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

Sponsor

National Institutes of Health Clinical Center (CC) (NIH)

Overall Status

Completed

CT.gov ID

NCT03581305

Collaborator

(none)

Enrollment

Location

Arms

40.5

Actual Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Depression HIV Infections HIV-Associated Cognitive Motor Complex	Drug: 18F-FDOPA Drug: 11C-DASB	Phase 1

Detailed 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

Study Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Nov 20, 2018

Actual Primary Completion Date :

Apr 6, 2022

Actual Study Completion Date :

Apr 6, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dopaminergic arm 25 eligible HIV-infected individuals and 50 eligible HIV-negative (HIV-) individuals for the dopaminergic arm	Drug: 18F-FDOPA High resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) system.
Active Comparator: Serotonergic arm 20 HIV-infected individuals and 20 HIV-negative individuals for the serotonergic arm	Drug: 11C-DASB High resolution positron emission tomography (PET) of the brain and radioligands targeted against the serotonergic (11C-DASB) system.

Arm

Intervention/Treatment

Active Comparator: Dopaminergic arm

25 eligible HIV-infected individuals and 50 eligible HIV-negative (HIV-) individuals for the dopaminergic arm

Drug: 18F-FDOPA

High resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) system.

Active Comparator: Serotonergic arm

20 HIV-infected individuals and 20 HIV-negative individuals for the serotonergic arm

Drug: 11C-DASB

High resolution positron emission tomography (PET) of the brain and radioligands targeted against the serotonergic (11C-DASB) system.

Outcome Measures

Primary Outcome Measures

Influx constant (Ki) for 18F-FDOPA PET. [Study Completion]
To learn how HIV affects dopamine in the brain
11C-DASB PET [Study Completion]
To learn how HIV affects serotonin in the brain.

Secondary Outcome Measures

Correlation of 18F-FDOPA with co-morbidities [Study Completion]
Correlation of 18F-FDOPA with co-morbidities
Correlation of 18F-FDOPA and 11C-DASB with HIV [Study Completion]
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).
Correlation of 11C-DASB with Neuropsychiatric evaluation [Study Completion]
Correlation of 11C-DASB with Neuropsychiatric evaluation (e.g. depressive and executive function/cognitive scores).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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):

Men and women, 18-70 years of age
Ability to sign informed consent by the subject
Subjects may be enrolled in or have been discharged from IRB approved NIH protocols OR subjects may be referred from outside providers/institutions.
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])

Known and documented HIV-1 infection
Plasma HIV-RNA BLD (<100 copies/mm3) for greater than one year since the last available documented viral load measurement..
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)

HIV-antibody negative
At least one or more of the following criteria:
Hypertension, as defined by treatment with medications for hypertension or with a systolic blood pressure at screening greater than or equal to 140mm Hg.
Diabetes mellitus, as defined by HgbA1C greater than or equal to 6.5% or known treatment for diabetes.
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.
History of previous but not current drug abuse.
History of previous but not current alcoholism (defined as alcohol intake that affect/affected the subject s work or home life).
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)

HIV-antibody negative
No history of any of the following:
Hypertension, as defined by treatment with medications for hypertension or with a systolic blood pressure at screening greater than or equal to 140mm Hg.
Diabetes mellitus, as defined HgbA1C greater than or equal to 6.5% or treatment for diabetes.
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.
History of previous drug abuse.
History of previous alcoholism. Alcoholism is based on alcohol having affected the subject s work or home life.
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).
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)

HIV-antibody negative

EXCLUSION CRITERIA:

All Subjects (Groups A-E):

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.
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.
A positive screening result for psychiatric diseases that are known to affect the dopaminergic or serotonergic systems.
Current substance abuse that would interfere with PET scan results at the investigators discretion.
Medications: use of any drug with known dopaminergic or serotonergic activity within 6 months prior to planned imaging date(s).
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.
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):

Use of any of the following drugs within 6 months from planned imaging date(s):
Haloperidol (increased intracerebral dopamine turnover caused by haloperidol may result in increased accumulation of 18F-DOPA)
Monoamine oxidase (MAO) inhibitors (may result in increased accumulation of 18F-DOPA in the brain)
Reserpine (reserpine-induced depletion of the contents of intraneuronal vesicles may prevent retention of 18F-DOPA in the brain)
Carbidopa/LDOPA (LDOPA competes with 18F-DOPA for DOPA decarboxylase activity)
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.