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Insomnia in HIV Infection: A Systematic Review of Prevalence, Correlates, and Management
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Psychosomatic Medicine 67:260-269 (2005)
Steven Reid, PhD, MRCPsych and Justin Dwyer, MB
From the Department of Psychological Medicine, Imperial College, London, UK (S.R.); and the Department of Liaison Psychiatry, St. Mary's Hospital, London, UK (S.R., J.D.).
"That psychologic morbidity, particularly depression, and insomnia are consistently related has been well-documented (3,56). A significant finding of this review is that in HIV infection, psychologic morbidity is the major contributor to insomnia rather than other factors such as disease progression or antiretroviral therapy..... Insomnia is a well-recognized feature of psychologic morbidity, and given the prevalence of anxiety and depression reported in HIV infection, it is not surprising that psychiatric disorders should be associated with sleep disturbance in this group..... Using the Hospital Anxiety and Depression Scale (49), Rubenstein and Selwyn found an increased prevalence of both depression (32%) and anxiety (55%) in 115 outpatient attenders of an HIV/AIDS clinic (24). Among patients experiencing insomnia, both depression (41% vs. 10%; p <.005) and anxiety (65% vs. 26%; p <.01) were more common, and multivariate analysis found that depression was an independent predictor of insomnia (OR, 1.17; CI, 1.01-1.36)."
ABSTRACT
Objective: Insomnia in people with HIV and AIDS has been widely but inconsistently reported. We present the results of a systematic review of the subject.
Methods: MEDLINE, EMBASE, PSYCHLIT, and CINAHL databases were searched, and inclusion criteria were applied. The study results were then collated and described.
Results: Twenty-nine studies were identified, and there was wide variation in both method and quality. Insomnia was reported frequently and at all stages of HIV infection. Early reports of sleep-specific electroencephalographic changes were not confirmed. The role of immune dysregulation, virus progression, and adverse drug effects in contributing to insomnia is unclear. The presence of cognitive impairment, an AIDS-defining illness, and treatment with efavirenz were found to be significant risk factors, but the most notable association was with psychologic morbidity. There was limited evidence for the effect of specific treatments for insomnia in HIV infection.
Conclusions: This review found that psychologic morbidity was a major determinant of insomnia in HIV infection. Further study would be of value in clarifying the role of other factors, as well as measuring the impact of insomnia on functioning and quality of life in this population.
Key Words: HIV infections · acquired immunodeficiency syndrome · sleep disorders · insomnia
Abbreviations: HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; PSG = polysomnography; EEG = electroencephalogram; CIDI = Composite International Diagnostic Interview; PSQI = Pittsburgh Sleep Quality Index; SWS = slow wave sleep; CDC = Centers for Disease Control and Prevention; REM = rapid eye movement; OR = odds ratio; CI = confidence intervals; GH = growth hormone.
DISCUSSION
This systematic review has found that, although the identified prevalence studies have many methodologic flaws, available evidence indicates that insomnia is a common complaint in people with HIV and AIDS. The early reports of sleep-specific EEG changes related to HIV infection, in particular an increase in SWS, have not been confirmed by controlled studies. Reports of insomnia are reported at all stages of HIV infection, but the presence of cognitive impairment or an AIDS-defining illness is a significant risk factor. However, the relationship between sleep quality and CD4 count remains unclear. Insomnia is an adverse effect frequently reported in association with antiretroviral therapy, but studies evaluating zidovudine and antiretroviral drugs as a class have not demonstrated a significant effect. The exception was efavirenz, which has been carefully evaluated and found to be an independent predictor of insomnia. Somewhat surprisingly, alcohol and illicit drug use were not found to have contributed to insomnia, although this is a likely consequence of the limitations of study design. The most notable finding to emerge from this review was the consistent and strong association between psychologic morbidity, in particular depression, and insomnia in asymptomatic seropositive patients.
The main limitation of this review is that it may not have identified all relevant studies, especially in those languages other than English. The search strategy did not identify studies that used symptom checklists for HIV, although such inventories frequently include insomnia. These studies are designed to provide a measure of overall symptom burden, including both constitutional and organ-specific symptoms, rather than focus on single symptoms such as insomnia. As such, they often lack an operational definition of insomnia and do not measure symptom severity.
The studies included in the review were also subject to a number of limitations. Of the 12 using polysomnography, only five used controls with numbers of at least 10 in each group. Furthermore, the comparability of the PSG studies is made difficult as a result of variations in method (10). Many of the studies investigating the correlates of insomnia were small, highly selective, and therefore possibly unrepresentative. The small sample sizes make the findings particularly susceptible to type II errors. Only one epidemiologic study was prospective in design (22), and the various definitions used for insomnia preclude the use of metaanalysis to summarize findings. There was little consideration of lifestyle and environmental factors such as caffeine intake or living conditions that may act as confounding variables (32). Living space was only considered in one cross-sectional study of a convenience sample (27). It found significant relationships between sleep quality and variables such as sleeping alone (p = .026), sleeping in a noisy bedroom (p <.01), and having a separate room for sleeping (p = .001). There was no evaluation of the history of insomnia before seroconversion in any of the identified studies. Therefore, the proportion of patients for whom insomnia is a continuation of a preexisting condition is unknown.
None of the studies measured the effect of insomnia on physical and social functioning or quality of life. There is evidence from primary care studies that insomnia is associated with substantial functional impairment independent of the effects of medical comorbidity or psychiatric disorder and greater use of healthcare services. Simon and VonKorff found that an additional 3.5 disability days per month and an excess of approximately 1 "bed day" per month were associated with insomnia (3). Sleep studies of medically ill (not HIV) patients have also shown that insomnia leads to an additional reduction in health-related quality of life (44,45). Further research could help to determine whether insomnia adds significantly to the burden of disability in HIV/AIDS, particularly in otherwise asymptomatic patients.
Early findings of enhanced SWS and disrupted REM cycles in asymptomatic seropositive patients led to the view that disordered sleep pattern was an early and consistent pathophysiological sign of HIV infection. A model was proposed in which sleep architecture was altered by elevated CNS levels of the cytokines, interleukin-1 (IL-1ß), and tumor necrosis factor (TNF-{alpha}). These immune mediators have been detected at increased levels in HIV-positive patients (51), and there is evidence from animal models for similar immune-mediated changes in sleep pattern (52,53). Darko and colleagues, in a small study, also observed a difference between HIV-positive subjects and controls in the timing of growth hormone secretion during SWS, suggesting that growth hormone dysregulation may also be implicated (16). However, this model has been challenged by subsequent studies that have not found similar alterations of sleep architecture. Furthermore, there does not appear to be a consistent relationship between altered sleep architecture and CD4 count or disease progression. The exception to this is that of late-stage HIV infection and AIDS associated with cognitive impairment when the abnormalities of sleep pattern are similar to those found in other disorders affecting the CNS (54,55).
That psychologic morbidity, particularly depression, and insomnia are consistently related has been well-documented (3,56). A significant finding of this review is that in HIV infection, psychologic morbidity is the major contributor to insomnia rather than other factors such as disease progression or antiretroviral therapy. Attempts to disentangle the relationship between sleep disturbance and depression encounter difficulty because of the overlap at both measurement and conceptual levels. Insomnia is one of the criteria for the diagnosis of depression, which creates an association by definition. An association remains, however, when the criteria for depression are restricted to mood symptoms and exclude sleep-related questions (22). Furthermore, this would not explain the relationship between insomnia and anxiety disorders in which sleep disturbance is not included in the diagnostic criteria. It remains unclear whether insomnia is merely a marker, an epiphenomenon, of an underlying process leading to depression or if it is an integral component of that process. There is evidence that mood disorders lead to changes in sleep patterns over time as well as prospective studies indicating that insomnia is predictive of later depression (57). As yet, there are no such long-term studies of insomnia in HIV infection.
Similar conceptual issues arise in studies of fatigue and HIV infection. Fatigue is frequently the most commonly reported symptom in surveys of seropositive patients and is associated with impaired physical functioning and with reduced quality of life (58). Although generally considered to be a constitutional symptom of HIV infection, fatigue is closely related to depression and anxiety (26), and in a large cross-sectional study, Breitbart and colleagues found that fatigue in seropositive subjects was significantly associated with psychologic distress and reduced physical functioning, but not CD4 count and antiretroviral therapy (59). The association was further demonstrated in a prospective study of 83 HIV-positive men, which found that over a 6-month period, the presence of fatigue was most powerfully predicted by depression and CDC stage IV illness (60).
As is the case with the general population, the majority of seropositive patients with insomnia remain untreated (41). The evidence base for the management of insomnia associated with HIV infection is small, although it has been shown that caffeine reduction may lead to an improvement in sleep quality (32). Clinical experience suggests that the use of benzodiazepines and other hypnotics is widespread. Recognized as an effective treatment in the short term, there is concern that in the longer term, they may result in tolerance and rebound insomnia, as well as impairment in motor function and coordination (61). Behavioral interventions, in particular stimulus control and sleep restriction, are as effective as drug treatments in persistent primary insomnia, but they are costly and have yet to be evaluated in people with HIV (50).
In conclusion, the studies reviewed here illustrate that although insomnia is a frequent complaint in people living with HIV, there is considerable uncertainty about its cause and significance. Psychologic morbidity was a major determinant of insomnia in asymptomatic infection, but the role of a number of variables, immune dysregulation, virus progression, and adverse drug effects remains unclear. Further epidemiologic study would be of value in clarifying these questions, particularly in samples representing the changing demographic of the seropositive population. In addition, the impact of insomnia on functioning and quality of life merits attention. As noted here, there is a burgeoning body of evidence indicating the benefit of various treatments for insomnia, and the efficacy of these interventions should be evaluated in this group. However, given that psychiatric disorders are often missed in general medical settings, from a clinical perspective an important first step would be to improve the assessment and management of anxiety and depression in people with HIV infection.
INTRODUCTION
The earliest clinical reports of HIV infection highlighted sleep disturbance as a prominent complaint (1,2). Insomnia has been described in all stages of HIV-related illness, and may lead to chronic fatigue, reduced physical and social functioning, and an overall reduction in quality of life (3). A number of studies have reported on factors thought to contribute to the development of insomnia in people with HIV and AIDS. Early investigations were primarily laboratory-based (2), analyzing sleep architecture through the use of polysomnography and with a focus on biologic correlates, in particular central nervous system (CNS) manifestations of HIV infection and altered immune response. This emphasis has subsequently shifted with epidemiologic studies evaluating subjectively reported insomnia and its associations. As well as the direct effects of HIV infection on sleep, some studies have considered the effect of other variables, including antiretroviral medication, psychiatric illness, and drug and alcohol use.
Despite the growing body of literature, there appears to have been little progress in the management of what remains a common and often debilitating complaint. This may in part be the result of the scattered distribution of the relevant literature and the difficulty in drawing robust conclusions. We have therefore conducted a systematic review of the literature on insomnia in HIV infection.
METHOD
We searched for relevant reports on the electronic databases MEDLINE, EMBASE, PSYCHLIT, and CINAHL from January 1985 to June 2003 and consulted reference lists of retrieved articles, reviews, and the Science Citation Index. The specific topic search terms used for MEDLINE were "HIV infections," "HIV seropositivity," "acquired immunodeficiency syndrome," "sleep disorders," "sleep initiation and maintenance disorders," and "insomnia." Similar strategies were used for other databases. All abstracts identified were inspected and the full text retrieved for all articles of likely relevance. Studies were included in the review if they presented original data on people with HIV who complained of insomnia or were investigated for sleep disturbance using polysomnography or questionnaire. Our intent was to identify a broad range of studies in which insomnia was investigated as a primary outcome. We did not, therefore, include studies reporting data from HIV symptom checklists. Reports were excluded if no English translation was available, and when one sample was used for two or more reports, the study providing the most relevant data included.
RESULTS
Sixty-nine studies were identified of which 29 studies met the inclusion criteria (4-32). These are summarized in Table 1.
Characteristics of the Studies
The studies may be divided into two broad categories. One group, predominantly earlier studies, focused on changes in sleep architecture that may or may not have resulted in symptomatic sleep disturbance. These studies involved the use of nocturnal polysomnography and consequently relied on small sample sizes. The second group examined subjective complaints of sleep disturbance, measured by questionnaire, and investigated the clinical correlates of insomnia in populations that were usually larger. With one exception, all of the studies were cross-sectional in design. The majority were conducted in the United States, with 10 (predominantly German) from Europe, and they all reported on adults only. Eleven of the studies included women (in two, gender was unreported). Two trials of treatment for insomnia in people with HIV infection were identified.
Assessing Insomnia in HIV Infection
Polysomnography (PSG) is used for the scientific investigation and clinical assessment of sleep. It includes a range of tests that, as well as recording sleep stage changes (Figure 1), allow for the measurement of physiological correlates. PSG always involves electroencephalography and may also include electrocardiography, electromyography, and measures of body temperature, movement, galvanic skin conductance, and penile tumescence. Electroencephalography (EEG) has been used to investigate the progression of HIV infection in the central nervous system (CNS), although its usefulness in the detection of early CNS involvement remains the subject of debate. Results have been contradictory with some studies showing diffuse changes, in particular slowing of background activity, in early stages of infection (33). Others, in contrast, have found that EEG abnormalities are restricted to later stages of illness (34).
As a tool for clinical assessment, PSG does have limitations. Its costliness typically limits data collection to 1 or 2 nights, which may lead to a biased appraisal of the subject's sleep pattern. Furthermore, sleeping in laboratory conditions can give a false representation of the subject's typical pattern because of exaggerated difficulties or even a paradoxic improvement in sleep. Although PSG is considered the "gold standard" in measuring sleep quality, it remains the case that laboratory-derived parameters rarely agree with subjective sleep reports, and the correlation between subjective estimates and objective measures of sleep is inconsistent (12,35). In part, this is the result of the difficulty in accurately self-reporting measures such as sleep duration, sleep latency, and number of wakenings. Importantly, however, given the largely subjective nature of sleep quality, in clinical practice, PSG-defined measures will only have limited value.
A number of self-report measures have been used to evaluate insomnia in HIV infection, and various methods were identified in the included studies. One method involved the summation of a limited number of items relating to insomnia, for example, an inventory (producing a score of 0-10) was derived from the Hamilton depression and anxiety rating scales (36,37). It asked about early, middle, and late insomnia and "difficulty in falling asleep, broken sleep, unsatisfying sleep and fatigue on waking, dreams, nightmares, night terrors" (22). A similar approach, from the Wheatley Stress Profile (38), rated 5 items on a scale of 0 to 2 (21). The remaining studies assessing sleep disturbance in clinical populations made use of a longer, detailed questionnaire. With the exception of one study in which the authors devised their own questionnaire (20), the Pittsburgh Sleep Quality Index (PSQI) was the preferred instrument, used in nine studies (12,18,19,24,26-28,31,32). The PSQI is a 19-item self-rated questionnaire that assesses sleep quality and disturbances over the preceding month (35). It has been used and validated in a range of settings. The questionnaire yields seven component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of hypnotics, and daytime dysfunction, which are then summed to produce a global score, which has a range of 0 to 21. This global PSQI score is used to distinguish good from poor (PSQI >5) sleepers with good diagnostic sensitivity (90%) and specificity (86%). A few studies included measures of daytime sleepiness such as the Epworth sleepiness scale (39), but because the subject of the review was nocturnal insomnia, these findings are not reported here.
Alterations in Sleep Architecture
The most frequently reported change in the sleep profile of HIV-positive subjects has been a significant increase in slow wave sleep (SWS), particularly during later sleep cycles (4,7,8,15). This was first described by Norman and colleagues in a series of small PSG studies of homosexual men who were seropositive but asymptomatic. This group also described persistent "alpha-intrusion" into SWS, suggestive of nonrestorative sleep (6). These studies lacked controls and made comparisons with normative population data. A further small study (five subjects) of people with cerebral manifestations of AIDS failed to find an increase (5), and with later case-control studies, the results have been less clear. One further controlled study (7) also found an increase in SWS in later sleep cycles. It has been suggested that changes in SWS may be dependent on illness progression, although other factors such as age, psychiatric illness, and use of psychotropic medication are potential confounders. One case-control study (15) found that CD4 count was a determining factor. Patients with a count of less than 400 were no different from seronegative controls, but a count of greater than 400 was associated with a significant increase in SWS, suggesting that severity and stage of illness may be important, although the controls in this study were not matched. In contrast, two European studies (10,14) and one from the United States (12), all of similar design, did not found an increase in SWS. Wiegand and colleagues found no effect of illness stage on SWS in 14 HIV-positive subjects with Centers for Disease Control and Prevention (CDC) stage III to IV C (10), and Ferini-Strambi observed a significant reduction in SWS in nine HIV-positive men compared with matched controls (14).
Like with SWS, variable findings have been reported from studies examining the duration and latency of rapid eye movement (REM) sleep. Uncontrolled studies suggested an increase in the number of REM periods in HIV-positive subjects with a reduction in their duration (5,8). Later studies have not found a difference between HIV-positive subjects and controls (7,10,12,14,15). Two studies reported significant differences in REM latency with one (15) reporting an increase the other a reduction (10). Wiegand and colleagues (10) found a number of significant changes all suggestive of a tendency to disrupted sleep. They found reduced sleep efficiency, increased sleep latency, a reduction in the percentage of stage 2 sleep, and an increase in the number of nocturnal awakenings. These finding had also been suggested by Norman's case series, and interestingly, there was no apparent effect of the stage of illness. However, further studies of similar size and design have not been able to find such a difference (7,12,14), and one study paradoxically found a reduced number of awakenings in those patients with a CD4 count greater than 400 compared with seronegative controls (15). Kubicki and colleagues, in a preliminary report of five patients with AIDS with cerebral complications, found a striking absence of sleep spindles, which has not been observed in either similar cerebral pathology or disorders of sleep (5). Although this finding has not been replicated elsewhere, a case-control study of patients with AIDS and clinically manifest cerebral disease observed sleep EEG abnormalities suggesting a reduction in sleep spindle activity (13). Wiegand and colleagues (10) found no group difference in spindle density, but in two individuals there was a marked reduction in their frequency. The significance of these findings and whether it is specific to AIDS remains unclear.
The lack of consistent findings challenges the hypothesis that changes in sleep architecture may be related to HIV disease progression. Not surprisingly, the exception is the appearance of marked EEG abnormalities in the presence of manifest cerebral pathology (5). A small cross-sectional study of nine HIV-positive men found no relationship between CD4 count and PSG variables (9). This finding was reinforced by a case-control study of 14 HIV-positive subjects from CDC stage III to IV C that found that stage of illness had no effect on any measures of outcome (10). White and colleagues found the only significant effect in an unmatched case-control study of 23 subjects (15). They found that subjects with a CD4 count greater than 400 differed from seronegative controls with reduced SWS and increased nocturnal wakenings, but they did not differ significantly from subjects with a CD4 count of less than 400.
Prevalence of Insomnia
Studies of insomnia in the general population, including both community and primary care studies, report a broad range of prevalence form 10% to 40% (3,40,41). Epidemiologic studies of insomnia generally use self-report measures, but the different measures used explain the variation in prevalence, with the lower figures reflecting the use of a higher diagnostic threshold. For example, the World Health Organization study of 5438 primary care attenders used the Composite International Diagnostic Interview (CIDI), which asks if the subject has had 2 weeks or more of difficulty in falling asleep, staying asleep, or waking too early, and found that 27% reported some form of sleep disturbance (3). A later study in primary care (3) also used the CIDI, but required that it took at least 2 hours to fall asleep, 1 hour of lying awake, or waking up at least 2 hours before wanted. This study found a 10% prevalence for current insomnia. The widespread use of the PSQI in a variety of populations, however, does allow for some comparison across studies. Zeitlhofer and colleagues classified 32% of a large European sample as poor sleepers, using a score greater than 5 as a cutoff (42). A similar prevalence of 30% was reported in 1800 Japanese adults (43). These studies undoubtedly show that insomnia is common in the general population. It is also recognized that there is an association between physical illness and insomnia, and this has been shown in several community studies (3). The PSQI has been used in samples of medically ill patients. In one study of patients with breast cancer, 61% were categorized as "poor sleepers" (44). A further study of 89 hemodialysis patients found that 63 (71%) were poor sleepers (45). The question is whether the prevalence of insomnia in people with HIV is comparable to that in the general population or people with other chronic diseases.
Although sleep disturbance is frequently reported in people with HIV and AIDS, there are few studies that systematically evaluate its prevalence. Only one study was identified that used the PSQI to classify poor sleepers. In a cross-sectional survey, Rubenstein and Selwyn found that 84 of 115 (73%) outpatients with HIV infection had insomnia (24). They required more than 1 hour to fall asleep compared with less than 15 minutes in good sleepers (p <.001) and slept for 2 hours less (p <.001). Two further studies reported the mean global PSQI score exceeding the cutoff for insomnia in HIV populations, 9.0 (standard deviation [SD] 4.4) (23) and 10.0 (SD 5.0) (27), but they did not report the prevalence of poor sleepers. Initial insomnia alone was reported by two studies using direct questioning and they found a prevalence of 29% (17) and 56% (23). None of these studies used controls, so they are subject to the effect of confounding variables.
Most studies using seronegative control groups had small sample sizes, so it is difficult to draw robust conclusions from their comparative data. Darko and colleagues in a study examining the effect of fatigue on functional activity found that 18% of the 54 HIV-positive participants reported initial insomnia, 25% reported frequent nocturnal wakening, and 24% reported early morning wakening (20). The only significant difference noted in comparison with controls was early morning wakening (24% vs. 3%; p = .02). One study found that complaints of sleep disturbance were near universal among 45 cases as well as their seronegative controls (96% vs. 91%, respectively), which raises questions about the validity of the study questionnaire, the Wheatley Stress Profile (21).
In contrast to the preceding studies, Perkins and colleagues in a relatively large study of 98 asymptomatic HIV-positive and 71 seronegative homosexual men found no difference in severity of sleep disturbance according to the insomnia subscales of the Hamilton Anxiety and Depression questionnaires (22). The study does not report on the prevalence of insomnia, but authors suggest that the low scores are the result of the relative good health of this seropositive sample. Histories of treatment with antiviral therapy, or heavy alcohol or drug use, were among the exclusion criteria.
Few of the studies identified considered the relationship between population characteristics and insomnia. This is, in part, the result of the lack of sufficient sample size to detect a difference and the use of purposive sampling. In those that did consider age, sex, and race of participants, four studies found no difference (21,23,24,27).
Stage of Illness
Hypotheses relating insomnia in HIV to immune function have led to a focus on severity of illness. No relationship has been found with the categorical CDC stages of HIV infection (19,21-24,26,27). An exception is late-stage illness (stage IV) in which patients are symptomatic (18,20). In this group, insomnia may be a direct consequence of an AIDS-defining illness. Rubinstein and Selwyn (24) found that in the 10% of their sample with cognitive impairment, reports of insomnia were universal, and multivariate analysis found that cognitive impairment was the best predictor of insomnia (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.7), suggesting an effect of central nervous system infiltration.
Findings are more equivocal when considering the association of insomnia with CD4 count. Although a number have found no effect (22-24,27), two studies have shown that reduced T-cell count is associated with subjective reports of sleep disturbance and nocturnal wakenings (19,20). One study found no relation between sleep disturbance and CD4 count, but did find a significant association with reduced CD8 cells (28). Path analysis suggested that psychologic morbidity may influence CD8 count by its effect on sleep quality (28).
Antiretroviral Therapy
Insomnia is generally considered an adverse effect associated with antiretroviral therapy. Phase II and III drug trials reporting on adverse effects record insomnia using the COSTART method (46), but although mentioned almost universally, the proportion of subjects complaining of disturbed sleep is less than 10% (47). This review identified relatively few published studies that systematically evaluate the risk of insomnia associated with antiretroviral drugs. In several studies, the effect of antiretroviral therapy was not considered (23), and in others, patients in receipt of treatment were excluded (22). Moeller and colleagues examined the effect of zidovudine in a case-control study and found that doses up to 1000 mg had no effect on sleep pattern as measured by the PSQI (18). The same group used PSG to measure insomnia in 24 HIV-positive men, 10 of whom were treated with zidovudine, and again found no difference. Two larger studies (21,24) considered the group effect of antiretroviral drugs and did not find an increase in insomnia, although neither study provided detailed data on the treatment regimens. In contrast, a cross-sectional study of 58 people found that antiretroviral therapy (specifically AZT, ddI, ddC, d4t, or 3tc) was associated with poor sleep quality according to the PSQI (p <.001) (27). To date, therefore, there is insufficient evidence to support a class effect of antiretroviral drugs. As a consequence of frequent reports of neuropsychiatric complications associated with the nonnucleoside reverse transcriptase inhibitor efavirenz, this drug has been subject to particular scrutiny. Nunez and colleagues (29) found a significant difference in a case-control comparison of insomnia in 51 patients taking efavirenz. In a multivariate analysis, an efavirenz plasma level greater than 3.5 μg/mL was an independent predictor for insomnia (OR, 6.3; 95% CI, 1.2-32.9). A further trial of an antiretroviral regimen including efavirenz vs. a protease inhibitor-containing regimen in 100 patients found that 35% of those prescribed efavirenz reported difficulty sleeping 4 weeks after initiation compared with 4% in the protease inhibitor group (p <.01) (30). Paradoxically, despite the high prevalence of CNS symptoms, this study found an improved quality of life associated with efavirenz, so the significance of the reported insomnia is unclear.
Psychiatric Disorder
Insomnia is a well-recognized feature of psychologic morbidity, and given the prevalence of anxiety and depression reported in HIV infection, it is not surprising that psychiatric disorders should be associated with sleep disturbance in this group. A number of smaller studies, using various measures of psychologic morbidity, have confirmed this (19,27,28). Wiegand and colleagues in a PSG study have also observed significant changes in the sleep architecture of depressed patients, notably a reduction in REM latency (p = .01) and an increase in the percentage of total REM sleep (p = .03) (10). These changes have been noted in EEG studies of depression and are not specific to HIV infection (48).
More detailed information comes from two U.S. epidemiologic studies. Perkins and colleagues followed up 98 HIV-positive men over 6 months measuring psychiatric symptoms using the Hamilton depression and anxiety scales as well as a structured clinical interview to establish Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised diagnoses (22). As would be expected, there was a significant association between a diagnosis of major depression and complaints of insomnia (p <.04), but not reduced CD4 counts or impaired cognitive functioning. The severity of depressive symptoms measured using a modified Hamilton depression scale (omitting somatic symptoms of depression, including insomnia and fatigue) was also associated with reported insomnia (p <.01), and in contrast to changes in CD4 count or clinical disease progression over 6 months, an increase in score on the depression scale was significantly associated with worsening severity of insomnia (p = .005).
Using the Hospital Anxiety and Depression Scale (49), Rubenstein and Selwyn found an increased prevalence of both depression (32%) and anxiety (55%) in 115 outpatient attenders of an HIV/AIDS clinic (24). Among patients experiencing insomnia, both depression (41% vs. 10%; p <.005) and anxiety (65% vs. 26%; p <.01) were more common, and multivariate analysis found that depression was an independent predictor of insomnia (OR, 1.17; CI, 1.01-1.36).
Alcohol and Substance Abuse
Although alcohol and illicit drugs are recognized as having a disruptive effect on sleep, few studies have considered their effect in people with HIV. Of the 27 studies included in this review, 10 of them make no mention of alcohol consumption or use of illicit drugs and 10 used alcohol or drug use as exclusion criteria. One difficulty affecting some studies is that admission of illicit drug use may result in criminal prosecution, so such information may not be reliable (27). In one study examining the question of alcohol and illicit drug use, 29 of 115 HIV-positive outpatients admitted to intravenous drug use in the preceding 6 months (24). Of these, 86% were considered to have insomnia, measured by the PSQI, compared with 69% of nondrug users, although this difference was not statistically significant (p <.07). Alcohol, cocaine, and heroine use in the previous 30 days were considered separately and no significant differences were found. The authors suggest that given the trend toward a difference, the lack of a positive finding may have been the result of an inadequate sample size.
Treatment Issues
There is a range of pharmacologic and behavioral treatments available for insomnia, but few of these have been evaluated in HIV infection (50). This review identified two treatment studies: an open study examining the effect of acupuncture (31) and a randomized, controlled study of caffeine reduction (32). Phillips and Skelton reported improvements in subjective sleep quality in a group of 21 people receiving 10 sessions of acupuncture (31). Given the small sample size, lack of a control group, and that sleep quality was measured over just 2 successive nights, the clinical significance of this finding is unclear. Dreher (32) randomized 120 HIV-positive subjects with sleep disturbance (PSQI >5) to caffeine withdrawal and abstinence for 30 days or continued caffeine consumption (in coffee, tea, cocoa, and soda). The study found a 35% improvement in sleep in subjects with a reduced intake (p <.001). The authors note that the mean posttreatment PSQI score (7.4) in the experimental group was still high, indicating continued poor sleep. This suggests the involvement of other contributory factors.
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