Impact of Everolimus on HIV Persistence Post Kidney or Liver Transplant

NCT02429869 | Completed Phase 4 Results

• 1 other identifier: HIVTR-EVE
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV; Kidney Transplant; Liver Transplant

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Cell-associated Total HIV RNA

  Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)

• Plasma HIV RNA

  Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)

Study Arms (1)

Everolimus

EXPERIMENTAL

Drug: everolimus

Interventions

everolimus DRUG

Also known as: Zortress

Everolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Solid organ (kidney, kidney/pancreas, or liver) transplant recipient
• Male or female ≥ 18 years of age.
• 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)
• 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.
• CD4+ T cell counts greater than 200 cell/µl within 16 weeks of enrollment and study drug initiation.
• Receiving combination antiretroviral therapy (at least 3 agents)
• Written informed consent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

You may not qualify if:

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

Sponsors & Collaborators

• University of California, San Francisco: lead
• amfAR, The Foundation for AIDS Research: collaborator
• Novartis: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (1)

• 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.

  PMID: 32780519 DERIVED

MeSH Terms

Interventions

Everolimus

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

This study had several obvious limitations, such as concomitant use of other immunomodulatory medications that may have masked or altered the effects of mTOR inhibition on HIV persistence. Sample size was also limited.

Results Point of Contact

• Title: Rodney Rogers
• Organization: University of California, San Francisco

Rodney.Rogers@ucsf.edu

415-514-6454

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Surgery

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: April 29, 2015
• Study Start: February 24, 2016
• Primary Completion: January 31, 2018
• Study Completion: January 31, 2018
• Last Updated: November 19, 2019
• Results First Posted: November 19, 2019

Record last verified: 2019-10

Locations

US (1)