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HIV Reservoir Reduction With Interleukin-2 (IL2)

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ClinicalTrials.gov Identifier: NCT03308786
Recruitment Status : Not yet recruiting
First Posted : October 13, 2017
Last Update Posted : October 13, 2017
Sponsor:
Information provided by (Responsible Party):
Benigno Rodriguez, MD, Case Western Reserve University

Brief Summary:
The purpose of this pilot study is to examine the effects of eight 5-day cycles of subcutaneous recombinant interleukin-2 (rIL-2) given every 8 weeks on levels of replication-competent HIV in CD4 cells and on the size of HIV viral reservoir in up to 20 participants with chronically suppressed HIV infection (viral load <50 copies/mL).

Condition or disease Intervention/treatment Phase
HIV Infection Drug: Recombinant Interleukin-2 Phase 2

Detailed Description:

Interleukin-2 (IL-2) has been extensively studied in HIV infected individuals with no demonstrated clinical benefit as far as improving survival or decreasing risk of progression to AIDS. The results of the two landmark, international, multicenter, phase III, randomized trials of IL-2 in HIV infected participants (SILCAAT and ESPRIT) have been recently published. These trials, which started more than a decade ago, enrolled over 5800 participants who were randomized to anti-retroviral therapy (ART) +/- IL-2 and showed no benefit to IL-2 treatment in survival or progression to AIDS. Many individuals with HIV infection can lead normal lives on ART but replication-competent virus remains within resting CD4+ cells, referred to as the "HIV reservoir". There is a renewed interest in strategies to decrease or eliminate the viral reservoir in an attempt to provide a sterilizing or a functional "cure" for HIV that would allow the discontinuation of ART, which currently must be taken life-long. These therapies have long-term metabolic and cardiovascular toxicities as well as substantial cost. More recent data suggest that IL-2 administration may decrease the size of the HIV reservoir, getting ART-treated participants closer to levels of HIV persistence that may ultimately allow for sterilizing or functional cure.

The purpose of this pilot study is to examine the effects of eight 5-day cycles of subcutaneous recombinant interleukin-2 (rIL-2) given every 8 weeks on levels of replication-competent HIV in CD4 cells and on the size of HIV viral reservoir in up to 20 participants with chronically suppressed HIV infection (viral load <50 copies/mL).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: HIV Reservoir Reduction With Interleukin-2
Estimated Study Start Date : December 31, 2017
Estimated Primary Completion Date : November 30, 2018
Estimated Study Completion Date : December 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arm Intervention/treatment
Experimental: IL2 treatment
Subcutaneous recombinant interleukin-2 (rIL2), 5 MIU twice daily for five consecutive days every 8 weeks for 8 weeks, in addition to combination antiretroviral therapy.
Drug: Recombinant Interleukin-2
Subcutaneous recombinant interleukin-2 (rIL2), 5 MIU twice daily for five consecutive days every 8 weeks for 8 weeks
Other Name: IL2, IL-2, rIL2, aldesleukin



Primary Outcome Measures :
  1. Latent HIV reservoir change by QVOA [ Time Frame: 15 months ]
    Change in the number of infectious units per million resting CD4+ T cells (IUPM) from baseline to the end of study treatment, as measured by the Quantitative Viral Outgrowth Assay (QVOA).


Secondary Outcome Measures :
  1. Correlation of latent reservoir measure by QVOA to latent reservoir measure by intact proviral DNA. [ Time Frame: 15 months ]
    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the intact proviral DNA assay.

  2. Correlation of latent reservoir measure by QVOA to latent reservoir measure by the Tat-rev inducible limiting dilution assay (TILDA). [ Time Frame: 15 months ]
    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Tat-rev inducible limiting dilution assay (TILDA).

  3. Correlation of latent reservoir measure by QVOA to latent reservoir measure by the Envelope Detection by Induced Transcription-based Sequencing (EDITS) [ Time Frame: 15 months ]
    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Envelope Detection by Induced Transcription-based Sequencing (EDITS).

  4. In vivo induction of HIV expression in vivo as measured by the Envelope Detection by Induced Transcription-based Sequencing (EDITS) [ Time Frame: 15 months ]
    Number of inducible cell-associated HIV mRNA copies per million CD4+ T cells at the beginning and end of rIL2 cycles 1, 4, and 8.

  5. Plasma HIV RNA during rIL2 exposure. [ Time Frame: 15 months ]
    Plasma HIV RNA copies/mL by PCR at the beginning and end of rIL2 cycles 1, 4, and 8.

  6. Natural killer (NK) cell phenotype during rIL2 exposure. [ Time Frame: 15 months ]
    Change in the proportion of NK cells expressing CD16, the proportion of NK cells expressing CD56, and the proportion of NK cells expressing NKG2A by flow cytometry from baseline to the end of study treatment.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent signed and dated by study participant.
  2. Male or female, at least 18 years of age and not older than 65 years of age.
  3. HIV-1 infection, documented by and FDA-approved ELISA, EIA, or rapid antibody detection method, and confirmed by a second approved antibody-based test or by a positive approved HIV RNA detection assay.
  4. CD4+ T cell count ≥ 350 cells/mm3;
  5. HIV-1 RNA < 50 copies/mL obtained within 60 days prior to study entry performed with an FDA-approved HIV-1 RNA assay.
  6. Adequate venous access and no other contraindications for leukapheresis
  7. Absolute neutrophil count (ANC) > 2000/mm3
  8. Hemoglobin level >10 g/dL (males); > 9.5 g/dL (females)
  9. Platelet count >150,000/mm3
  10. Serum creatinine <1.5 mg/dL
  11. AST and ALT <2.5 times the upper limit of normal
  12. Willing to comply with study-mandated evaluations; including not changing antiretroviral regimen (unless medically indicated) during the study period.
  13. Females of childbearing potential must have a negative serum or urine pregnancy test at screening and negative serum pregnancy test at the baseline visit prior to infusion. All such participants must be using two forms of contraception. A female participant is considered to be of childbearing potential if she is postmenarchial, has an intact uterus and at least 1 ovary, and has had a spontaneous menstrual period in the last 2 years.

    NOTE: The following are acceptable methods of birth control:

    Condoms (male or female) with or without a spermicidal agent Intrauterine device (IUD) Diaphragm or cervical cap with spermicide Hormonal-based contraception

  14. All participants must have received HAART, and had viral loads below the limit of quantification of the assay for at least 1 year. Participants who had intermittent isolated episodes of detectable low-level viremia < 500 copies RNA/mL flanked by viral loads below the limit of quantification of the assay will remain eligible.
  15. On a stable 3-drug combination antiretroviral regimen (no changes to treatment within 4 weeks of enrollment) and willing to continue on current antiretroviral therapy for the duration of the study, unless otherwise medically indicated. The study principal investigator can approve a 2-drug antiretroviral regimen on a case-by-case basis.

Exclusion Criteria:

  1. Acute or chronic hepatitis C infection, defined as a positive plasma HCV RNA using any FDA-approved qualitative or quantitative test in a participant with a positive HCV antibody (HCV RNA testing is not required in participants with a negative HCV antibody). Participants who have completed a course of a direct-acting antiviral agent for hepatitis C and have a confirmed plasma HCV RNA level below the limit of detection of the assay 12 weeks or longer after completion of therapy will be eligible.
  2. Acute or chronic hepatitis B infection, defined as a positive HBV surface antigen or a positive HBV DNA.
  3. History of advanced chronic liver disease, including cirrhosis, advanced liver fibrosis, severe portal hypertension, or manifestations or hepatic failure.
  4. History of malignant disease that is not considered to be surgically or medically eradicated or that has required any form of therapy in the past 5 years.
  5. Current diagnosis of congestive heart failure, uncontrolled angina or uncontrolled arrhythmias. Treated, compensated heart failure with preserved ejection fraction is not exclusionary.
  6. History or any features on physical examination indicative of a bleeding diathesis.
  7. Use of chronic corticosteroids, hydroxyurea, or immune-modulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to enrollment.

    NOTE: Use of inhaled or topical steroids is not exclusionary.

  8. Breast-feeding, pregnant or unwilling to use acceptable methods of birth control for the duration of the study. Participants who become pregnant during treatment must inform the investigator of their pregnancy, be withdrawn from treatment, and agree to provide follow-up information at time of delivery.
  9. Use of aspirin, warfarin or any other antithrombotic or antiplatelet agent during the 2-week period prior to leukapheresis.
  10. History of autoimmune disorders, including but not limited to Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, myasthenia gravis, glomerulonephritis, systemic lupus erythematous, and vasculitis.
  11. History of thyroid disease requiring ongoing antithyroid or thyroid hormonae replacement therapy.
  12. Current continued use, or anticipated continued medical indication for nephrotoxic agents, including but not limited to aminoglycosides and other potentially nephrotoxic antimicrobials, indomethacin, high scheduled doses of other NSAIDs, and lithium salts. NOTE: Low doses or limited duration of these agents (i.e., ≤14 days) is not exclusionary.
  13. Current continued use, or anticipated continued medical indication for hepatotoxic agents, including but not limited to amiodarone, methotrexate, and anticonvulsants and antimicrobials with elevated hepatotoxic potential.

    NOTE: Low doses or limited duration of these agents (i.e., ≤14 days) is not exclusionary.

  14. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
  15. Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry that in the judgement of the investigator may compromise study participation or pose additional risks to the participant.
  16. Currently participating in another clinical trial or participation in such a trial within 30 days prior to screening visit.
  17. Any other condition that, in the opinion of the clinical investigator or sponsor, might compromise any aspect of this trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03308786


Contacts
Contact: Cheryl Smith 216-844-8052 smith.cheryl@clevelanactu.org
Contact: Jane Baum, RN 216-844-2546 baum.jane@clevelandactu.org

Sponsors and Collaborators
Case Western Reserve University
Investigators
Study Chair: Benigno Rodriguez, MD Case Western Reserve University
Study Chair: Michael Lederman, MD Case Western Reserve University

Responsible Party: Benigno Rodriguez, MD, Principal Investigator, Case Western Reserve University
ClinicalTrials.gov Identifier: NCT03308786     History of Changes
Other Study ID Numbers: AIDS 400: IL2
First Posted: October 13, 2017    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs