Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Integrity of the Fibroblastic Reticular Cell Network (FRCn)
研究概览
简要总结
This study was designed to test the hypothesis that treatment of HIV infected subjects with losartan, an agent with specific anti-inflammatory and anti-fibrotic actions, will:
- reverse existing lymphoid tissue fibrosis,
- restore lymphoid tissue architecture,
- increase the number and improve the function of peripheral and lymphatic CD4 T cells,
- decrease levels of systemic immune activation (IA),
- decrease size of the HIV reservoir, and
- be safe and well tolerated.
详细描述
This is a randomized, double-blind, placebo-controlled trial of 50 HIV-1 infected individuals on stable ART randomized in a 1:1 ratio to losartan (50 mg orally daily titrated to 100 mg daily) vs placebo for 30 months. We plan to enroll a total of 63 HIV infected subjects to ensure that 50 complete the protocol. All HIV infected subjects will undergo biopsies of inguinal lymph node (LN) and gut associated lymphatic tissue (GALT) for primary endpoint analysis at baseline, 12 and 30 months after study enrollment. Blood will be collected at least quarterly throughout the study and an intensive blood pharmacokinetic (PK) study will be conducted at month 1. All HIV infected subjects will be vaccinated with the quadrivalent human papillomavirus (HPV) vaccine at months 23, 25 and 29.5 to measure immune function. 5 HIV uninfected control subjects will also be enrolled.
The primary endpoint is to determine the impact of losartan on lymphoid tissue fibrosis in HIV infected, ART treated adults. This will be determined by measuring the amount of collagen deposition in lymphoid tissues and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must meet all of the following inclusion criteria to participate in this study:
- •HIV-1 infected.
- •≥ 18 years of age.
- •Baseline peripheral CD4+ T cell count 200-600 cells/mm3 for at least two measures over the 6 months prior to study enrollment.
- •≥ 12 months of stable ART, defined as use of a given drug regimen without disruption lasting ≥ 1 week in the period leading up to study enrollment.
- •HIV viral load (VL) < 50 copies/mL for at least two consecutive measures over the 6 months prior to study enrollment.
- •No contraindication to proposed study procedures.
- •Women of child-bearing potential must be willing to use a form of effective contraception for the duration of the study. Effective contraception includes hormonal injection, implant or oral medication, IUD, diaphragm, or cervical cap with spermicide. Condoms cannot be used as the sole form of contraception.
排除标准
- •Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:
- •Use of any immunomodulator within the 12 months prior to study enrollment. An immunomodulator for the purposes of this study is defined as a drug known to either diminish or augment a patient's immune system. Examples of these include, but are not limited to, systemic corticosteroids (use of topical steroids will be permitted), TNF-inhibitors, rituximab, cyclophosphamide, abatacept,cyclosporine, azathioprine, 6-mercaptopurine, methotrexate, sulfasalazine, cyclosporine, tacrolimus,sirolimus, and intravenous immune globulin.
- •Current use of an ARB or ACEi.
- •Current use of rifaximin, fluconazole or lithium given potential for drug interactions with losartan.
- •Prior reaction or intolerance to an ARB or ACEi.
- •Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence as diagnosed by a primary care physician or specialist. Examples of these include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, mixed connective tissue disease, psoriasis, polymyositis, dermatomyositis, vasculitis, sarcoidosis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, gastrointestinal pemphigoid, eosinophilic colitis, Crohn's disease, ulcerative colitis, autoimmune hepatitis, and hepatitis C.
- •Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
- •Baseline blood pressure < 110/
- •Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation or history of advanced renal disease.
- •AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment.
- •Potassium > 5.0 within 4 weeks of study enrollment.
- •Pregnancy.
- •In women of childbearing age, unwillingness to use birth control for the duration of the study.
- •Breast feeding.
- •Prior vaccination with an HPV vaccine, including Cervarix (GlaxoSmithKline) or Gardasil (Merck).
- •History of hypersensitivity or severe allergic reactions to yeast.
- •HIV-uninfected:
- •Inclusion Criteria
- •Participants must meet all of the following inclusion criteria to participate in this study:
- •HIV uninfected.
- •≥ 18 years of age.
- •No contraindication to proposed study procedures.
- •Exclusion Criteria: Participants meeting any of the following exclusion criteria at baseline will be excluded from study participation:
- •Use of any immunomodulator within the 12 months prior to study enrollment (as defined above).
- •Current use of an ARB or ACEi.
- •Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence (as defined above).
- •Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as diagnosed by a primary care physician or specialist (Marfan's syndrome, Ehlers-Danlos syndrome).
- •Pregnancy.
研究组 & 干预措施
Losartan
干预措施: Losartan (Drug)
Sugar Pill
干预措施: Placebo (Drug)
结局指标
主要结局
Integrity of the Fibroblastic Reticular Cell Network (FRCn)
时间窗: 30 months
The Impact of Losartan Treatment on Lymphoid Tissue (LT) Fibrosis will be determined by measuring the Integrity of the fibroblastic reticular cell network (FRCn) using immunohistochemistry (IHC) and quantitative image analysis (QIA). LT will be obtained at baseline, month 12 and month 30.
Collagen Deposition in LT
时间窗: 30 months
The Impact of Losartan Treatment on Lymphoid Tissue (LT) Fibrosis will be determined by measuring the amount of collagen deposition in LT using immunohistochemistry (IHC) and quantitative image analysis (QIA). LT will be obtained at baseline, month 12 and month 30.
次要结局
- Intracellular Concentration of IL-17 in PBMCs(30 months)
- Frequency TUNEL+CD3+CD8+ T Cells(30 months)
- Serum Concentration of TGF-beta(30 months)
- Percent of Activated Macrophages in PBMCs - Flow Cytometry(30 months)
- Intracellular Concentration of IFNg in PBMCs(30 months)
- Immune Response to HPV Vaccination(30 months)
- Frequency of Activated T-cell Populations - Immunofluorescent Staining(30 months)
- Intracellular Concentration of IFNg in LT(30 months)
- Intracellular Concentration of GM-CSF in LT(30 months)
- Plasma Concentration of IL-1RA(30 months)
- Concentration of Losartan and Antiretrovirals (ARVs)(30 months)
- Frequency of CD4+ T Cells(30 months)
- Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta(30 months)
- Percent of Activated Dendritic Cells in PBMCs - Flow Cytometry(30 months)
- Percent of Activated T Cells in LT - Flow Cytometry(30 months)
- Percent of Activated Macrophages in LT - Flow Cytometry(30 months)
- Intracellular Concentration of IL-10 in PBMCs(30 months)
- Intracellular Concentration of GM-CSF in PBMCs(30 months)
- Serum Concentration of IL-7(30 months)
- Percent of Activated T Cells in PBMCs - Flow Cytometry(30 months)
- Percent of Activated Dendritic Cells in LT - Flow Cytometry(30 months)
- Intracellular Concentration of IL-2 in PBMCs(30 months)
- Intracellular Concentration of IL-10 in LT(30 months)
- Plasma Concentration of IL-6(30 months)
- Intracellular Concentration of TNF in PBMCs(30 months)
- Intracellular Concentration of TNF in LT(30 months)
- Plasma Concentration of IL-1b(30 months)
- Plasma Concentration of TNF(30 months)
- Plasma Concentration of Amyloid A(30 months)
- Frequency of HIV RNA+ and DNA+ Cells in GALT - Radiolabeled in Situ Hybridization (ISH)(30 months)
- Frequency of HIV RNA+ and DNA+ Cells in GALT - RNAscopeTM in Situ Technology(30 months)
- Intracellular Concentration of Losartan and Antiretrovirals (ARVs)(30 months)
- Intracellular Concentration of IL-17 in LT(30 months)
- Intracellular Concentration of IL-2 in LT(30 months)
- Plasma Concentration of LPS(30 months)
- Plasma Concentration of sCD14(30 months)
- Plasma Concentration of CRP(30 months)
- Plasma Concentration of D-dimer(30 months)
- Plasma Concentration of I-FABP(30 months)
- Frequency of HIV RNA+ and DNA+ Cells in LN - Radiolabeled ISH(30 months)
- Frequency of HIV RNA+ and DNA+ Cells in LN - RNAscopeTM in Situ Technology(30 months)