Poor Sleep and Inflammation in HIV-Infected Adults

Not Applicable

Completed

Conditions: HIV-1-infection
Sleep Deprivation
Inflammation

Interventions: Behavioral: Sleep deprivation

Registration Number: NCT03848325

Lead Sponsor: University of Pittsburgh

Brief Summary: People living with HIV (PLWH) often have poor sleep, which may put them at a higher risk for many chronic diseases, including cardiovascular disease. One of the mechanisms by which this may occur is via chronic inflammation and endothelial dysfunction. Adenosine plays an important role in sleep homeostasis, with levels increasing in the CSF in response to sleep deprivation and falling with sleep. Peripherally, adenosine, via its signaling pathway, plays an important role in immunoregulation by suppressing the inflammatory response. PLWH, even on antiretroviral therapy, have suppressed peripheral adenosine levels which are predictive of adverse cardiovascular outcomes. The hypothesis underlying this study is that acute sleep deprivation in PLWH does not result in a compensatory increase in extracellular adenosine and its signaling peripherally, and this failure to appropriately compensate, leads to an increase in systemic inflammation and endothelial dysfunction.

Detailed Description: People living with HIV infection (PLWH) are known to be at higher risk of cardiovascular disease and also have a higher prevalence of poor sleep than people who do not have HIV infection. Understanding the underlying mechanisms for the elevated risk of cardiovascular disease in PLWH is important to developing novel strategies to mitigate this risk. Poor sleep has been postulated to mediate some of the elevated cardiovascular risk in PLWH given the high prevalence of poor sleep in PLWH and the epidemiologic association of poor sleep with adverse cardiovascular outcomes among people who do not have HIV infection. However, the mechanisms by which PLWH may be more sensitive to sleep loss from a cardiovascular standpoint are unclear. One potential explanation for any elevated sensitivity would be via alterations in the adenosine signaling pathway.

Changes in extracellular adenosine levels in the brain and central nervous system play an important homeostatic role in sleep-wake regulation. Sleep deprivation results in a rise in extracellular adenosine levels while sleep itself leads to a rapid decline in levels. Peripheral adenosine signaling is a central feature of immunoregulation, primarily through its effects on inflammatory cytokine expression and lymphocyte adenosine receptor expression. PLWH tend to have a suppressed level of peripheral adenosine signaling and this level of suppression predicts risk of cardiovascular disease. The purpose of this study is to explore the impact of acute sleep deprivation among PLWH on measures of inflammation and endothelial function and to assess the extent to which any changes may be explained by alterations in peripheral adenosine signaling.

The study will enroll 40 PLWH, age 18-75, who have been on ART for greater than 48 weeks. Screening with questionnaires, actigraphy and polysomnography will eliminate individuals with underlying chronic sleep abnormalities. A prior night of polysomnography in the sleep lab will also habituate subjects to sleeping while monitored in the sleep lab.

Participants will arrive in the sleep laboratory in the evening and be allowed to sleep for 8 hours timed to their usual sleep patterns. On waking, participants will provide a urine sample that will be assayed for adenosine and adenosine metabolites. Blood will be drawn to measure markers of inflammation as well as markers of activation of the peripheral adenosine signaling system. Endothelial function will be assessed using flow mediated dilation.

Participants will be kept awake for the subsequent 24 hours including the 8 hour normal sleep period. On the second morning, subjects will again provide urine and blood samples for the same bioassays described above and then undergo repeat assessment of endothelial function.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

HIV positive
On continuous anti-retroviral therapy regimen for at least 48 weeks
CD4+ cell count greater than or equal to 200 cells/mm^3

Exclusion Criteria

Irregular or insufficient habitual sleep patterns
Severe advanced or delayed sleep phase
Primary sleep disorder
Autoimmune disorder
Use of immunosuppressant medications
Use of medications impacting adenosine pathway
Heavy caffeine use
Active alcohol or drug abuse
Elevated risk of adverse health effects from sleep deprivation (e.g., bipolar disorder, epilepsy, or suicidal ideation in the past 6 months)
Pregnancy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sleep deprivation	Sleep deprivation	All subjects will be provided an 8 hour opportunity for sleep (Night 1) followed by outcome assessment the next morning (Day 1). They will then be kept awake the subsequent 24 hours including Night 2, followed by outcome assessment the following morning (Day 2).

Primary Outcome Measures

Name	Time	Method
IL6	Baseline sleep replete state and after 24 hours of sleep deprivation	Plasma concentration of interleukin-6
Soluble CD14	Baseline sleep replete state and after 24 hours of sleep deprivation	Plasma concentration of soluble CD14
Soluble CD163	Baseline sleep replete state and after 24 hours of sleep deprivation	Plasma concentration of soluble CD163

Secondary Outcome Measures

Name	Time	Method
Monocyte Expression of TNF-alpha	Baseline sleep replete state and after 24 hours of sleep deprivation	Percentage of circulating CD14+ peripheral blood mononuclear cells expressing tumor necrosis factor-alpha
Flow Mediated Brachial Artery Dilation	Baseline sleep replete state and after 24 hours of sleep deprivation	Percent change was calculated by measuring the brachial artery diameter at baseline and then the percent dilation from this baseline after release of occlusion at each time point.
CD4+ T-cell Expression of HLA-DR and CD38	Baseline sleep replete state and after 24 hours of sleep deprivation	Percentage of CD3+ CD4+ T-lymphocytes co-expressing HLA-DR and CD38
CD8+ T-cell Expression of HLA-DR and CD38	Baseline sleep replete state and after 24 hours of sleep deprivation	Percentage of CD3+ CD8+ T-lymphocytes co-expressing HLA-DR and CD38
Monocyte Expression of IL6	Baseline sleep replete state and after 24 hours of sleep deprivation	Percentage of circulating CD14+ peripheral blood mononuclear cells expressing interleukin-6