Clinicians have long been aware of the frequency with which insomnia and fatigue figure in the complaints of individuals living with HIV. Fatigue and sleep disturbance can affect a wide range of activities and even health itself in this population, as the healing benefits of sleep are lost at the time when patients have the greatest need of rest and renewal. A study that compared HIV-positive and HIV-negative homosexual men found that the HIV-infected patients were significantly more likely to report a problem with fatigue, although they slept more and napped more than the HIV-negative subjects. This fatigue interfered with important activities such as employment and driving and was also correlated with measures of immunosuppression and inflammation (Darko et al., 1992). Why do HIV-positive individuals feel fatigued and sleep poorly? Although these two complaints are obviously interrelated, they are not synonymous. Some patients with HIV infection may sleep relatively well, wake up rested, but develop fatigue as the day progresses, while those with insomnia sleep poorly, wake up unrefreshed, feel tired all day, and yet are still unable to fall asleep or remain asleep when night falls.
Fatigue is discussed in Chapter 16; this chapter will focus more specifically on the sleep disorders seen among individuals living with HIV infection.
Formal sleep studies and self-reports (Norman et al., 1990, Moeller et al., 1991) have shown that sleep in individuals living with HIV is impaired in both quantity and quality, although studies have been inconsistent as to whether these impairments are significantly related to stage of illness. A study by Wiegand and colleagues (1991) found a number of changes suggestive of disrupted sleep in individuals living with HIV, including increased sleep latency and nocturnal awakening and a decrease in the percentage of stage II sleep. The International Classification of Sleep Disorders divides sleep disorders into the primary disorders, which include dysomnias and parasomnias, and the more common secondary sleep disorders related to another mental, neurological, or medical disorder or induced by the use of substances (Silber, 2005). The recently released NIH Draft Statement on Insomnia (2005), by contrast, recommends the use of the term ''comorbid insomnia,'' both to avoid undertreatment of the insomnia and because of the still limited understanding of causality. The forms of insomnia found in an HIV-positive population most often fall into this category of the secondary or comorbid insomnias, with all of the comorbid causes of insomnia mentioned above having a high prevalence in this population. Thus, treatment should focus first on identification and treatment of the comorbid causes of the insomnia, taking a broad biopsychoso-cial approach in this complex population, then on addressing the primary insomnia if the complaint persists.
HIV infection itself has been linked to insomnia. Studies in sleep laboratories have identified changes in sleep architecture among even asymptomatic HIV-infected patients (Terstegge et al., 1993). In asymptomatic HIV infection, slow-wave sleep is increased, particularly toward the later portion of the sleep period (Norman et al., 1992; Ferini-Strambi et al., 1995). This finding is unique to HIV infection and may be due to immune peptides, including tumor necrosis factor and interleukin. These peptides are elevated in the blood of HIV-infected individuals and have been found to be somnogenic in both clinical studies and animal models (Darko et al., 1995, Pollmacher et al., 1995). The human immunodeficiency virus and other lenti viruses may affect sleep more directly by resetting circadian rhythms, leading to altered sleep patterns and fatigue (Clark et al., 2005). Dysregulation of the growth hormone axis has also been implicated as a possible cause of sleep disturbance, with studies showing differences in the coupling between delta-frequency sleep EEG amplitude and growth hormone secretion in HIV-positive versus HIV-negative subjects, a change that occurs early in the course of the infection (Darko et al., 1998).
Looking at the problem from another direction, in non-HIV-infected populations, chronic insomnia has been found to affect immune function, with good sleepers having higher levels of CD3+, CD4+, and CD8+ cells than those with sleep difficulties (Savard et al., 2003). Studies with animal models have found that prolonged sleep deprivation can lead to compromised immune function and even death from sepsis (Bergman et al., 1996). Thus, insomnia may be both a cause of and a result of immune dysfunction.
Mood disorders, anxiety disorders, and cognitive disorders, all of which have a high prevalence in populations living with HIV, have been linked with both acute and chronic insomnia. A study of 115 HIVpositive individuals, including women and injection drug users, found that overall, 73% met criteria for having a sleep disturbance, while 100% ofthe patients diagnosed with a cognitive disorder also had comorbid insomnia. Both cognitive impairment and depression were the best predictors of insomnia, although there was also a trend toward a higher prevalence among drug-using patients. Despite the high prevalence of disturbed sleep in all groups in this study, only 33% of the patients with insomnia had any mention of sleep disturbance in their medical records (Rubenstein and Selwyn, 1998). Reid and Dwyer (2005) undertook a systematic review of 29 articles dealing with insomnia in HIV infection and found that while an AIDS-defining illness, cognitive impairment, and treatment with efavirenz were all significant risk factors for insomnia, the most notable association was with psychological morbidity. Another recent study found both depression and anxiety among the variables related to sleep quality in an HIV-infected population (Robbins et al., 2004).
Studies in other populations have found an extensive comorbidity between psychiatric disorders and insomnia, with depression being the psychiatric diagnosis most commonly associated with insomnia (Martin and Ancoli-Israel, 2003). Patients with depression often report difficulties falling asleep and staying asleep, as well as early morning awakening. REM sleep has been found to occur earlier in sleep in depressed subjects and to decrease as the night progresses, reversing the normal cycle (Kloss and Szuba, 2003). Major depression is common in an HIV-infected population, with a prevalence estimated at 15%-40% (American Psychiatric Association, 2000), leaving this cohort vulnerable to the range ofsleep disorders seen in conjunction with depression. Insomnia has been found to be more closely correlated with worsening depression in an HIV-infected population than CD4 count and disease progression (Perkins et al., 1995).
If insomnia develops during an episode of major depression, treatment of the depressive symptoms should take priority, as the insomnia will often resolve as the depression remits. An antidepressant with sedation as a side effect, such as mirtazapine, may relieve symptoms of insomnia while treating the depression. Another option is to combine antidepressant treatment with the short-term use of a sedative-hypnotic agent. The addition of cognitive-behavioral therapy may help remedy both depression and insomnia (Kloss and Szuba, 2003).
Less need for sleep and difficulty falling asleep are common symptoms of mania. In individuals living with HIV, mania may represent exacerbation of a preexisting bipolar disorder, may be part of the organic manic syndrome that can be seen in the context of advanced HIV infection, or may be associated with treatment with steroids or zidovudine (Della Penna and Triesman, 2005). Identification and treatment of the underlying cause of the organic mania and treatment of the mania itself with mood stabilizers or an-tipsychotics may resolve the insomnia, although hypnotics can be added if necessary.
Anxiety can occur at any stage of HIV infection, as patients must adapt to ever-changing circumstances. From the initial diagnosis, the patient may experience a number of anxiety-producing events, including changes in health or medication regimens, anticipation of results of tests and procedures, and changing family and financial circumstances, to mention just a few. Anxiety disorders may antedate seroconversion, and symptoms of anxiety may also occur in the context of substance abuse or withdrawal. In patients with more advanced illness or those who have lost loved ones to HIV infection, anxiety may take the form of resistance to falling asleep for fear of never awakening. Studies of patients with anxiety in other settings have found that 50%-70% report sleep difficulties affecting all stages of sleep (Kloss and Szuba, 2003).
Anxiolytics and/or antidepressants are usually effective in decreasing anxiety, although the use of anxiolytics in patients with a history of substance abuse may raise another set of issues. The possibility of drug-drug interactions with highly active antiretroviral therapy (HAART) may also limit the choice of agent.
It has been suggested that individuals living with HIV may experience a higher prevalence of posttraumatic stress disorder (PTSD) than that among the general population (Della Penna and Triesman, 2005) and that the diagnosis of HIV itself may lead to PTSD (Kelly et al., 1998). Painful medical treatments or intensive-care unit stays can also lead to PTSD. Disturbing nightmares are part of the symptom cluster of PTSD and may reflect changes in REM sleep, such as increased REM density and, in most studies, an increased REM percent (Kloss and Szuba, 2003). Treatment with a selective serotonin reuptake inhibitor (SSRI) is recommended for the primary symptom, and use of a sedative-hypnotic may be helpful while waiting for the full SSRI effect.
Because HIV infection can affect multiple members of a family, a social network, or even a community, loss and bereavement are not uncommon. Acute grief can lead to insomnia, which may be relieved by short-term use of hypnotics. Lack of social support or pre existing poor coping skills may interfere with adaptation to loss and lead to persistence of insomnia and other markers ofbereavement. Individual or group psychotherapy may provide emotional support and teach adaptational skills.
As previously mentioned, studies have found an association between the presence of dementia and insomnia in advanced HIV infection. In non-HIV-infected populations, the level of dementia has been found to contribute to poor sleep quality. Those individuals with cognitive impairment who reside in nursing homes have been found to have more disturbed circadian rhythm, more fragmented sleep, and even reversal of the sleep-wake cycle (Martin and Ancoli-Israel, 2003). Both these findings could be relevant to sleep disorders in the later stages of HIV infection.
Pain clearly can interfere with all stages of sleep. Chronic pain in HIV-positive patients may still be underestimated and undertreated despite data demonstrating that pain is a common symptom in this population (Breitbart et al., 1996; Larue et al., 1997) Disrupted sleep may result when doctors are hesitant to prescribe sufficient analgesic medications to treat complaints of pain from patients with a history of substance abuse, or they may undertreat pain when the cause of pain in an HIV-infected patient remains uncertain even after a thorough workup.
Diarrhea is a common complaint of patients living with opportunistic infections and can lead to fragmented and non-restful sleep, as can urinary frequency, hot flashes, muscle cramping, pruritus, dyspnea, and other physical complaints. Obstructive sleep ap-nea due to adenotonsillar hypertrophy has been estimated to have a prevalence of 7% among individuals living with HIV, even in the absence of obesity (Epstein et al., 1995). It has also been associated with increased neck fat hypertrophy, which is due to the deposit of adipose tissue around the neck as part of HIV-associated lipodystrophy (Schulz et al., 2003). Decreased levels of testosterone can also lead to insomnia.
Methylphenidate and other psychostimulants used to treat apathy and fatigue in HIV-infected patients can cause insomnia, although restriction of dosing schedules to the earlier part of the day should avoid this side effect. Insomnia and non-restful sleep have been-reported early in treatment with efavirenz and may also cause more chronic sleep difficulty. Studies have found longer sleep latency and shorter duration of deep sleep in patients treated with efavirenz compared with controls as well as higher efavirenz plasma levels in patients with insomnia and/or reduced sleep efficiency than in those being treated with efavirenz who did not have sleep complaints (Gallego et al., 2004). In addition, efavirenz has been associated with vivid dreams and nightmares (American Psychiatric Association, 2000) that may result in disturbed and less restful sleep. Abacavir, stavudine, didanosine, and zi-dovudine (AZT) have also been linked to insomnia, with placebo-controlled studies showing more insomnia in patients treated with AZT than in those given placebo treatment (Worth and Volberding, 1994; Fel-lay et al., 2001). Other medications, including steroids, caffeine, theophylline, calcium channel agonists, L-dopa, amntadine, certain antineoplastic agents, and even buspirone, have also been implicated in sleep disturbance (Sateia and Nowell, 2004; Krahn and Richardson, 2005). Both use and abrupt discontinuation of substances of abuse, including alcohol and nicotine, can lead to sleep disturbance, as can abrupt discontinuation of many prescribed medications.
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