Obstructive Sleep Apnea Endotypes and Impact on Phenotypes of People Living With HIV
Condition: Human Immunodeficiency Virus; Obstructive Sleep Apnea
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Immunologic Deficiency Syndromes
Study type: Observational

Summary: 
      The investigators seek to understand how the different underlying causes of OSA affect the
      way people living with HIV (PLWH) experience OSA. The investigators also want to understand
      how symptoms of obstructive sleep apnea improve with treatment, and if this too, is affected
      by the underlying cause of OSA in that individual
    

Detailed description: 
      Overnight Visit #1. Subjects will arrive to the research sleep laboratory at approximately
      7PM and undergo the following procedures:

        1. Polysomnography: Monitoring for standard clinical polysomnography study will be applied
           to the subject, as follows: The subject will have EEG, EMG, EOG, and ECG electrodes, an
           adhesive body position sensor placed in standard locations. Pulse oximetry sensor will
           be attached either to a finger or ear lobe and secured by tape. The following parameters
           will be measured during sleep: electroencephalogram, eye movement, electrocardiogram,
           electromyogram, leg movement, snoring sounds, nasal pressure, and nasal-oral airflow by
           thermistor, respiratory effort and body position by piezo-electric bands of the thorax
           and abdomen or magnetometers, position sensors, and pulse oximetry. This equipment is
           standard for diagnostic polysomnography and should not be uncomfortable.

           Once all of this equipment has been comfortably and securely fastened, the subject will
           be allowed to fall asleep and data recording will begin. Subjects will be asked to
           remain in the supine position as much as possible. All data will be acquired on a 1401
           plus interface and Spike 2 software. The study will end at approximately 6 AM, at which
           time the monitoring equipment will be removed, and the subject will undergo a blood draw
           in this fasting state.

        2. Phlebotomy: Venipuncture will be performed by a certified research staff or physician
           using standard techniques and appropriate blood borne pathogen precautions.
           Approximately 10-15 cc of blood will be drawn in the morning at wake into serum
           separator and EDTA tubes. Serum samples will be immediately processed to separate serum,
           which will be stored in darkness at -70 F to preserve until analysis can be conducted.
           EDTA tubes will be processed and refrigerated for use within 24 hours. Blood will also
           be collected to measure high sensitivity C Reactive Protein (hsCRP), insulin, glucose
           (to calculate HOMA-IR), cytokines such as IL-6 and TNF-alpha.119 The investigators will
           also store plasma for other potential markers, to explore other interactions, such as
           markers of liver disease like ALT and AST.

      Subjects will then be able to go home. They will leave the actiwatch for the investigators.
      The investigators anticipate that Overnight Visit #1 will last 10 hours (most of which will
      be spent asleep).

      If subjects are not found to have OSA, they will not continue with the study. (End of Aim #1)

      Aims #2 and #3 Subjects found to have OSA (with AHI >5 events/hour) will be referred for
      clinical evaluation (by a sleep physician not involved in the study) and treatment, and will
      also return for overnight visit #2, and continue to be followed with weekly phone calls and a
      repeat assessment 3 months after starting OSA treatment.

      Overnight Visit #2 (Aim #2) Measurement of Endotypic Traits

      This visit will be scheduled to occur within 1 month of visit 1, and will be prior to any
      clinical OSA treatment. Subjects will come to the sleep research laboratory about 2-3 hours
      before their usual bedtime. They will undergo polysomnography, as described above, without
      the physiological CPAP testing procedure. To review, the subject will have EEG, EMG, EOG, and
      ECG electrodes, an adhesive body position sensor placed in standard locations. Pulse oximetry
      sensor will be attached either to a finger or ear lobe and secured by tape. The following
      parameters will be measured during sleep: electroencephalogram, eye movement,
      electrocardiogram, electromyogram, leg movement, snoring sounds, nasal pressure, and
      nasal-oral air flow by thermistor, respiratory effort and body position by piezo-electric
      bands of the thorax and abdomen or magnetometers, position sensors, and pulse oximetry. This
      equipment is standard for diagnostic polysomnography and should not be uncomfortable.

      Additional equipment for the physiological sleep study will also be applied to the subject,
      as follows:

      A thin esophageal catheter (6-8 french) with an electrode array to measure diaphragm
      electromyography will be placed via the nares. Prior to the cannula placement the subject
      will received 2 sprays of a nasal decongestant (0.05% oxymetazoline hydrochloride), followed
      by 4% lidocaine topical spray for local anesthesia. The catheter will be confirmed to be in
      the proper position by examining the signal, then taped to the nose (and later secured to the
      CPAP mask). The esophageal catheter placement may be omitted by subject or investigator
      request; in this case subjects can still remain in the study.

      A standard CPAP mask will be placed over the nose and secured with velcro straps. If
      necessary, the subject's mouth will be either taped closed or a chin strap applied to ensure
      nasal breathing. A specially modified continuous positive airway pressure (CPAP) device
      (ResMed, San Diego, CA) that delivers both positive and negative airway pressure will be
      connected to the mask. Once all of this equipment has been comfortably and securely fastened,
      the subject will be allowed to fall asleep and data recording will begin. Subjects will be
      asked to remain in the supine position as much as possible. All data will be acquired on a
      1401 plus interface and Spike 2 software (Cambridge Electronics Design Ltd, Cambridge, UK).

      After sleep onset, airway pressure will be increased in order to abolish flow limitation.
      During sleep, a previously validated sequence of pressure reductions will be performed in
      order to measure respiratory control and upper airway characteristics, as follows: The
      holding pressure will be abruptly changed to atmospheric pressure for several breaths, then
      returned to holding pressure. After a short time, the pressure will be gradually reduced over
      the course of several minutes, until an arousal occurs on the EEG (generally not associated
      with any awareness by the subject). The subject will be given several minutes to resume
      normal sleep, and the procedure will be repeated until three stable readings are obtained.
      Subsequently, the procedure will be repeated, but with a reduction in pressure to a level
      that does not induce arousal. After a short period of time with stable breathing at this
      pressure, the pressure will be returned to the holding pressure to measure ventilatory
      response. This will be repeated until 3 stable values are obtained.

      The study will end at approximately 4 AM, at which time the monitoring equipment will be
      removed, and the subject will be allowed to go home. However, if the subject is still sleepy,
      they will be allowed to sleep with CPAP applied until they feel rested.

      Aim #3 investigates the impact of CPAP on the phenotypic traits.

      The investigators anticipate that Overnight Visit #2 will last 8 hours (most of which will be
      spent sleeping).

      Weekly Phone calls: Subjects will be referred to a sleep physician for PAP therapy. The
      treatment is expected every day to be worn when participants are asleep (including naps). In
      addition to usual clinical care provided to ensure optimal adherence to PAP therapy, the
      research staff will be in weekly contact with subjects to provide encouragement, and identify
      and troubleshoot impediments to all-night, every-night use of PAP therapy. These phone calls
      will be 10-15 minutes each for 12 weeks.

      2 weeks prior to returning for Daytime Visit #2, subjects will be mailed or delivered an
      actiwatch to wear for 2 weeks.

      Daytime Visit #2: Impact of OSA treatment on Sleep and Activity Phenotypes

      After three months of OSA treatment, subjects will return to the sleep lab to repeat all of
      the same measurements described under Visit 1 with the exception of the lung function testing
      (see Daytime Visit #1). This visit will generally occur in the morning at which time another
      fasting blood sample will be collected.

      Additionally for subjects using PAP therapy for treatment of OSA, the investigators will
      obtain a PAP download which will report therapeutic holding pressure, residual apnea-hypopnea
      index, as well as multiple parameters of adherence such as days of use, number of days >4
      hours per night, etc. Mask type (nasal vs. oronasal, etc) will be recorded. The actiwatch
      will be returned to the investigators to assess the impact of PAP therapy on activity levels,
      pattern of activity and sleep duration.

      The investigators anticipate that Daytime Visit #2 will be 2 hours.

      The total duration of the participant's involvement in the study is expected to be a total of
      18 weeks.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        People living with HIV on ART and demonstrated viral suppression will be recruited into the
        study to undergo a standard sleep study, a research sleep study, and other procedures
        designed to measure phenotypic expression of sleep/OSA. All of the planned experiments will
        take place at UCSD.

        This study does not contain any exclusion by race, gender or ethnicity. We will only study
        subjects able to give self-consent. Thus, patients with existing severe dementia, children,
        prisoners, etc. will not be included. We believe that duration of HIV infection, HIV
        medication use and duration of use may be potentially important. However, while we will
        gather such information as completely as possible, we will not limit participation based on
        these factors. Finally, our preliminary data suggest that many PLWH use medications that
        might affect sleep, such as benzodiazepines, cannabinoids, etc. We plan to INCLUDE these
        subjects to increase the generalizability of our findings.
      
Biospecimen description: 
      Approximately 10-15 cc of blood will be drawn in the morning at wake into serum separator and
      EDTA tubes. Serum samples will be immediately processed to separate serum, which will be
      stored in darkness at -70 F to preserve until analysis can be conducted. EDTA tubes will be
      processed and refrigerated for use within 24 hours. Blood will also be collected to measure
      high sensitivity C Reactive Protein (hsCRP), insulin, glucose (to calculate HOMA-IR),
      cytokines such as IL-6 and TNF-alpha.119 The investigators will also store plasma for other
      potential markers, to explore other interactions, such as markers of liver disease like ALT
      and AST.
    
Keywords: HIV; OSA; PLWH; Sleep; Obstructive Sleep Apnea; Human Immunodeficiency Virus; CPAP