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A Review of Fatigue in People With HIV Infection
JANAC Vol. Barroso / A Review 10, No.of 5, Fatigue September/October 1999
A Review of Fatigue in People With HIV Infection Julie Barroso, PhD, ANP, CS Fatigue is often cited by clinicians as a debilitating symptom suffered by the many who are infected with HIV. This article provides a review of HIV-related fatigue, including research on possible physiological causes such as anemia, CD4 count, impaired liver function, impaired thyroid function, and cortisol abnormalities. Psychological causes of fatigue, particularly depression, are reviewed as well. Measurement issues, such as the use of inappropriate tools, the problem of measuring the presence or absence of fatigue, and the use of tools developed for other groups of patients, are reviewed. The need for a comprehensive fatigue tool that is appropriate for people with HIV is discussed. Current treatment research, including thyroid replacement, hyperbaric oxygen, and dextroamphetamine, is presented. Finally, the implications for further research, including the need for qualitative studies to learn more about the phenomenon, develop an instrument to measure fatigue, and examine variables together to get a complete picture of this complex concept, are reviewed. Key words: Fatigue, HIV
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atigue is the most frequent and debilitating complaint of HIV-positive people, with a prevalence that ranges from 20% to 60% (Breitbart, McDonald, Rosenfeld, Monkman, & Passik, 1998; Briggs & Beazlie, 1996; Cunningham et al., 1998; Darko, Mitler, & Henriksen, 1995; de Boer, van Dam, Sprangers, Frissen, & Lange, 1993; Derry, 1996; Hoover et al., 1993; O’Dell, Meighen, & Riggs, 1996; Semple et al., 1993; Walker, McGown, Jantos, & Anson, 1997; Whalen, Antani, Carey, & Landefeld, 1994). Fatigue is strongly correlated with perceptions of life satisfaction,
ratings of average health, ratings of mental health, and the overall quality of life (Breitbart et al., 1998; Cleary et al., 1993; Cunningham et al., 1998; Darko, Mitler, et al., 1995). HIV-related fatigue has been shown to be a strong predictor of limitations in activities of both daily living and disability days (Cleary et al., 1993; Walker et al., 1997), and it is associated with significantly poorer physical functioning (Breitbart et al., 1998). Seropositive women have reported that fatigue resulted in a lack of stamina at work, a lowered quality of work, and frequent absenteeism; they were afraid that they might lose their jobs as a result (Semple et al., 1993). In one study, people with HIV exhibited increasing limitations in vigorous activities over a 1-year period. Declines in functioning were related to increasing disease severity, to prior reports of fatigue, and to poor self-rated health (Fleishman & Crystal, 1998).
Causes of Fatigue The causes of fatigue in HIV-positive people remain unclear. O’Dell, Meighen, and Riggs (1996), in a study of the relationship of fatigue to physiological parameters, found no significant associations in 20 seropositive men between hemoglobin, hematocrit, albumin and total protein, and physical dimension score of the Sickness Impact Profile. They concluded that, among people with HIV infection, fatigue is more strongly associated with psychosocial than with physiological parameters. Intravenous (IV) drug users were found to be more likely to report persistent fatigue than homosexual men (Breitbart et al., 1998; Palenicek et al., Julie Barroso is an assistant professor at the University of North Carolina at Chapel Hill, School of Nursing.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 10, No. 5, September/October 1999, 42-49 Copyright © 1999 Association of Nurses in AIDS Care
Barroso / A Review of Fatigue
1993). In the author’s experiences in working with HIV-positive patients, many of the IV drug users attribute their fatigue in part to the damage that they believe was inflicted through their drug use. In one study of IV drug users, reports of fatigue did not vary by CD4 count (Vlahov et al., 1994). In a study of male and female IV drug users, women were significantly more likely to report fatigue than men (Breitbart et al., 1998). In addition, patients older than age 35 have reported significantly higher levels of fatigue and depression than younger patients (Singh, Squier, Sivek, Wagener, & Yu, 1997). Other investigators have also found no association between fatigue and CD4 count (Breitbart et al., 1998; de Boer et al., 1993; Perkins et al., 1995). However, Walker et al. (1997) found that increased fatigue was associated with lower CD4 counts in a sample of gay men. Currently, there is no data linking HIV-related fatigue and viral load; this may be because the test of viral load, which is relatively new, has only recently been incorporated into the standard of care. The causes of fatigue in HIV-positive people may include magnesium deficiencies (Skurnick et al., 1996) and zidovudine-induced myopathy (Cupler et al., 1995; Sinnwell et al., 1995). In a sample of 438 ambulatory AIDS patients, fatigue was significantly associated with the number of current AIDS-related physical symptoms, current treatment for HIV-related medical disorders, anemia, and pain (Breitbart et al., 1998). Anemia is the most common hematologic abnormality in patients with HIV, and it increases in frequency as the disease advances. One of the cardinal symptoms of anemia is fatigue, caused by the body’s response to tissue hypoxia. Anemia may occur as a result of HIV-induced ineffective hematopoiesis, opportunistic infections, infiltrative disease of the bone marrow, nutritional deficiencies, hemolysis, and antiretroviral or other therapy (Groopman, 1998). Pulmonary impairment, from opportunistic infections or HIV-related malignancies, is another possible cause of fatigue, as are low testosterone levels and nutritional deficiencies (Groopman, 1998). Although testosterone replacement has been noted to reduce fatigue for some men with low testosterone levels, it has not been studied as a treatment for HIV-related fatigue. There may also be endocrine causes of HIV-related fatigue. HIV is known to have a direct effect on interleukins, which are immunologic cytokines; some
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cytokines, such as tumor necrosis factor, are known to affect endocrine processes and to have a somatogenic effect in animals. There may also be endocrine tissue damage from the virus and its associated malignancies and opportunistic infections. However, the clinical effects of these abnormalities are unclear (Briggs & Beazlie, 1996). Cytokines can act as circulating and local regulators of the endocrine system; at the same time, during lymphocyte activation, different subpopulations of immune cells are able to release substances with hormone-like functions. Hence, hormonal secretion can influence the response of the immune system in a bidirectional way. Because endocrine secretions, like immune functions, have circadian organization (Rondanelli et al., 1997), endocrine values may be important in influencing the patterns of fatigue. Hypothyroidism has fatigue as a cardinal symptom (Watson & Jaffe, 1995). In one study of HIV-positive subjects, thyroid-stimulating hormone (TSH) was found to be flattened over a 24-hour period (Rondanelli et al., 1997), and the amplitude of TSH circadian fluctuations was significantly less than in healthy control subjects. Cytokines released by the host in response to infection could influence thyroid homeostasis (Schurmeyer, Muller, von zur Muhlen, & Schmidt, 1997), and thus bring on fatigue. HIV can involve the liver directly, as demonstrated by the presence of HIV p24 in Kupffer cells and hepatic endothelial cells, and HIV messenger RNA in hepatocytes. Hepatic macrophages and endothelial cells express the CD4 molecule and have been shown to support viral replication in vitro. It remains unclear, however, whether HIV itself directly damages the liver, or whether the damage is secondary to another disorder such as hepatitis (Koch, Kim, & Friedman, 1998). Studies of HIV infected patients show that up to 75% have abnormal liver function (Bartlett, 1996). The impairment can be a result of the HIV itself, the treatment regimen, hepatitis infection, or some other disease process. Fatigue is a common manifestation of hepatic disorders; thus, abnormal liver function, whether caused by hepatitis or some other entity, could be linked to fatigue. Another possible physiological cause of fatigue in HIV-positive people is cortisol abnormalities (Abbott, Khoo, Hammer, & Wilkins, 1995; Norbiato, Galli, Righini, & Moroni, 1994; Piedrola et al., 1996).
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Salivary cortisol has proven to be a valid and reliable reflection of the respective unbound hormone in the blood. Psychological stress, such as that seen in HIV infection, can increase the activity of the hypothalamus-pituitary-adrenal axis. Especially in situations with low predictability and low controllability (such as HIV infection), corticotropin releasing hormones (CRH) and adrenocorticotropic hormones (ACTH) are released with a subsequent rise in cortisol levels (Kirschbaum & Hellhammer, 1994). Mean cortisol levels have been consistently higher in HIVpositive subjects than in HIV-negative, healthy control subjects (Clerici et al., 1997; Enwonwu, Meeks, & Sawiris, 1996; Rondanelli et al., 1997); the cortisol response to ACTH stimulation is reduced in these patients, probably as a consequence of the chronically elevated concentration of glucocorticoids (Clerici et al., 1997; Stolarczyk, Rubio, Smolyar, Young, & Poretsky, 1998). Elevated mean salivary cortisol concentrations have also been found in patients with chronic fatigue syndrome (Wood, Wessely, Papadopoulos, Poon, & Checkly, 1998), making this an intriguing variable for study in fatigued people with HIV. Bioelectrical impedance analysis (BIA), which estimates body composition and cell membrane integrity, may prove to be a proxy marker for disease progression and, therefore, an indirect marker of physiological deterioration, not identified by CD4 count or viral load, that could cause symptoms such as fatigue. Indeed, one study found phase angle to be a stronger predictor of survival with HIV disease than CD4 count (Ott et al., 1995). It is possible that people with HIVrelated fatigue are in a cytokine-reactive state, which would affect the integrity of the cell membrane. Resting energy expenditure has been shown to be higher in HIV-infected individuals than in healthy controls in several studies (Grinspoon et al., 1998; Heijligenberg, Romjin, Westererp, Jonkers, & Sauerwein, 1997; Mulligan, Tai, & Schambelan, 1998; Sharpstone et al., 1996), and it is possible that this elevation is contributing to a cellular environment that is reactive. The mechanism of increased resting energy expenditure in HIV infection is unknown; however, it may be due to cytokine release secondary to the rate of viral turnover.
Often, treatment for HIV can contribute to fatigue. Physical problems may also contribute to fatigue through loss of sleep, due to pain, nausea, diarrhea, and urinary frequency (Grady, Anderson, & Chase, 1998). In a study of the extent and severity of fatigue in a cohort of 50 HIV-positive men, those who received interleukin-2 reported a significant increase in their level of fatigue, although the increase was transient (Grady et al., 1998). Little, if any, relationship was seen between the level of fatigue and the amount or quality of sleep, which supports their view that sleep or rest does not dispel chronic or clinical fatigue. With regard to the commonly used antiretroviral therapies, according to the package inserts, five of them—stavudine, delavirdine, indinavir, ritonavir, and nelfinavir— list fatigue or asthenia as an adverse effect of the drug. Although there are anecdotal reports that people with HIV are experiencing a Lazarus syndrome, recovering their health with these medications (e.g., Sowell, 1997), there are reports that point to serious and debilitating side effects such as fatigue that accompany the use of these medications. In any event, systematic research on the various drug combinations and their effects on fatigue, whether relieving it or worsening it, is necessary.
Fatigue and Psychological Parameters Some researchers, pointing to the high rate of depression among seropositive people, speculate that the fatigue seen in HIV disease is psychological. Unfortunately, sorting out the relationship between fatigue and depression is difficult (Hoover et al., 1993; Walker et al., 1997). Fatigue may cause depression, but depression may cause fatigue. Many of the tools used to measure depression include somatic complaints, which are similar to the symptoms of fatigue. Thus, when Kalichman, Sikkema, and Somlai (1995) examined the relationship between scores on the Beck Depression Inventory and symptoms of HIV infection, they found that the somatic symptoms of depression were closely associated with the number of AIDSrelated diagnoses. Nearly half of their sample reported at least some cognitive and affective depressive symptoms, and more than two thirds reported fatigue. The authors concluded that persons who have experienced
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HIV-related symptoms should be assessed for depression using only instruments without somatic symptoms. Perkins et al. (1995) examined the relationship of fatigue and insomnia to indicators of mood severity and HIV disease severity, and they found that the severity of depressive symptoms was significantly related to the level of fatigue and insomnia. They also noted that reduced motor neuropsychological function was significantly associated with more complaints of fatigue, independent of indicators of depression, and they concluded that fatigue and insomnia in otherwise asymptomatic patients are probably related to psychological disturbances. Walker et al. (1997) also found a strong positive correlation between fatigue and depression. HIV-positive patients with fatigue have a significantly greater degree of overall psychological distress, significantly more depressive symptoms, and a greater sense of hopelessness (Breitbart et al., 1998). They concluded that fatigue is a symptom of depression in some, but not all, fatigued patients with AIDS, and that the impact of fatigue on psychological functioning and quality of life is not merely a reflection of underlying depression.
Sleep and Fatigue Darko, McCutchan, Kripke, Gillin, and Golshan (1992) found that HIV-infected patients were significantly more likely than noninfected persons to feel fatigued, and the patients slept more, napped more, and experienced diminished midmorning alertness. These authors also found a significant inverse correlation between CD4 count and hours of daily fatigue. Darko, Miller, et al. (1995) found nocturnal cyclic variations in plasma levels of tumor necrosis factor α (TNF-α) in seropositive subjects; they speculated that elevated brain levels of TNF-α interfere with a normal slow-wave sleep-control mechanism, which could contribute to hypersomnia and fatigue. Darko, Mitler, et al. (1995) found that interleukin-1 contributed to the sleep changes and fatigue seen in early HIV infection. An increase in slow-wave sleep might result in a subjective experience of poor sleep quality, with a feeling during the day that not enough sleep has been achieved and accompanied by a feeling of suboptimal alertness. Darko, Mitler, and Miller (1998) examined six HIV-
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positive and eight HIV-negative subjects to determine whether the relationship between delta-frequency sleep electroencephalograph (EEG) amplitude and growth hormone (GH) secretion differed between the two types of subjects. A linear relationship change across the night’s sleep was found in the coupling between delta-frequency sleep EEG amplitude and GH secretion. The phase-coupling change was in opposite directions in HIV-positive and HIV-negative subjects. The authors concluded that GH dysregulation in HIV might contribute to sleep pathology (Darko et al., 1998). Thus, it appears likely that some of the physiological changes seen in HIV infection lead to altered sleep patterns that could, in turn, lead to a feeling of fatigue during the waking hours.
Measurement Issues The ways in which fatigue has been measured in HIV-positive people are problematic. Researchers have asked participants to rate their fatigue on a 0 to 4 scale (Abbott et al., 1995). Darko et al. (1992) developed their own instrument to measure fatigue, sleepiness, and sleep habits among seropositive people; there are eight questions in the fatigue section, mostly related to the presence of fatigue and its effect on employment. Walker et al. (1997) also used this tool. Another group (Cupler, Otero, Hench, Luciano, & Dalakas, 1996) used the Piper Fatigue Scale, which was developed for use with oncology patients. The Visual Analog Scale (O’Dell, Meighen, et al., 1996; Wagner, Rabkin, & Rabkin, 1997; Walker et al., 1997), the Fatigue Assessment Inventory (O’Dell, Meighen, et al., 1996), the Profile of Mood States (Perkins et al., 1995; Singh et al., 1997), and the Karnofsky Performance Scale (Reillo, 1993) have been used to measure fatigue. There are four questions on the Medical Outcomes Survey (MOS) short form that deal with the perception of degree of vitality; these were used in several studies (Bozzette, Hays, Berry, & Kanouse, 1994; Cleary et al., 1993; Copfer et al., 1996; Larrabee, Monga, Eriksen, and Helfgott, 1996; O’Dell, Hubert, Lubeck, & O’Driscoll, 1996). One study used the MOS short form questions and the Karnofsky Performance Scale (O’Dell, Lubeck, O’Driscoll, & Matsuno, 1995). Another used the MOS short form and the Dyspnea-Fatigue Index as measures of fatigue (Tsevat
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et al., 1996). The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, which has three items related to fatigue, was used in another study (de Boer et al., 1993). In other studies, fatigue was assessed as part of a chart review (a self-reported symptom), or patients were simply asked about its presence (Hoover et al., 1993; Palenicek et al., 1993; Penkower et al., 1995; Piedrola et al., 1996; Vlahov et al., 1994; Whalen et al., 1994). One study did not report how they measured fatigue or improvement in fatigue (Derry, 1995). Some of the tools used to measure fatigue are inappropriate; the Karnofsky Performance Scale measures functional ability, which may or may not be related to fatigue, and the Dyspnea-Fatigue Index should be used in conditions in which dyspnea causes fatigue, which is not the case in HIV infection. Almost all of the instruments used to measure fatigue are very brief (four questions or less). Although most of them have acceptable psychometric properties, they simply measure the presence or absence of fatigue. They do not elicit descriptions of the nature of fatigue. It is not known whether these instruments capture the experience of fatigue for people with HIV because most were developed to measure fatigue in other samples. Fatigue in HIV is likely to be multifactorial, with cognitive, emotional, and organic components; therefore, an instrument is needed that captures the intensity, circumstances, and consequences of fatigue in this group.
Treatment Research Derry (1995) found that HIV-positive patients reported feeling better, having more energy, and having a better quality of life as long as they took thyroid medication in pharmacological doses, although there was no evidence of hypothyroidism reported in the article. Other successful treatments for depression and low energy in AIDS patients include dextroamphetamine (Wagner et al., 1997) and hyperbaric oxygen therapy (Jordan, 1998; Reillo, 1993). However, some of the interventions that are being implemented may have serious consequences for seropositive people. For example, treatment with dextroamphetamine, a drug with a high potential for abuse, could cause problems in patients who are substance abusers. HIV wasting syndrome could also be accelerated by
dextroamphetamine use. Fukunishi et al. (1997) examined the efficacy of relaxation training in a sample of seropositive patients, and they found that scores for anxiety, fatigue, depression, and confusion were significantly lower after relaxation. However, when depression and fatigue are both affected by an intervention, it becomes difficult to sort out the two. In a pilot trial of an educational intervention to improve the self-management skills of 71 men with symptomatic HIV/AIDS, the symptom severity index decreased in the experimental group and increased in the control group; however, symptoms of fatigue did not significantly differ between the two groups (Gifford, Laurent, Gonzales, Chesney, & Lorig, 1998). In a qualitative study of women with HIV, 59% of the participants stated that they rested, slept, and reduced strenuous activities in an effort to control their symptoms, especially fatigue (van Servellen, Sarna, & Jablonski, 1998).
Nursing Implications The challenge of finding the causes of and treatments for HIV-related fatigue is one for all health care providers, and for nurses in particular. Few other providers are in contact with the HIV-positive patient as much as nurses are, and we see the impact of fatigue on their daily lives. We see our patients leave jobs that they love, give up activities that keep them psychologically healthy, and become prisoners of fatigue in their homes. We know how shallow it sounds when others say, “Well, just get more rest.” It is up to us to document fatigue, to inquire of our patients about its characteristics, and to research its causes and solutions. With regard to documentation of fatigue, tools need to be developed that are specific to the type of fatigue that is experienced by people with HIV, and the tools should include items that measure intensity, circumstances surrounding fatigue, and the consequences of fatigue in order to get a full picture of its impact on the patient’s life. One of the first challenges confronting clinicians and researchers with regard to HIV-related fatigue is to get adequate descriptions of it, using qualitative research methodologies. Then, the variables, both physiological and psychological, that are associated with it need to be examined. One of the problems in
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much of the research that was cited above is that most of these studies looked at one or a few variables in relation to fatigue. Research done to date on isolated variables or small groups of variables points to the following as possible physiologic causes of HIV-related fatigue: • • • • • • •
CD4 count Hemoglobin/hematocrit Liver function Thyroid function Cortisol Cytokines Growth hormone
Possible psychological factors include depression and possibly anxiety. What is needed now is qualitative research to further illuminate the phenomenon from the patients’ point of view, which would lead to the development of an instrument to measure fatigue in people with HIV, and lead to research examining these variables together to determine their relationships to fatigue and to one another in patients with fatigue. Eventually, the goal is to develop a theoretical model that can guide interventions to ameliorate fatigue. At the present time, based on the published research, there are no interventions that health care providers can recommend to people with HIV who are suffering from fatigue. Therapy to reduce fatigue could give HIV-positive patients vigor and an improved quality of life, and it could reduce societal costs (Darko, Mitler, et al., 1995) through the enhancement of their ability to maintain employment. Because HIV-positive patients can live for extended periods, clinicians need to develop longterm therapy that addresses life goals and quality of life (Breitbart et al., 1998; Miles, 1997). New approaches to managing HIV disease must include strategies to deal with patient fatigue and other symptoms. Miles (1997) advocates an oncologic model of medical management for HIV patients that recognizes and supports the relationship between patient concerns and the management of disease. Although there are no published data on this, the economic costs associated with HIV-related fatigue are likely to be large because of the number of people who suffer from it and
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the extent of disability that it causes. For example, when people with HIV have to stop working due to fatigue, they often lose their health insurance, and many must turn to public assistance for health care and daily living expenses, including housing. New approaches to managing HIV disease must therefore include strategies to deal with patient fatigue and other symptoms. In the quest to find a way to slow or stop HIV, the quality of life for some has been sacrificed in exchange for longevity. Now that health care providers can extend the length of an HIV-positive person’s life, it is time to deal with symptoms that affect the quality of that life. It is hoped that a model of HIV-related fatigue can be developed to explain the relationships among the variables affecting fatigue, because this model can be used as a basis for developing interventions to reduce or ameliorate fatigue and improve the quality of life.
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Barroso / A Review of Fatigue and Rehabilitation, 18, 249-254. Ott, M., Fischer, H., Polat, H., Helm, E. B., Frenz, M., Caspary, W. F., & Lembcke, B. (1995). Bioelectrical impedance analysis as a predictor of survival in patients with human immunodeficiency virus infection. Journal of Acquired Immune Deficiency Syndrome and Human Retrovirology, 9, 20-25. Palenicek, J., Nelson, K. E., Vlahov, D., Galai, N., Cohn, S., & Saah, A. J. (1993). Comparison of clinical symptoms of human immunodeficiency virus disease between intravenous drug users and homosexual men. Archives of Internal Medicine, 153, 1806-1812. Penkower, L., Dew, M. A., Kingsley, L., Zhou, S. Y., Lyketsos, C. G., Wesch, J., Senterfitt, J. W., Hoover, D. R., & Becker, J. T. (1995). Alcohol consumptiom as a cofactor in the progression of HIV infection and AIDS. Alcohol, 12, 547-552. Perkins, D. O., Leserman, J., Stern, R. A., Baum, S. F., Liao, D., Golden, R. N., & Evans, D. L. (1995). Somatic symptoms and HIV infection: Relationship to depressive symptoms and indicators of HIV disease. American Journal of Psychiatry, 152, 1776-1781. Piedrola, G., Casado, J. L., Lopez, E., Moreno, A., Perez-Elias, M. J., & Garcia-Robles, R. (1996). Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome. Clinical Endocrinology, 45, 97-101. Reillo, M. R. (1993). Hyperbaric oxygen therapy for the treatment of debilitating fatigue associated with HIV/AIDS. Journal of the Association of Nurses in AIDS Care, 4, 33-38. Rondanelli, M., Solerte, S. B., Fioravanti, M., Scevola, D., Locatelli, M., Minoli, L., & Ferrari, E. (1997). Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection. AIDS Research and Human Retroviruses, 13, 1243-1249. Schurmeyer, T. H., Muller, V., von zur Muhlen, A., & Schmidt, R. E. (1997). Thyroid and adrenal function in HIV-infected outpatients. European Journal of Medical Research, 2, 220-226. Semple, S. J., Patterson, T. L., Temoshok, L. R., McCutchan, J. A., Straits-Troster, K. A., Chandler, J. L., & Grant, I. (1993). Identification of psychobiological stressors among HIV-positive women. Women & Health, 20, 15-36. Sharpstone, D. R., Murray, C. P., Ross, H. M., Hancock, M. R., Phelan, M. S., Crane, R. C., Menzies, I. S., Reaveley, D. A., Lepri, A. C., Nelson, M. R., & Gazzard, B. G. (1996). Energy balance in asymptomatic HIV infection. AIDS, 10, 13771384.
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Singh, N., Squier, C., Sivek, C., Wagener, M. M., & Yu, V. L. (1997). Psychological stress and depression in older patients with intravenous drug use and human immunodeficiency virus infection: Implications for intervention. International Journal of STD & AIDS, 8, 251-255. Sinnwell, T. M., Sivakumar, K., Soueidan, S., Jay, C., Frank, J. A., McLaughlin, A. C., & Dalakas, M. C. (1995). Metabolic abnormalities in skeletal muscle of patients receiving zidovudine therapy observed by 31P in vivo magnetic resonance spectroscopy. Journal of Clinical Investigation, 96, 126-131. Skurnick, J. H., Bogden, J. D., Baker, H., Kemp, F. W., Sheffet, A., Quattrone, G., & Louria, D. B. (1996). Micronutrient profiles in HIV-1–infected heterosexual adults. Journal of Acquired Immune Deficiency Syndrome, 12, 75-83. Sowell, R. L. (1997). Reconstruction case management. Journal of the Association of Nurses in AIDS Care, 8, 43-45. Stolarczyk, R., Rubio, S. I., Smolyar, D., Young, I. S., & Poretsky, L. (1998). Twenty-four-hour urinary free cortisol in patients with acquired immunodeficiency syndrome. Metabolism, 47, 690-694. Tsevat, J., Solzan, J. G., Kuntz, K. M., Ragland, J., Currier, J. S., Sell, R. L., & Weinstein, M. C. (1996). Health values of patients infected with human immunodeficiency virus: Relationship to mental health and physical functioning. Medical Care, 34, 44-57. van Servellen, G., Sarna, L., & Jablonski, K. J. (1998). Women with HIV: Living with symptoms. Western Journal of Nursing Research, 20, 448-464. Vlahov, D., Munoz, A., Solomon, L., Astemborski, J., Lindsay, A., Anderson, J., Galai, N., & Nelson, K. E. (1994). Comparison of clinical manifestations of HIV infection between male and female injecting drug users. AIDS, 8, 819-823. Wagner, G. J., Rabkin, J. G., & Rabkin, R. (1997). Dextroamphetamine as a treatment for depression and low energy in AIDS patients: A pilot study. Journal of Psychosomatic Research, 42, 407-411. Walker, K., McGown, A., Jantos, M., & Anson, J. (1997). Fatigue, depression, and quality of life in HIV-positive men. Journal of Psychosocial Nursing, 35, 32-40. Watson, J., & Jaffe, M. S. (1995). Nurse’s manual of laboratory and diagnostic tests (2nd ed.). Philadelphia: F. A. Davis. Whalen, C. C., Antani, M., Carey, J., & Landefeld, C. S. (1994). An index of symptoms for infection with human immunodeficiency virus: Reliability and validity. Journal of Clinical Epidemiology, 47, 537-546. Wood, B., Wessely, S., Papadopoulos, A., Poon, L., & Checkley, S. (1998). Salivary cortisol profiles in chronic fatigue syndrome. Neuropsychobiology, 37, 1-4.
A Review of Fatigue in People With HIV Infection Julie Barroso, PhD, ANP, CS Fatigue is often cited by clinicians as a debilitating symptom suffered by the many who are infected with HIV. This article provides a review of HIV-related fatigue, including research on possible physiological causes such as anemia, CD4 count, impaired liver function, impaired thyroid function, and cortisol abnormalities. Psychological causes of fatigue, particularly depression, are reviewed as well. Measurement issues, such as the use of inappropriate tools, the problem of measuring the presence or absence of fatigue, and the use of tools developed for other groups of patients, are reviewed. The need for a comprehensive fatigue tool that is appropriate for people with HIV is discussed. Current treatment research, including thyroid replacement, hyperbaric oxygen, and dextroamphetamine, is presented. Finally, the implications for further research, including the need for qualitative studies to learn more about the phenomenon, develop an instrument to measure fatigue, and examine variables together to get a complete picture of this complex concept, are reviewed. Key words: Fatigue, HIV
F
atigue is the most frequent and debilitating complaint of HIV-positive people, with a prevalence that ranges from 20% to 60% (Breitbart, McDonald, Rosenfeld, Monkman, & Passik, 1998; Briggs & Beazlie, 1996; Cunningham et al., 1998; Darko, Mitler, & Henriksen, 1995; de Boer, van Dam, Sprangers, Frissen, & Lange, 1993; Derry, 1996; Hoover et al., 1993; O’Dell, Meighen, & Riggs, 1996; Semple et al., 1993; Walker, McGown, Jantos, & Anson, 1997; Whalen, Antani, Carey, & Landefeld, 1994). Fatigue is strongly correlated with perceptions of life satisfaction,
ratings of average health, ratings of mental health, and the overall quality of life (Breitbart et al., 1998; Cleary et al., 1993; Cunningham et al., 1998; Darko, Mitler, et al., 1995). HIV-related fatigue has been shown to be a strong predictor of limitations in activities of both daily living and disability days (Cleary et al., 1993; Walker et al., 1997), and it is associated with significantly poorer physical functioning (Breitbart et al., 1998). Seropositive women have reported that fatigue resulted in a lack of stamina at work, a lowered quality of work, and frequent absenteeism; they were afraid that they might lose their jobs as a result (Semple et al., 1993). In one study, people with HIV exhibited increasing limitations in vigorous activities over a 1-year period. Declines in functioning were related to increasing disease severity, to prior reports of fatigue, and to poor self-rated health (Fleishman & Crystal, 1998).
Causes of Fatigue The causes of fatigue in HIV-positive people remain unclear. O’Dell, Meighen, and Riggs (1996), in a study of the relationship of fatigue to physiological parameters, found no significant associations in 20 seropositive men between hemoglobin, hematocrit, albumin and total protein, and physical dimension score of the Sickness Impact Profile. They concluded that, among people with HIV infection, fatigue is more strongly associated with psychosocial than with physiological parameters. Intravenous (IV) drug users were found to be more likely to report persistent fatigue than homosexual men (Breitbart et al., 1998; Palenicek et al., Julie Barroso is an assistant professor at the University of North Carolina at Chapel Hill, School of Nursing.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 10, No. 5, September/October 1999, 42-49 Copyright © 1999 Association of Nurses in AIDS Care
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1993). In the author’s experiences in working with HIV-positive patients, many of the IV drug users attribute their fatigue in part to the damage that they believe was inflicted through their drug use. In one study of IV drug users, reports of fatigue did not vary by CD4 count (Vlahov et al., 1994). In a study of male and female IV drug users, women were significantly more likely to report fatigue than men (Breitbart et al., 1998). In addition, patients older than age 35 have reported significantly higher levels of fatigue and depression than younger patients (Singh, Squier, Sivek, Wagener, & Yu, 1997). Other investigators have also found no association between fatigue and CD4 count (Breitbart et al., 1998; de Boer et al., 1993; Perkins et al., 1995). However, Walker et al. (1997) found that increased fatigue was associated with lower CD4 counts in a sample of gay men. Currently, there is no data linking HIV-related fatigue and viral load; this may be because the test of viral load, which is relatively new, has only recently been incorporated into the standard of care. The causes of fatigue in HIV-positive people may include magnesium deficiencies (Skurnick et al., 1996) and zidovudine-induced myopathy (Cupler et al., 1995; Sinnwell et al., 1995). In a sample of 438 ambulatory AIDS patients, fatigue was significantly associated with the number of current AIDS-related physical symptoms, current treatment for HIV-related medical disorders, anemia, and pain (Breitbart et al., 1998). Anemia is the most common hematologic abnormality in patients with HIV, and it increases in frequency as the disease advances. One of the cardinal symptoms of anemia is fatigue, caused by the body’s response to tissue hypoxia. Anemia may occur as a result of HIV-induced ineffective hematopoiesis, opportunistic infections, infiltrative disease of the bone marrow, nutritional deficiencies, hemolysis, and antiretroviral or other therapy (Groopman, 1998). Pulmonary impairment, from opportunistic infections or HIV-related malignancies, is another possible cause of fatigue, as are low testosterone levels and nutritional deficiencies (Groopman, 1998). Although testosterone replacement has been noted to reduce fatigue for some men with low testosterone levels, it has not been studied as a treatment for HIV-related fatigue. There may also be endocrine causes of HIV-related fatigue. HIV is known to have a direct effect on interleukins, which are immunologic cytokines; some
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cytokines, such as tumor necrosis factor, are known to affect endocrine processes and to have a somatogenic effect in animals. There may also be endocrine tissue damage from the virus and its associated malignancies and opportunistic infections. However, the clinical effects of these abnormalities are unclear (Briggs & Beazlie, 1996). Cytokines can act as circulating and local regulators of the endocrine system; at the same time, during lymphocyte activation, different subpopulations of immune cells are able to release substances with hormone-like functions. Hence, hormonal secretion can influence the response of the immune system in a bidirectional way. Because endocrine secretions, like immune functions, have circadian organization (Rondanelli et al., 1997), endocrine values may be important in influencing the patterns of fatigue. Hypothyroidism has fatigue as a cardinal symptom (Watson & Jaffe, 1995). In one study of HIV-positive subjects, thyroid-stimulating hormone (TSH) was found to be flattened over a 24-hour period (Rondanelli et al., 1997), and the amplitude of TSH circadian fluctuations was significantly less than in healthy control subjects. Cytokines released by the host in response to infection could influence thyroid homeostasis (Schurmeyer, Muller, von zur Muhlen, & Schmidt, 1997), and thus bring on fatigue. HIV can involve the liver directly, as demonstrated by the presence of HIV p24 in Kupffer cells and hepatic endothelial cells, and HIV messenger RNA in hepatocytes. Hepatic macrophages and endothelial cells express the CD4 molecule and have been shown to support viral replication in vitro. It remains unclear, however, whether HIV itself directly damages the liver, or whether the damage is secondary to another disorder such as hepatitis (Koch, Kim, & Friedman, 1998). Studies of HIV infected patients show that up to 75% have abnormal liver function (Bartlett, 1996). The impairment can be a result of the HIV itself, the treatment regimen, hepatitis infection, or some other disease process. Fatigue is a common manifestation of hepatic disorders; thus, abnormal liver function, whether caused by hepatitis or some other entity, could be linked to fatigue. Another possible physiological cause of fatigue in HIV-positive people is cortisol abnormalities (Abbott, Khoo, Hammer, & Wilkins, 1995; Norbiato, Galli, Righini, & Moroni, 1994; Piedrola et al., 1996).
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Salivary cortisol has proven to be a valid and reliable reflection of the respective unbound hormone in the blood. Psychological stress, such as that seen in HIV infection, can increase the activity of the hypothalamus-pituitary-adrenal axis. Especially in situations with low predictability and low controllability (such as HIV infection), corticotropin releasing hormones (CRH) and adrenocorticotropic hormones (ACTH) are released with a subsequent rise in cortisol levels (Kirschbaum & Hellhammer, 1994). Mean cortisol levels have been consistently higher in HIVpositive subjects than in HIV-negative, healthy control subjects (Clerici et al., 1997; Enwonwu, Meeks, & Sawiris, 1996; Rondanelli et al., 1997); the cortisol response to ACTH stimulation is reduced in these patients, probably as a consequence of the chronically elevated concentration of glucocorticoids (Clerici et al., 1997; Stolarczyk, Rubio, Smolyar, Young, & Poretsky, 1998). Elevated mean salivary cortisol concentrations have also been found in patients with chronic fatigue syndrome (Wood, Wessely, Papadopoulos, Poon, & Checkly, 1998), making this an intriguing variable for study in fatigued people with HIV. Bioelectrical impedance analysis (BIA), which estimates body composition and cell membrane integrity, may prove to be a proxy marker for disease progression and, therefore, an indirect marker of physiological deterioration, not identified by CD4 count or viral load, that could cause symptoms such as fatigue. Indeed, one study found phase angle to be a stronger predictor of survival with HIV disease than CD4 count (Ott et al., 1995). It is possible that people with HIVrelated fatigue are in a cytokine-reactive state, which would affect the integrity of the cell membrane. Resting energy expenditure has been shown to be higher in HIV-infected individuals than in healthy controls in several studies (Grinspoon et al., 1998; Heijligenberg, Romjin, Westererp, Jonkers, & Sauerwein, 1997; Mulligan, Tai, & Schambelan, 1998; Sharpstone et al., 1996), and it is possible that this elevation is contributing to a cellular environment that is reactive. The mechanism of increased resting energy expenditure in HIV infection is unknown; however, it may be due to cytokine release secondary to the rate of viral turnover.
Often, treatment for HIV can contribute to fatigue. Physical problems may also contribute to fatigue through loss of sleep, due to pain, nausea, diarrhea, and urinary frequency (Grady, Anderson, & Chase, 1998). In a study of the extent and severity of fatigue in a cohort of 50 HIV-positive men, those who received interleukin-2 reported a significant increase in their level of fatigue, although the increase was transient (Grady et al., 1998). Little, if any, relationship was seen between the level of fatigue and the amount or quality of sleep, which supports their view that sleep or rest does not dispel chronic or clinical fatigue. With regard to the commonly used antiretroviral therapies, according to the package inserts, five of them—stavudine, delavirdine, indinavir, ritonavir, and nelfinavir— list fatigue or asthenia as an adverse effect of the drug. Although there are anecdotal reports that people with HIV are experiencing a Lazarus syndrome, recovering their health with these medications (e.g., Sowell, 1997), there are reports that point to serious and debilitating side effects such as fatigue that accompany the use of these medications. In any event, systematic research on the various drug combinations and their effects on fatigue, whether relieving it or worsening it, is necessary.
Fatigue and Psychological Parameters Some researchers, pointing to the high rate of depression among seropositive people, speculate that the fatigue seen in HIV disease is psychological. Unfortunately, sorting out the relationship between fatigue and depression is difficult (Hoover et al., 1993; Walker et al., 1997). Fatigue may cause depression, but depression may cause fatigue. Many of the tools used to measure depression include somatic complaints, which are similar to the symptoms of fatigue. Thus, when Kalichman, Sikkema, and Somlai (1995) examined the relationship between scores on the Beck Depression Inventory and symptoms of HIV infection, they found that the somatic symptoms of depression were closely associated with the number of AIDSrelated diagnoses. Nearly half of their sample reported at least some cognitive and affective depressive symptoms, and more than two thirds reported fatigue. The authors concluded that persons who have experienced
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HIV-related symptoms should be assessed for depression using only instruments without somatic symptoms. Perkins et al. (1995) examined the relationship of fatigue and insomnia to indicators of mood severity and HIV disease severity, and they found that the severity of depressive symptoms was significantly related to the level of fatigue and insomnia. They also noted that reduced motor neuropsychological function was significantly associated with more complaints of fatigue, independent of indicators of depression, and they concluded that fatigue and insomnia in otherwise asymptomatic patients are probably related to psychological disturbances. Walker et al. (1997) also found a strong positive correlation between fatigue and depression. HIV-positive patients with fatigue have a significantly greater degree of overall psychological distress, significantly more depressive symptoms, and a greater sense of hopelessness (Breitbart et al., 1998). They concluded that fatigue is a symptom of depression in some, but not all, fatigued patients with AIDS, and that the impact of fatigue on psychological functioning and quality of life is not merely a reflection of underlying depression.
Sleep and Fatigue Darko, McCutchan, Kripke, Gillin, and Golshan (1992) found that HIV-infected patients were significantly more likely than noninfected persons to feel fatigued, and the patients slept more, napped more, and experienced diminished midmorning alertness. These authors also found a significant inverse correlation between CD4 count and hours of daily fatigue. Darko, Miller, et al. (1995) found nocturnal cyclic variations in plasma levels of tumor necrosis factor α (TNF-α) in seropositive subjects; they speculated that elevated brain levels of TNF-α interfere with a normal slow-wave sleep-control mechanism, which could contribute to hypersomnia and fatigue. Darko, Mitler, et al. (1995) found that interleukin-1 contributed to the sleep changes and fatigue seen in early HIV infection. An increase in slow-wave sleep might result in a subjective experience of poor sleep quality, with a feeling during the day that not enough sleep has been achieved and accompanied by a feeling of suboptimal alertness. Darko, Mitler, and Miller (1998) examined six HIV-
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positive and eight HIV-negative subjects to determine whether the relationship between delta-frequency sleep electroencephalograph (EEG) amplitude and growth hormone (GH) secretion differed between the two types of subjects. A linear relationship change across the night’s sleep was found in the coupling between delta-frequency sleep EEG amplitude and GH secretion. The phase-coupling change was in opposite directions in HIV-positive and HIV-negative subjects. The authors concluded that GH dysregulation in HIV might contribute to sleep pathology (Darko et al., 1998). Thus, it appears likely that some of the physiological changes seen in HIV infection lead to altered sleep patterns that could, in turn, lead to a feeling of fatigue during the waking hours.
Measurement Issues The ways in which fatigue has been measured in HIV-positive people are problematic. Researchers have asked participants to rate their fatigue on a 0 to 4 scale (Abbott et al., 1995). Darko et al. (1992) developed their own instrument to measure fatigue, sleepiness, and sleep habits among seropositive people; there are eight questions in the fatigue section, mostly related to the presence of fatigue and its effect on employment. Walker et al. (1997) also used this tool. Another group (Cupler, Otero, Hench, Luciano, & Dalakas, 1996) used the Piper Fatigue Scale, which was developed for use with oncology patients. The Visual Analog Scale (O’Dell, Meighen, et al., 1996; Wagner, Rabkin, & Rabkin, 1997; Walker et al., 1997), the Fatigue Assessment Inventory (O’Dell, Meighen, et al., 1996), the Profile of Mood States (Perkins et al., 1995; Singh et al., 1997), and the Karnofsky Performance Scale (Reillo, 1993) have been used to measure fatigue. There are four questions on the Medical Outcomes Survey (MOS) short form that deal with the perception of degree of vitality; these were used in several studies (Bozzette, Hays, Berry, & Kanouse, 1994; Cleary et al., 1993; Copfer et al., 1996; Larrabee, Monga, Eriksen, and Helfgott, 1996; O’Dell, Hubert, Lubeck, & O’Driscoll, 1996). One study used the MOS short form questions and the Karnofsky Performance Scale (O’Dell, Lubeck, O’Driscoll, & Matsuno, 1995). Another used the MOS short form and the Dyspnea-Fatigue Index as measures of fatigue (Tsevat
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et al., 1996). The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, which has three items related to fatigue, was used in another study (de Boer et al., 1993). In other studies, fatigue was assessed as part of a chart review (a self-reported symptom), or patients were simply asked about its presence (Hoover et al., 1993; Palenicek et al., 1993; Penkower et al., 1995; Piedrola et al., 1996; Vlahov et al., 1994; Whalen et al., 1994). One study did not report how they measured fatigue or improvement in fatigue (Derry, 1995). Some of the tools used to measure fatigue are inappropriate; the Karnofsky Performance Scale measures functional ability, which may or may not be related to fatigue, and the Dyspnea-Fatigue Index should be used in conditions in which dyspnea causes fatigue, which is not the case in HIV infection. Almost all of the instruments used to measure fatigue are very brief (four questions or less). Although most of them have acceptable psychometric properties, they simply measure the presence or absence of fatigue. They do not elicit descriptions of the nature of fatigue. It is not known whether these instruments capture the experience of fatigue for people with HIV because most were developed to measure fatigue in other samples. Fatigue in HIV is likely to be multifactorial, with cognitive, emotional, and organic components; therefore, an instrument is needed that captures the intensity, circumstances, and consequences of fatigue in this group.
Treatment Research Derry (1995) found that HIV-positive patients reported feeling better, having more energy, and having a better quality of life as long as they took thyroid medication in pharmacological doses, although there was no evidence of hypothyroidism reported in the article. Other successful treatments for depression and low energy in AIDS patients include dextroamphetamine (Wagner et al., 1997) and hyperbaric oxygen therapy (Jordan, 1998; Reillo, 1993). However, some of the interventions that are being implemented may have serious consequences for seropositive people. For example, treatment with dextroamphetamine, a drug with a high potential for abuse, could cause problems in patients who are substance abusers. HIV wasting syndrome could also be accelerated by
dextroamphetamine use. Fukunishi et al. (1997) examined the efficacy of relaxation training in a sample of seropositive patients, and they found that scores for anxiety, fatigue, depression, and confusion were significantly lower after relaxation. However, when depression and fatigue are both affected by an intervention, it becomes difficult to sort out the two. In a pilot trial of an educational intervention to improve the self-management skills of 71 men with symptomatic HIV/AIDS, the symptom severity index decreased in the experimental group and increased in the control group; however, symptoms of fatigue did not significantly differ between the two groups (Gifford, Laurent, Gonzales, Chesney, & Lorig, 1998). In a qualitative study of women with HIV, 59% of the participants stated that they rested, slept, and reduced strenuous activities in an effort to control their symptoms, especially fatigue (van Servellen, Sarna, & Jablonski, 1998).
Nursing Implications The challenge of finding the causes of and treatments for HIV-related fatigue is one for all health care providers, and for nurses in particular. Few other providers are in contact with the HIV-positive patient as much as nurses are, and we see the impact of fatigue on their daily lives. We see our patients leave jobs that they love, give up activities that keep them psychologically healthy, and become prisoners of fatigue in their homes. We know how shallow it sounds when others say, “Well, just get more rest.” It is up to us to document fatigue, to inquire of our patients about its characteristics, and to research its causes and solutions. With regard to documentation of fatigue, tools need to be developed that are specific to the type of fatigue that is experienced by people with HIV, and the tools should include items that measure intensity, circumstances surrounding fatigue, and the consequences of fatigue in order to get a full picture of its impact on the patient’s life. One of the first challenges confronting clinicians and researchers with regard to HIV-related fatigue is to get adequate descriptions of it, using qualitative research methodologies. Then, the variables, both physiological and psychological, that are associated with it need to be examined. One of the problems in
Barroso / A Review of Fatigue
much of the research that was cited above is that most of these studies looked at one or a few variables in relation to fatigue. Research done to date on isolated variables or small groups of variables points to the following as possible physiologic causes of HIV-related fatigue: • • • • • • •
CD4 count Hemoglobin/hematocrit Liver function Thyroid function Cortisol Cytokines Growth hormone
Possible psychological factors include depression and possibly anxiety. What is needed now is qualitative research to further illuminate the phenomenon from the patients’ point of view, which would lead to the development of an instrument to measure fatigue in people with HIV, and lead to research examining these variables together to determine their relationships to fatigue and to one another in patients with fatigue. Eventually, the goal is to develop a theoretical model that can guide interventions to ameliorate fatigue. At the present time, based on the published research, there are no interventions that health care providers can recommend to people with HIV who are suffering from fatigue. Therapy to reduce fatigue could give HIV-positive patients vigor and an improved quality of life, and it could reduce societal costs (Darko, Mitler, et al., 1995) through the enhancement of their ability to maintain employment. Because HIV-positive patients can live for extended periods, clinicians need to develop longterm therapy that addresses life goals and quality of life (Breitbart et al., 1998; Miles, 1997). New approaches to managing HIV disease must include strategies to deal with patient fatigue and other symptoms. Miles (1997) advocates an oncologic model of medical management for HIV patients that recognizes and supports the relationship between patient concerns and the management of disease. Although there are no published data on this, the economic costs associated with HIV-related fatigue are likely to be large because of the number of people who suffer from it and
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the extent of disability that it causes. For example, when people with HIV have to stop working due to fatigue, they often lose their health insurance, and many must turn to public assistance for health care and daily living expenses, including housing. New approaches to managing HIV disease must therefore include strategies to deal with patient fatigue and other symptoms. In the quest to find a way to slow or stop HIV, the quality of life for some has been sacrificed in exchange for longevity. Now that health care providers can extend the length of an HIV-positive person’s life, it is time to deal with symptoms that affect the quality of that life. It is hoped that a model of HIV-related fatigue can be developed to explain the relationships among the variables affecting fatigue, because this model can be used as a basis for developing interventions to reduce or ameliorate fatigue and improve the quality of life.
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