Skip to main content
OpenTrials
Completed

NCT Number: NCT02440789

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

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.

Completed

Looking for future studies?

Notify Me

Key information

Conditions

HIV-1 Infection

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

801 University of California, San Francisco HIV/AIDS CRS, San Francisco, California, United States

Loading trial locations.

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

sirolimus

Drug

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.

Primary outcomes

  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 outcomes

  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)

Sponsors and collaborators

Lead sponsor

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

Network

Collaborators

  • National Institute of Allergy and Infectious Diseases (NIAID)

Registry information

Official study title

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

Important dates

Study start
2015
Primary completion
2017
Study completion
2018
First posted
May 12, 2015
Registry last updated
Aug 3, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.