HIV, Kidney Transplant, Liver Transplant
Conditions
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.
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).
Interventions
DRUGeverolimus
Sponsors
amfAR, The Foundation for AIDS Research
Novartis
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cell-associated HIV DNA | 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
| Measure | Time frame | Description |
|---|---|---|
| Cell-associated Total HIV RNA | 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. |
| Plasma HIV RNA | 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. |
Countries
United States
Participant flow
Recruitment details
Ten HIV-infected adult solid organ transplant participants on stable ART and were taking non-mTOR based immune suppressive regimens for allograft rejection were recruited at the University of California, San Francisco in this open label, single-arm everolimus trial.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Subjects on mTOR inhibitor (everolimus) for 6 months, added to standard of care immunosuppressive regimen | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Continuous | 58.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
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.
Time frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)
Population: CD4+ T Cell count was not collected at Month 6 for one participant who did not show up for the visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Cell-associated HIV DNA | Baseline | 35 nucleic acid copies per million cells |
| Everolimus | Cell-associated HIV DNA | Month 2 | 43 nucleic acid copies per million cells |
| Everolimus | Cell-associated HIV DNA | Month 6 | 81 nucleic acid copies per million cells |
| Everolimus | Cell-associated HIV DNA | Month 12 | 16 nucleic acid copies per million cells |
Secondary
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.
Time frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)
Population: CD4+ T Cell count was not collected at Month 6 for one participant who did not show up for the visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Cell-associated Total HIV RNA | Baseline HIV RNA CD4+ | 423 nucleic acid copies per million cells |
| Everolimus | Cell-associated Total HIV RNA | Month 2 HIV RNA CD4+ | 310 nucleic acid copies per million cells |
| Everolimus | Cell-associated Total HIV RNA | Month 6 HIV RNA CD4+ | 702 nucleic acid copies per million cells |
| Everolimus | Cell-associated Total HIV RNA | Month 12 HIV RNA CD4+ | 354 nucleic acid copies per million cells |
Secondary
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.
Time frame: Baseline, Month 2, Month 6, Month 12 (6 months post discontinuation of everolimus)
Population: CD4+ T Cell count was not collected at Month 6 for one participant who did not show up for the visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Plasma HIV RNA | Baseline | 0.291 nucleic acid copies per million cells |
| Everolimus | Plasma HIV RNA | Month 6 | 1.042 nucleic acid copies per million cells |
| Everolimus | Plasma HIV RNA | Month 12 | 0.941 nucleic acid copies per million cells |
| Everolimus | Plasma HIV RNA | Month 2 | 0.584 nucleic acid copies per million cells |