Published in the Bulletin of Experimental Treatments for AIDS Spring 2001 issue, by the San Francisco AIDS Foundation.

Spring 2001 Table of Contents

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beta@sfaf.org

Liz Highleyman

Fatigue can be one of the most debilitating symptoms experienced by people with HIV disease. Fortunately, there are several measures that people experiencing fatigue can take to improve their energy levels and overall quality of life.

Fatigue, also known as asthenia or prostration, is an unusual and prolonged tiredness, exhaustion, or lack of energy. It often develops slowly and worsens over time. Fatigue may be intermittent or chronic. Chronic fatigue is persistent exhaustion that is not associated with exertion and that may not be relieved by rest. According to Lisa Capaldini, MD, of the University of California at San Francisco (UCSF), fatigue can be divided into physical, psychological, and emotional components. Physical fatigue is associated with activity. People with this type of fatigue may experience muscle weakness, limb heaviness, or soreness. They may be unable to perform daily physical tasks such as shopping or preparing meals; those with severe fatigue may even find it difficult to get out of bed or carry on a conversation. Physical fatigue is often related to a specific physical malfunction, such as heart, lung, endocrine (hormone), or nervous system problems. People with psychological fatigue may find it difficult to concentrate, calculate, or remember things; such symptoms are easily confused with the early stages of HIV-associated dementia. Emotional fatigue involves a decrease in motivation and lack of interest or pleasure in normal activities (also called anhedonia), what Dr. Capaldini calls a lack of "get-up-and-go." Emotional fatigue may also be associated with feelings of frustration and irritability.

How Common Is Fatigue in People with HIV?

Many providers believe that fatigue is one of the most prevalent—yet under-reported, under-recognized, and under-treated—aspects of HIV disease. Several studies suggest that most people with HIV/AIDS experience fatigue at some point during their illness, with estimates ranging from less than 50% to more than 80%. The prevalence (rate) of fatigue increases as HIV disease progresses. During the initial, acute period of HIV infection, many people experience a flu-like illness that includes fatigue. After this initial period, the incidence of fatigue decreases, but then rises again later in the course of illness; people with advanced AIDS are more likely to report fatigue than people at earlier stages of HIV infection. Stephen Ferrando, MD, and colleagues found that HIV positive men with CD4 cell counts below 500 cells/mm3 experienced more fatigue than men with CD4 cell counts above 500 cells/mm3. However, studies so far have not found a consistent correlation between viral load levels and fatigue.

According to a study by William Breitbart, MD, and colleagues of the Memorial Sloan-Kettering Cancer Center in New York City, fatigue is common during acute HIV infection, as well as at later stages. Dr. Breitbart’s study included over 400 people with HIV, and involved both self-reports and clinician assessments; seven different scales were used to measure fatigue, physical and psychological distress, and activity levels. He found that 54% of participants experienced fatigue, and that women were significantly more likely to do so than men. Fatigue was associated with number of AIDS-related symptoms, pain, anemia (see below), poor physical functioning, psychological distress, and depression. Dr. Breitbart’s results were reported in the March 2001 issue of the Journal of Pain and Symptom Management. Denis Darko, MD, and colleagues of the Scripps Research Institute in La Jolla, CA, found that compared with HIV negative persons, those with HIV felt fatigued for more hours of the day, slept and napped more, and were less alert in the morning.

Factors that Contribute to HIV-Related Fatigue

As the studies above suggest, fatigue in HIV disease is associated with a variety of factors. Among these are anemia, hormonal imbalances (especially low levels of the male hormone testosterone and adrenal hormones), depression and anxiety, poor nutrition, insufficient or poor quality sleep, lack of physical activity, and medication side effects. Active infections, including AIDS-related opportunistic infections (OIs), also play a role. In addition, use of caffeine, alcohol, and/or illicit drugs may interfere with sleep and otherwise contribute to unusual tiredness. Often, several factors act together to cause HIV-related fatigue. The most common factors are discussed in more detail below.

HIV-related fatigue has not been extensively studied and is not particularly well understood. Much of what is known about fatigue in people with HIV comes from studying people with cancer, who also commonly experience the symptom. It is not known exactly how various factors cause fatigue. Researchers believe that multiple mechanisms may be involved in the pathogenesis (development) of fatigue. People with cancer and HIV disease both experience prolonged physical and psychological stress, which can lead to an unusual expenditure of energy that can result in fatigue. Some researchers propose a neurophysiologic model, in which impairment of the central and peripheral nervous system results in lack of motivation, exhaustion of hypothalamic brain cells (involved in the functioning of the autonomic nervous system [involuntary processes]), and reduced nerve function at neuromuscular junctions. Nervous system impairment could potentially be caused by HIV itself, by medications, or by other unknown factors. Another theory suggests that muscle wasting may require individuals to expend an unusual amount of energy in order to generate enough contractile force to move their muscles, even simply to stand or sit up. Such muscle wasting may be related to elevated levels of tumor necrosis factor (TNF), which are increased in persons with both cancer and HIV disease.

Assessment and Diagnosis of Fatigue

Because so many factors can lead to fatigue, it is important for people with HIV to discuss their symptoms with their health-care providers to determine the various contributing causes and how best to manage them. They should also let their providers know how long they have been experiencing fatigue and how severe it is. Other things to note and report are changes in energy levels, physical activity (e.g., exercise, ability to walk long distances, amount of weight that can be carried), sleep patterns, and whether fatigue strikes at certain times of the day or after specific activities. Keeping a journal can help people track changes over time and evaluate how fatigue affects daily activities. Dr. Capaldini suggests that people with HIV and their providers do a "fatigue inventory" every six months. Providers should ask similar questions each time to better determine changes over months or years.

Several tests may be used to help determine the cause of fatigue. Complete blood count, hemoglobin (concentration of oxygen-carrying molecules), and hematocrit (HCT, red cell percentage) tests are used to detect anemia. Various other blood tests are used to measure hormone and nutrient levels. Providers may request tests to determine muscle enzyme levels, electrolyte (blood salt) levels, and/or liver, kidney, and thyroid function. Additional tests (such as sputum [chest mucus] tests and antibody assays) may be used to detect specific infections other than HIV that may contribute to fatigue. Various psychological screening tests can help determine depression and anxiety levels. The Karnofsky Scale may be used to assess overall daily functional impairment. The Chalder Fatigue Scale (CFS), which was developed to assess physical and mental fatigue in people with chronic fatigue syndrome, has been used by some researchers to rate fatigue levels in people with HIV. Specific diagnostic tests are discussed below in the sections on the most common causes of HIV-related fatigue.

Treating HIV-Related Fatigue

While there is no universal approach to the evaluation and treatment of HIV-related fatigue, a variety of measures are commonly used to reduce fatigue in people with HIV. The overriding goal is to determine and treat the specific underlying causes. Treatments may range from blood transfusions and medications to boost red blood cell production, to hormone replacement or anabolic (muscle building) steroid therapy, antidepressant or psychostimulant drugs, or nutritional supplementation. Specific treatments are discussed in detail below in the sections covering the various causes of fatigue, and general fatigue management tips are offered in the final section. Once treatment begins, providers should evaluate their patients regularly to determine whether various interventions are effective.

Specific Causes of HIV-Related Fatigue

Active Infection

The bodies of people with active HIV infection—or any other infection—expend considerable energy fighting invaders. When an infection is present, the body draws upon its stored energy (in fat and muscle) for fuel; if this energy is not replenished, fatigue is the usual result. Increased levels of inflammatory cytokines (intercellular messenger molecules) released by an active immune system can also lead to fatigue. Fever—a sign that the body is fighting infection—is commonly associated with exhaustion. In fact, fatigue is one of the earliest and most common symptoms of a wide range of illnesses, including influenza, mononucleosis (Epstein-Barr virus infection), and the common cold. Chronic viral hepatitis and tuberculosis (TB)—both common coinfections in people with HIV—can cause persistent, severe exhaustion. Several AIDS-related OIs can contribute to fatigue in various ways, and fatigue may be the first sign of such an infection. For example, Pneumocystis carinii pneumonia (PCP) can impair a person’s ability to get enough oxygen. Prolonged infection can lead to "anemia of chronic disease," and OIs such as Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) can damage the bone marrow, also leading to anemia (discussed below). Dr. Capaldini reports that the fungal diseases histoplasmosis and coccidioidomycosis, and the parasitic diseases toxoplasmosis and crypto- sporidiosis, all have been associated with fatigue. Any symptoms of infection in a person experiencing fatigue should be evaluated, and the appropriate antibiotic or antiviral treatments should be started.

HIV infection itself may be an important cause of fatigue. According to Dr. Capaldini, fatigue is associated with high levels of HIV viremia (virus in the blood), and many people have experienced a reduction in fatigue after starting potent antiretroviral therapy. However, as noted earlier in this article, studies have not found a direct, consistent correlation between viral load levels and fatigue. In fact, according to Julie Barroso, MD, who reported on a study of fatigue in people with HIV at the 13th National HIV/AIDS Update Conference in March 2001, "Patients with very good viral suppression actually had the highest levels of fatigue." Similarly, Dr. Capaldini has reported that some 10–15% of her patients who have had an excellent virological response to combination therapy still experience tiredness, and that "simply controlling the virus does not necessarily fix fatigue." These findings suggest that some fatigue is a side effect of HAART or its components.

Anemia

Anemia refers to diminished oxygen transport by red blood cells (also called erythrocytes). This may be due to a low level of hemoglobin (the pigment in red blood cells that binds to oxygen), a reduced number of red blood cells, or an impairment of the cells’ ability to carry oxygen. When a person has anemia, the heart must work harder to circulate more blood to carry enough oxygen to the body’s tissues. People with anemia often feel tired, are easily overexerted, have poor endurance, and may be short of breath. Other symptoms of anemia may include mental lethargy, weakness, mouth sores, headache, and dizziness.

There are several different types of anemia, which are caused by a variety of factors related either to inadequate red blood cell production or excessive cell loss or destruction. Anemia can result from loss of blood, for example due to trauma (injury), chronic internal bleeding (e.g., due to an ulcer), or heavy menstruation. Red blood cells develop from stem cells in the bone marrow, the spongy tissue inside certain bones. Aplastic anemia occurs when the stem cells are damaged (also known as myelosuppression), for example due to chemotherapy, radiation, or an autoimmune reaction. Red blood cell production is regulated by erythropoietin (EPO), a hormone secreted by kidney cells, and people with damaged kidneys often develop anemia.

The body requires certain nutrients to manufacture functional red blood cells. Iron is an essential component of hemoglobin, and inadequate iron in the diet—or an inability to absorb or transport iron—can lead to iron deficiency anemia. Vitamin B12 (cobalamin) and folic acid (folate) are also necessary for red blood cell production; pernicious anemia occurs when the small intestine is unable to absorb vitamin B12. Deficiencies in folic acid may be due to either inadequate levels in the diet or poor absorption; people with HIV often have poor nutritional intake and/or malabsorption (described below). Without adequate vitamin B12 and folic acid, red blood cells do not mature properly, resulting in large, irregularly shaped, and short-lived cells (megaloblastic anemia).

Hemolytic anemia occurs when red blood cells are abnormally destroyed faster than they can be replenished. This may happen because of one of several inherited (genetic) disorders (e.g., sickle cell anemia or G-6-PD deficiency), an immune response in which antibodies destroy red blood cells (e.g., erythroblastosis fetalis, or Rh incompatibility), or diseases such as malaria. Pregnant women may develop anemia if they cannot produce enough new red blood cells to supply the developing fetus. Finally, anemia of chronic disease results from a combination of a shortened red blood cell life span, inadequate production of or response to EPO, poor incorporation of iron, and/or an inability of the bone marrow to compensate for increased cell destruction.

HIV-related anemia is quite common, and is thought to be the most common cause of fatigue in people with HIV. Dr. Barroso’s recent study found that HIV positive people with low hematocrit, hemoglobin, and CD4 cell levels experienced more fatigue than those who had low levels on any one of the three measurements alone. Various studies have found that 60–90% of people with HIV have some degree of anemia at some time during the course of their illness, and that the incidence of anemia increases as HIV disease progresses to AIDS. Studies by Richard Moore, MD, and colleagues from Johns Hopkins University in Baltimore, and by Patrick Sullivan, DVM, PhD, and colleagues of the Centers for Disease Control and Prevention (CDC), have shown that anemia in people with HIV is significantly associated with increased disease progression and shorter survival.

Anemia is diagnosed by means of blood tests that measure the number of red blood cells and how much oxygen they carry. A complete blood count is an inventory of all the major types of cells in the blood. A peripheral smear involves looking at a blood sample under a microscope to determine cell size and shape, if computer analysis suggests a potential abnormality. A hematocrit is the percentage of whole blood that is made up of red cells (about 99% of all blood cells are red blood cells). A normal adult hematocrit is 40–52% for men and 36–46% for women; a hematocrit below 36% for women or 38% for men indicates anemia. (Note that normal values may vary slightly from laboratory to laboratory.) A hemoglobin test measures the concentration of hemoglobin. A normal blood hemoglobin concentration is 14–18 grams/deciliter (g/dL) for men and 12–16 g/dL for women; hemoglobin concentrations of less than 14 g/dL in men and less than 12 g/dL in women indicate anemia, and levels below 8 g/dL are life-threatening. Additional useful measurements include blood levels of iron, transferrin, ferritin, vitamin B12, folic acid, and red cell size.

Proper treatment of anemia requires a determination of the cause. Although deficiency-related anemias are most common in the general population, among people with HIV, bone marrow damage is the most typical cause. In addition to adequate nutrition (discussed below) and treatment of underlying causes such as gastrointestinal (stomach to colon) bleeding, the most effective interventions for anemia might require EPO (Epogen, Procrit) injections and/or blood transfusions. Genetically engineered EPO works to stimulate red blood cell production in the bone marrow. It is useful for anemia due to decreased blood cell production, but not for anemia due to blood loss, nutritional deficiencies, or increased blood cell destruction; it is most likely to be effective if the person has a low blood EPO level before treatment. The drug is administered by subcutaneous (under the skin) injection, usually two to three times per week. Side effects may include increased blood pressure, headache, and joint pain. It usually takes four to six weeks after starting EPO before red blood cell counts begin to increase. Clinical trials have shown that HIV positive people with anemia who took EPO reported higher energy levels and less fatigue that those receiving a placebo.

Transfusions of packed red blood cells are the quickest way to relieve anemia, especially anemia related to a temporary cause such as blood loss due to injury. Although transfusions have an immediate effect, the benefits are often temporary, as they usually do not treat the underlying cause of anemia. Blood transfusions also carry risks, including the transmission of blood-borne infections and hypersensitivity or immune reactions; in people with HIV, transfusions may increase the rate of disease progression. In severe and persistent cases of aplastic anemia, a bone marrow transfer may be necessary, and severe hemolytic anemia is sometimes treated by the surgical removal of the spleen, since the spleen is the primary site of red blood cell destruction. Whenever possible, people with HIV who require red cell transfusions should request removal of the white cells (creating "leukocyte-poor" blood) prior to the blood being transfused. This removes the white cells that carry viral infections that can be transmitted by transfusion, including CMV, the most common cause of blindness in untreated people with AIDS.

Hormonal Imbalances

Another factor contributing to fatigue in people with HIV is hormonal imbalances. A low level of testosterone (hypogonadism in men) is the most common hormonal deficiency in HIV positive people. An estimated 45% of men with untreated AIDS and 25% of asymptomatic, untreated HIV-infected men experience low testosterone levels. Although testosterone is usually thought of as a male hormone—and is present in men in greater amounts—both men and women produce testosterone, and both may be negatively affected by testosterone deficiency. The hormone is involved in mood regulation and nutrient metabolism. In addition to causing fatigue, low testosterone levels can lead to loss of appetite (anorexia), weight loss, depression, difficulty concentrating, and lack of interest in sex (low libido). Possible causes of low testosterone include testicular damage, medication side effects, and inadequate production due to low stimulation by brain hormones. Blood tests are used to assess testosterone levels; these include total testosterone, free (biologically active) testosterone, and bound (to protein) testosterone.

Testosterone levels differ widely among individuals, and to determine whether someone has a testosterone deficiency it is important to establish the normal level for that person. For example, while 300–1,100 nanograms/dL is typically considered normal, a man may be deficient at a level of 400 nanograms/dL if his normal, pre-HIV level is 700 nanograms/dL. Overall, the mean testosterone level for HIV positive men is less than that for age-matched HIV negative men.

Men with hypogonadism are typically treated with testosterone or synthetic anabolic steroids (collectively known as androgens); these may be administered in the form of injections, pills, creams or gels, or a patch (Androderm, Testoderm). Androgen supplementation can reduce wasting, relieve depression, and increase energy levels. Side effects may include acne, testicular atrophy (wasting), decreased fertility (since the use of supplemental androgens decreases their natural production by the body), and increased libido. Large (supraphysiologic) doses of anabolic steroids used for bodybuilding can cause behavioral problems, liver damage, cardiovascular disease (relating to the heart and blood vessels), and possible "steroid rage," but these effects do not typically result from the physiological replacement doses used to treat HIV-related symptoms due to low levels.

In women, androgens can have undesirable virilizing, or masculinizing, effects (e.g., facial hair growth, deepening of the voice, clitoral enlargement, or changes in menstruation), some of which may not be reversible when treatment stops. Other anabolic steroids (such as oxandrolone [Oxandrin] or nandrolone [Durabolin]) are typically recommended for women instead of testosterone itself; sometimes a combination of estrogen and testosterone (Estratest) is used.

Several studies have shown that testosterone alleviates fatigue in men with HIV/AIDS. For example, Glenn Wagner, PhD, and colleagues from the New York State Psychiatric Institute and Columbia University studied over 100 HIV positive men with hypogonadism who received intramuscular testosterone injections twice weekly for twelve weeks. Eighty percent of the men reported significant improvements in their energy levels. However, researchers were unsure whether testosterone itself reduced fatigue, or whether it was effective in combating fatigue because it reduced depression (discussed below). Results were reported in the July 1998 issue of General Hospital Psychiatry. Different anabolic steroids have different effects; for example, oxandrolone is good for treating wasting but less effective in reversing depression and fatigue. Sometimes experimentation may be necessary to determine which form is superior for treating fatigue in a specific individual. In addition to anabolic steroids, injections of human growth hormone (Serostim), which is used to treat HIV-related wasting, have also been shown in studies to increase energy levels. However, Serostim is extremely expensive.

Adrenal insufficiency, characterized by low levels of glucocorticoid hormones (e.g., cortisol), may also lead to severe fatigue in people with HIV (the adrenal glands are located on top of each kidney). These hormones play a role in metabolism and many other body processes, and low levels can result in weight loss, decreased blood pressure, dizziness, and even death. This condition may be caused by adrenal gland damage due to HIV, OIs such as CMV, or by certain medications. Adrenal insufficiency is considerably less common than hypogonadism in people with HIV, but its incidence increases in advanced HIV disease. Adrenal insufficiency is diagnosed by means of an ACTH (adrenal corticotropin hormone, a pituitary hormone) stimulation test, in which synthetic ACTH is administered and cortisol levels are measured to determine whether the adrenal cortex is producing hormones in response to ACTH stimulation. Adrenal insufficiency is treated with hydrocortisone or dexamethasone replacement therapy.

In addition, thyroid dysfunction is also associated with fatigue (the thyroid gland is located at the front of the throat). Levels of thyroid hormone in the blood can be measured, and thyroid supplements can be taken if levels are low.

Psychological Factors

Fatigue and depression are closely related in people with HIV. In fact, it can be difficult to sort out cause and effect, since depression can cause fatigue, and the inability to carry out normal activities due to fatigue can in turn lead to depression. Anxiety disorders, including generalized anxiety and panic attacks, are also associated with fatigue. The social isolation, stigma, pain, and stress of living with a chronic illness often result in depression and anxiety in HIV positive people. Depression and anxiety can lead to lack of appetite, poor eating habits, and insomnia, which can exacerbate fatigue. Dr. Barroso and colleagues found that among a subgroup of participants with normal hemoglobin, hematocrit, and CD4 cell counts (indicating that their fatigue was not due to anemia or low CD4 cell counts), those reporting fatigue had high levels of depression and anxiety. According to Dr. Barroso, "Depression and anxiety showed a statistically significant correlation with fatigue severity." However, Dr. Breitbart found that about half the participants in his study who reported fatigue did not have elevated depression scores. He concluded that more research is needed to differentiate fatigue that is related to depression from fatigue arising as a direct symptom of HIV disease.

Depression is most likely to be a contributing factor for fatigue in people with a personal or family history of mood disorders. In addition, patterns of activity and rest can indicate whether fatigue is a result of depression. People who feel fatigued in the morning, rather than later in the day, are likely to be suffering from depression. Also, depression-related fatigue is less likely to be brought on by physical activity. Other symptoms of depression include difficulty concentrating, loss of libido or sexual dysfunction, and inability to enjoy once-pleasurable activities (anhedonia).

Various psychological questionnaires (for example, the Beck Depression Inventory) can be used to determine depression levels. However, Dr. Capaldini notes that depression is one of the most easily missed factors contributing to fatigue in HIV positive people, because many of the symptoms associated with fatigue are common in HIV disease itself. Many providers tend to assume that feelings of sadness, frustration, or hopelessness are a natural result of having HIV disease, and do not associate them with biochemical depression.

According to Dr. Capaldini, antidepressants are as effective in treating people with HIV as they are in treating HIV negative people. Biochemical depression is typically caused by abnormally low levels of neurotransmitters in the brain, particularly serotonin. Antidepressant drugs that increase serotonin levels by inhibiting reabsorption of the chemical by brain cells are often effective in treating depression; these so-called selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). Bupropion (Wellbutrin, Zymax) is another effective antidepressant, and is also used to help people with nicotine addiction quit smoking tobacco. Venlafaxine (Effexor) is used to treat both depression and anxiety disorders, as are several of the SSRI drugs above. If pain due to neuropathy (nerve damage) is also present, the nonsedating tricyclic antidepressants amitriptyline (Elavil), nortriptyline (Pamelor), and desipramine (Norpramin) may relieve both pain and depression. It may take a few weeks before the full benefit of an antidepressant drug is realized. Some people do not continue antidepressant drugs because of adverse side effects. Side effects of SSRIs may include nausea, diarrhea, tremors, excessive sweating, anxiety, insomnia, anorexia, weight change, sexual dysfunction, and—ironically—fatigue. Side effects of tricyclic antidepressants may include dry mouth and constipation. Side effects are often worse when starting a drug and may lessen over time. Neither the SSRIs nor tricyclics are considered to be addictive. Antidepressants may interact with various anti-HIV medications, especially when more than one drug must be metabolized by the same P450 enzyme system in the liver; sometimes reducing the dose of one or more medications may lessen adverse reactions. People with HIV who take antidepressant drugs should work with a provider who is knowledgeable about and experienced with both antidepressant and antiretroviral drugs.

Psychostimulants have also been shown to be effective in treating HIV-related fatigue associated with depression. These drugs include methylphenidate (Ritalin), pemoline (Cylert), and dextroamphetamine (Dexedrine). Side effects of psychostimulants may include hyperactivity, anorexia, weight loss, insomnia, paranoia, and mood swings. Extensive studies of people with cancer have shown that psychostimulants are effective in alleviating depression, apathy, low energy, poor concentration, and weakness; they may also promote an overall sense of well-being. Another study by Dr. Breitbart and colleagues found that both methylphenidate and pemoline are effective in reducing fatigue in people with HIV. One hundred and nine HIV positive subjects with severe and persistent fatigue (most of whom met the diagnostic criteria for AIDS) took one of the two drugs or a placebo (inactive pill) for six weeks. Significant improvement in fatigue occurred in 41% of the participants taking methylphenidate and 36% of those taking pemoline, compared with 15% of those receiving a placebo. The treated participants also had less depression, less psychological distress, and a higher overall quality of life. The drugs were well tolerated; hyperactivity or "jitteriness" was the most common side effect, reported by over 50% of those taking either drug. Dr. Breitbart characterizes psychostimulant drugs as "an umbrella kind of therapy that helps you deal with fatigue of any cause." The research was published in the February 12, 2001 issue of the Archives of Internal Medicine. However, the potential benefits must be balanced against the potential for addiction.

As an alternative or as an adjunct to medications, psychotherapy or counseling may also be used to treat depression. It is important for people with HIV to select a therapist who is familiar with HIV disease.

Poor Nutrition

People with HIV—like HIV negative people—may feel fatigued if their diet is inadequate. The body requires a certain number of calories and nutrients to produce energy to carry out normal physical activity and functions. When the body does not have enough fuel, it attempts to conserve energy by reducing activity. Insufficient caloric and nutrient intake can lead to tiredness, weakness, and an inability to carry out normal daily activities. According to Dr. Capaldini, inadequate intake of protein and fatty acids can lead to muscle fatigue. A diet lacking essential nutrients can lead to fatigue as well as a host of other problems. As discussed above, deficiencies in iron, folic acid, and vitamin B12 can impair the production of red blood cells resulting in anemia, a common cause of HIV-related fatigue. In addition, insufficient levels of vitamin A, vitamin C, beta carotene, and zinc can also contribute to fatigue. Several factors contribute to poor nutrition in people with HIV. Symptoms of HIV disease itself, OI symptoms, and drug side effects—including loss of appetite, nausea, mouth or throat sores, and changes in taste—can make it difficult to consume enough calories and nutrients. Gastrointestinal infections such as MAC and cryptosporidiosis can lead to nutrient malabsorption and consequent vitamin deficiencies. Iron deficiency can arise from chronic bleeding, for example, as a result of intestinal Kaposi’s sarcoma (KS) or CMV infection. Diarrhea—due to HIV, OIs, or anti-HIV medications—can also potentially interfere with proper absorption of nutrients.

Beans and peas Fortified cereals and grains Leafy green vegetables (spinach, kale) Dried fruit (apricots, prunes, raisins) Liver Meat and poultry (beef, lamb, pork, chicken) Shellfish (cooked oysters, shrimp [risk if raw]) Tofu Molasses Beans and peas Sunflower seeds Peanuts Fortified cereals, grains, and pasta Green vegetables (asparagus, broccoli, spinach) Orange juice Liver Brewer’s yeast Meat and poultry (beef, lamb, pork, chicken) Fish Liver Dairy products (milk, cheese, yogurt) Eggs

There are several methods for assessing nutritional status, including weight, body tissue composition analysis, and blood tests for specific vitamins and minerals. The best way to improve nutritional status is to eat a well-balanced diet. Most nutritionists recommend that people get their calories and nutrients from food if possible. However, if a person is unable to consume enough of certain foods to make up an adequate diet, or if he or she is unable to absorb nutrients from the foods eaten, nutritional supplements can help offset the difference. If gastrointestinal absorption is a problem, nutrients can be delivered parenterally (given intravenously or by injection). A nutritionist who has experience with HIV disease can help develop a personalized nutritional plan to address individual needs.

Sleep and Activity

Not surprisingly, patterns of sleep and physical activity can have a great effect on daytime fatigue levels. People with HIV may have trouble falling asleep, fail to get an adequate amount of sleep, wake up frequently throughout the night, or experience poor quality sleep that does not fully restore the body. Healthy sleep involves a regular cycle of stages, and failure to reach the deepest stages of sleep can leave a person feeling tired during the day even if he or she has spent a sufficient number of hours in bed at night. HIV positive people may have difficulty achieving adequate sleep due to a variety of factors, including symptoms such as diarrhea or pain. Certain anti-HIV drugs (and recreational drugs such as caffeine, alcohol, and amphetamines) can cause insomnia or poor sleep, and others (such as efavirenz [Sustiva]) can cause nightmares or unusual dreams. In addition, medication schedules or certain chronic conditions may necessitate waking up during the night, making it difficult to sleep without interruption. Depression and anxiety can also interfere with the quantity and quality of sleep. According to Dr. Capaldini, some studies suggest that people with HIV have trouble sleeping normally even when none of these factors are involved, suggesting that HIV itself may affect the brain mechanisms that regulate sleep.

Fortunately, inadequate sleep can often be successfully addressed. HIV positive people suffering from fatigue should take note of any changes in sleep patterns and discuss them with a health-care provider. Several measures may be taken to improve sleep, including sleep-inducing medications. A study by Francis Buda, MD, evaluated six HIV positive people experiencing fatigue, excessive daytime sleepiness, or insomnia. Most were found to have some underlying medical cause, including sleep apnea (periods of stopped breathing), restless leg syndrome (muscle spasms that occur during the night and may disrupt sleep), or enlarged tonsils that interfered with breathing. In all cases, treatment of the medical disorder reduced or eliminated insomnia and daytime fatigue.

It makes sense that strenuous activity can lead to fatigue but, paradoxically, lack of adequate physical activity may have the same effect. Several studies of people with cancer have shown that light or moderate exercise can enhance energy levels, reduce depression, and improve overall quality of life. Dr. Capaldini recommends that people with HIV who experience fatigue should attempt to get some light exercise each day, unless they are feeling feverish or very ill. If moderate physical activity makes fatigue worse, the person may have an underlying condition such as anemia.

Medication Side Effects

Drug side effects are a major cause of fatigue in people with HIV. Fatigue is a direct side effect of many drugs; in addition, other side effects may indirectly lead to fatigue. For example, certain drugs (including AZT [Retrovir], ganciclovir [Cytovene], TMP-SMX [Bactrim, Septra], and hydroxyurea [Hydrea, Droxia]) can damage the bone marrow, resulting in anemia due to decreased production of red blood cells. In clinical trials, 15–20% of people with AIDS who were taking AZT developed some degree of anemia, although anemia was less common at earlier stages of HIV disease. Drugs such as indinavir (Crixivan) and ritonavir (Norvir, also as Kaletra), which cause general malaise, may contribute to a feeling of enervation (lack of energy). Many anti-HIV drugs can cause diarrhea, which may both interfere with proper nutrient absorption and make it difficult to achieve restful sleep. Other drugs can cause insomnia or fitful sleep, leading to excessive daytime tiredness. Medications that affect the central nervous system, including antianxiety, antidepressant, and beta-blocker drugs, are known to cause fatigue in some people, as can chemotherapeutic drugs used to treat HIV-related cancers.

People with HIV and their providers should suspect a drug-related cause if fatigue worsens when a new drug or combination regimen is started. Often, dosage adjustments or drug substitution can be done to relieve fatigue. In cases of severe fatigue, it may be desirable to temporarily or even permanently stop a specific drug; doing so should only be done under the supervision of a practitioner experienced in treating HIV disease.

In persons infected with both HIV and hepatitis C virus (HCV), treating HCV with ribavirin (Rebetol) and interferon alpha (Roferon, Intron, Pegasys, Peg-Intron) commonly causes anemia that usually responds to epoietin injections. These injections are preferable to decreasing or stopping ribavirin as is recommended in the Food and Drug Administration (FDA)-approved package insert (product information).

Fatigue is also a common side effect of recreational drug use, particularly during or after amphetamine ("speed," "crystal"), MDMA ("ecstasy," "e"), and cocaine use.

Managing Fatigue

In addition to the particular measures discussed above in the sections on specific causes of fatigue, some general measures may also be taken to reduce tiredness and enable people with HIV to engage in normal daily activities.

First, people with HIV—and HIV negative people as well—should do their best to eat healthy, well-balanced meals; exercise regularly; get adequate rest; and limit caffeine, alcohol, and recreational drug use. These basic good health habits can greatly improve energy levels and overall quality of life.

Several alternative and complementary therapies have been used to treat HIV-related fatigue, although for the most part their safety and effectiveness have not been studied in controlled clinical trials. Herbal treatments for fatigue include ginseng and yohimbe, both of which are natural stimulants. Supplements such as carnitine (used to build muscle) and dehydroepiandrosterone (DHEA, a natural chemical that is converted to testosterone or estrogen) have also been used for fatigue and weakness. Many people have reported that regular acupuncture treatments relieve fatigue and improve quality of life. Some people find that massage therapy, tai chi, and qigong (a Chinese medicine-based form of exercise) can have a restorative effect. And at least one small study has shown that hyperbaric oxygen therapy, in which participants with HIV were treated with high-pressure oxygen two to three times per week, was effective in relieving debilitating fatigue.

Management of chronic fatigue may require lifestyle changes that help a person conserve energy for activities that he or she considers most important. Many people with HIV find that they must cut back on certain activities, possibly including employment. However, others may find that the following tips can help reduce their levels of fatigue and improve their quality of life:

	Schedule important activities at times of the day when energy levels are highest
	Reduce or eliminate nonessential tasks
	Get assistance, if needed, with tasks such as shopping, cleaning, and preparing meals
	Alternate restful activities with more physically strenuous ones
	Take naps or rest during the day as needed (but not within six hours of bedtime, if insomnia is a problem)
	Set realistic goals for what you can accomplish in a given period of time

In summary, fatigue is common in people with HIV, and may be caused by a variety of factors—or a combination of factors. To best manage HIV-related fatigue, it is important to discover and address the underlying cause or causes. Fortunately, many different treatment options are available. People with HIV and fatigue are encouraged to keep track of how levels of fatigue and activity and sleep patterns vary over time, and discuss any changes with their health-care providers.

Liz Highleyman is a freelance medical writer and editor based in San Francisco.

Selected Sources

Barroso, J. A review of fatigue in people with HIV infection. Journal of the Association of Nurses in AIDS Care 10(5): 42–49. September 1999.

Breitbart, W. and others. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Archives of Internal Medicine 161(3): 411–420. February 12, 2001.

Breitbart, W. and others. Fatigue in ambulatory AIDS patients. Journal of Pain and Symptom Management 15(3): 159–167. 1998.

Buda, F.B. Sleep disorders in HIV-positive patients: Curable causes of daytime fatigue and sleepiness. XI International Conference on AIDS, Vancouver, Canada, July 7–12, 1996. Abstract MoB301.

Capaldini, L. Symptom Management Guidelines. HIV InSite Knowledge Base (hivinsite.ucsf.edu/InSite.jsp?doc=kb-03-01-06&page=kb-03). June 1998. 

Page last updated 30 May 2001