HIV Reservoir Reduction With Interleukin-2 (IL2)

• ClinicalTrials.gov Identifier: NCT03308786
• Recruitment Status: Terminated
• First Posted: October 13, 2017
• Results First Posted: September 28, 2022
• Last Update Posted: September 28, 2022
• Sponsor: Case Western Reserve University
• Information provided by (Responsible Party): Michael M. Lederman MD, Case Western Reserve University

Study Description

Brief Summary:

The purpose of this pilot study is to examine the effects of eight 4-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 4-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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: HIV Reservoir Reduction With Interleukin-2
• Actual Study Start Date: April 1, 2019
• Actual Primary Completion Date: August 20, 2020
• Actual Study Completion Date: August 20, 2020

Arms and Interventions

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

Outcome Measures

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: baseline, day 7 ]
   Plasma HIV RNA copies/mL by PCR at the beginning and end of rIL2 cycle 1.
6. Natural Killer (NK) Cell Phenotype During rIL2 Exposure [ Time Frame: baseline, day 7 ]
   Change in the percent of NK cells expressing CD16+CD56+ by flow cytometry from baseline to the end of study treatment.
7. Natural Killer (NK) Cell Phenotype During rIL2 Exposure [ Time Frame: baseline, day 7 ]
   Change in the percent of NK cells expressing CD56+CD16- by flow cytometry from baseline to the end of study treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older 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. TSH, T3, and T4 levels within the normal range of the processing laboratory.
13. Anti-thyrosine peroxidase (TPO) within the normal range of the processing laboratory.
14. Willing to comply with study-mandated evaluations; including not changing antiretroviral regimen (unless medically indicated) during the study period.
15. 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.
16. 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. Childbearing potential for female participants. For the purposes of this study, a woman is considered to be of childbearing potential if she is postmenarche, has not had a documented surgical sterilization procedure, has an intact uterus and at least 1 ovary, and has had a spontaneous menstrual period in the last 2 years.
2. 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.
3. Acute or chronic hepatitis B infection, defined as a positive HBV surface antigen or a positive HBV DNA.
4. History of advanced chronic liver disease, including cirrhosis, advanced liver fibrosis, severe portal hypertension, or manifestations or hepatic failure.
5. 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.
6. Current diagnosis of congestive heart failure of any severity, uncontrolled angina or uncontrolled arrhythmias.
7. History of chronic lung disease that has required pharmacologic treatment, oxygen supplementation, medical monitoring, or hospitalization in the previous year, or that is expected to cause persistent or recurrent pulmonary symptoms or impairment. Examples of the latter include but are not limited to chronic bronchitis, emphysema, and pulmonary fibrosis.
8. History or any features on physical examination indicative of a bleeding diathesis.
9. History or current diagnosis of thromboembolic disease, including deep vein thrombosis and pulmonary embolism, or family history of the same.
10. History of hypersensitivity to radiological contrast media or anticipated need for exposure to radiological contrast media during the study period.

11. 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.

12. Breast-feeding.
13. Use of aspirin, warfarin or any other antithrombotic or antiplatelet agent during the 2-week period prior to leukapheresis.
14. History of autoimmune disorders, including but not limited to Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, myasthenia gravis, glomerulonephritis, systemic lupus erythematous, and vasculitis.
15. Type 1 diabetes mellitus.
16. History of thyroid disease that has required antithyroid or thyroid hormone replacement therapy at any time in the past.

17. 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.

18. 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.

19. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
20. 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.
21. Any other condition that, in the opinion of the clinical investigator or sponsor, might compromise any aspect of this trial.

Contacts and Locations

Locations

United States, Ohio

AIDS Clinical Trials Unit

Cleveland, Ohio, United States, 44106

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

  Study Documents (Full-Text)

Documents provided by Michael M. Lederman MD, Case Western Reserve University:

Study Protocol and Statistical Analysis Plan  [PDF] December 17, 2019

Informed Consent Form  [PDF] April 14, 2020

More Information

• Responsible Party: Michael M. Lederman MD, Principal Investigator, Case Western Reserve University
• ClinicalTrials.gov Identifier: NCT03308786
• Other Study ID Numbers: AIDS 400: IL2
• First Posted: October 13, 2017
• Results First Posted: September 28, 2022
• Last Update Posted: September 28, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Aldesleukin; Interleukin-2; Antineoplastic Agents; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents