Inflammation and Depression in People With HIV

Inclusion Criteria:

• HIV infected on continuous antiretroviral therapy (ART) with plasma HIV RNA <200copies/ml for at least 12 months (on at least two previous clinic visits andconfirmed at screening)

• Current cluster of differentiation 4 (CD4+) > 350 cells/microliter for at leasttwelve months (on at least two previous clinic visits and confirmed at screening)

• A primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, FifthEdition (DSM-V) major depression, current, or Bipolar, depressed type as diagnosedby the SCID-V

• Score of ≥10 on the 9-item Patient Health Questionnaire (PHQ-9)

• Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers,antipsychotics, and sedative hypnotics) for at least 4 weeks (8 weeks forfluoxetine) or on a stable psychotropic regimen for at least 4 weeks prior tobaseline visit

• Significant anhedonia as reflected by a score ≥ 2 on item #1 of the PHQ-9

• CRP≥2mg/L

• Women of reproductive age will have a negative serum pregnancy test at study entryand both mend and women must agree to adequate contraception while

Exclusion Criteria:

• < 18 years of age or > 65 years of age

• Pregnancy or breastfeeding

• Significant hematological abnormalities at screening (ANC < 1500, Hgb<10, platelet< 100,000)

• History of progressive multifocal leukoencephalopathy

• Untreated latent tuberculosis infection (which will be screened for prior to entry)

• Having taken the following immunosuppressive medications within the past 6 months:

1. Oral corticosteroids

2. Biologic treatments such as etanercept, infliximab, certolizumab, adalimumab,golimumab, tocilizumab, abatacept, Ustekinumab, ixekizumab, secukinumab, oranakinra

3. Cyclophosphamide (or any other cytotoxic agent), belimumab, or anifrolumab (oranother anti-interferon (IFN) therapy)

4. Rituximab, any other B cell depleting therapies, or intravenous immunoglobulin (IVIg)

5. any Janus kinase (JAK) inhibitor

• History of deep venous thrombosis

• Cardiovascular disease:

1. Coronary artery disease or history of myocardial infarction

2. Congestive heart failure with left ventricular ejection fraction ≤40% perAmerican Heart Association guidelines

3. Stroke history

• Hematologic malignancies including lymphoma and leukemia

• Major surgery within 8 weeks prior to screening or will require major surgery duringthe study

• Current or recent (<4 weeks prior to randomization) clinically serious viral (including coronavirus disease 2019 (COVID-19)), bacterial, fungal, or parasiticinfection or any other active or recent infection

• Symptomatic herpes simplex at the time of randomization

• Symptomatic herpes zoster infection within 12 weeks prior to randomization

• History of disseminated/complicated herpes zoster (for example, ophthalmic zoster orCNS involvement)

• Positive test for hepatitis B virus (HBV) defined as:

1. positive for hepatitis B surface antigen (HBsAg), or

2. positive for hepatitis B core antibody (HBcAb) and positive for hepatitis Bvirus deoxyribonucleic acid (HBV DNA)

• Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleicacid [RNA]-positive)

• Cirrhosis of the liver from any cause

• Any of the following specific abnormalities on screening laboratory tests:

1. alanine transaminase (ALT) or aspartate aminotransferase (AST) >2 x upperlimits of normal (ULN)

2. alkaline phosphatase (ALP) ≥2 x ULN

3. total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, whomust have total bilirubin <2 x ULN)

• Chronic kidney disease with estimated glomerular filtration rate (eGFR) <40mL/min/1.73 m^2

• History of any (non-mood-related) psychotic disorder; active psychotic symptoms ofany type; substance abuse/dependence within 6 months of study entry, as determinedby severe combined immunodeficiency (SCID)

• A positive urine drug screen for illicit drugs at any time during the studyexcluding marijuana

• An active suicidal plan as determined by a score >3 on item #3 on the HamiltonRating Scale for Depression (HAM-D)

• An active eating disorder or antisocial personality disorder

• History of dementia

• Chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg ofaspirin), glucocorticoid containing medications or minocycline within 2 weeks ofbaseline or at any time during the study

• Any contraindication for MRI scanning

• Failure of more than 2 antidepressant trials (at least 6 weeks at recommended dose)in the current episode or 5 antidepressant trials lifetime

• BMI >42 (to exclude severe obesity) or at the investigator's discretion based on thepatient's ability to fit in the MRI scanner