November 30, 1999
Constitutional symptoms, reported by more than 50% of people with advanced HIV disease, often significantly compromise both physical functioning and quality of life.1-3 The most common constitutional symptoms include weight loss, fatigue, fever and sweats. These symptoms can be related to myriad potential etiologies including opportunistic infections, malignancy, metabolic dysregulation, medication-related toxicities and advanced AIDS itself.
Attempts should be made to determine and, when possible, treat the underlying causes of constitutional symptoms. Yet some underlying causes are refractory to treatment, and in many settings the necessary resources remain unavailable. Even where highly active antiretroviral therapy (HAART) is available and the chronic phase of HIV disease is prolonged for many patients, constitutional symptoms may arise from or be exacerbated by cumulative co-existing morbidities or by toxicities of the antiretroviral medications themselves.
Nevertheless, particularly in the late stages of HIV disease, aggressive symptom management often can improve a patient's quality of life regardless of the effects of more disease-specific therapies. Thus, it is important that clinicians in all settings be skillful both in controlling uncomfortable constitutional symptoms and in combining HIV-specific and palliative interventions for optimal patient care. The following sections and Table 5-1 (PDF) address the management of HIV wasting, fatigue, fever and sweats.
HIV wasting syndrome is a common AIDS-defining diagnosis in the United States, with an estimated lifetime frequency of 70% to 90% among AIDS patients who receive no antiretroviral therapy.4 It is defined by the Centers for Disease Control and Prevention as an involuntary loss of more than 10% of baseline body weight in conjunction with fever, weakness or diarrhea for more than 30 days. However, less stringent definitions, such as loss of 5% to 10% of ideal body weight, are widely employed in clinical practice.5
Mechanisms of HIV wasting are complex and include the following:
Causes of inadequate nutritional intake often include one or more of the following: dysphagia or odynophagia due to candidiasis, cytomegalovirus, herpes simplex virus, or aphthous ulceration; anorexia, nausea, or vomiting due to infection, malignancy, medication side effects, or other symptoms such as pain; and psychological factors such as depression, anxiety, grief and loneliness.
Excessive nutrient loss may be due to chronic infectious, malabsorptive, or medication-related diarrhea or idiopathic AIDS enteropathy.8
While there is evidence that HAART can reduce the severity of weight loss and malnutrition in HIV disease, as many as 24% to 48% of patients may continue to lose weight while on potent combination antiretroviral therapy.11-16
The first step in managing HIV wasting is to make every effort to increase the patient's caloric intake comfortably to meet the elevated metabolic demand seen in HIV disease. Potentially reversible causes of inadequate nutrient intake and nutrient loss, such as gastrointestinal infections or medication side effects, should be identified and addressed if possible. Additional measures to manage HIV wasting include appetite stimulants and anabolic agents such as androgens and growth hormone.
Two agents used to combat HIV wasting by stimulating the appetite are megestrol acetate and dronabinol. Corticosteroids may also be effective.
Megestrol acetate, a synthetic progestational agent, can reduce anorexia and lead to weight gain primarily by increasing fat mass. Randomized controlled trials have shown a statistically significant increase over placebo in food intake, weight gain, and overall sense of well-being over an 8-12 week period.17, 18 The recommended dose in HIV-associated wasting is 400-800 mg/day in a single oral dose. It may be used in conjunction with anabolic agents, resistance exercise or both. There is probably no benefit (and may be additional risk) in adding megestrol acetate to the regimen of a patient already taking a corticosteroid at moderate or high doses, but studies have not been done.
While side effects of megestrol acetate generally have been considered rare or mild, recent evidence suggests that they may be more frequent and severe than previously recognized.19, 20 Reported side effects related to its corticosteroid activity include induction or exacerbation of diabetes mellitus and, in the long term, Cushing's syndrome and -- with abrupt discontinuation of therapy -- adrenal insufficiency. With prolonged administration, megestrol acetate also diminishes gonadotropin secretion and thus can cause or exacerbate hypogonadism, and an association with hypercoagulability and osteonecrosis also has been suggested.7, 21-27 As with any intervention, clinicians should weigh the potential benefits and burdens of megestrol acetate in the context of an individual patient's goals, values and life expectancy.
Corticosteroids have been shown to improve appetite and food intake in cancer patients. In the same population, they can also reduce pain, nausea and vomiting, and fatigue while improving mood, strength, performance status, and overall quality of life.19 It is likely that AIDS patients with similar symptoms may benefit from corticosteroids, but this has not been well studied.
There is some evidence that any decreases in anorexia, weakness, and fatigue from corticosteroids may be temporary.28 In addition, the risk of serious side effects from corticosteroids increases with time; these side effects include gastrointestinal bleeding, adrenal insufficiency, myopathy, additive immunocompromise and opportunistic infections. It is prudent to reserve prolonged use for patients with a short life expectancy and severely distressing symptoms that may be eased by corticosteroids. In this situation, prednisone may be started at 20-80 mg orally once daily, while dexamethasone can be initiated in a dose of 2-8 mg orally or intravenously twice per day. Once beneficial effects are noted, the dosage can be reduced to the lowest dose that maintains the beneficial effect. Short-term side effects may include hyperglycemia, fluid retention and psychosis.
Dronabinol has been shown to increase appetite and decrease nausea, yet little or no weight gain has been reported.29, 30 The usual starting dose is 2.5 mg orally twice daily before lunch and dinner; this may be increased to 5 mg orally thrice daily. Central nervous system side effects such as confusion, anxiety, emotional lability, euphoria or hallucinations have been reported in as many as 10% of patients, yet in most patients these side effects resolve after one to three days of continued use.30 If symptoms persist or are severe, reducing dosage to as little as 2.5 mg once a day before dinner or at bedtime may be helpful.
Hypogonadism has been reported in as many as 50% of men and women with HIV wasting. Several studies have shown that testosterone deficiency may contribute to HIV wasting in both sexes.31 In this setting, hypogonadism most often is due to impaired gonadotropin secretion resulting from malnutrition, chronic disease, or medications such as phenothiazines or megestrol acetate.32 Less frequently, hypogonadism may be primary and result from HIV or opportunistic infection of the gonads, medication side effects, or malignant infiltration.7
Androgen deficiency leads to loss of lean body mass and also may cause or exacerbate chronic anemia and depression. Replacement therapy may thus have a significant impact on a patient's overall well-being.33 Randomized controlled trials of testosterone replacement in men with HIV disease have shown significant weight gain, increases in lean body mass, and improvements in quality of life scores, libido, mood and energy.31, 34
Once a diagnosis of testosterone deficiency is established in men, appropriate replacement may be undertaken via transdermal patch, androgen gel or intramuscular injection (oral preparations are associated with liver toxicity). Daily scrotal and non-scrotal transdermal patches are available, and a dose of 5 mg/day has been shown to increase lean body mass. Skin irritation at the application site may be relieved by applying a small amount of 0.1% triamcinolone cream to the skin under the reservoir. One percent transdermal testosterone gel is given in a dosage of 2.5-7.5 g/day and should not be applied to the genital area. Finally, the intramuscular preparations, testosterone cypionate and enanthanate, are given in doses of 200 mg every two weeks.31
The administration of androgens to women with HIV wasting and low serum-free testosterone is currently under investigation. A pilot study showed that physiological doses of testosterone (150 µg transdermally daily) can increase weight and improve quality of life.35 Further studies are needed to evaluate the safety and efficacy of androgen replacement for these women.
Two testosterone analogues, oxandrolone and nandrolone, have been shown to promote weight gain in patients with HIV-associated weight loss.36-38 However, both drugs can cause hepatic toxicity, their long-term effects are unknown, and neither drug is more effective than testosterone for patients with both HIV wasting and hypogonadism.7
In eugonadal men with HIV wasting, oxandrolone may promote weight gain and lean body mass at a dosage of 20 mg orally per day in two to four divided doses. It should be used with great caution in women and patients with liver disease.
Recombinant human growth hormone (rhGH) has been shown to increase weight, lean body mass, and strength in patients with HIV wasting in a daily dose of 0.1 mg/kg given subcutaneously for up to 12 weeks.39-41 Side effects may include edema, arthralgia and hyperglycemia. Because long-term side effects are unknown, rhGH is not considered first-line treatment. The current cost of rhGH therapy is about $1750 per week.
Exercise in the form of supervised, progressive resistance and fitness training may be useful in HIV wasting, but few data are available. Cytokine modulators, such as thalidomide and pentoxifylline, are experimental and not recommended.
Fatigue is a common symptom and may affect as many as 85% of AIDS patients.2 It can severely compromise quality of life by diminishing physical functioning and causing psychological distress. As is the case with fatigue associated with other life-threatening illnesses, HIV/AIDS-related fatigue is usually multifactorial. Frequent etiologies include anemia, infections, HIV disease progression, hormonal insufficiencies, metabolic derangements, medication side effects, malnutrition, wasting, depression, insomnia, malignancy, and end-stage organ disease.6 (See Chapter 3: Assessment of Physical Symptoms, Table 3-1, PDF.)
If possible and appropriate for the clinical situation, interventions should address the underlying cause(s) of fatigue. For example, erythropoietin can be used to treat AIDS patients whose fatigue appears to be due primarily to anemia and whose anemia is not caused by bleeding, hemolysis, or deficiency of iron, B12 or folate. The dose is 40,000 units subcutaneously weekly along with iron supplementation.42 Testosterone replacement can be used for hypogonadal men with fatigue as described in the section on HIV wasting above.
Treatments for fatigue of multiple etiologies include psychostimulants and corticosteroids.
Methylphenidate is frequently used to treat fatigue or depression in the palliative care of patients with advanced life-threatening illnesses of almost any etiology.43, 44 Its rapid onset of action makes it especially useful for depression in patients with a life expectancy of days or weeks, when the usefulness of selective serotonin reuptake inhibitors is limited. It also is useful for treating sedation due to opioid analgesics. In very frail patients, it can be started in a dosage as low as 2.5-5 mg orally at 8 a.m. or twice per day at 8 a.m. and noon. It should not be given in the afternoon or evening. The dosage can be increased daily as tolerated to effect or to a maximum daily dose of 60 mg.
While generally well-tolerated, methylphenidate should be used with caution in patients with anxiety, delirium, agitation, or tachyarrhythmias. Any jitteriness, mild anxiety, or hyperactivity that develop during treatment often can be managed with a dose reduction.
Dextroamphetamine has indications and properties very similar to those of methylphenidate.43 The recommended dosage is the same.
Pemoline, which is chemically unrelated to amphetamine and has milder sympathomimetic effects, also may be effective against fatigue and depression in advanced medical illness including HIV disease.45 In the only randomized controlled trial of psychostimulants for fatigue in HIV-positive people, methylphenidate (7.5 mg twice daily) and pemoline (18.75 mg/day) were significantly better than placebo at improving not only fatigue but also depression, psychological distress, and overall quality of life.46 The starting dosage of pemoline is 18.75 mg orally at 8 a.m. or twice per day at 8 a.m. and noon. The dosage can be increased as tolerated to effect or to a maximum daily dose of 112.5 mg. However, due to its potential for severe hepatotoxicity, pemoline should be used with caution and should not be used in patients with liver disease.
Corticosteroids have been shown to temporarily improve fatigue in cancer patients.28 It is possible that many HIV/AIDS patients may experience similar benefits in the palliative care setting. Information on the use of corticosteroids for fatigue and other indications in general palliative care can be found in this chapter, in the section on HIV wasting above.
There is direct evidence that corticosteroids improve fatigue in one sub-population of HIV/AIDS patients: those with disseminated mycobacterium avium complex (MAC) with progressive disease despite combination antimycobacterial therapy. Low-dose dexamethasone (4-6 mg/day) led to a rapid decrease in fatigue, fever and night sweats within one week of initiating treatment in a series of 12 patients. In similar studies of (low-dose) corticosteroids in small numbers of patients, weight gain, fever reduction, and improved sense of well-being were documented.47, 48 While randomized controlled trials have not been done, corticosteroids appear to be useful in the palliative care of patients with end-stage AIDS and MAC refractory to antimycobacterial therapy.49
Fevers and Sweats
Fevers, sweats, or both are frequent causes of suffering and poor quality of life in AIDS patients. Fever increases metabolic rate, and persistent fever is associated with anorexia, weight loss and wasting.6 Etiologies of fever include infections, HIV-associated malignancies, side effects of drugs (e.g., trimethoprim-sulfamethoxazole and other sulfa drugs, abacavir and other antiretrovirals, amphotericin B), hormonal dysfunction, and auto-immune disorders.
While any source of fever can cause sweats, sweats without fever may occur in the setting of some infections, malignancies, endocrinopathies and medications. For example, both opioids and withdrawal from opioids may cause sweats in the absence of fever. If possible and appropriate, efforts should be made to identify and treat the underlying etiology of fevers or sweats. Medications used to treat fever and sweats of many etiologies include antipyretics, corticosteroids and anticholinergics.
In the palliative management of fever in patients with HIV/AIDS, it is important to maintain body temperature within a comfortable range. Usually patients are most comfortable at normal or near-normal body temperature, but not all fevers cause discomfort. The most common antipyretic used is acetaminophen, given in a dosage of 650 to 1000 mg orally or rectally every 6 hours as needed or around the clock. Non-steroidal anti-inflammatory drugs (NSAIDs) are particularly helpful in patients with fevers related to neoplasms and/or when an additional antiinflammatory effect is desired. The gastrointestinal toxicity of NSAIDs can be reduced by using choline magnesium trisalicylate (500 to 1000 mg orally twice-thrice daily), using a selective cyclooxygenase-2 inhibitor such as rofecoxib (12.5 to 50 mg orally every day), and/or adding a cytoprotective agent such as an H2 antagonist, proton pump inhibitor, or misoprostol (100 to 200 µg orally twice to four times per day).
For severe, unremitting fever, acetaminophen and an NSAID both can be given every 6 hours in a staggered fashion with the patient receiving one or the other every 3 hours. Corticosteroids provide an alternative that can cut down on the number and frequency of medications, and may be equally effective in some situations. As described above in the section on fatigue, low-dose dexamethasone (4 to 6 mg/day) led to a rapid decrease in fever, night sweats and fatigue within one week of initiating treatment in a series of 12 patients with disseminated MAC refractory to antimycobacterial therapy.47-49
Keeping the patient warm and dry will help to prevent chills and shivering.6 If fluid and electrolyte loss from fever and sweats is considerable, the clinician must weigh the benefits and burdens of aggressive hydration to restore and maintain fluid balance in light of the patient's goals, values, and prognosis.
Sweats associated with fever are treated as above. If sweats are unrelated to fever, NSAIDs as described above still may prove helpful. Anticholinergics also may be tried, such as scopolamine (0.2-0.6 mg subcutaneously or intravenously every 1-4 hours, or by 1.5 mg transdermal patch, 3-5 patches every 72 hours) or hyoscyamine (0.125-0.25 mg orally every 1-4 hours). An anticholinergic with minimal central nervous system effects is glycopyrrolate (1-2 mg orally once daily at bedtime or up to thrice daily or 0.1-0.2 mg subcutaneously or intravenously once daily at bedtime or up to every 6 hours). In addition, the use of the H2 antagonist cimetidine (400-800 mg orally twice daily) may provide symptomatic relief. 28, 50
In people with HIV/AIDS, constitutional symptoms such as wasting, fatigue, fever and sweats often severely compromise quality of life and overall sense of well-being. Careful management of these symptoms throughout the course of the illness is an important component in overall HIV/AIDS care. As with any intervention, clinicians should weigh the potential benefits and burdens of treatments for constitutional symptoms for each individual patient in each clinical situation. When a patient's life expectancy is short and maximizing his or her quality of life is an important goal, possible long-term side effects of a treatment become less relevant if the treatment is likely to improve short-term quality of life.