Besedovsky, Lange, and Born provide a thorough synthesis of the evidence supporting the relationships between sleep, circadian rhythm, and immunity [28]. The following section summarizes key conclusion drawn in their article that support the relationships between sleep and immunity. The onset of sleep is associated with downregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and the sympathetic nervous system (SNS). During that same period, growth hormone , prolactin, melatonin , and leptin steeply rise. These hormones participate in the regulation of the immune response, by stimulating activation, proliferation, and differentiation of immune cells, which then produce proinflammatory cytokines. Proinflammatory cytokines include interleukin-1 (IL-1), tumor necrosis factor (TNF-alpha) and interferon (IFN-gamma). When the HPPA (increasing production of cortisol) and the SNS (increasing the production of catecholamines) are upregulated, proinflammatory immune functions are suppressed. Therefore, during sleep, particularly during slow-wave sleep (SWS) , proinflammatory functions peak and during wakefulness anti-inflammatory activity becomes apparent. It has also been demonstrated that immune cell numbers in early differentiation peak during the early sleep period. Production of IL-12, a proinflammatory cytokine, increases and there is a shift of the Th1/Th2 balance toward the production of proinflammatory cytokines. Downregulation of the stress hormones during early sleep may lead to increased proliferation of T helper cell proliferation and migration of naïve T cells to the lymph nodes. Wakefulness is associated with an increase in cytotoxic T lymphocytes and natural killer cells.

An inverse relationship was found between frequency of sleep complaint and CD4 + cells which suggests that sleep disturbances may increase as the disease progresses. Relationships between SWS and certain immune variables (i.e., NKCA, antibody production, T cell proliferation and differentiation, and cytotoxic T cell proliferation and differentiation) have been observed. These findings suggest that insomnia adversely affects immunity. Darko et al. hypothesize that IL-1-β and TNF-α may be responsible for the changes in SWS in PWHA [29].

Cruess and colleagues examined the relationship between psychological distress (Impact of Event Scale), subjective sleep disturbance (PSQI) and immune status (CD3 + CD4 + [T helper/inducer cells] and CD3 + CD8 + [T suppressor cells]) in 57 PWHA. The sample consisted of both men ( n = 41) and women ( n = 16) with a mean age 38.8 ± 8.5. Neither psychological distress nor sleep quality was significantly related to T helper/inducer cells, but both were significantly associated with T suppressor cell even after controlling for age, T helper/inducer cells, and viral load. They concluded that sleep quality mediated the relationship between psychological distress and T suppressor cells [30].

HIV/AIDS-related insomnia is associated with a significant burden for PWHA in that it further adds to functional impairment and reduces quality of life (QOL) [19, 27]. Insomnia contributes to fatigue , disability, eventual unemployment, and decreased QOL in PWHIV [8]. Insomnia occurs frequently in PWHIV prior to diagnosis and continues throughout the course of the disease. In fact, excessive daytime sleepiness may be one of the presenting symptoms of HIV disease , [31] and insomnia may even serve as an early marker of HIV disease [13].

Changes in sleep architecture in HIV/AIDS have been studied in small samples. Most of these studies did not include seronegative case controls. Little attention was given to the HIV stage of illness in these small studies. Therefore, the changes in sleep architecture have not been clearly characterized.

Early studies demonstrated an increase in SWS , particularly during the latter half of the sleep period. Norman and colleagues [32] examined sleep architecture in a sample of eight asymptomatic HIV-positive men and compared their sleep to three HIV-negative men. They reported an increase in total percentage of SWS, with most of the SWS occurring in the latter half of the sleep period. This finding has not been replicated in any other study.

A subsequent study by Norman and colleagues compared the sleep architecture of ten HIV-positive men to that of five HIV-negative men. They reported a significant difference (8 % more) in the amount of delta (slow wave) sleep in the HIV-positive men [31] . In another study of six asymptomatic HIV-positive men, they reported that alpha-delta patterns were consistently observed throughout the sleep period [33].

Kubicki and colleagues examined sleep architecture in five men with AIDS . They reported a greater number of awakenings and arousals, reduced REM sleep, and a decrease in sleep efficiency in persons who have progressed to AIDS [34].

Wiegand and colleagues [14, 35] on the other hand, found no SWS disruptions in PWHA. Using nocturnal sleep encephalography, they found more frequent shifts to stage 1 sleep equated to a reduction in stage 2 sleep. Sleep-onset latency increased, but total sleep time and sleep efficiency decreased. The number of REM periods increased, but the average duration of a REM episode decreased.

Ferini-Strambi et al. examined sleep architecture in nine HIV-positive men and eight age matched controls. Their study showed a significant reduction in SWS and higher cyclic alternating patterns (CAP), representing the stability of sleep in PWHA compared to controls [36]. A significant relationship was found between a higher CAP rate and poor subjective sleep quality. Unlike Norman and colleagues, this group of researchers did not find a higher percentage of SWS in the second half of the night [36].

Wheatley and Smith found that HIV + patients reported greater delay in sleep onset, earlier morning awakening, more frequent nocturnal awakenings, and poorer well-being on waking. A higher degree of insomnia was observed in individuals who were not taking antiretroviral therapy. They suggested that the observed sleep architecture changes might be related to depression .

Many medications used to treat HIV/AIDS and its complications have insomnia as a side effect.

In studies involving the general population, researchers recognize the major correlates of diminished quality of sleep as (a) fatigue , (b) excessive daytime sleepiness , (c) perceived stress, and (d) depression. All of these exist in PWHA in addition to anxiety and pain [3, 6, 17] . In an integrated literature review examining insomnia in PWHA, Reid and Dwyer noted that all of the associated correlates are entangled due to “overlap at both measurement and conceptual levels” (p. 267) [9]. Similarly, Nokes and Kendrew [17] reported that the intercorrelations between symptom severity, excessive sleepiness , depression , state anxiety, and functional status precluded attempts to statistically “untangle the effects of the variables” (p. 21). The fact that PWHA usually present with multiple symptoms [50] compounds the difficulty. While both physiologic and psychological variables affect quality of sleep in PWHA, the latter (depression, stress, and anxiety) display strongest statistical correlation. For the PWHA, this manifests as marked delays in sleep onset, more awakenings during the night, and less transition into non-REM sleep [3]. In turn, the resultant insomnia exacerbates the psychological distress of the chronically ill [51].

While existing data sources do not allow calculation of incidence [52], fatigue leads as the most prevalent complaint of PWHA with estimates ranging from less than 50 % to more than 80 %. Whereas Lerdal et al. [53] simply define fatigue as a “sense of exhaustion, lack of energy, tiredness unrelieved by a night of good quality sleep” (p. 2204), other authors capture a more graphic characterization. In what is considered a classic analysis of the phenomenon, Ream and Richardson, as cited in Barroso and Voss [52], described fatigue as a “subjective, unpleasant symptom that incorporates total feelings ranging from tiredness to exhaustion, creating an unrelenting overall condition that interferes with individuals’ ability to function to their normal capacities” (p. S5). Asked to explain it, PWHA attribute their fatigue to either the disease itself or existing physical attributes (e.g., being overweight), overexertion, or medication side effects [54]. Despite instrument scores indicating significant pathology, respondents have been known to rate the quality of their sleep as “fairly good” [3].

Diminished quality of life arises from the awareness of the imbalance of resources, capacity, and performance [52, 55]. Significantly correlated with quality of sleep, fatigue is a constant across all stages of the disease [56] resulting in persistent impaired daytime functioning [10, 47, 48] and, somewhat paradoxically, increased sleep-onset difficulties [20]. In turn, daytime dysfunction has been significantly related to adherence to antiretroviral therapy regimens [27, 55]. Studying fatigue and insomnia in homosexual men (62 HIV + and 50 HIV −), Darko et al. [8] found that HIV + subjects were more likely to: be unemployed, feel fatigued throughout the day, sleep more, nap more, and have diminished alertness. Both fatigue and insomnia significantly contributed to morbidity and mortality in the HIV + subjects. They concluded that the cognitive dysfunction seen in early HIV infection (asymptomatic) is related more to loss of sleep than to actual neurological impairment.

Twenty years later, Harmon et al. documented that the fatigue PWHA experience differs in both quality and severity than that experienced before becoming infected [57]. HIV-Related Fatigue Scale (HRFS) scores from their study sample ( N = 128) indicated that fatigue interfered with cognition (mental clarity and facility), task performance (activities of daily living), and socialization (work and leisure). The researchers determined that those who have lived the longest with the diagnosis have lower self-reported rates of fatigue attributed to learned coping mechanisms . From this study’s findings, increased rates of fatigue can be predicted both in the presence of lower monthly income and pharmacologic treatment of depression . In 2009, Lee et al. [5] reported on clinical characteristics of symptom experiences among PWHA ( N = 350 adults) noting that most prevalent were “lack of energy” and “feeling drowsy” due to “trouble sleeping.” These states resulted in difficulty concentrating as well as mild symptoms of depression and anxiety.

A more recent study by Lerdal et al. [53] began exploring patterns of fatigue among PWHA. A sample of 318 PWHA completed self-report questionnaires related to symptoms Memorial Symptom Assessment Scale (MSAS), fatigue (Lee Fatigue Scale; Fatigue Severity Scale 7), sleep quality (PSQI), depression (CES-D), anxiety (POMS), and quality of life (Medical Outcome Study Health Related QOL). Participants were asked to complete the assessments 30 min after awakening and again 30 min before going to sleep for three consecutive days. Overall, evening fatigue level scores were significantly higher than morning fatigue level scores. While 30 % reported fatigue either in the morning or in the evening only, it was noted that those who reported high fatigue in the morning were likely also to report high fatigue in the evening. Using those who reported low levels of fatigue both in the morning and evening (35 % of respondents) as a reference group, three patterns were identified: (a) high-fatigue levels only in the morning; (b) high-fatigue levels only in the evening; and (c) high-fatigue levels both morning and evening. High-fatigue levels only reported in the morning were associated with higher anxiety and depression scores; while high-fatigue levels reported only in the evening were associated with high-anxiety scores. Labeled the most debilitating and distressing, high-fatigue levels in both the morning and evening were associated with high-anxiety scores, high-depression scores, and significant sleep disturbances. It is important to note that anxiety is an important antecedent of fatigue regardless of diurnal patterns. Acknowledging the cyclical interaction of psychological variables and quality of sleep suggests once again that mental health states are more predictive of fatigue than the HIV/AIDS disease state. And in turn, while psychological correlates affect sleep, only fatigue maintains statistical significance when exploring the association with sleep quality [3].

EDS is an inability to stay awake in quiet, sedentary situations (such as when reading, watching television, or even driving). While drowsiness (a milder form of daytime sleepiness) may be a by-product of lack of sleep or medication, EDS is usually associated with pathological sleep disorders such as obstructive sleep apnea (OSA) [5, 51]. Prevalence of OSA in PWHA has not been explored or documented despite the presence of several risk factors such as ART-associated lipodystrophy and opioid dependence [51]. In the majority of the studies examining sleep correlates, EDS is determined using the Epworth Sleepiness Scale (ESS) , an 8-item self-administered questionnaire validated in obstructive sleep apnea, narcolepsy , and idiopathic hypersomnia . Using this instrument, EDS is defined using a standard cut-point of ESS ≥ 10.

Crum-Cianflone and colleagues examined sleep quality (PSQI) and daytime sleepiness (Epworth Daytime Sleepiness Scale) in 193 HIV-infected participants and compared them with 50 HIV-negative participants. The HIV-infected group did not differ from the HIV-negative group by mean age, gender, race, rank, or duty status, but they did differ in that the HIV-infected group was slightly better educated, more depressed (Beck Depression Inventory), and were more likely to be hypertensive than the HIV-negative group. No differences were found between the HIV-infected group and the HIV-negative group on the total sleep quality score, any of the seven sleep quality component scores, or on daytime sleepiness. The authors concluded that HIV-infected patients who are diagnosed and treated early may have similar rates of sleep disturbances as the general population [12].

In a similar study examining correlates of sleep in 58 PWHA, Nokes and Kendrew noted that the majority of the participants were unemployed and 79 % reported taking daytime naps at varying frequency [17]. Wanting to determine if sleep quality mediated the stress–fatigue relationship, Salahuddin et al. examined levels of fatigue, sleep quality, and daytime sleepiness in 128 PWHA (majority African-American males; median age 44 years) most of whom had lived with the infection for 10 or more years [58]. Using scores from the HIV-Related Fatigue Scale (HRFS), PSQI, ESS , and a checklist of possibly stressful life events, they found weak correlations between EDS and both fatigue and sleep quality despite the fact that PSQI scores indicated pathological problems. While there was a significant relationship between and among sleep quality, fatigue, and daytime functioning, excessive sleepiness did not add to symptom. Furthermore, Salahuddin et al. found that the association between stress and fatigue-related daytime dysfunction was only marginally explained by EDS and sleep quality yet remains significant when examining daytime dysfunction [58].

The relationship between fatigue and depression is well documented in both the general population and PWHA. Indeed, Lerdal et al. [53] observes that “tiredness” is the second most prevalent symptom among depressed adults while Harmon et al. [57] cites depression as the most influential concomitant accompanying fatigue. Reid and Dwyer noted that the most notable finding of their integrated review of research literature is that the prevalence of depression in PWHA is markedly and significantly related to quality of sleep rather than CD4 count or disease stage [9]. Moneyham et al. observe that it is possible that many of the symptoms manifested in PWHA are manifestations of depression [59].

Working with a sample ( N = 278) of predominantly African-American women, Moneyham and colleagues found that depressive symptoms vary significantly with education, income levels, and living arrangements [59]. These findings are similar to those from studies examining the role of fatigue in the lives of PWHA and support the observed interrelationship between and among the correlates of sleep quality. In this case, analysis of data from a longitudinal study supported their hypothesis that social support and coping strategies can intervene in the relationship between stress (symptom burden and daily functioning) and depression . Indeed, the intensity of symptom burden plus its impact on ability to function in performance of daily activities becomes a significant predictor of depression. These findings are supported by Low et al. who reported that, if present, depression is the central companion of fatigue [60].

Noting that depression levels may decrease as years living with the diagnosis increase [57, 58], contemporary researchers advocate studies that include lifestyle, environmental, cultural, and health belief factors in order to identify and implement interventions leading to effective symptom management [9, 55, 59]. Such interventions might serve to break the patterns of anxiety that have been shown to be associated with therapeutic regimen adherence and quality of life [5, 61].

As life expectancy of PWHA increases, more attention is being given to quality of life. In 2009, Lee et al. reported that reported prevalence of pain in PWHA ranged from 30 to 90 %. The wide range was attributed to varying stages of disease among research participants and the use of different measurement instruments by the researchers. In one of the few studies examining the relationship of pain and sleep quality, Aouizerat and colleagues compared differences in fatigue, sleep disturbances , anxiety, and depression in PWHA with and without pain [50]. They reported significantly greater problems across all variables in the group experiencing pain than in participants reporting no pain. The concern is that providers have been underestimating the relationship between pain and sleep, and therefore, not effectively intervening. From findings of their study of the experience of pain in PWHA, Kowal et al. concluded that interventions strengthening effective coping strategies and improving daily functioning will result in decreased vulnerability to depressive symptoms [62].

Psychological interventions for PWHA with chronic insomnia offer many benefits when compared to sedative hypnotics [63, 64]. Therefore, it is reasonable and prudent that the first line of treatment should be a psychological intervention.