PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection
Condition: HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      HIV affects millions of people. The disease may "hide" in the brain, even in people with
      well-controlled HIV without cancer. Then it may "wake up" and continue. The drug
      pembrolizumab uses the body's immune system to fight cells like cancer cells. It is approved
      to treat some cancers but not HIV. Researchers want to see if it is safe for HIV-positive
      people without cancer. This study is not for HIV treatment; only one dose of the drug will be
      used.

      Objective:

      To learn if the drug pembrolizumab, used to treat certain cancers, is safe for HIV-positive
      people.

      Eligibility:

      Adults ages 18 and older with HIV who are in another NIH protocol

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical and neurological exams

        -  Blood tests

        -  Lumbar puncture. The lower back will be numbed. A needle will remove fluid from between
           back bones.

        -  FDG-PET/CT. A radioactive sugar will be injected in a thin plastic tube (catheter)
           inserted in an arm vein. Participants will rest for an hour, urinate, then lie in the
           scanner. A mask will hold the head still.

        -  Leukapheresis. An optional procedure at baseline. White blood cells are removed from you
           using a serum cell separator machine

      Women who can become pregnant cannot take pembrolizumab. Men who take it must use 2 kinds of
      contraception.

      Participants will have up to 7 more visits, which repeat some screening tests.

      At 1 visit, participants will get one dose of pembrolizumab by catheter for 30 minutes. They
      will get allergy and pain medicines.

      At 2 visits, participants will have a brain MRI. They will get a contrast agent by catheter.
      They will lie in a metal cylinder that takes pictures for 1-2 hours. They will get earplugs
      for loud sounds.
    

Detailed description: 
      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
      are examining 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 37.6 million people globally, with 690,000 deaths and 1.5 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 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 are collected every 3 to 6 weeks for the duration of the
      study.

      Outcome Measures

      The primary outcome is the safety and tolerability of pembrolizumab, which is 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 is 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 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
    

Intervention name(s): Pembrolizumab
Intervention type(s): Drug
Intervention description(s): Participants will receive one dose of 2mg/kg of pembrolizumab IV at Week 0.
Intervention MeSH terms: Pembrolizumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV; Brain; Immunotherapy