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Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02440789
Recruitment Status : Completed
First Posted : May 12, 2015
Results First Posted : December 30, 2019
Last Update Posted : December 30, 2019
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Brief Summary:
The purpose of this study was to find out about the safety of sirolimus in individuals with HIV infection who were also being treated with ART. The investigators wanted to learn whether sirolimus decreases inflammation and immune activation in the body; whether sirolimus changes the level of HIV in the participants' blood; and how sirolimus interacts with ART in the blood. Sirolimus is approved by the Food and Drug Administration (FDA) to prevent organ rejection in patients aged 13 years and older receiving kidney transplants. Sirolimus had also been used for the prevention of complications after stem cell transplants and as a treatment for certain kinds of cancers in HIV-infected patients.

Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: Sirolimus Phase 1 Phase 2

Detailed Description:

The study was conducted with an initial lead-in period of 12 weeks where participants remained on ART, without study intervention. Samples were collected to define the pre-intervention steady-state of HIV, inflammation and immune activation parameters.

At week 12, sirolimus therapy was initiated for the planned 20 weeks of treatment. In order to achieve therapeutic levels, sirolimus therapy was initiated with lead-in dose of 0.025 or 0.05 mg/kg/day, depending on the ART regimen. Doses for each participant were then adjusted, based on trough blood sirolimus concentrations, to achieve target concentrations between 5 and 10 ng/mL. There were frequent initial visits for sirolimus trough concentration monitoring and potential dose adjustments, at weeks 12.5, 13, 13.5, 14, 14.5, 15, 15.5 and 16. Then visits occurred at weeks 18, 20, 24, 28 and 32. After the week 32 visit, the planned end of study treatment, there was an additional 12 weeks of post-sirolimus follow-up, with a final visit at week 44.

Study visits included physical examinations, clinical assessments, safety monitoring, and blood and oral swab collection. Anal swabs were collected at week 12 and 32. Samples were stored for subsequent protocol testing for the study outcomes.

In the primary analysis, the significance level was 0.05 for all analyses.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy
Actual Study Start Date : December 21, 2015
Actual Primary Completion Date : November 2, 2017
Actual Study Completion Date : February 1, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Sirolimus

Arm Intervention/treatment
Experimental: Sirolimus

Participants on a non-protease inhibitor (PI), non-non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, and for those on a non-PI, rilpivirine (RPV) based regimen received 0.025 mg/kg/day initial dose for 20 weeks.

Participants on an NNRTI regimen with the exception of RPV received 0.05 mg/kg/day initial dose for 20 weeks.

Drug: Sirolimus



Primary Outcome Measures :
  1. Number of Participants Who Met the Study-defined Composite Safety Endpoint [ Time Frame: Screening to study week 32 (week 20 of Sirolimus) ]
    The study-defined primary safety endpoint was a composite endpoint. A participant was considered to have met the endpoint if the participant 1) experienced a new Grade ≥3 Adverse Event (AE), including signs/symptoms, lab toxicity or clinical event, that was definitely, probably or possibly related to study treatment, as judged by the core team, or 2) had a change in CD4+ cell count ( confirmed >50% decline or to <300 cells/mm3) while on sirolimus. The screening visit occurred within 60 days of study entry.

  2. Efficacy - Immunologic: Frequency of HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Frequency of HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  3. Efficacy - Immunologic: Change in HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma (week 32 measurement minus baseline measurement)

  4. Efficacy - Virologic: CD4+ T-cell-associated HIV-1 RNA [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    CD4+ T-cell-associated HIV-1 RNA. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  5. Efficacy - Virologic: Change in CD4+ T-cell-associated HIV-1 RNA [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in CD4+ T-cell-associated HIV-1 RNA (week 32 measurement minus baseline measurement)

  6. Efficacy - Virologic: Plasma HIV-1 RNA by SCA [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Plasma HIV-1 RNA by SCA

  7. Efficacy - Virologic: Change in Plasma HIV-1 RNA by SCA [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]

    Change in plasma HIV-1 RNA by SCA (week 32 measurement minus baseline measurement).

    Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).



Secondary Outcome Measures :
  1. Measurement of CD4+ T-cell Counts [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    CD4+ T-cell counts. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  2. Change in CD4+ T-cell Counts [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in CD4+ T-cell counts (week 32 measurement minus baseline measurement)

  3. Measurement of HIV-1 RNA Levels [ Time Frame: weeks 0, 12, (pre-Sirolimus) 16, 24, 32 (4, 12, 20 weeks on Sirolimus) and 44 ]
    HIV-1 RNA levels by conventional assay

  4. Cell-associated HIV-1 DNA Levels in Total CD4+ Cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    HIV-1 DNA levels in CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  5. Change in Cell-associated HIV-1 DNA Levels in Total CD4+ Cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in HIV-1 DNA levels in CD4+ T-cells (week 32 measurement minus baseline measurement)

  6. Measurement of HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific CD107a+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  7. Change in HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific CD107a+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  8. Measurement of HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific CD40L+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  9. Change in HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific CD40L+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  10. Measurement of HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific IL-2+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  11. Change in HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific IL-2+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  12. Measurement of HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific MIP1B+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  13. Change in HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific MIP1B+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  14. Measurement of HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific TNF-alpha+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  15. Change in HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific TNF-alpha+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  16. Measurement of HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific CD4+ T-cells by intracellular staining for IFN-gamma. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  17. Change in HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in HIV-1 Gag-specific CD4+ T-cells by intracellular staining for IFN-gamma (week 32 measurement minus baseline measurement)

  18. Measurement of HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific CD107a+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  19. Change in HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific CD107a+ CD4+ T-cells (week 32 measurement minus baseline measurement)

  20. Measurement of HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific CD40L+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  21. Change in HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific CD40L+ CD4+ T-cells (week 32 measurement minus baseline measurement).

  22. Measurement of HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific IL-2+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  23. Change in HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific IL-2+ CD4+ T-cells (week 32 measurement minus baseline measurement)

  24. Measurement of HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific MIP1B+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  25. Change in HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific MIP1B+ CD4+ T-cells (week 32 measurement minus baseline measurement).

  26. Measurement of HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Frequency of HIV-1 Gag-specific TNF-alpha+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  27. Change in HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in frequency of HIV-1 Gag-specific TNF-alpha+ CD4+ T-cells (week 32 measurement minus baseline measurement).

  28. Measurement of %CD69+ CD4+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %CD69+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  29. Change in of %CD69+ CD4+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %CD69+ CD4+ T-cells (week 32 measurement minus baseline measurement).

  30. Measurement of %CD69+ CD8+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %CD69+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  31. Change in of %CD69+ CD8+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %CD69+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  32. Measurement of %Ki67+ CD4+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %Ki67+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  33. Change in of %Ki67+ CD4+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %Ki67+ CD4+ T-cells (week 32 measurement minus baseline measurement).

  34. Measurement of %Ki67+ CD8+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %Ki67+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  35. Change in of %Ki67+ CD8+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %Ki67+ CD8+ T-cells (week 32 measurement minus baseline measurement)

  36. Measurement of %PD1+ CD4+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %PD1+ CD4+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  37. Change in of %PD1+ CD4+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %PD1+ CD4+ T-cells (week 32 measurement minus baseline measurement)

  38. Measurement of %PD1+ CD8+ T-cells [ Time Frame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44 ]
    Measurement of %PD1+ CD8+ T-cells. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  39. Change in of %PD1+ CD8+ T-cells [ Time Frame: At study weeks 0, 12 and 32 (week 20 on Sirolimus) ]
    Change in of %PD1+ CD8+ T-cells (week 32 measurement minus baseline measurement)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • HIV-1 infection
  • On continuous ART for ≥24 months prior to study entry.
  • CD4+ cell count ≥350 cells/mm^3
  • Plasma HIV-1 RNA below the level of quantification for ≥24 months.
  • White blood cell (WBC) ≥3000/mm^3
  • Platelet count ≥125,000/mm^3
  • Absolute neutrophil count (ANC) >1300/mm^3
  • Aspartate aminotransferase (AST) <1.25 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) <1.25 x ULN
  • Calculated creatinine clearance (CrCl) ≥60 mL/min
  • Fasting or non-fasting triglyceride level ≤350 mg/dL
  • Fasting or non-fasting LDL <160 mg/dL
  • Urine protein to urine creatinine ratio ≤1 g/g from random urine collection

Exclusion Criteria:

  • Serious illness requiring systemic treatment and/or hospitalization
  • Documentation of any CDC Category C AIDS-indicator condition or oropharyngeal candidiasis (thrush)
  • Intended modification of ART during the study.
  • Latent tuberculosis (TB) infection
  • TB disease within 48 weeks prior to study entry requiring treatment.
  • History of active hepatitis B (HBV) infection.
  • Hepatitis C virus (HCV) RNA-positive
  • Previous myelodysplasia syndrome, lymphoproliferative disease, lung disease, malignancies, congestive heart failure, life-threatening fungal infection or herpes-zoster/varicella-zoster viral infection requiring treatment.
  • Detectable Epstein-Barr virus (EBV) in blood
  • Active infection other than HIV that required receipt of systemic antibiotic therapy by intravenous infusion
  • History of major hypersensitivity reaction to macrolide drugs including angioedema, anaphylaxis, drug-induced dermatitis, or hypersensitivity vasculitis.
  • Currently pregnant or breastfeeding, or planning to become pregnant prior to or during the study.
  • Use of immunomodulators (eg, interleukins, interferons, and cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy.
  • Active drug or alcohol use or dependence
  • Vaccination within 14 days prior to study entry.
  • On or planned to change to a PI-based ART or cobicistat-boosted regimen
  • Anti-human papillomavirus (HPV) therapies

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02440789


Locations
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United States, California
801 University of California, San Francisco HIV/AIDS CRS
San Francisco, California, United States, 94110
United States, District of Columbia
Whitman Walker Health CRS (31791)
Washington, District of Columbia, United States, 20005
United States, Florida
Univ. of Miami AIDS CRS (901)
Miami, Florida, United States, 33136
United States, Georgia
The Ponce de Leon Center CRS (5802)
Atlanta, Georgia, United States, 30308
United States, Missouri
Washington University CRS (2101)
Saint Louis, Missouri, United States, 63110
United States, New York
Weill Cornell Uptown CRS (7803)
New York, New York, United States, 10011
31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS
Rochester, New York, United States, 14642
United States, Ohio
Univ. of Cincinnati CRS (2401)
Cincinnati, Ohio, United States, 45267
United States, Texas
Houston AIDS Research Team CRS (31473)
Houston, Texas, United States, 77030
United States, Washington
University of Washington AIDS CRS (1401)
Seattle, Washington, United States, 98104
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Timothy Henrich, MD University of California, San Francisco
Study Chair: Priscilla Hsue, MD University of California, San Francisco
  Study Documents (Full-Text)

Documents provided by AIDS Clinical Trials Group:
Statistical Analysis Plan  [PDF] May 9, 2019
Study Protocol  [PDF] January 26, 2017

Additional Information:
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Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT02440789    
Other Study ID Numbers: ACTG A5337
2UM1AI068636 ( U.S. NIH Grant/Contract )
First Posted: May 12, 2015    Key Record Dates
Results First Posted: December 30, 2019
Last Update Posted: December 30, 2019
Last Verified: December 2019
Additional relevant MeSH terms:
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Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs