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Sleep Disturbances in HIV-Infected Patients

Sleep disturbances are very common in patients with HIV infection and have been identified as a serious problem ever since the early stage of the HIV epidemic. They have been reported at all stages of HIV infection, including its progression to AIDS [30-32]. Sleep disorders have been recognized as frequent and disabling illnesses for people living with HIV and AIDS both in the pre-combined antiretroviral therapy (cART) and post-cART epoch with a reported prevalence ranging from 30 to 100% [30, 33-36] as compared to 10-35% [37, 38] in the general population.

In one recent study, the prevalence of self-reported sleep disturbances in HIV- infected people was 58.0% (95% CI = 49.6-66.1) based on meta-analysis, taking into account variations in geographic region, gender, age group, CD4 counts, and instrument used to measure sleep disturbances [30].

The mechanisms of sleep disturbances in HIV-infected patients are not very well understood and largely unknown. Previous reports have suggested possible hints, which include the ability of HIV to affect the CNS, opportunistic infections, mental health issues, pharmacological impact of antiretroviral medications, and substance abuse [37-40].

Sleep disturbances have clinically important consequences in this population which include daytime sleepiness, fatigue, depression, cognitive impairment, neurobehavioral dysfunctions, and reduced quality of life in HIV-infected patients [35, 41-44]. Moreover, HIV-infected patients complaining of sleep disturbances are more likely to demonstrate decreased compliance with recommended cART [40, 45], which potentially can cause loss of virologic control, development of drug-resistant strains of HIV, and treatment failure [46, 47]. Daytime fatigue and insomnia are also prevalent symptoms in HIV disease. Between 33 and 88% of adults with HIV experience fatigue [48-50], and 56% have difficulty sleeping. Fatigue in HIV is related to depression, anxiety, sleep problems, comorbidity, and use of cART [48-52].

A recent study showed that self-reported sleep quality, total sleep time (using wrist actigraphy), and fatigue were significantly associated with perception of cognitive problems in adults with HIV, even after controlling for relevant demographic and clinical characteristics. However, disrupted nighttime sleep (WASO) was unrelated to perception of cognitive problems [53]. Moderate-to-severe poor quality of sleep was independently associated with adherence to HAART. Assessing the quality of sleep and complaints about fatigue may be helpful in the comprehensive evaluation of HIV patients which could lead to effective intervention that with greater impact on improving cognition function and quality of life.

The prevalence of insomnia in the HIV-seropositive population is estimated to be 29-97%, far greater than the 10-33% general population prevalence [36, 5456]. The roles of immune dysregulation, virus progression, and adverse drug effects in contributing to insomnia are unclear. Psychological morbidity is a major determinant of insomnia in HIV infection. It is recommended that sleep quality should be routinely assessed in order to identify the medical treatment needs and the potential impact of sleep problems on antiretroviral therapy outcomes in this population [36].

There are a limited number of studies dedicated to evaluation of sleep architecture in this population. Early reports of sleep-specific electroencephalographic changes were not confirmed.

During the early stages of HIV, before AIDS onset, patients have excess stage 4 non-rapid eye movement (NREM) sleep during the latter half of the night [55]. Alterations in sleep architecture in HIV disease have been associated with increased circulating levels TNF-a and interleukin 1-beta (IL-1b) [56, 57], which have som- nogenic effects that may interrupt sleep and daytime function [58-61].

Other sleep disorders including obstructive sleep apnea (OSA) have been reported commonly in HIV-infected patients [62]. Based on recent studies, the prevalence of OSA is ranging from 3.9 to 70% [62, 63]. These patients share the same major risk factors for OSA with the general population, including aging and obesity. The prevalence of OSA among HIV-infected patients has been elevated even among those who are not overweight or obese. Several factors may be responsible in this finding. These factors include:

  • 1. cART-induced adverse events could predispose to OSA. Lipohypertrophy associated with antiretroviral therapy is an increasingly well-recognized problem that may have a range of deleterious effects [63, 64]. Theoretically, HIV- associated lipohypertrophy could be affecting fat deposition around the posterior oropharyngeal airway and adversely affecting pharyngeal mechanics. HIV patients could also experience upper airway neuromuscular dysfunction and neuromuscular instability in ventilator control, although rigorous data remain sparse. Some antiretroviral drugs (i.e., dideoxynucleoside reverse transcription inhibitors) have been associated with neuromyopathy, and thus these drugs should be avoided in patients reliant on upper airway dilator muscle reflexes for the maintenance of pharyngeal airway patency [65-67]. Certain therapeutic agents commonly used in persons living with HIV infection (anxiolytics, antidepressants, analgesics) have sedating properties and as such would be predicted to raise arousal threshold (i.e., difficult to wake up) [67].
  • 2. cART may simply be facilitating restoration of health and concomitant weight gain such that obesity occurs via the natural history of current diet and exercise patterns [67, 68].
  • 3. The prolonged survival of contemporary HIV-infected patients with improved cART may extend the effects of HIV viremia and immune activation/inflamma- tion over time. Systemic inflammation could affect OSA risk via impaired pharyngeal mechanics and/or could affect the risk of OSA cardiometabolic
  • 3 HIV Infection of Human Nervous System: Neurologic Manifestations, Diagnosis
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complications via inflammatory pathways [67-69]. cART may be prolonging survival such that aging effects on the upper airway may have time to manifest. A variety of these factors likely contribute to the observed link between HIV infection and OSA.

Excessive daytime sleepiness is very common in HIV-infected patients (25-30%) [62].

Men with moderate to severe OSA were more likely than men with mild OSA to have sleepiness. One notable finding was that excessive sleepiness was associated with sleep-disordered breathing as defined by the respiratory disturbance index, but not as defined using the apnea-hypopnea index (AHI). Since recurrent arousals are well known to result in sleepiness [70-73], this disparity most likely reflects the fact that the RDI includes respiratory-related arousals in its definition, while the AHI definition does not.

Fatigue is a common symptom in persons living with HIV, and thus OSA may contribute via sleep disruption in these individuals [62]. Recent studies showed that witnessed apnea was the strongest independent predictor of fatigue. Other predictors included opioid use, depression, antidepressant use, and sleep duration < 6 h.

These data taken together strongly support the need for increased efforts directed at early screening and treatment of OSA and other sleep disturbances in patients with HIV infection [74].

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