The first cases of AIDS were brought to national attention in June 1981, after five young gay men in Los Angeles developed a rare lung infection known as Pneumocystis carinii pneumonia.1 HIV infection is a chronic viral illness that results in a progressive decline in cellular immunity. AIDS is diagnosed when the T-helper cell (CD4+) count drops below 200 cells per µL and is no longer high enough to prevent opportunistic malignancies and overcome opportunistic infections.

With an estimated 56,000 new infections per year2 and a steady decline in mortality rate over the past decade,3 the number of people living with HIV/AIDS (PLWHA) has increased in the United States and in other countries where diagnosis occurs earlier, antiretroviral medications are readily available, and prophylaxis and treatment for opportunistic infections and malignancies have improved. Now, in just over 27 years, it is estimated that 1.2 million people are living with HIV/AIDS in the United States,4 and more than 33 million people may be living with the disease worldwide.4

In 1981, HIV was diagnosed in most infected people in the final stage of AIDS, and their life expectancy was less than 2 years after diagnosis. While HIV/AIDS can be effectively treated, there remains neither a cure nor a vaccine. Combination antiretroviral therapy (cART), however, makes it possible to slow viral replication, to reconstitute severely compromised immune systems, and to increase life expectancy by more than 13 years.5 A person who starts cART at age 20 can expect to live to age 63.6 With longer survival, it has become possible for health care providers to focus greater attention on quality-of-life issues such as sleep disturbances, depression, and fatigue.

INSOMNIA AND HIV

Insomnia is self-reported difficulty getting to sleep, trouble staying asleep, waking up early, or a feeling that one’s sleep has not been restorative. Insomnia is a common problem reported by people living with HIV/AIDS that begins early in HIV disease, often prior to diagnosis and treatment, and continues throughout the illness.7-9 Reid and Dwyer10 report difficulty obtaining robust estimates of sleep problems in PLWHA, but studies of human subjects, particularly those using self-report measures, have typically reported higher prevalence rates, ranging from 43% to 100%.11-13 In the United Kingdom, Anderson and Weatherburn13 evaluated the needs of 1,821 people living with HIV/AIDS who responded to a survey and found that 32% reported that they were unhappy with their sleep.

PHASE OF ILLNESS AND SLEEP

The classification most widely used in the United States to stage HIV disease was created in 1986 and updated in 1993 by the US Centers for Disease Control and Prevention.14 Staging is based on the CD4+ count, which is normally 600 to 1,200 cells per µL. To avoid confusion with stages of sleep, the term phase of illness will be used to refer to the stages of HIV disease. In phase 1, the CD4+ cell count remains at or above 500 cells per µL. The individual looks and feels healthy, even though HIV is rapidly replicating and CD4+ cells are steadily declining. In phase 2, CD4+ cell counts range from 200 to 499 cells per µL. During phase 2, PLWHA experience constitutional symptoms such as fever, night sweats, and mild weight loss. Fungal infections of the skin and nails may appear. In phase 3, the CD4+ cell count drops below 200 cells per µL and the individual is categorized as having AIDS. Life-threatening opportunistic infections such as P. carinii pneumonia may appear, and opportunistic malignancies such as Kaposi sarcoma may develop.

There are inconsistent findings in the literature as to whether sleep disturbance is associated with phase of illness. Early studies prior to the advent of cART9,15,16 indicated that in phase 1, PLWHA reported mild insomnia and fatigue and the percentage of slow-wave sleep (SWS, delta sleep) increased, and more SWS occurred in the latter half of the sleep period. In phase 2, insomnia and fatigue progressed and maintaining sleep became more difficult. SWS decreased, sleep efficiency lowered, and cycles of non-rapid-eye movement (NREM) and rapid-eye-movement (REM) sleep became less organized. In phase 3, SWS all but disappeared, sleep efficiency continued to decline, and NREM-REM cycles became unrecognizable. The sleep-architecture changes, described by Norman et al,9,15,16 have also been supported in other research.17-19 Some studies, particularly those relying on self-report measures of sleep disturbance, have found no relationship with phase of HIV disease.11,12,18,20 A systematic review of the literature by Reid and Dwyer10 concluded that sleep disturbances are frequent in all stages of HIV disease and are not related to severity of illness or categorical stages of HIV infection.

SLEEP AND HIV PARTICLES

Evidence obtained in animal models has demonstrated that HIV may produce changes in sleep, and this may help explain the early onset of sleep disturbances prior to diagnosis and treatment. In one study, Prospero-Garcia et al21 found that feline immunodeficiency virus (FIV) glycoprotein (gp) 120 decreased SWS-2 and REM sleep and increased the waking state and SWS-1 in 15 adult male Sprague-Dawley rats. In a similar study, Sanchez-Alavez et al22 showed that both HIV gp120 and FIV gp120 increased the waking state during the light period and decreased the waking state during the dark period in adult male Wistar rats. HIV gp120 increased SWS-1 only at 13:00, 21:00, and 01:00 hours. They found that SWS-2 and REM sleep diminished following the administration of either HIV gp120 or FIV gp120.

In another study, Diaz-Ruiz et al23 found that HIV gp120 increased REM sleep and concluded that it did so through its effect on the extracellular signal-regulated kinase (ERK) signal transduction pathway. They found that an inhibitor of the ERK-activating enzyme prevented these changes. Further advancing the understanding of sleep and HIV particles, Gemma and Opp24 concluded that both gp160 and gp41 increased NREM, fragmented sleep, altered slow-frequency components of the electroencephalogram, and induced modest febrile responses. Opp et al25 suggested that the effects of HIV on sleep are mediated through changes in cytokines. Conflicting results may be due to the various models and dosages of viral particles used. Further research is needed in this area.

INSOMNIA, DEPRESSION, AND FATIGUE

Insomnia, depression, and fatigue form a cluster of symptoms in HIV/AIDS. Of PLWHA, depression may affect up to 50%,26 insomnia may affect as many as 43% to 100%,11,13,20 and fatigue may affect up to 78%.27 Several studies9,15-18 have reported sleep disturbances and daytime fatigue early in HIV disease, before its progression to AIDS.

Fatigue is a key factor in physical functioning, and in a nationally representative sample, PLWHA reported difficulty working at a job, working around the house, and attending school. Difficulty was also reported in performing physical tasks such as climbing stairs (43%), walking more than one block (26%), or bathing and dressing (14%).28 Sleep quality and depression also significantly predicted the degree of fatigue in PLWHA.27 Several physiological and psychological factors in PLWHA may help to explain this cluster of symptoms. HIV infection activates the proinflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor a (TNF-a), each of which has roles in sleep, depression, and fatigue.8,25,29-35

INSOMNIA AND IMMUNITY

Infection increases the need for sleep, and sleep is thought to be restorative. Ample evidence exists to suggest that IL-1 and TNF-a contribute to the regulation of NREM sleep,29-31 and the body of evidence that IL-6 is also a somnogenic cytokine is growing.36 Psychological distress is known to disrupt sleep quality and also to alter immunity in many different ways. To demonstrate this relationship, Cruess et al37 tested the relationships among psychological distress (Impact of Events Scale), subjective sleep quality (Pittsburgh Sleep Quality Index), and immune status (CD3+/CD4+ and CD3+/CD8+ cell counts) in HIV-positive men and women. The results of the study indicated that both psychological distress and sleep quality were significantly related to CD3+/CD8+ (T-suppressor/cytotoxic) cells.

INSOMNIA AND ADHERENCE

More than 95% adherence to therapy with antiretroviral medications is necessary to prevent virologic failure,38 and insomnia may be an important factor in nonadherence to treatment using these drugs. Illustrating this point, Ammassari et al39 found that insomnia was significantly related to adherence in 358 people living with HIV/AIDS in the Italian Cohort Study.

Poor sleep quality may also be a barrier to adherence. Proctor et al40 studied the barriers to medication adherence in HIV/AIDS and found that poor sleep quality and other physical needs (hunger and thirst) were significant obstacles to adherence. In other research, Phillips et al41 studied adherence in 173 HIV-infected women living in the rural southeastern United States. They found that poorer sleep quality and greater depression were associated with poorer adherence to therapy with medications in that sample, and that depression mediated the relationship between sleep quality and adherence.

TREATMENT OF INSOMNIA

Relatively few interventions for insomnia have been tested in people living with HIV/AIDS. Despite the lack of studied interventions, some researchers have started to analyze different approaches. Phillips and Skelton42 tested the efficacy of an individualized acupuncture intervention for the treatment of insomnia in 21 PLWHA. They administered individualized acupuncture twice weekly for 5 weeks (a total of 10 sessions) in a single-group pretest–posttest pre-experimental design. Subjective sleep quality, as measured by the Pittsburgh Sleep Quality Index, improved by an average of 3.4.

In another study, Dreher43 randomly assigned 120 HIV-positive subjects with disturbed sleep to caffeine withdrawal and abstinence for 30 days or continued caffeine consumption. In subjects with a reduced intake, results indicated a 35% improvement in sleep. Other interventions have also yielded promising findings. Hudson, Portillo, and Lee44 tested a tailored sleep protocol in 30 HIV-infected women using a one-group pretest–posttest design. Sleep was measured before the intervention and 1 week later using the General Sleep Disturbance Scale. The participants wore wrist actimetry sensors for 48 hours prior to the intervention and for 48 hours a week later. After initiating healthy sleep-hygiene practices, subjects showed an improved 24-hour activity rhythm, less daytime napping, and improved sleep perception. In view of the severity of sleep disturbances for people living with HIV/AIDS, it is unimaginable that greater attention has not been given to the efficacy of interventions.

INSOMNIA, QUALITY OF LIFE, AND METABOLISM

Undoubtedly, better sleep quality is associated with a better quality of life. Nokes and Kendrew45 found that better sleep quality is associated with better general well-being and better functional status. Other studies have documented similar findings. Phillips et al46 compared health-related quality of life for good sleepers and poor sleepers. Good sleepers scored higher than poor sleepers on all eight dimensions of health-related quality of life, as measured by the SF-36® health survey. In that study, sleep quality accounted for more of the variance in health-related quality of life than the phase of HIV disease did.

Metabolic disorders such as lipodystrophy, diabetes mellitus, and hyperlipidemia are frequent in AIDS patients, including those receiving highly active antiretroviral therapy.47 Evidence is accumulating that partial sleep deprivation increases the risk of metabolic disorders such as the metabolic syndrome,48,49 obesity,50,51 and diabetes.52 Three hormones have received special attention in the relationship between sleep quality and metabolism: leptin (an appetite suppressant), ghrelin (an appetite stimulant), and adiponectin. These three hormones are influenced by partial sleep deprivation. Studying the role of sleep in relationship to these hormones could provide useful information on the metabolic complications of HIV/AIDS patients.

Sleep disturbances are very prevalent in HIV/AIDS, and they affect many aspects of quality of life for people living with HIV/AIDS. While the research that has been conducted has produced much knowledge about sleep in HIV/AIDS, more research related to effective treatments is needed. In particular, understanding the role of sleep deprivation in the metabolic complications of HIV/AIDS could lead to quality-of-life improvements for people living with HIV/AIDS.

Kenneth D. Phillips, PhD, RN, is professor and associate dean for research, College of Nursing at University of Tennessee. Scobie Branson, DC, is owner of Branson Chiropractic. The authors can be reached at [email protected].

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