Impact of Everolimus on HIV Persistence Post Kidney or Liver Transplant (HIVTR-EVE)

Impact of Everolimus on HIV Persistence Post Kidney (and Kidney/Pancreas) or Liver Transplant

Zortress (everolimus), the 40-O-(2-hydroxyethyl)-derivative of rapamycin, is an mTOR inhibitor approved for rejection prophylaxis in kidney transplant recipients. mTOR inhibition may favorably impact the HIV viral reservoir, and we hypothesize that adding everolimus to the transplant immunosuppressive regimen of HIV positive transplant recipients will decrease HIV persistence in CD4+ lymphocytes.

Study Overview

• Status: Completed
• Conditions: HIV; Liver Transplant; Kidney Transplant
• Intervention / Treatment: Drug: everolimus

Detailed Description

Open-label, single arm study that will enroll antiretroviral-treated HIV-infected adults who are doing well post-liver or post-kidney transplant who are eligible and willing to add everolimus to their immunosuppressive regimen (with a target trough level between 3-8 ng/ml). Calcineurin inhibitors will be decreased to obtain a 50% reduction in trough levels with the addition of everolimus. Subjects will be maintained on that regimen for 6 months.

Biologic specimens for intensive immunology and virology studies will be obtained before, during and after exposure to everolimus. Samples will be analyzed at screening, baseline (prior to addition of everolimus), and at weeks 8 and 26 (while on everolimus), and week 52 (6 months post everolimus discontinuation).

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Solid organ (kidney, kidney/pancreas, or liver) transplant recipient
2. Male or female ≥ 18 years of age.
3. Documentation of HIV-1 infection diagnosis as evidenced by any licensed ELISA and confirmation by Western Blot, or documented history of detectable HIV-1 RNA)
4. HIV-1 plasma RNA <50 copies/ml for at least 2 years with at least one measurement per year and most recent viral load within 16 weeks of enrollment and study drug initiation. Episodes of a single HIV plasma RNA 50 - 500 copies/ml will not exclude participation if the subsequent HIV plasma RNA was <50 copies/ml.
5. CD4+ T cell counts greater than 200 cell/µl within 16 weeks of enrollment and study drug initiation.
6. Receiving combination antiretroviral therapy (at least 3 agents)
7. Written informed consent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
2. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
3. Patients who are intending to modify antiretroviral therapy in the next 6 months for any reason.
4. Serious illness requiring hospitalization or parenteral antibiotics within preceding 3 months.
5. A screening hemoglobin below 11.5 g/dL.
6. A screening TSH consistent with hypothyroidism.
7. Significant renal disease (eGFR < 60 ml/min) or acute nephritis
8. Clinically active hepatitis as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities.
9. Hepatic cirrhosis or decompensated chronic liver disease.
10. Concurrent treatment with immunomodulatory drugs, such an interferon-alpha, or exposure to any immunomodulatory drug in past 16 weeks (outside of standard immunosuppression).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus	Drug: everolimus; Other Names: Zortress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell-associated HIV DNA	Peripheral blood mononuclear cells were isolated from whole blood using the Ficoll density gradient technique. Peripheral blood CD4 T cells were enriched by negative selection using antibody-coupled magnetic beads (Stem Cell Technologies) prior to simultaneous RNA and DNA isolation using cell-sparing protocols (AllPrep, Qiagen). Bulk CD4+ T cell or PBMC-associated HIV DNA and unspliced RNA were quantified using real-time PCR methods.The primer and probe sequences targeted conserved regions to enable quantification of a broad range of HIV subtypes. Values were normalized to DNA quantification of a human housekeeping gene (CCR5) in order to determine nucleic acid copies per million CD4+ T cell or PBMC as described. In addition to traditional quantitative PCR, a novel single-cell-in-droplet (scd)PCR method was used to quantify the absolute number or frequency of individual purified CD4+ T cells that express unspliced HIV RNA.	Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell-associated Total HIV RNA	Peripheral blood mononuclear cells were isolated from whole blood using the Ficoll density gradient technique. Peripheral blood CD4 T cells were enriched by negative selection using antibody-coupled magnetic beads (Stem Cell Technologies) prior to simultaneous RNA and DNA isolation using cell-sparing protocols (AllPrep, Qiagen). Bulk CD4+ T cell or PBMC-associated HIV DNA and unspliced RNA were quantified using real-time PCR methods.The primer and probe sequences targeted conserved regions to enable quantification of a broad range of HIV subtypes. Values were normalized to DNA quantification of a human housekeeping gene (CCR5) in order to determine nucleic acid copies per million CD4+ T cell or PBMC as described. In addition to traditional quantitative PCR, a novel single-cell-in-droplet (scd)PCR method was used to quantify the absolute number or frequency of individual purified CD4+ T cells that express unspliced HIV RNA.	Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)
Plasma HIV RNA	Plasma HIV RNA was quantified in a highly sensitive single-copy assay (SCA) using repetitive sampling in the Panther system (Hologic) at the Blood Systems Research Institute. Up to 18 replicates were tested for each sample in order to determine plasma RNA levels as low as 0.18 copies/mL.	Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Novartis; amfAR, The Foundation for AIDS Research

Publications and helpful links

General Publications

• Henrich TJ, Schreiner C, Cameron C, Hogan LE, Richardson B, Rutishauser RL, Deitchman AN, Chu S, Rogers R, Thanh C, Gibson EA, Zarinsefat A, Bakkour S, Aweeka F, Busch MP, Liegler T, Baker C, Milush J, Deeks SG, Stock PG. Everolimus, an mTORC1/2 inhibitor, in ART-suppressed individuals who received solid organ transplantation: A prospective study. Am J Transplant. 2021 May;21(5):1765-1779. doi: 10.1111/ajt.16244. Epub 2020 Sep 15.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2016
• Primary Completion (Actual): January 31, 2018
• Study Completion (Actual): January 31, 2018

Study Registration Dates

• First Submitted: April 24, 2015
• First Submitted That Met QC Criteria: April 24, 2015
• First Posted (Estimate): April 29, 2015

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: October 29, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: HIVTR-EVE