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

• ClinicalTrials.gov Identifier: NCT02429869
• Recruitment Status: Completed
• First Posted: April 29, 2015
• Results First Posted: November 19, 2019
• Last Update Posted: November 19, 2019
• Sponsor: University of California, San Francisco
• Collaborators: amfAR, The Foundation for AIDS Research; Novartis
• Information provided by (Responsible Party): Peter Stock, University of California, San Francisco

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV; Kidney Transplant; Liver Transplant	Drug: everolimus	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Impact of Everolimus on HIV Persistence Post Kidney (and Kidney/Pancreas) or Liver Transplant
• Actual Study Start Date: February 24, 2016
• Actual Primary Completion Date: January 31, 2018
• Actual Study Completion Date: January 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Everolimus	Drug: everolimus; Other Name: Zortress

Outcome Measures

Primary Outcome Measures :

1. Cell-associated HIV DNA [ Time Frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus) ]
   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.

Secondary Outcome Measures :

1. Cell-associated Total HIV RNA [ Time Frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus) ]
   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.
2. Plasma HIV RNA [ Time Frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus) ]
   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.

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

United States, California

University of California, San Francisco

San Francisco, California, United States, 94143

Sponsors and Collaborators

University of California, San Francisco

amfAR, The Foundation for AIDS Research

Novartis

  Study Documents (Full-Text)

Documents provided by Peter Stock, University of California, San Francisco:

Study Protocol and Statistical Analysis Plan  [PDF] March 11, 2016

More Information

• Responsible Party: Peter Stock, Professor of Surgery, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02429869
• Other Study ID Numbers: HIVTR-EVE
• First Posted: April 29, 2015
• Results First Posted: November 19, 2019
• Last Update Posted: November 19, 2019
• Last Verified: October 2019

Additional relevant MeSH terms:

Everolimus; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs