Anakinra, A Recombinant Human IL-1 Receptor Antagonist for Neuroinflammation in HIV-1 Infection

Objective: HIV persists as a reservoir in the brain in several different cell types,
including macrophages, microglia and astrocytes, and this reservoir persists even when
antiretroviral therapy (ART) suppresses the virus in blood. This viral persistence in the CNS
is thought to cause neuroinflammation through the release of inflammatory cytokines and
chemokines. HIV-infected patients who have evidence of neuroinflammation in CSF are more
likely to have cognitive impairment even when the virus is optimally treated with ART. This
cognitive impairment, currently named HIV-associated neurocognitive disorder (HAND), affects
20-37% of the HIV-infected and ART-treated population. Without ART, the rates of severe HAND
are incredibly high, but in the current era in areas where ART is widely available, the
cognitive deficits are often subtle. Despite this reduction in the degree of impairment and
fewer cases of overt dementia, patients with HAND have poor medication adherence, problems
with decision making, vocational disability, and an overall reduced quality of life compared
to HIV-infected patients without cognitive impairment.

This phase 1 study of anakinra will investigate the safety of anakinra in patients with HIV
on antiretroviral therapy. Anakinra, an IL-1 receptor antagonist that has broad
anti-inflammatory effects, has demonstrated safety and efficacy in two other inflammatory
diseases (rheumatoid arthritis and neonatal onset multisystem inflammatory disorder) for
which it is FDA-approved. It has not yet been used in patients with HIV infection.

Study Population: The study will be conducted simultaneously at two centers: the NIH Clinical
Center and the Johns Hopkins University (JHU) Department of Neurology and will enroll twelve
participants with HIV infection on antiretroviral therapy. Approximately half of the patients
will be enrolled at each site. The study will not enroll patients with evidence of dementia.

Design: This is a single-arm, open-label study of anakinra. Participants will self-administer
daily injections of anakinra for 8 weeks. The dose will be increased over the first four
weeks to minimize injection site reactions. Participants will be evaluated prior to the first
dose of anakinra, weekly during the first five weeks, at the end of anakinra administration,
and after an 8-week follow-up period without anakinra.

Patients enrolled at the NIH will complete all visits there. Patients enrolled at JHU will
complete all visits there with the exception of the three study MRI s which will be completed
at the NIH.

Outcome Measures: Safety will be assessed throughout the 8 weeks of treatment and during the
8-week followup period. The anti-inflammatory effects of anakinra will be explored through
analyses of cerebrospinal fluid and magnetic resonance imaging results before and after
treatment.

- INCLUSION CRITERIA

- Age 18-61 years old

- Laboratory-confirmed HIV-1 infection

- CD4 count >350 cells/mm^3

- Plasma HIV RNA <50 copies/mL for at least 12 months prior to screening. Participants
who have a viral blip of up to 200 copies/mL may be included if they have a preceding
and following VL <50 copies/mL.

- Stable antiretroviral therapy regimen for greater than or equal to 3 months prior to
screening

- Weight greater than or equal to 50 kg

- Have participated in NIH protocol 13 N-0149 or the JHU Clinical Outcomes Core

- Completion of at least 7th grade (according to subject report) and ability to speak,
read, and understand English to allow use of standard neurocognitive batteries

- An established primary care provider

- Willingness to have blood and CSF samples stored for future research

- Willingness to undergo serial lumbar punctures (LPs) per study schedule

- Willingness to undergo genetic testing

- For women of childbearing potential, willingness to use 2 forms of effective birth
control beginning 2 weeks before and continuing until 12 weeks after the start of
anakinra. One method must be a condom and the other may be a diaphragm or cervical cap
with spermicide, oral contraceptive, implant, contraceptive patch, IUD placed at least
3 months ago or having a male partner who had a vasectomy at least 3 months ago.

EXCLUSION CRITERIA

- Presence of a neurologic condition that would confound study evaluations (eg, multiple
sclerosis, Parkinson s disease). Neurologic conditions that would not interfere with
study evaluations (eg, migraine, peripheral neuropathy) will be allowed.

- Presence of a condition, other than HAND, associated with cognitive impairment (e.g.
untreated severe sleep apnea) at screening

- Presence of HIV-associated dementia as determined through participation in NIH
protocol 13-N-0149 or the JHU Clinical Outcomes Core

- Inability to provide informed consent

- Past or current psychiatric illness that may interfere with protocol adherence (eg
schizophrenia or bipolar disorder)

- Use of any psychiatric medications unless stable greater than or equal to 3 months at
the time of screening

- Current asthma requiring treatment

- History of any AIDS-defining opportunistic infection in the past two years or any
history of a CNS opportunistic infection

- History of lymphoma or melanoma

- Any medical condition (eg, congestive heart failure, coronary artery disease, chronic
obstructive pulmonary disease, severe osteoarthritis) that would make frequent study
visits and travel difficult for the participant

- Positive urine drug screen or active abuse of illegal drugs, narcotics or alcohol as
determined by the study investigator at the time of screening or at baseline
evaluations

- Women who are pregnant or actively seeking to become pregnant

- Women who are breastfeeding

- Use of any systemic immunosuppressive medication, including TNF inhibitors, within
five half lives of the drug prior to of screening

- Contraindications to LP including: International Normalized Ratio (INR) >1.5,
platelets <100,000/Microlitre, or inability to temporarily discontinue aspirin for
7-10 days and nonsteroidal anti-inflammatory drugs for 3 days prior to LP

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x laboratory
upper limit of normal

- Absolute neutrophil count <1000/mm^3 or hemoglobin <10mg/dL

- Estimated glomerular filtration rate <60 mL/min or a history of renal dialysis

- Other laboratory abnormality that would make the study risky for the patient as
determined by the study investigator

- Acute or chronic hepatitis C virus infection determined by a detectable VL

- Acute or chronic hepatitis B determined by detectable hepatitis B surface antigen
(HbsAg) or hepatitis B core antibody (HbcAb) IgM

- History of tuberculosis (TB), or positive TB test at screening (QuantiFERON or
tuberculin skin test)

- Other infection (eg, influenza, urinary tract infection) that would affect response to
anakinra, or that would represent a risk of significant infection based upon the known
effects of anakinra, and the likely effects of anakinra on this population.

- Receipt of live vaccine within four weeks of starting anakinra or planned within three
months after study completion

- Contraindication to MRI including pacemakers or other implanted electrical devices,
brain stimulators, some types of dental implants, some types of aneurysm clips (metal
clips on the wall of a large artery), some types of metallic prostheses (including
metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, or
shrapnel fragments. Participants who require sedation for claustrophobia during the
MRI will not be excluded.

- Known hypersensitivity or contraindication to gadolinium or any component of anakinra

- Participation in a clinical protocol (e.g. anti-inflammatory drug intervention study)
which includes an intervention that may affect the results of the current study.

- Any condition that would increase risk to the subject or would interfere with the
subject s ability to comply with protocol requirements (e.g. inability to travel to
the study site frequently).