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

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 protocol
#13-N-0149 ("Screening and Recruitment for HIV-associated Neurocognitive Disorders (HAND)
Studies" and "An Evaluation of HIV-associated Neurocognitive Disorders in Virologically
Controlled Patients", PI Dr. Avindra Nath; ALL HANDS protocol) 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

- 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, 18-66 years of age

2. Ability to sign informed consent by the subject

3. Enrollment in protocol number 13-N-0149 ( Screening and Recruitment for HIV-associated
Neurocognitive Disorders (HAND) Studies and An Evaluation of HIV-associated
Neurocognitive Disorders in Virologically Controlled Patients , PI Dr. Avindra Nath;
ALL HANDS protocol)

4. Outside primary 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 <40 copies/mm^3 for greater than one year since the last available
documented viral load measurement under protocol 13-N-0149.

3. At least one year of continuous ART prior to last documented suppressed viral load
measurement under protocol 13-N-0149 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 drug abuse triggered by a positive response to the 13-N-0149 (ALL
HANDS protocol) screening questions: "Have you ever used cocaine? Heroin? Or
Amphetamines?" and confirmed by the investigator.

5. History of alcoholism: A positive response to the 13-N-0149 (ALL HANDS protocol)
screening question, "Has alcohol ever affected your 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 drug abuse triggered by a positive response to the 13-N-0149 (ALL
HANDS protocol) screening questions: "Have you ever used cocaine? Heroin? or
Amphetamines?" and confirmed by the investigator.

5. History of alcoholism: A positive response to the screening Client Diagnostic
Questionnaire, "Has alcohol ever affected your 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 Major Depressive Disorder, Bipolar disease,
Post-Traumatic Stress Disorder, Psychotic Disorder, Panic Disorder, or Generalized
Anxiety Disorder from the Client Diagnostic Questionnaire.

4. Current substance use by positive screen for drugs including opiates, cocaine,
amphetamine or THC metabolites at the time of enrollment. Active heavy alcohol use (>8
drinks per week for women and >15 drinks per week for men) is an exclusion. Use of
nicotine containing products will not be considered an exclusion.

5. Medications: use of narcotics, psychiatric (including anti-psychotics and
anti-depressants especially selective serotonin reuptake inhibitors (SSRIs)) and any
drug with potential 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.

Eligibility Checklists based on inclusion/exclusion criteria for all groups are included as
attachments 1 to 5. The attached checklists (appendices A-E) will be used by the
investigators at the time of screening for admission to the protocol.