Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 32
- 试验地点
- 10
- 主要终点
- Efficacy - Immunologic: Frequency of HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Sirolimus
干预措施: Sirolimus (Drug)
结局指标
主要结局
Efficacy - Immunologic: Frequency of HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma
时间窗: 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).
Number of Participants Who Met the Study-defined Composite Safety Endpoint
时间窗: 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.
Efficacy - Immunologic: Change in HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma
时间窗: 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)
Efficacy - Virologic: Change in Plasma HIV-1 RNA by SCA
时间窗: 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).
Efficacy - Virologic: Change in CD4+ T-cell-associated HIV-1 RNA
时间窗: 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)
Efficacy - Virologic: CD4+ T-cell-associated HIV-1 RNA
时间窗: 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).
Efficacy - Virologic: Plasma HIV-1 RNA by SCA
时间窗: At study weeks 0, 12 and 32 (week 20 on Sirolimus)
Plasma HIV-1 RNA by SCA
次要结局
- Change in Cell-associated HIV-1 DNA Levels in Total CD4+ Cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of %CD69+ CD4+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 RNA Levels(weeks 0, 12, (pre-Sirolimus) 16, 24, 32 (4, 12, 20 weeks on Sirolimus) and 44)
- Measurement of HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in HIV-1 Gag-specific IL-2+ CD8+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of %CD69+ CD8+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of %Ki67+ CD8+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of %PD1+ CD8+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of CD4+ T-cell Counts(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in CD4+ T-cell Counts(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Cell-associated HIV-1 DNA Levels in Total CD4+ Cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in HIV-1 Gag-specific CD107a+ CD8+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific CD40L+ CD8+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of HIV-1 Gag-specific MIP1B+ CD8+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 Gag-specific TNF-alpha+ CD8+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in HIV-1 Gag-specific CD4+ T-cell by Intracellular Staining for IFN-gamma Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific MIP1B+ CD4+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of %Ki67+ CD4+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Measurement of %PD1+ CD4+ T-cells(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in of %PD1+ CD4+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in HIV-1 Gag-specific CD107a+ CD4+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in of %CD69+ CD4+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in of %Ki67+ CD4+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific CD40L+ CD4+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in HIV-1 Gag-specific IL-2+ CD4+ T-cell Responses(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Measurement of HIV-1 Gag-specific TNF-alpha+ CD4+ T-cell Responses(At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44)
- Change in of %CD69+ CD8+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in of %Ki67+ CD8+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))
- Change in of %PD1+ CD8+ T-cells(At study weeks 0, 12 and 32 (week 20 on Sirolimus))