Obstructive Sleep Apnea Endotypes and Impact on Phenotypes of People Living With HIV

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% oxymetazolime 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 velco 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.

Inclusion Criteria:

- Physician diagnosis of HIV and viral suppression

- Ages 18-65 years old

- BMI 20 - 35 kg/m2

Exclusion Criteria:

- Pregnancy

- Inability to complete study procedures, such as questionnaires that are only
available/validated in English.

- Known OSA already on effective therapy and adherent to treatment

- Other known untreated sleep fragmenting disorder, such as periodic limb movement
disorder, or narcolepsy. We will NOT exclude based on insomnia, given that OSA and
insomnia frequently exist together.

- Chronic lung disease requiring the use of supplemental oxygen, or with evidence of
hypercapnia due to obstructive lung disease.