PET Imaging of the Dopaminergic and Serotonergic Systems in Treated HIV Positive Subjects

Depression Clinical Trial

Official title:

PET Imaging of the Dopaminergic and Serotonergic Systems in Treated HIV Positive Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03581305
• Other study ID #: 180117
• Secondary ID: 18-CC-0117
• Status: Completed
• Phase: Phase 1
• Start date: November 20, 2018
• Est. completion date: April 6, 2022

Study information

• Verified date: April 7, 2022
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Human immunodeficiency virus (HIV) infection is a serious disease with no cure. Some people with HIV have depression and other mood problems. They can have problems with thinking and memory. Researchers think 2 chemicals in the brain may cause those problems. The chemicals are serotonin and dopamine. The researchers want to take images to learn more about those chemicals in HIV patients.

Objective:

To learn how HIV affects serotonin and dopamine in the brain.

Eligibility:

Adults ages 18-70 with HIV who have been on antiretroviral treatment for at least 1 year

Healthy adults ages 18-70

All participants must be already enrolled in protocol 13-N-0149.

Design:

• Participants will be screened with a urine drug test. The results could be shared with insurance companies.

• Participants who could be pregnant will have a pregnancy test.

• Participants may have a physical exam and blood tests.

• Participants will have 1 or 2 positron emission tomography (PET) scans. A needle will guide a thin plastic tube (catheter) into an arm vein. A radioactive drug will be injected into the plastic tube. This is a tracer that helps researchers understand the PET images.

• Participants who have the dopamine scan will have to fast for 4-6 hours before the scan. They will take a pill to help direct the tracer to the brain one hour before the scan.

• Each scan will last about 1.5 hours.

• Participants will be asked to drink a lot of fluids and empty their bladder frequently for the rest of the day after each scan.

Description:

Background: An extensive body of literature points towards neuronal brain injury in human immunodeficiency virus positive (HIV-positive) subjects despite virological suppression of the virus in the periphery under the effect of antiretroviral therapies (ART). Existing evidence suggests that the central nervous system (CNS) could be an important reservoir for human immunodeficiency virus (HIV) regardless of cumulative time on treatment. This results in progressive neurocognitive dysfunction despite optimal treatment and peripheral control of the infection. Even though structural imaging studies have described abnormalities in optimally-treated HIV-positive subject population, there has been only a few attempts at deciphering the cellular levels of brain damage in those subjects using in vivo molecular imaging biomarkers. As part of CNS involvement, specific neurotransmitter systems including the dopaminergic and serotonergic systems are thought to be affected by the infection with distinct neurological, cognitive and psychological manifestations, even in optimally-treated subjects.

Objective: This protocol aims at identifying aspects of dopaminergic and serotonergic dysfunction in optimally-treated HIV-positive subjects using high resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) and serotonergic (11C-DASB) systems.

Study population: We will identify 25 eligible HIV-infected individuals and 50 eligible HIV-negative (HIV-) individuals for the dopaminergic arm, and 20 HIV-infected individuals and 20 HIV-negative individuals for the serotonergic arm. Subjects will be selected from IRB approved NIH protocols, self-referred or will be referred form outside providers/institutions and those who meet eligibility criteria will be offered enrollment in our study.

Design: Subjects will undergo either a one-time 18F-FDOPA PET scan or a one-time 11C-DASB PET scan or both, if eligible. HIV-positive subjects and HIV-negative individuals will be included in the study.

Outcome Measures: Influx constant (Ki) for 18F-FDOPA PET and Binding potential relative to

non-displaceable binding (BPND) values for 11C-DASB PET

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: April 6, 2022
• Est. primary completion date: April 6, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

• INCLUSION CRITERIA:

Subject groups:

• Dopaminergic arm:

• Group A: HIV-positive subjects with or without co-morbidities

• Group B: HIV-negative subjects with co-morbidities

• Group C: HIV-negative subjects without co-morbidities

• Serotonergic arm:

• Group D: HIV-positive subjects with or without co-morbidities

• Group E: HIV-negative subjects with or without co-morbidities

All Subjects (Groups A-E):

1. Men and women, 18-70 years of age

2. Ability to sign informed consent by the subject

3. Subjects may be enrolled in or have been discharged from IRB approved NIH protocols OR subjects may be referred from outside providers/institutions.

4. Has the ability to be seen by an outside medical doctor who provides care.

All HIV-positive Subjects with or without co- morbidities (Groups A [dopaminergic arm, n=25)] and Group D [serotonergic arm, n=20])

1. Known and documented HIV-1 infection

2. Plasma HIV-RNA BLD (<100 copies/mm3) for greater than one year since the last available documented viral load measurement..

3. At least one year of continuous ART prior to last documented suppressed viral load measurement and no history of ART modification or interruption since then.

HIV-negative Subjects WITH Co-morbidities (Group B, n=25)

1. HIV-antibody negative

2. At least one or more of the following criteria:

1. Hypertension, as defined by treatment with medications for hypertension or with a systolic blood pressure at screening greater than or equal to 140mm Hg.

2. Diabetes mellitus, as defined by HgbA1C greater than or equal to 6.5% or known treatment for diabetes.

3. Hepatitis C infection as documented by lab results of a positive Hepatitis C antibody and/or detectable Hepatitis C viral load. Subjects who responded to HCV treatment (SVR) will be included.

4. History of previous but not current drug abuse.

5. History of previous but not current alcoholism (defined as alcohol intake that affect/affected the subject s work or home life).

6. Clinical atherosclerotic cardiovascular disease (ASCVD) (e.g. history of acute coronary syndromes, or myocardial infarction, stable or unstable angina, coronary or other arterial revascularization or peripheral arterial disease of atherosclerotic origin) and/or 10-year heart disease risk score (ASCVD risk score) >7.5% (7.5 % score is the threshold for starting statin therapy as per the 2013 American College of Cardiology [ACC] / American Heart Association [AHA] guidelines).

HIV-negative Subjects WITHOUT co-morbidities (Group C, n=25)

1. HIV-antibody negative

2. No history of any of the following:

1. Hypertension, as defined by treatment with medications for hypertension or with a systolic blood pressure at screening greater than or equal to 140mm Hg.

2. Diabetes mellitus, as defined HgbA1C greater than or equal to 6.5% or treatment for diabetes.

3. Hepatitis C infection as documented by lab results of positive Hepatitis C antibody and/or detectable Hepatitis C viral load. Subjects who responded to HCV treatment (SVR) will not be included.

4. History of previous drug abuse.

5. History of previous alcoholism. Alcoholism is based on alcohol having affected the subject s work or home life.

6. Clinical ASCVD (e.g. history of acute coronary syndromes, or myocardial infarction, stable or unstable angina, coronary or other arterial revascularization or peripheral arterial disease of atherosclerotic origin) and/or 10-year heart disease risk score (ASCVD risk score) >7.5% (7.5 % score is the threshold for starting statin therapy as per the 2013 ACC/AHA guidelines 35).

7. Any other disease entities including chronic infections (e.g. Hepatitis B, Lyme disease), neurological diseases (e.g. Multiple sclerosis, vasculitis) or systemic diseases (e.g. Sjogren s diseases, sarcoidosis, systemic lupus erythematosus [SLE]) that in the opinion of the investigator would be considered a significant co-morbidity.

HIV-negative Subjects with or without co- morbidities (Group E, n=20)

1. HIV-antibody negative

EXCLUSION CRITERIA:

All Subjects (Groups A-E):

1. Illness or other condition that, in the opinion of the PI, may interfere with study participation at the time of enrollment, including known history of significant intracranial structural damage such as previous stroke(s) or history of intracranial benign or malignant tumors.

2. Conditions other than HAND associated with cognitive impairment or dementia such as Alzheimer s, Parkinson s disease, head injury with loss of consciousness >30 minutes, or seizure disorders.

3. A positive screening result for psychiatric diseases that are known to affect the dopaminergic or serotonergic systems.

4. Current substance abuse that would interfere with PET scan results at the investigators discretion.

5. Medications: use of any drug with known dopaminergic or serotonergic activity within 6 months prior to planned imaging date(s).

6. Pregnant or Lactating women: Women of childbearing potential must have a negative serum or urine pregnancy test within 1 week prior to study entry. Pregnancy testing will also be performed in enrolled female participants prior to any radiation exposure.

7. Prior or planned/anticipated exposure to radiation due to clinical care or participation in other research protocols, which would exceed the recommended acceptable annual limit of radiation exposure once accounting for the requirements of the current study.

Additional Exclusion Criteria for the Dopaminergic Arm (Groups A, B and C):

1. Use of any of the following drugs within 6 months from planned imaging date(s):

1. Haloperidol (increased intracerebral dopamine turnover caused by haloperidol may result in increased accumulation of 18F-DOPA)

2. Monoamine oxidase (MAO) inhibitors (may result in increased accumulation of 18F-DOPA in the brain)

3. Reserpine (reserpine-induced depletion of the contents of intraneuronal vesicles may prevent retention of 18F-DOPA in the brain)

4. Carbidopa/LDOPA (LDOPA competes with 18F-DOPA for DOPA decarboxylase activity)

2. Allergy to carbidopa

Note that HBV is not an exclusion criterion for groups A, B, D or E since it s not known to have direct CNS pathology in the absence of advanced liver disease and cirrhosis.

Related Conditions & MeSH terms

• AIDS Dementia Complex
• Depression
• HIV Infections
• HIV-Associated Cognitive Motor Complex

Intervention

Drug:
• 18F-FDOPA
High resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) system.
• 11C-DASB
High resolution positron emission tomography (PET) of the brain and radioligands targeted against the serotonergic (11C-DASB) system.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institutes of Health Clinical Center (CC)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Influx Constant (Ki) for 18F-FDOPA PET.	in order to learn how HIV affects dopamine in the brain, we performed dynamic PET scans for 90 minutes in each patient, after injection of FDOPA.; Analysis: After the scans were reconstructed, we extracted the Time activity curves and performed compartmental analysis using Patlak linear graphical analysis with reference region.; The extracted outcome measure is the influx constant referred to as Ki and reflecting the rate of FDOPA uptake in specific brain regions.	90 minutes of scanning
Primary	11C-DASB PET Binding Potential	Binding potential is a measure of the density of available serotonin transporter in specific brain locations. This is extracted from time activity curves of dynamic PET data acquired over 90 minutes after injection of 11C-DASB.	90 minutes of scanning
Secondary	Correlation of 18F-FDOPA With Co-morbidities	Correlation of 18F-FDOPA uptake in the brain with co-morbidities such as cardiovascular disease	Study and statistical analysis Completion
Secondary	Correlation of 18F-FDOPA and 11C-DASB With HIV	Correlation of 18F-FDOPA and 11C-DASB with HIV infection parameters (e.g. time since HIV diagnosis, duration of infection before treatment initiation, nadir CD4).	Study and statistical analysis Completion
Secondary	Correlation of 11C-DASB With Neuropsychiatric Evaluation	Correlation of 11C-DASB with Neuropsychiatric evaluation (e.g. depressive and executive function/cognitive scores).	Study and statistical analysis Completion

External Links

•   NIH Clinical Center Detailed Web Page