Effect of Galantamine on Inflammation and Cognition

Although anti-retroviral therapy (ART) enhances life expectancy and overall quality of life
(QoL), HIV-infected individuals are increasingly vulnerable to non-AIDS-related diseases
including HIV-associated neurocognitive disorders (HAND). Inflammation is a primary mechanism
in the pathogenesis of HAND and tobacco use may further exacerbate inflammation. Conversely,
nicotine alone has anti-inflammatory effects suggesting that stimulating the cholinergic
pathway via pharmacological treatment [e.g., galantamine (GAL)] may suppress inflammation and
reverse or prevent neurocognitive deficits in HIV-1 infection. In this double-blind,
placebo-controlled crossover study, HIV-infected individuals (N=120; 60 smokers, 60
nonsmokers) will be randomized to 12 weeks of GAL or placebo, followed by a 4-week washout,
then 12 weeks of GAL or placebo (arms switched). All subjects will be stable on ART and the
GAL dose will follow FDA guidelines. At the beginning and end of each treatment phase,
inflammatory biomarkers and viral load will be assessed. Monocyte transcriptomics will also
be assessed on a subset of the sample (n=60; 30/group). Neurocognition and clinical outcomes
(e.g., QoL) will be measured at baseline and at 4-week intervals during each treatment phase.
The primary outcomes are monocyte/macrophage and T-cell activation (CD16, CD163, and CC
chemokine receptor type 2 or CCR2 expression; plasma CC chemokine ligand type 2 or CCL2
[MCP-1 or monocyte chemoattractant protein-1], sCD14; CD38/HLA-DR [cluster of differentiation
38/Human Leukocyte Antigen- antigen D Related] on CD8 [cluster of differentiation 8] cells)
and neurocognitive performance (processing speed, verbal learning/memory, executive
function). Exploratory outcomes include monocyte gene expression patterns and broad plasma
cytokine analysis. This study will provide insight into the interactions among nAChR
activation, HIV immune activation and pathogenesis, and tobacco use and has translational and
therapeutic implications that could improve health outcomes among HIV-infected individuals.

Inclusion Criteria:

Eligible subjects will be males and females:

1. At least 30 years old

2. Diagnosed with HIV-1 infection

3. On stable ART regimens (no changes to treatment within 4 weeks of Intake visit)

4. Viral load of less than or equal to 200 copies/mL

5. Current cluster of differentiation (CD4) counts greater than 200

6. If current or past diagnosis of bipolar disorder, eligible if:

1. No psychotic features

2. Montgomery-Asberg Depression Rating Scale (MADRS): total score less than 8 (past
4 weeks), suicidal item score less than 1 (past 4 weeks)

3. Young Mania Rating Scale (Y-MRS): total score less than 8 (past 4 weeks),
irritability, speech content, disruptive or aggressive behavior items score less
than 3 (past 4 weeks)

4. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in
the past 6 months

5. No aggressive or violent acts or behavior in the past 6 months

7. Able to communicate in English and provide written informed consent

8. Will be residing in the geographic area for at least 7 months

9. Not currently trying to quit smoking

10. Smoking Status

1. Smokers (HIV+S) will report smoking at least 5 cigarettes per day, on average for
the past year and provide a breath carbon monoxide (CO) sample greater than 5 ppm
at Intake and at the beginning of each treatment period

2. Non-smokers (HIV+NS) will report smoking fewer than 100 cigarettes in their
lifetime, or less than 5 pack years of smoking and no cigarettes in the last
year. They will self-report no current use of any tobacco or nicotine product and
will provide a CO sample of less than 3 ppm at Intake and at the beginning of
each treatment period. If CO sample does not reflect self-report, the PI will be
consulted to determine eligibility.

Exclusion Criteria:

Subjects who present with and/or self-report the following criteria will not be eligible to
participate in the study.

Smoking Behavior

1. Current enrollment or plans to enroll in another smoking cessation program in the next
7 months.

2. Regular (daily) use of electronic cigarettes, chewing tobacco, snuff, snus, cigars,
cigarillos, or pipes.

3. Current use or plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) or
smoking cessation treatments in the next 7 months.

Alcohol/Drug Use

1. Current untreated and unstable diagnosis of substance abuse or dependence (if past use
and if receiving treatment and stable for at least 30 days, eligible)

2. Breath alcohol concentration (BrAC) greater than 0.00 at Intake or Lab visits

3. Positive urine drug screen for cocaine, methamphetamines, phencyclidine (PCP),
barbiturates, ecstasy (MDMA), at Intake or Lab visits. Those who screen positive for
amphetamines, benzodiazepines, methadone, oxycodone, and/or opiates (low level cut-off
300 ng/mL) and who are prescribed these medications will be reviewed on a case-by-case
basis by the study physician and PIs (see Measures and Table 1 for details).
Participants believed to have a false-positive result on the drug screen may continue
in the study, with investigator approval.

Medical/Psychiatric Conditions

1. Women who are pregnant, planning a pregnancy or lactating

2. Current diagnosis of unstable and untreated major depression (if stable for at least
30 days, eligible)

3. Current or past diagnosis of psychotic disorder

4. A history or current diagnosis of cancer

5. Major heart disease or stroke within the past 6 months

6. Uncontrolled hypertension (systolic blood pressure greater than 160 or diastolic blood
pressure greater than 100).

7. Medical conditions contraindicated for use with galantamine:

1. Diagnosis of Alzheimer's disease or dementia

2. Epilepsy or other seizure disorder

8. Bladder outflow obstruction

9. Active or recent hepatitis C virus (HCV) co-infection

10. Liver function tests more than 20% outside of the normal range; Gamma-glutamyl
transpeptidase (GGT) values more than 20% outside of the normal range. If
Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be
evaluated for clinical significance by the Study Physician and eligibility will
determined on a case-by-case basis.

11. Renal disease or renal dysfunction (e.g., serum creatinine levels greater than 1.5 X
upper limit of normal). Those with moderate hepatic impairment or creatinine clearance
9 to 59 mL/min shall not exceed the 16 mg/day dose.

12. Peptic ulcer disease (requires study physician approval)

13. Suicide risk as indicated by at least one of the following on the Columbia Suicide
Severity Rating Scale (the PI and/or study psychologist will be consulted to assess
safety and determine eligibility in cases close to the eligibility cutoffs):

1. Current suicidal ideation (within 30 days of ernollment)

2. Two or more lifetime suicide attempts or episodes of suicidal behavior

3. Any suicide attempt or suicidal behavior within 2 years of enrollment

Medication

1. Current use or discontinuation within the last 14 days of:

1. Quit smoking medications including varenicline (Chantix), bupropion (Wellbutrin)

2. Anti-psychotic medications (e.g., Zyprexa, Clozaril, Seroquel, Risperdal). If
used to treat psychotic symptoms. Other uses may be eligible pending physician
approval).

3. Systemic Steroids (e.g., Prednisone).

4. Alzheimer's disease medications (e.g., Acetylcholinesterase inhibitors (ACIs),
Aricept/donepezil, Exelon/rivastigmine, Tacrine, or memantine)

5. Irritable bowel syndrome medication (e.g., Dicyclomine/Bentyl)

6. Heart medications (e.g., quinidine).

7. Muscle relaxants (e.g., Anectine/succinylcholine)

8. Anti-seizure medications (e.g. Ativan, Banzel, Carbatrol, Dilantin, Lamictal,
Gabitril, Lyrica, Neurontin, Tegretol, Topomax) if used to treat a seizure
disorder or epilepsy. Other uses may be eligible.

9. Urinary retention medications (e.g., Duvoid/bethanechol, Proscar/finasteride,
Avodart/dutasteride, Dibenzyline/ phenoxybenzamine, Regitine/phentolamine)

10. Eye medication (e.g., Atropine)

2. Daily use of:

1. Opiate-containing medications for chronic pain (Duragesic/fentanyl patches,
Percocet, Oxycontin). Smokers who report taking opiate-containing medications on
an "as-needed" basis will be instructed to refrain from use until their study
participation is over and that they will be tested to ensure they have complied
with this requirement.

2. Chronic obstructive pulmonary disease (COPD) medication (e.g.,
Atrovent/Ipratropium Bromide)

3. Known allergy to study medication.

Subjects will be instructed to refrain from using any study prohibited drugs/medications
(both recreational and prescription) throughout their participation in the study.