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Early, active management of fatigue is preferable before the symptom becomes chronic. Education is an important initial step in this respect, particularly because patients tend not to report fatigue unless directly asked. Patients and members oftheir support networks should be taught how to recognize signs and symptoms of fatigue to aid in its detection and treatment. Precipitating factors, such as acute physical stresses and psychological stresses, should be identified, as should perpetuating factors such as physical inactivity and ongoing psychological or social stresses (Sharpe and Wilks, 2002). Finally, clinicians should engage in discussion with the patient, giving ample information so that the patient knows what to expect from the treatment of their fatigue.

Given the multidimensional nature of HIV-related fatigue, a broad biopsychosocial approach is recommended for treatment of fatigue in this population (Sharpe and Wilks, 2002). Cella and colleagues (1998) have proposed a three-stage hierarchy for the management of fatigue: (1) identify and treat any underlying causes of fatigue; (2) treat the symptoms of fatigue directly while the etiology of fatigue is determined; and (3) address and manage the consequences of fatigue. Outlined below are fatigue intervention strategies in HIV/AIDS; these are summarized in Table 16.7.

Treatment of Physiological Causes of Fatigue

In accordance with the paradigm proposed by Cella et al. (1998), potential physiological causes of fatigue should be identified and treated, and nonessential centrally acting drugs should be eliminated. If anemia is the main cause of fatigue, for example, the physician should determine the necessity of a transfusion in severely symptomatic patients. Recombinant human erythropoietin (rHuEPO) is recommended for patients with hemoglobin levels below 11g/dl, regardless of whether they are being treated with zidovudine (Fischl et al., 1990; Henry et al., 1992; Phair et al., 1993). Clinical trials have shown that anemic patients have improved energy and less fatigue after rHuEPO treatment. Therapy with rHuEPO can be administered either intravenously or subcutaneously, three times weekly. It is generally well tolerated.

If hypogonadism is identified as the underlying cause of fatigue, exogenous testosterone or synthetic anabolic steroids may be administered (Dufour et al., 2005). However, patients receiving this treatment are susceptible to anabolic and androgenic effects such as increased heart rate, increased blood pressure, and hirsutism. Testosterone therapy may take the form of injections, pills, patches, gels, or creams. This treatment has been shown to have a beneficial effect on not only fatigue but also sexual interest, appetite, wasting, energy levels, and even concomitant depression. It table 16.7. Fatigue Intervention Strategies in HIV/AIDS

Cause-Specific Interventions

Anemia Hypogonadism Adrenal insufficiency Hypothyroidism Infections Malnutrition Depression Inactivity

Sleep disturbances

Nonspecific Pharmacological Interventions

Selective serotonin-reuptake inhibitors Tricyclic antidepressants Psychostimulants Methylphenidate Dextroamphetamine Pemoline Modafinil

Anti-cytokine agents Thalidomide Pentoxifyline

Nonpharmacological Interventions

Good sleep hygiene Education

Meditation, relaxation

Energy conservation and restoration

Cognitive-behavioral therapy

Source: Dufour N, Dube B, Breitbart W (2005). HIV-related fatigue. In J DeLuca (ed.), Fatigue as a Window to the Brain (pp. 188-207). Cambridge, MA: The MIT Press, with permission.

Transfusions, rHuEPO Testosterone Corticosteroids Levothyroxine

Antibiotic, antiviral, or antifungal therapy Nutritional supplement, megestrol acetate Antidepressants, psychotherapy Exercise, training Sleep aids can be used in women, although patients must be carefully monitored for any potential virilizing effects, which may be irreversible.

Primary adrenal insufficiency can be treated with oral hydrocortisone or dexamethasone replacement therapy (Dufour et al., 2005). Hypothyroidism improves with levothyroxine administration, which has also been found to improve quality of life and energy levels in HIV patients with no evidence of hypothyroidism (Derry, 1995).

Treatment of Psychological Causes of Fatigue

Once potential underlying organic causes of fatigue have been ruled out and treated, psychotherapeutic and pharmacologic treatments may be explored for the management of any mood disturbances.

Pharmacologic Interventions

Underlying depression should be treated with selective serotonin reuptake inhibitors (SSRIs), which are generally better tolerated than tricyclic antidepressants by patients with HIV and AIDS (Elliot et al., 1998; Schwarz and McDaniel, 1999). The notable exception is fluvoxamine, which is less well tolerated despite its efficacy in treating depression (Grassi, 1995). Since fatigued patients with HIV and AIDS are especially sensitive to antidepressant side effects compared to patients without fatigue (Sharpe and Wilks, 2002), treatment should be initiated at very low doses. Because concomitant antiretroviral therapy is frequently used, drug-drug interactions should also be carefully monitored by prescribing physicians. Excellent reviews of such psychopharmacologic considerations have been carried out by Robinson and Qagish (2002) and

Thompson et al. (2006). Psychopharmacologic treatment issues in AIDS psychiatry are also addressed in depth in Chapter 32 of this book.

Psychotherapeutic Interventions

Much less research, however, has been conducted about psychotherapeutic interventions for depressed HIV patients. Most of this literature supports group cognitive-behavioral therapy approaches as a means of improving mental health-related quality of life indices (Lechner et al., 2003) and relieving depression (Blanch et al., 2002). Although individual psychotherapy has not been as well investigated, it is an integral part of the American Psychiatric Association's practice guidelines for the treatment of patients with HIV/AIDS (American Psychiatric Association, 2000).

Direct Treatment of Fatigue

Once the potential physiological and psychological causes of fatigue have been addressed, residual effects of fatigue can be treated directly. There are several pharmacologic agents that may be used to directly treat fatigue in persons with HIV and AIDS who may or may not be depressed.

Psychostimulants such as methylphenidate, pem-oline, and dextroamphetamine have shown great promise in the treatment of fatigued patients with cancer and multiple sclerosis (Krupp et al., 1989a; Weinshenker et al., 1992). These drugs have also been used safely and successfully in HIV patients with fatigue (Holmes et al., 1989; Wagner and Rabkin, 2000; Breitbart et al., 2001). Breitbart and colleagues (2001) conducted the first randomized, double-blind, placebo-controlled trial of two psychostimulants for the treatment of fatigue in ambulatory patients with HIV disease. They found that both methylphenidate hydrochloride (Ritalin) and pemoline (Cylert) were equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects. Fifteen patients (41%) of 144 ambulatory HIV patients taking methylphenidate and 12 patients (36%) taking pemoline experienced clinically significant improvement, as compared to 6 patients (15%) taking placebo. The significantly improved fatigue was also associated with improved quality of life, decreased depression, and decreased psychological distress. Although subjects experienced minimal side effects, "jitteriness'' was reported by some patients (31.8% of subjects taking methylphenidate; 25.6% of subjects taking pemoline). Thus, the use of psychostimulants may be appropriate as part of a comprehensive approach to the treatment of fatigue in HIV patients (Breitbart et al., 2001).

Modafinil, a norepinephrine agonist in the human hypothalamus (McClellan and Spencer, 1998), is a wakefulness-promoting agent that has been used offlabel to augment antidepressants in small studies (Menza et al., 2000; Schwartz et al., 2002). It is currently used as a first-line agent for the treatment of severe fatigue in multiple sclerosis (MacAllister and Krupp, 2005). One pilot study has shown promising results for modafinil in the alleviation of HIV-related fatigue (Rabkin et al., 2004a). Further research will be necessary to validate these results.

Finally, one study has shown that testosterone administration may be effective for the treatment of fatigue in depressed men with HIV and AIDS. Rabkin et al. (2004b) conducted a double-blind, randomized, placebo-controlled trial comparing the outcomes of fluoxetine, testosterone, and placebo administration in 123 HIV-seropositive men with a depressive disorder. The Clinical Global Impressions Scale for mood and fatigue, the Hamilton Rating Scale for Depression, and the Chalder Fatigue Scale were used to assess patient symptoms. The conclusions did not support prescription of testosterone as a first-line treatment for depression in men with HIV disease. However, testosterone was significantly superior to both fluoxetine and placebo in terms of reducing fatigue.

Managing the Consequences of Fatigue

The negative impact of HIV-related fatigue on quality of life has been emphasized throughout this chapter. Addressing the consequences of fatigue is also crucial to improve the patient's quality of life. Treatment of fatigue should not merely involve the restoration or amelioration of energy, but also the preservation of energy to improve the patient's level of functioning. This may entail appropriate rest, pacing of energy-consuming activities, stress reduction, meditation or relaxation techniques, aerobic exercise (if it is not contraindicated), and participation in pleasurable activities. Counseling and communication can help patients re-prioritize their activities, adjust to their limitations, and restructure their goals and expectations accordingly. Throughout this process sustaining a sense of purpose and meaningfulness is vital (Win-ningham et al., 1994).

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