Longitudinal Evaluation of HIV-associated Lung Disease Phenotypes (LEAP)

The Study is a Multicenter, Prospective Observational Study of Pathogenesis of HIV Pulmonary Disease.

The overall hypotheses of this proposal are that discrete phenotypes of HIV Chronic Obstructive Pulmonary disease (COPD) differ in their trajectories, biomarkers, and risk factors and that persistent viral infection including residual HIV is linked to HIV COPD.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease; Emphysema; HIV
• Intervention / Treatment: Procedure: blood draw; Procedure: questionnaires; Procedure: Lung function testing; Procedure: Six-Minute walk test; Radiation: Quantitative CT scans; Procedure: Nasal secretion and cell collection; Procedure: Echocardiogram

Detailed Description

The study is a multicenter, prospective observational study of pathogenesis of HIV pulmonary disease. We will determine the prevalence and risk factors for lung dysfunction as quantified by pulmonary function testing in HIV+ subjects. We will build on our existing longitudinal cohorts while adjusting for important co-variates such as antiretroviral therapy (ART), smoking history, co-infections, and illicit drug use. Evaluations will be scheduled at baseline, 18 months, and 36 months. (6, 12, 18 and 36 months for ART initiators at the UCSF). Study visits will consist of blood draw, questionnaires, pulmonary function testing, 6-minute walk test, CT of the chest at visit two. Oral specimen collection and glycocalyx and echocardiogram (visit two) at the Pittsburgh site only.

• Study Type: Observational
• Enrollment (Actual): 232

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The study population will be HIV positive subjects previously seen for other studies. There will be three centers enrolling, the University of Pittsburgh, the University of California San Francisco, and the University of California Los Angeles. Recruitment will occur from participants in ongoing lung studies at these sites.

Description

Inclusion Criteria:

• HIV-1 infection, documented in medical record at any time prior to study entry.
• Men and women age 18 to 80.
• Ability and willingness to complete all tests.
• Participant in HLRC studies, MACS, Women's Interagency Health Study, and local HIV clinics.
• For UCSF only, new ART initiators from Women's Interagency Health Study or the HIV clinic

Exclusion Criteria:

• Pregnancy or breast-feeding.
• Contraindication to pulmonary function testing (i.e. abdominal or cataract surgery within 3 months, recent myocardial infarction, etc.).
• Increasing respiratory symptoms or febrile (temperature >100.40F [380C]) within 4 weeks of study entry.
• Hospitalization within 4 weeks prior to study entry (excluding mental health).
• Uncontrolled hypertension at screening visit (systolic > 180 mm Hg or diastolic > 100 mm Hg) from an average of two or more readings. Subject may return for screening after blood pressure is controlled.
• Active cancer requiring systemic chemotherapy or radiation.
• Active infection of lungs, brain, or abdomen.
• Intravenous drug use or alcohol use that will impair ability to complete study investigations in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HIV positive normal pulmonary function; HIV positive DLCO percent predicted >=.80 FEV1/FVC percent predicted >=0.70	Procedure: blood draw; Blood will be drawn for plasma, serum, and PBMCs. Clinical labs drawn will be for hepatitis, CMV, hemoglobin and carboxyhemoglobin.; Procedure: questionnaires; The following questionnaires are administered to participants by study personnel at each visit: LEAP questionnaire, St. George's, and MMRC.; Procedure: Lung function testing; The routine lung function endpoints of FVC, FEV1, FEV1/FVC, and FEF25-75% will be measured before and after bronchodilator administration (4 puffs of albuterol). The best of three reproducible forced expiratory attempts is used in analysis. Percent- predicted spirometric values are based on age, height, gender, and ethnicity. DLco will be measured using the automated single-breath procedure of the integrated testing system, which conforms to ATS standards. DLco will be adjusted for hemoglobin and carboxyhemoglobin.; Other Names: Spirometry; Procedure: Six-Minute walk test; Six-minute walk tests are performed in a 100 foot (30.48 m) segment of straight hallway marked at 10 foot (3 m) intervals. In addition to the usual ATS protocol, the patient is monitored, when available, with Bluetooth wireless pulse oximetry and the time and distance recorded after six minutes and if they desaturate to <88%. Dyspnea (Borg 0-10) and perceived exertion (Borg 6-20) scales are completed at the beginning and the end of test.; Radiation: Quantitative CT scans; Subjects will undergo a standard chest CT. The CT scans will use a phantom shipped between sites to standardize results and capture contiguous volume scans acquired at slice thicknesses of 5.0 mm in the axial plane and reconstructed with 512 x 512 pixel matrices. CT examinations will encompass the entire thorax and be performed during a breath-hold at end-inspiration. We will measure % of lung tissue below a threshold for emphysema (i.e. -950 Hounsfield units). Measurements have been histologically-verified and give reproducible measurements. The data set is assembled and analyzed with the image data anonymized.; Other Names: CT scan of the chest; Procedure: Nasal secretion and cell collection; Participants will be instructed to blow their nose to remove accumulated mucus. Two sprays of commercially available nasal saline will be instilled in each nostril. The participant will then be ask to exhale through the rinsed nostril into a specimen cup. We will repeat this up to 5 times on each side depending on the participants' tolerance to the procedure. Using an otoscope, a small curette will then be used to collect 3 to 5 samples of nasal cells from each nostril. These samples will be used immediately for analysis or banked for future study.; Other Names: Nasal wash; Nasal scrapping; Procedure: Echocardiogram; The cardiac ultrasound will use standard ultrasound techniques to image two-dimensional slices of the heart using 3D real-time imaging.; Other Names: Echo
HIV positive with pulmonary dysfuntion; HIV positive DLco percent predicted <=0.80% FEV1/FVC percent predicted<=0.70%	Procedure: blood draw; Blood will be drawn for plasma, serum, and PBMCs. Clinical labs drawn will be for hepatitis, CMV, hemoglobin and carboxyhemoglobin.; Procedure: questionnaires; The following questionnaires are administered to participants by study personnel at each visit: LEAP questionnaire, St. George's, and MMRC.; Procedure: Lung function testing; The routine lung function endpoints of FVC, FEV1, FEV1/FVC, and FEF25-75% will be measured before and after bronchodilator administration (4 puffs of albuterol). The best of three reproducible forced expiratory attempts is used in analysis. Percent- predicted spirometric values are based on age, height, gender, and ethnicity. DLco will be measured using the automated single-breath procedure of the integrated testing system, which conforms to ATS standards. DLco will be adjusted for hemoglobin and carboxyhemoglobin.; Other Names: Spirometry; Procedure: Six-Minute walk test; Six-minute walk tests are performed in a 100 foot (30.48 m) segment of straight hallway marked at 10 foot (3 m) intervals. In addition to the usual ATS protocol, the patient is monitored, when available, with Bluetooth wireless pulse oximetry and the time and distance recorded after six minutes and if they desaturate to <88%. Dyspnea (Borg 0-10) and perceived exertion (Borg 6-20) scales are completed at the beginning and the end of test.; Radiation: Quantitative CT scans; Subjects will undergo a standard chest CT. The CT scans will use a phantom shipped between sites to standardize results and capture contiguous volume scans acquired at slice thicknesses of 5.0 mm in the axial plane and reconstructed with 512 x 512 pixel matrices. CT examinations will encompass the entire thorax and be performed during a breath-hold at end-inspiration. We will measure % of lung tissue below a threshold for emphysema (i.e. -950 Hounsfield units). Measurements have been histologically-verified and give reproducible measurements. The data set is assembled and analyzed with the image data anonymized.; Other Names: CT scan of the chest; Procedure: Nasal secretion and cell collection; Participants will be instructed to blow their nose to remove accumulated mucus. Two sprays of commercially available nasal saline will be instilled in each nostril. The participant will then be ask to exhale through the rinsed nostril into a specimen cup. We will repeat this up to 5 times on each side depending on the participants' tolerance to the procedure. Using an otoscope, a small curette will then be used to collect 3 to 5 samples of nasal cells from each nostril. These samples will be used immediately for analysis or banked for future study.; Other Names: Nasal wash; Nasal scrapping; Procedure: Echocardiogram; The cardiac ultrasound will use standard ultrasound techniques to image two-dimensional slices of the heart using 3D real-time imaging.; Other Names: Echo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
differences in the trajectory of FEV1 in clinical COPD phenotypes,	PFT's at baseline, 18 months and 36months to determine modifying risk factors and relationship of phenotypes to mortality, and delineate the association of ART and lung dysfunction.	36 months

Secondary Outcome Measures

Outcome Measure	Time Frame
will measure biomarkers of these phenotypes and ability to predict HIV COPD	36 months

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Drummond MB, Huang L, Diaz PT, Kirk GD, Kleerup EC, Morris A, Rom W, Weiden MD, Zhao E, Thompson B, Crothers K. Factors associated with abnormal spirometry among HIV-infected individuals. AIDS. 2015 Aug 24;29(13):1691-700. doi: 10.1097/QAD.0000000000000750.
• Gingo MR, Nouraie M, Kessinger CJ, Greenblatt RM, Huang L, Kleerup EC, Kingsley L, McMahon DK, Morris A. Decreased Lung Function and All-Cause Mortality in HIV-infected Individuals. Ann Am Thorac Soc. 2018 Feb;15(2):192-199. doi: 10.1513/AnnalsATS.201606-492OC.
• Qin S, Clausen E, Nouraie SM, Kingsley L, McMahon D, Kleerup E, Huang L, Ghedin E, Greenblatt RM, Morris A. Tropheryma whipplei colonization in HIV-infected individuals is not associated with lung function or inflammation. PLoS One. 2018 Oct 4;13(10):e0205065. doi: 10.1371/journal.pone.0205065. eCollection 2018.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): March 2, 2020
• Study Completion (Actual): March 2, 2020

Study Registration Dates

• First Submitted: September 4, 2014
• First Submitted That Met QC Criteria: September 9, 2014
• First Posted (Estimate): September 12, 2014

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: biomarkers; pulmonary function; Antiretroviral therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Emphysema
• Other Study ID Numbers: PRO14070355; 1R01HL125049-01 (U.S. NIH Grant/Contract)