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Prevalence and Factors Associated With Sleep Disturbances Among Early-Treated HIV-Infected Persons: 'Forty-six percent of HIV-infected persons had insomnia, 38% in HIV-unifected, no statistical difference found'
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Clin Infect Dis. March 19, 2012
from Jules: this study was conducted in patients in military personnel prior & current with early HIV disease, nadir cd4 340, current cd4 586. Frankly, i'm not convinced these results apply to all with HIV.
"In summary, insomnia and daytime sleepiness are common among HIV-infected persons, but in the setting of early HIV diagnosis and management, the prevalence of these disorders does not seem higher than matched HIV-uninfected persons. Among HIV-infected persons, depression and increased waist size were significantly associated with insomnia (illicit drug use was marginally associated with sleep disturbances, p=0.06). Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life."
HIV history
Duration of HIV seropositivity, mean (SD), y 7.2 (6.3)
Prior AIDS-defining condition 12 (6.2)
Patients with "later" HIV infectionb 96 (49.7)
Current CD4+ count, mean (SD), cells/mm3 586.8 (230.1)
Nadir CD4+ count, mean (SD), cells/mm3 343.2 (166.6)
Current HIV RNA, undetectable (≤50 copies/mL) 105 (55.3)
Current HAART use 127 (65.8)
"We performed a cross-sectional study among 200 HIV-infected and 50 HIV-uninfected persons who were 18-50 years of age. Participants were US military beneficiaries (active duty members, retirees, or dependents); active duty members are HIV seronegative on entry into military service and undergo mandatory HIV testing every 1-5 years. Given the routine screening and open access to care for military beneficiaries, our HIV cohort consisted of patients with early diagnosed and managed HIV infection."
Regarding the association of insomnia and depression by BDI scores among HIV-infected persons, insomnia was present in 37% of those without depression, 71% with mild depression, 89% with moderate depression, and 93% with severe depression
Finally, we examined whether HIV infection itself was associated with insomnia. In a multivariate model that included ethnicity, years of education, positive depression score (BDI ≥20), and HIV status (negative vs positive), HIV infection was not associated with insomnia (P = .70). Additionally, using the outcome of total PSQI score, there was also no association with HIV status in a multivariate linear regression model (P = .44) (data not shown).
These data suggest that in the HAART era, patients with early-diagnosed, early-treated HIV infection may have similar rates of sleep disturbances as the general population.
Data from prior studies among HIV-infected persons found higher rates of insomnia (up to 73%) and suggested that this group was at elevated risk for sleep disturbances compared with the general population [3-7, 29-31]. However, these studies were conducted in the pre-HAART era when patients often had concurrent opportunistic diseases, and studies included a number of illicit drug users. Our population consisted of HIV-infected persons with free access to antiretroviral therapy, few AIDS-related conditions, and low rates of illicit drug use.
The strongest factor associated with insomnia among HIV-infected persons in our study was depression.....Increased waist size was associated with sleep disturbances in our study......We found no relationship between stable, long-term efavirenz use and insomnia.
We did not find a relationship between sleep and measured cognitive impairment (by neuropsychological tests) but did note an association with self-reported cognitive difficulties. A prior study conducted in the pre-HAART era showed an association between insomnia and cognitive impairment as measured using abbreviated testing
Abstract
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0-142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4-5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7-.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
Sleep disturbances among persons infected with human immunodeficiency virus (HIV) were recognized early in the HIV epidemic [1], with changes in sleep structure being one of the earliest and most consistent physiologic changes noted [2]. Although the prevalence of sleep disturbances is reportedly high among HIV-infected persons [3-8], few studies exist in the literature during the highly active antriretroviral therapy (HAART) era. Recent studies have largely focused on the impact of specific antiretroviral agents (eg, efavirenz) on sleep quality [9-13], or the impact of weight gain and lipohypertrophy on obstructive sleep apnea (OSA) [14-16]. The most recent study performed to assess the overall prevalence of insomnia in a well-defined HIV cohort found a prevalence rate of 73% [7]; however, this study had no control group and was conducted over 15 years ago.
The pathophysiology of sleep disturbances among HIV-infected patients is unclear, but may be related to the ability of HIV to infect the central nervous system (CNS), impact of antiretroviral medications, CNS opportunistic infections, mental health issues, and substance abuse [17, 18]. Regardless of its etiology, insomnia is clinically important in this population for several reasons, including its potential impact on quality of life, adherence to antiretroviral medications, and cognition [7, 8, 19].
Our aim was to determine the prevalence of sleep disturbances in the late HAART era among HIV-infected persons and compare this rate to a matched HIV-negative control group. In this study, we evaluated the factors associated with insomnia among HIV-infected persons and the association between insomnia and cognitive function, as well as activities of daily living (ADLs).
RESULTS
Study Characteristics of HIV-Infected Persons
We evaluated 193 HIV-infected persons with a mean age of 36 years (SD, 9), 95% were male, and 50% were white (Table 1). The mean BMI was 27.5 kg/m2 (SD, 4.5), and 25% were obese. Lipodystrophy was noted among 52%, metabolic syndrome in 26%, depression (BDI, ≥20) in 7%, and diabetes in 3%. The mean time from HIV seropositivity to study enrollment was 7 years (SD, 6), 6% had a prior AIDS-defining condition, and 15% had a CD4+ cell count nadir of <200 cells/mm3. The mean CD4+ count at enrollment was 587 cells/mm3; 66% of patients were receiving HAART, and 55% had an undetectable HIV RNA level.
Prevalence of Sleep Disturbances Among HIV-Infected Persons
Eighty-nine HIV-infected persons (46.1%; 95% CI, 39.0%-53.2%) had insomnia based on the PSQI (>5) (Table 2). The mean amount of sleep per night reported was 6.5 hours (SD, 1.3) with 46% reporting <7 hours of sleep on average per night. Subjective sleep quality was reported as "bad" among 23%. Sleep latency was >60 minutes on ≥3 nights per week among 12% of HIV-infected persons and 31-60 minutes at least weekly among 19%, for a total of 31% having an extended sleep latency. Some amount of daytime dysfunctioning due to sleepiness was reported by 53% of patients. On the ESS, 29.5% of HIV-infected persons (95% CI, 23.0%-36.0%) had evidence of daytime drowsiness (score, ≥10). Finally, 18% reported taking a medication for sleep at least weekly.
On the self-reported questionnaire, 69 persons (36%) responded affirmatively to the question, "Do you feel that you have a problem sleeping?" of whom 24 (35%) stated that the problem had a moderate or severe impact on their life. Among HIV-infected persons with insomnia, these percentages were 72% and 38%, respectively.
Prevalence of Sleep Disturbances Among HIV-Infected vs HIV-Uninfected Persons
Among the 50 HIV-uninfected persons evaluated, the mean age was 35 years (SD, 9), 96% were male, and 50% were white (Table 1). HIV-uninfected persons were similar to the HIV-infected persons except that they were more likely to be of Hispanic or "other" ethnicity and less likely to meet criteria for depression (Table 1).
The prevalence of insomnia in the HIV-uninfected group was 38.0% (95% CI, 24.1%-51.9%), which was not statistically significantly different compared with the HIV-infected cohort (P = .30). There were also no differences in any of the 7 components of the PSQI between groups (Table 2), nor in daytime sleepiness of HIV-uninfected (20.0%; 95% CI, 8.5%-31.5%) vs HIV-infected persons (P = .18). HIV-infected and HIV-uninfected persons had similar rates of use of sleep medications ≥1 times/week (18% vs 16%; P > .79).
Factors Associated With Sleep Disturbances Among HIV-Infected Persons
In the univariate analyses, factors associated with a insomnia (PSQI >5) included fewer years of education (OR, 0.8 per year; 95% CI, .7-.9; P = .005), obesity (OR, 2.3; 95% CI, 1.0-4.9; P = .04), increased waist size (OR, 3.0; 95% CI, 1.7-5.5; P < .001), current cigarette use (OR, 2.8; 95% CI, 1.3-6.4; P = .01), history of serious head trauma (OR, 3.1; 95% CI, 1.4-6.9; P = .006), depression (OR, 17.6; 95% CI, 2.3-137.6; P = .006), and peripheral neuropathy (OR, 2.1; 95% CI, 1.3-4.0; P = .02) (Table 3). The military rank of officer (OR, 0.3; 95% CI, .1-.9; P = .04) was associated with a lower prevalence of insomnia, compared with enlisted rank. There were no significant associations between HIV-specific factors including HAART use (including efavirenz-containing regimens) and sleep. In the final multivariate model (Table 4), factors associated with insomnia based on the PSQI included depression (OR, 16.8; 95% CI, 2.0-142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4-5.1; P = .002), and fewer years of education (OR, 0.8 per year; 95% CI, .7-.95; P = .006).
Regarding the association of insomnia and depression by BDI scores among HIV-infected persons, insomnia was present in 37% of those without depression, 71% with mild depression, 89% with moderate depression, and 93% with severe depression (P < .001). Moreover, higher BDI scores were significantly associated with higher PSQI scores (r = 0.57; P < .001). Regarding antidepressant use, antidepressants were being taken by 7 (50%) of the 14 participants with a BDI ≥20, and 20 (11%) of the 179 with a BDI <20. Among participants with a BDI <20, those who were taking antidepressants had a 6-fold higher odds of insomnia than those who were not (OR 6.6; 95% CI, 2.1-20.7; P = .001), whereas those with a BDI ≥20 had a 21-fold higher odds of insomnia relative to those with a BDI <20, regardless of whether or not they were taking antidepressants (OR, 21.4; 95% CI, 2.7-168.1; P = .004). Among those with a BDI ≥20, it was impossible to compare those taking with those not taking an antidepressant, because all participants in this group who were not taking an antidepressant had insomnia.
Associations between increased waist size and components of the PSQI and ESS were also examined. HIV-infected participants with increased waist size were at increased odds for loud snoring (OR, 4.2; 95% CI, 1.7-10.2; P = .001), daytime dysfunction (OR, 2.3; 95% CI, 1.2-4.8; P = .02), and daytime sleepiness (ESS ≥10; OR, 2.0; 95% CI, 1.1-3.7; P = .03).
Finally, we examined whether HIV infection itself was associated with insomnia. In a multivariate model that included ethnicity, years of education, positive depression score (BDI ≥20), and HIV status (negative vs positive), HIV infection was not associated with insomnia (P = .70). Additionally, using the outcome of total PSQI score, there was also no association with HIV status in a multivariate linear regression model (P = .44) (data not shown).
Impact of Insomnia Among HIV-Infected Persons
We examined neurocognitive impairment (GDS ≥0.5), which was present in 36 (19%) of the HIV-infected participants. There was no association found between sleep and overall neurocognitive impairment by GDS (Table 5). We also evaluated 7 individual neuropsychological domains, and found only 1 to be associatedÑthose with impaired verbal fluency were less likely to have insomnia (OR, 0.4; 95% CI, .2-.9; P = .03).
We studied the association between PSQI score and self-reported cognitive impairment ("Do you feel that you have a problem with memory loss or cognitive functioning?"); among those with insomnia, 43% reported memory loss compared with 16% without insomnia (OR, 3.8; 95% CI, 2.0-7.4; P < .001). This finding remained after excluding participants with depression. Finally, we examined the presence of insomnia and ADLs; 22% of participants with insomnia reported a decline in ADLs in ≥2 items compared with 9% of those without insomnia (OR, 3.1; 95% CI, 1.3-7.1; P = .01).
DISCUSSION
This study represents one of the largest epidemiologic studies of the prevalence of insomnia among HIV-infected persons that included a frequency-matched HIV-negative control group [6, 29]. We found that HIV-infected persons have a high prevalence of sleep disturbances (insomnia and daytime sleepiness) as measured by standardized questionnaires. Despite the high prevalence of insomnia, HIV-infected persons did not have a statistically significantly higher rate compared with matched HIV-uninfected persons. These data suggest that in the HAART era, patients with early-diagnosed, early-treated HIV infection may have similar rates of sleep disturbances as the general population.
Data from prior studies among HIV-infected persons found higher rates of insomnia (up to 73%) and suggested that this group was at elevated risk for sleep disturbances compared with the general population [3-7, 29-31]. However, these studies were conducted in the pre-HAART era when patients often had concurrent opportunistic diseases, and studies included a number of illicit drug users. Our population consisted of HIV-infected persons with free access to antiretroviral therapy, few AIDS-related conditions, and low rates of illicit drug use.
The strongest factor associated with insomnia among HIV-infected persons in our study was depression. This finding is consistent with other studies [7, 32], and exemplifies that psychological morbidity is a major factor in insomnia among HIV-infected patients. Given the bidirectional relationship between sleep and depression, management of one condition may improve the other. For example, treating depression might improve sleep quality, and the treatment of sleep disturbances may decrease the incidence of depression [32].
Increased waist size was associated with sleep disturbances in our study. Prior studies have associated increases in BMI, as well as waist and neck circumferences with disordered night breathing and OSA [14-16]. Although we found an association with increased waist size and insomnia or daytime sleepiness, the exact etiology of this association is unclear, because we did not perform formal sleep studies. In addition to OSA, there are other potential mechanisms (eg, difficulty in achieving a comfortable sleeping position) by which abdominal adiposity may cause insomnia.
Regarding HIV-specific factors, we did not find an association between insomnia and HAART use in either direction. Antiretroviral agents with high CNS penetration effectiveness scores may be protective of HIV's effects on the CNS. On the other hand, some drugs may be associated with adverse sleep effects (eg, efavirenz, raltegravir), especially at higher plasma levels [4, 9, 11-13, 31, 33]. We found no relationship between stable, long-term efavirenz use and insomnia.
The impact of sleep disturbances may be several-fold. HIV-infected persons with insomnia reported a decline in performance of ADLs. We did not find a relationship between sleep and measured cognitive impairment (by neuropsychological tests) but did note an association with self-reported cognitive difficulties. A prior study conducted in the pre-HAART era showed an association between insomnia and cognitive impairment as measured using abbreviated testing [7]. The divergence of findings may be due to the differences in neuropsychological tests used or to the fact that the prior study was conducted in the pre-HAART era when HIV perhaps played a more direct role in both sleep and cognitive issues. Despite a high prevalence of insomnia among HIV-infected persons, only 17% were regularly using a medication for sleep. Prior studies have also noted that most patients with insomnia remain untreated and often have a poor understanding of available treatment options [7, 34].
Our study had several potential limitations. Sleep disturbances were diagnosed based on questionnaire data rather than polysomnograms; however, we used standardized instruments [20, 21] comparable to those used in other studies, and some experts suggest that self-reported data may be more representative of sleep issues [8]. The cross-sectional study design did not allow for assessing the temporal relationship between insomnia and factors (eg, depression and reduction in ADLs), nor for the assessment of whether sleep disturbances were transient or chronic in nature. Although we used an HIV-negative control group, our study was not powered to estimate small differences in insomnia rates between the 2 groups; the current study was performed concurrently with an evaluation of neurocognitive deficits among HIV-infected vs HIV-uninfected persons and the sample size was based on this objective. However, the 8% difference in the prevalence of insomnia between the 2 groups (46% vs 38%) may not be of enough clinical significance to warrant a larger study. Further, our rates of insomnia in the HIV-uninfected group were similar to those in prior reports [35-37]. Because our study was conducted among a cohort of military beneficiaries with early-diagnosed, early-managed HIV infection, results may not be generalizable to other HIV populations. Finally, we found that increased waist size was associated with sleep disturbances; however, whether this was due to abdominal lipohypertrophy was not confirmed by objective measures such as dual-energy x-ray absorptiometry scans.
Our study had several strengths. This study is one of the largest to date among HIV-infected patients and included an HIV-negative control group [4, 7]. The study used validated measures for both insomnia and daytime sleepiness, which are quick and inexpensive to implement into clinical practice [20, 21]. Furthermore, the study evaluated a comprehensive set of sociodemographic characteristics and clinical factors and also included evaluations of neurocognitive functioning and daily activities.
In summary, insomnia and daytime sleepiness are common among HIV-infected persons, but in the setting of early HIV diagnosis and management, the prevalence of these disorders does not seem higher than matched HIV-uninfected persons. Among HIV-infected persons, depression and increased waist size were significantly associated with insomnia. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
METHODS
Study Design and Participants
We performed a cross-sectional study among 200 HIV-infected and 50 HIV-uninfected persons who were 18-50 years of age. Participants were US military beneficiaries (active duty members, retirees, or dependents); active duty members are HIV seronegative on entry into military service and undergo mandatory HIV testing every 1-5 years. Given the routine screening and open access to care for military beneficiaries, our HIV cohort consisted of patients with early diagnosed and managed HIV infection.
HIV-infected patients were offered enrollment on presentation for routine care at HIV subspecialty clinics in 3 US geographic areas (San Diego, California; Washington, DC; and San Antonio, Texas). HIV-uninfected persons were enrolled at primary health care clinics. Exclusion criteria were current or recent suicidal ideation and the presence of an acute medical condition that could impact the participant's ability to complete the study (eg, febrile illness or any new onset or worsening condition deemed by patient's physician that could acutely impact sleep or neurocognitive functioning).
Recruitment into the HIV arm was balanced across the participants' current HIV status: "earlier" (<6 years of infection, no prior AIDS-defining condition, and CD4+ cell count nadir >200 cells/mm3) and "later" (not meeting all 3 criteria). Of the 200 original study participants, 193 (97%) provided complete sleep and neuropsychological test data and were included in this analysis. In the majority (n = 185), HIV infection had been diagnosed >6 months before study enrollment. HIV-uninfected participants (required to have an HIV-negative enzyme-linked immunosorbent assay test within the last year) were frequency matched to the HIV-infected participants by age (<35 vs 35-50 years), sex, race or ethnicity (white vs other), and military rank (officer vs enlisted vs other; retirees and dependents were placed in the "other" category). All participants provided written informed consent, and the study was approved by a central military institutional review board.
Main Outcomes
Insomnia and daytime sleepiness were the main outcomes examined. Each participant completed the Pittsburgh Sleep Quality Index (PSQI), a 19-item questionnaire that assesses 7 sleep components (sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of hypnotics, and daytime dysfunction) during the prior month, and insomnia was defined as a global score of >5 (sensitivity of 90% and specificity of 87% in the general population [20]). An Epworth Sleepiness Scale (ESS) score of ≥10 indicated daytime sleepiness [21].
Additional Data Collected
Factors potentially associated with sleep outcomes were collected including demographics, military rank and duty status, education, self-reported substance use (tobacco, alcohol, and illicit drugs), and history of serious head trauma. A self-assessment of sleep problems (categorized as present or absent, and if present having very little effect, mild effect, moderate effect, or severe effect on daily activities), and self-assessment of cognitive impairment were obtained via participant questionnaires. The Beck Depression Inventory (BDI) II (depression defined as a BDI score ≥20) and a modified version of the Activities of Daily Living (ADL) Questionnaire (a decline was defined as a reduction from prior best to current score in ≥2 items) were performed [22, 23]. HIV-infected participants completed questionnaires on lipodystrophy and peripheral neuropathy [24]. Lipoatrophy was defined as an affirmative response to loss of fat in the face, arms, or legs. Fat gain in the abdominal area was used as potential indicator of lipohypertrophy and referred to as increased waist size.
Participants underwent a comprehensive battery of standardized neuropsychological tests (administration time, 3.5-4 hours) derived from prior work [25] and composed of 9 measures shown to be sensitive to HIV-associated neurocognitive disorders. Neuropsychological tests were scored by trained psychometrists, and a global deficit score (GDS) of ≥0.5 was defined as neurocognitive impairment [26].
Clinical data were abstracted from medical records among HIV-infected participants, including body mass index (BMI), fasting lipid levels, and medical conditions. The metabolic syndrome was defined by modified Adult Treatment Panel III guidelines [27] and diabetes and hypertension by physician diagnoses. HIV-specific data were collected, including date of HIV seropositivity, history of AIDS-defining conditions [28], CD4+ cell counts (including nadir CD4+ cell counts), HIV RNA levels, and antiretroviral therapy.
Statistical Analyses
Participant characteristics were summarized by HIV status. Descriptive statistics are presented as means with standard deviations (SDs), or counts with proportions, as appropriate. Two-sample t tests were used to compare means, and χ2 tests were used to compare proportions across HIV-infected vs HIV-uninfected groups. Univariate and multivariate associations of factors (listed above) with insomnia were determined by logistic regression. Odds ratios (OR) for the prevalence of insomnia were estimated with 95% confidence intervals (CIs). Factors with a P value ≤ .10 in univariate models were initially included in the multivariate model and were then eliminated using backward selection. Linear regression and the Pearson correlation coefficient were used to explore the relationship between the PSQI score and BDI score. All P values were 2-sided, and P values < .05 were considered significant. Analyses were conducted using SAS software, version 9.2 (SAS Institute) and R software, version 2.9.
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