Poor Sleep and Inflammation in HIV-Infected Adults (SASH)

Impact of Poor Sleep on Inflammation and the Adenosine Signaling Pathway in HIV Infection

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.

Study Overview

• Status: Completed
• Conditions: Inflammation; Sleep Deprivation; HIV-1-infection
• Intervention / Treatment: Behavioral: Sleep deprivation

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Behavioral: Sleep deprivation; Eight hour opportunity for sleep followed by 24 hours of sleep deprivation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Soluble CD14	Plasma concentration of soluble CD14	Baseline sleep replete state and after 24 hours of sleep deprivation
Soluble CD163	Plasma concentration of soluble CD163	Baseline sleep replete state and after 24 hours of sleep deprivation
IL6	Plasma concentration of interleukin-6	Baseline sleep replete state and after 24 hours of sleep deprivation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Monocyte Expression of IL6	Percentage of circulating CD14+ peripheral blood mononuclear cells expressing interleukin-6	Baseline sleep replete state and after 24 hours of sleep deprivation
Monocyte Expression of TNF-alpha	Percentage of circulating CD14+ peripheral blood mononuclear cells expressing tumor necrosis factor-alpha	Baseline sleep replete state and after 24 hours of sleep deprivation
CD4+ T-cell Expression of HLA-DR and CD38	Percentage of CD3+ CD4+ T-lymphocytes co-expressing HLA-DR and CD38	Baseline sleep replete state and after 24 hours of sleep deprivation
CD8+ T-cell Expression of HLA-DR and CD38	Percentage of CD3+ CD8+ T-lymphocytes co-expressing HLA-DR and CD38	Baseline sleep replete state and after 24 hours of sleep deprivation
Flow Mediated Brachial Artery Dilation	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.	Baseline sleep replete state and after 24 hours of sleep deprivation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Adenosine	Plasma adenosine concentration	Baseline sleep replete state and after 24 hours of sleep deprivation
Plasma Inosine	Plasma inosine concentration	Baseline sleep replete state and after 24 hours of sleep deprivation
Urine 3'5'-cAMP	Urine 3'5'-cyclic adenosine monophosphate concentration normalized to creatinine	Baseline sleep replete state and after 24 hours of sleep deprivation
CD4+ T-cell Expression of CD39 and/or CD73	Percentage of CD3+ CD4+ T-lymphocytes expressing CD39 and/or CD73	Baseline sleep replete state and after 24 hours of sleep deprivation
CD8+ T-cell Expression of CD39 and/or CD73	Percentage of CD3+ CD8+ T-lymphocytes expressing CD39 and/or CD73	Baseline sleep replete state and after 24 hours of sleep deprivation

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Bernard J Macatangay, MD, University of Pittsburgh; Principal Investigator: Sanjay R Patel, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2020
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: February 13, 2019
• First Submitted That Met QC Criteria: February 18, 2019
• First Posted (Actual): February 20, 2019

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: adenosine
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Inflammation; Infections; Sleep Deprivation
• Other Study ID Numbers: PRO17120573; R01HL142118 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No