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

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.

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.

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.

Duration of participation in the study, which varied according to each study participant. Those subjects who were PLWH-OSA completed the study generally in 7-10 days. Subjects who were PLWH+OSA completed an additional overnight sleep study and then used CPAP therapy for 12 weeks. Their participation in the study might be up to 6 months depending on the timing of procedures.

Research and clinical procedures were interrupted by the COVID pandemic. In particular, the planned treatment phase (e.g. CPAP) of the study had greater than expected participant drop out and lower than expected adherence to CPAP.