PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection

Objective:

In this Phase I, proof-of-concept study, we aim to determine the safety and tolerability of
pembrolizumab, an FDA-approved monoclonal antibody against programmed cell death protein
(PD)-1, in viremically suppressed human immunodeficiency virus-1 (HIV) positive patients. We
will also examine the correlation of immune activation and suppression markers in viremically
suppressed HIV positive patients with the effects of pembrolizumab on immune restoration
function (e.g. CD4 count, HIV viral load) and immune activation (e.g. HIV-specific T-cell
responses).

Study Population:

HIV is estimated to infect 36.7 million people globally, with 1.1 million deaths and 2.1
million new infections occurring yearly. There is no cure. Opportunistic infections and
neoplasms contribute to a large portion of mortality and morbidity within the HIV-positive
population. Even in well-controlled, viremically suppressed patients, neurologic
complications including HIV-associated neurocognitive disorder, continue to contribute to
disease morbidity and mortality.

There is evidence that HIV reservoirs contribute to the inability to cure HIV infection. In
the brain, macrophages and astrocytes harbor HIV. It is theorized that the brain is a
potential reservoir for replication competent HIV. PD-1 expression is elevated in patients
with HIV compared to uninfected controls. Upregulated PD-1 expression is associated with
higher viral load and increased mortality in infections.1 PD-1 co-expression on regulatory
T-cells has been shown to correlate with disease progression in perinatally-infected
HIV-positive children. Drugs targeting the PD-1 pathway in HIV infection have shown
upregulation of T-cell responses that are potentially critical to eradication of infection.
Pembrolizumab is an attractive option due to its mechanism of action, although it has been
rarely used in the HIV population.

Design:

In this single-center, single-arm, open label, baseline-versus-treatment phase I clinical
trial, twelve patients with HIV-1 infection will receive a one-time dose of 200mg
pembrolizumab with a baseline study period of 3 weeks, a one-day treatment phase, and a
6-month post treatment phase. Outcome measures will be collected every 3 to 6 weeks for the
duration of the study.

Outcome Measures:

The primary outcome will be the safety and tolerability of pembrolizumab, which will be
measured by clinical exam, laboratory studies and adverse event tabulations using the Common
Terminology Criteria for Adverse Events (CTCAE) v5.0.

In addition, viral and immunologic outcome measures investigating the impact of pembrolizumab
on HIV-1 biology and its effects on immune function will be measured in the CSF and
periphery, including single copy HIV analysis, CD4+ T-cell count, PD-1 lymphocyte expression
and T-cell phenotype analysis, T-cell proliferation against HIV-proteins, CSF cytokine
analysis and/or CSF antibody profiling (LIPS). These additional studies will offer indirect
proof of a HIV viral reservoir in the CNS as well as potential efficacy of pembrolizumab in
reversing immune exhaustion against latent HIV.

- INCLUSION CRITERIA:

- 18 years or older

- Diagnosis of HIV-1 infection, with positive HIV 1 antibody testing

- HIV RNA less than or equal to 40 copies/mL in plasma in the last 12 or greater months

- CD4 count above 350 cells/uL

- Antiretroviral therapy for 12 months prior to trial

- Patient must be willing and able to comply with all the aspects of trial design and
follow-up.

- Patients must be able to provide informed consent

- Participants who are physically able to father a child must agree to use 2 effective
methods of contraception (birth control) from the time you enroll in the study until 4
months after your last exposure to pembrolizumab

- Effective methods of contraception for this study include:

- hormonal contraception (birth control pills, birth control patches, injected
hormones, hormonal implants or vaginal ring),

- Intrauterine device,

- Barrier methods (condom or diaphragm) combined with spermicide, and

- Surgical sterilization (hysterectomy, tubal ligation, or vasectomy).

- If you have had a hysterectomy, tubal ligation, or vasectomy (or have a
partner with a hysterectomy, tubal ligation or vasectomy), you do not have
to use 2 methods of birth control.

EXCLUSION CRITERIA:

- Clinically significant medical disorders that might expose the patient to undue risk
of harm confound study outcomes or prevent the patient from completing the study as
identified on screening studies and by patient history. Examples of such conditions
include known cardiac disease such as congestive heart failure, chronic obstructive
pulmonary disease, uncontrolled hypertension, kidney disease, liver disease, endocrine
disease, pulmonary disease, heart disease, progressive CNS disease such as Parkinson s
disease, dementia, prior tuberculosis infection or ongoing CNS opportunistic
infection.

- Female sex of reproductive potential (this does not include women who are menopausal,
post-hysterectomy, post-tubal ligation, or other methods of sterilization/inability to
reproduce)

- Patient has received immunomodulatory/immunosuppressive therapy (including IV steroids
but excluding local injections) in the preceding 6 months.

- Patient with known autoimmunity that would include but is not limited to disorders
such as hypo/hyperthyroidism, myasthenia gravis, diabetes mellitus type 1, hemolytic
anemia, and immune mediated hepatitis (but excluding patients with hypothyroidism
already on thyroid replacement therapy).

- Prior history of cancer (excluding non-invasive squamous and basal cell carcinoma)

- Any opportunistic infection in the prior 2 years (excluding thrush) including latent
TB (or a positive TB Quantiferon Gold test)

- Patient has received other investigational drugs within 3 months before enrollment

- Positive serological or PCR evidence of active or prior infection with HTLV-1/II,
Hepatitis B or C. Patients with hepatitis B core (+), surface antibody (+), surface
antigen ( ) and hepatitis B DNA (-) eligible to participate in the study (provided
they are on tenofovir, lamivudine or TAF). Participants with prior hepatitis C who are
hepatitis C antibody (+) but hepatitis C RNA (-) with normal liver enzymes and no
evidence of cirrhosis on clinical liver ultrasound will be eligible to participate in
the study.

- Metal in the body which would make having an MRI scan unsafe, such as pacemakers,
stimulators, pumps, aneurysm clips, metallic prostheses, artificial heart valves,
cochlear implants or shrapnel fragments, or history of welding or metal worker

- Claustrophobia

- Inability to lie comfortably on the back for up to two hours. Abnormal
screening/baseline blood tests exceeding any of the limits defined below or as deemed
exclusionary by the investigators on review:

- AST and ALT values >1.1 times ULN

- Fasting triglyceride > 300 mg/dL

- Total bilirubin >1.1 times ULN (unless participant is taking atazanavir or has
Gilbert syndrome)

- Creatinine Clearance or eGFR <60 ml/minute (adjusted for race)

- Hemoglobin < 10 g/dL

- Absolute neutrophil count < 1000/microliter

- Platelet count <100,000/mm(3) (if platelet clumping is present on hematology
slide review, platelet count <100,000/mm3 will be considered exclusionary to
study)

- Hemoglobin A1c greater than or equal to 6%

- Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) within
normal limits. If TSH is not within normal limits then the participant may be
eligible if thyroxine (T4) is within normal limits. Participants will not be
excluded if they are on a stable dose of replacement thyroid medication; dose may
be adjusted as needed.

- An employee or staff of the NIH