercise studies performed in AIDS patients is quite high. Furthermore, fatigue is a common complaint among AIDS patients as well as cancer patients, and is not necessarily related to altered muscle metabolism. The relationship between exercise and cardiac dysfunction in HIV-seropositive patients raises additional concerns about exercise as a prescription for improved health [44]. Thus, it is unclear whether exercise may contribute to excessive stress in some HIV-infected or advanced cancer patients. Exercise in combination with a therapy that increases energy intake may mitigate this potential adverse effect. However, an exercise prescription, alone or in combination with pharmacologic interventions, is an option only in highly motivated and highly selected patients, regardless of the underlying condition.

Anabolic Aagents The difficulty in replenishing lean body mass in patients with involuntary weight loss highlights the need for interventions with greater anabolic effects. Anabolic agents are being evaluated in patients with HIV infection and warrant consideration in the advanced cancer population as well. Growth Hormone The potentially beneficial metabolic effects of growth hormone include the anabolic effect of increasing protein synthesis and anticatabolic protein-sparing effects. In a short-term, metabolic ward study in patients with HIV-associated wasting, pharmacologic doses of recombinant human growth hormone (rhGH [Serostim]) produced weight gain and nitrogen retention [45]. Six HIV-seropositive men with an average weight loss of 19% were treated with 0.1 mg/kg/d of rhGH for Page 6 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) 7 days. Treated patients gained an average of 2 kg and had a marked decrease in urinary nitrogen and potassium, suggesting an incorporation of these elements into lean tissue. In light of these results, a multicenter, double-blind, randomized, placebo-controlled trial of rhGH was performed [46]. In this trial, 185 patients with HIV-associated weight loss were randomized to receive 12 weeks of therapy with either rhGH (0.1 mg/kg/d) or placebo. Eligibility criteria were similar to those required for enrollment in the randomized trials of megestrol acetate for AIDS-related cachexia (discussed above), with the important exception that patients enrolled in the growth hormone trial were required to have adequate oral intake. Treatment with rhGH led to a significant increase in weight (+1.6 ± 0.5 kg), an even greater increase in lean body mass (+3.0 ± 0.4 kg), and a decrease in fat mass (-1.7 ± 0.2 kg), as determined by dual energy x-ray absorptiometry. Placebo-treated patients exhibited no significant changes in body weight or composition during the trial. Changes in lean body mass correlated directly with changes in treadmill work performance and a number of a quality-of-life variables, including general health perceptions, energy, physical functioning, and health index. Growth hormone treatment was well tolerated. Only mild to moderate side effects were reported, which responded to dose reductions. The major side effects identified were joint stiffness and puffiness and paresthesias. The finding of increased lean body mass, which correlated with improved functional performance, suggests rhGH as a promising therapy for patients with HIV-associated weight loss. However, as patients with decreased appetite were excluded from these trials, and oral intake is the primary determinant of HIV-related weight loss, it is unclear whether these results are broadly applicable. An evaluation of alternate schedules and doses of rhGH, either alone or in combination with an appetite stimulant, has not been done, but would be of particular interest. Insulin-Like Growth Factor 1 Insulin-like growth factor 1 (IGF-1) mediates many of the biologic effects of growth hormone, suggesting a therapeutic role for IGF-1 in the treatment of AIDS-related weight loss. In 10 subjects with AIDS-related cachexia, intravenous recombinant IGF-1 resulted in positive nitrogen retention, but this effect was transient [47]. Repeated administration of IGF-1 led to decreased IGF-binding protein 3 levels, limiting its therapeutic efficacy. Alternate routes of administration or coadministration of IGF-1 with growth hormone is being considered in an attempt to bypass the attenuation of IGF-1 action.

Anabolic Steroids Anabolic steroids, although inadequately tested, are a potential intervention for the treatment of anorexia. Testosterone has two distinct biologic properties: androgenic (or virilizing) activity and anabolic activity. In HIV-infected men with hypogonadism, testosterone replacement resulted in improved energy, appetite, mood, and sexual function, as well as an increase in weight [48]. Because of the anabolic properties of testosterone, it has been used anecdotally for HIV-associated wasting with beneficial results [49]. Chemical modification of testosterone can produce compounds with relatively greater anabolic potency. Oxandrolone (Oxandrin), for example, is a synthetic anabolic steroid with anabolic activity 3- to 13-fold greater than testosterone. It is currently approved to enhance weight gain following extensive surgery, severe infections, or trauma. Trials to evaluate oxandrolone for the treatment of HIV-related cachexia are just getting underway. It has not yet been evaluated for cancer cachexia. Nandrolone is another anabolic steroid with greater anabolic than androgenic activity (relative activity, 4:1 to 2.5:1) when compared with testosterone (relative activity, 1:1). In patients with advanced non-small-cell lung cancer randomized to receive chemotherapy with or without nandrolone decanoate (200 mg/wk IM for 4 weeks), Chlebowski reported a trend for less severe weight loss in the nandrolone-treated patients [50]. The AIDS Clinical Trials Group is currently conducting studies of nandrolone in HIV-infected women with weight loss. Concerns over potential side effects of androgens, such as hepatotoxicity and virilization, particularly in women, may have delayed evaluation of these agents for the treatment of cachexia.

Cytokine Suppression Cytokine-mediated alterations in host metabolism may play an essential role in the cachexia associated with advanced cancer or HIV infection. Although a number of cytokines, including TNF, IL-1, IL-6, and interferon-gamma, have been proposed as mediators of cachexia, it has been difficult to show an association between serum levels of these factors and weight loss [11-14]. Because of Page 7 of 10

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) the potential role of cytokines in the pathogenesis of cachexia, cytokine modulation and/or inhibition is currently being evaluated as a therapeutic strategy for involuntary weight loss. Pentoxifylline Pentoxifylline (Trental), a methyl-xanthine derivative, is a nonspecific inhibitor of TNF. A pilot study of pentoxifylline (400 mg three times daily) in 25 patients with advanced HIV disease reported a decrease in TNF messenger RNA levels without a decrease in viral replication or improvement in lean body mass [51]. Pentoxifylline therapy was well tolerated. In a placebo-controlled, double-blind, randomized trial, 70 patients with cancer-related weight loss were randomized to receive placebo or pentoxifylline (400 mg orally three times daily) [52]. Pentoxifylline failed to improve patient-reported appetite, perceived food intake, or body weight. Thalidomide Thalidomide is a specific inhibitor of TNF, resulting in decreased TNF gene transcription. Trials of thalidomide as an adjunct to therapy for tuberculosis and as primary treatment for HIV- or cancer-associated cachexia are in progress. If therapy with thalidomide shows promise in these trials, the teratogenic effects of this agent will need to be readdressed.

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Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Published on Physicians Practice (http://www.physicianspractice.com) growth factor-1 in cachectic patients with Acquired Immunodeficiency Syndrome. J Clin Endocrinol Metab 78:404-410, 1994. 48. Rabkin JG, Rabkin R, Wagner G: Testosterone replacement therapy in HIV illness. General Hospital Psychiatry 17:37-42, 1995. 49. Jeantils V, Nguyen G, Bacle F, et al: Weight gain under oral testosterone undecenoate in AIDS. Therapie 48:59-72, 1993. 50. Chlebowski RT, Herold J, Ali I, et al: Influence on nandrolone decanoate on weight loss in advanced non-small cell lung cancer. Cancer 58:183-186, 1986. 51. Dezube BJ, Fridovich-Keil JL, Bouvard I, et al: Pentoxifylline and well-being in patients with cancer. Lancet 335-662, 1990. 52. Goldberg RM, Loprinzi CL, Mailliard JA, et al: pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. J Clin Oncol 13:2856-2859, 1995. Source URL: http://www.physicianspractice.com/review-article/anorexiacachexia-patients-hiv-lessons-oncologist-0 Links: [1] http://www.physicianspractice.com/review-article [2] http://www.physicianspractice.com/authors/jamie-hayden-von-roenn-md [3] http://www.physicianspractice.com/authors/kevin-knopf-md

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