Inflammation and Depression in People With HIV

The purpose of this 10-week, double-blind, placebo-controlled study is to determine whether inflammation impacts reward and motor neural circuitry to contribute to depressive symptoms like anhedonia and psychomotor slowing in people with Human Immunodeficiency Virus (HIV) and depression. Sixty male and female patients with HIV who have depression, anhedonia and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either the anti-inflammatory drug baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study.

Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity and mortality. Risk for depression is further increased in PWH with elevated biomarkers of inflammation, e.g., the acute phase reactant C-reactive protein (CRP), that contribute to resistance to antidepressant therapies. Moreover, increased inflammation in the context of chronic depression in PWH is characterized by worsened cognitive function including impaired processing speed and motor activity. The investigator's recent neuroimaging studies in HIV-negative patients with major depression (MD) demonstrate that endogenous elevations in inflammation (as reflected by increased plasma CRP) are associated with decreased functional connectivity (FC) within corticostriatal reward and motor circuits involving the ventral and dorsal striatum and frontal cortical regions in relation to symptoms of anhedonia and psychomotor retardation. Anhedonia and psychomotor slowing represent fundamental aspects of research domain criteria (RDoC) of Positive and Negative Valence systems, and are closely aligned with a symptom cluster overrepresented in PWH referred to as apathy, which is thought to be driven by similar medial prefrontal and subcortical circuitry. Previous work from the investigators also suggests that reducing inflammation with a traditional cytokine antagonist improves symptoms of anhedonia and psychomotor retardation in HIV-negative patients with MD, but only in patients with higher levels of CRP. These data suggest the hypothesis that inflammation plays a role in anhedonia and motor slowing through effects on corticostriatal reward and motor circuits in PWH.

Members of the study team have performed extensive pre-clinical and clinical work on the Janus Kinase (JAK 1/2) inhibitor drug class for disorders associated with immune dysregulation including inflammation. Baricitinib is one of these compounds and is an FDA-approved, orally bioavailable agent for treatment of rheumatoid arthritis (RA) with recent FDA-approval for treatment of acute COVID-19. The JAKs are members of the cytoplasmic tyrosine kinase group that act to phosphorylate various signal transducers and activators of transcription (STATs) that then translocate to the nucleus and bind to specific transcription sites. This binding promotes the production of a variety of inflammatory mediators including interleukin (IL)-6, tumor necrosis factor (TNF), CRP and others. Thus, the key hallmark of the efficacy of baricitinib in human studies across disease states is its ability to significantly reduce plasma IL-6, TNF, and CRP and ultimately inflammation.

This study uses a biomarker-driven approach to test the hypotheses that inhibition of inflammation through specific inhibition of JAK 1/2 inflammatory signaling pathways will increase FC in corticostriatal reward and motor circuits (Aim 1) and improve anhedonia and psychomotor slowing (Aim 2) in association with reduced plasma inflammatory markers, as well as additional CSF, neuroimaging, peripheral blood immune cell, and markers of inflammation and the HIV reservoir and/or safety (Aim 3), in PWH with MD and high inflammation.

Sixty male and female patients with HIV who have depression and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study.

Eligibility Criteria:
Inclusion Criteria:

* HIV infected on continuous antiretroviral therapy (ART) with plasma HIV RNA \<200 copies/ml for at least 12 months (on at least two previous clinic visits and confirmed at screening)
* Current cluster of differentiation 4 (CD4+) \> 350 cells/microliter for at least twelve months (on at least two previous clinic visits and confirmed at screening)
* A primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) major depression, current, or Bipolar, depressed type as diagnosed by 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 for fluoxetine) or on a stable psychotropic regimen for at least 4 weeks prior to baseline 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 entry and 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, or anakinra
  3. Cyclophosphamide (or any other cytotoxic agent), belimumab, or anifrolumab (or another 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% per American 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 during the study
* Current or recent (\<4 weeks prior to randomization) clinically serious viral (including coronavirus disease 2019 (COVID-19)), bacterial, fungal, or parasitic infection 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 or CNS 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 B virus deoxyribonucleic acid (HBV DNA)
* Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleic acid \[RNA\]-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 upper limits of normal (ULN)
  2. alkaline phosphatase (ALP) ≥2 x ULN
  3. total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must have total bilirubin \<2 x ULN)
* Chronic kidney disease with estimated glomerular filtration rate (eGFR) \<40 mL/min/1.73 m\^2
* History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry, as determined by severe combined immunodeficiency (SCID)
* A positive urine drug screen for illicit drugs at any time during the study excluding marijuana
* An active suicidal plan as determined by a score \>3 on item #3 on the Hamilton Rating 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 of aspirin), glucocorticoid containing medications or minocycline within 2 weeks of baseline 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 the patient's ability to fit in the MRI scanner