Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist

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 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(Drug information on sulfamethoxazole) for the treatment of Pneumocystis carinii pneumonia or clarithromycin(Drug information on 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(Drug information on 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 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.