Clinical trial NCT02440789: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART)
Official title: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2015-05-12
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants Who Met the Study-defined Composite Safety Endpoint
timeFrame: Screening to study week 32 (week 20 of Sirolimus)
measure: Efficacy - Immunologic: Frequency of HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Efficacy - Immunologic: Change in HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Efficacy - Virologic: CD4+ T-cell-associated HIV-1 RNA
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Efficacy - Virologic: Change in CD4+ T-cell-associated HIV-1 RNA
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Efficacy - Virologic: Plasma HIV-1 RNA by SCA
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Efficacy - Virologic: Change in Plasma HIV-1 RNA by SCA
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
Secondary outcomes:
measure: Measurement of CD4+ T-cell Counts
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in CD4+ T-cell Counts
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 RNA Levels
timeFrame: weeks 0, 12, (pre-Sirolimus) 16, 24, 32 (4, 12, 20 weeks on Sirolimus) and 44
measure: Cell-associated HIV-1 DNA Levels in Total CD4+ Cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in Cell-associated HIV-1 DNA Levels in Total CD4+ Cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %CD69+ CD4+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %CD69+ CD4+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %CD69+ CD8+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %CD69+ CD8+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %Ki67+ CD4+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %Ki67+ CD4+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %Ki67+ CD8+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %Ki67+ CD8+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %PD1+ CD4+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %PD1+ CD4+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
measure: Measurement of %PD1+ CD8+ T-cells
timeFrame: At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44
measure: Change in of %PD1+ CD8+ T-cells
timeFrame: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: 801 University of California, San Francisco HIV/AIDS CRS
state: California
city: Washington
country: United States
facility: Whitman Walker Health CRS (31791)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: New York
country: United States
facility: Weill Cornell Uptown CRS (7803)
state: New York
city: Rochester
country: United States
facility: 31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
Study officials:
affiliation: University of California, San Francisco
name: Timothy Henrich, MD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Priscilla Hsue, MD
role: STUDY_CHAIR
References: