Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

Conditions
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HIV Infection, HIV Infections

Intervention / Treatment
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* Drug: Losartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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HIV infected participants: Inclusion Criteria: 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. 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. 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 < 110/70. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan<br> | Drug: Losartan<br>* Participants will start with 50 mg of losartan by mouth daily. The dose will be increased to 100 mg by mouth daily after 14 days. The maximal tolerable dosage (up to 100mg by mouth daily) will be continued for a total of 30 months.<br>* Other names: Cozaar;|
| Placebo Comparator: Sugar Pill<br> | Drug: Placebo<br>* one tablet by mouth daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Collagen Deposition in LT | 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. | 30 months | 
| Integrity of the Fibroblastic Reticular Cell Network (FRCn) | 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. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of CD4+ T Cells | Impact of losartan on immune reconstitution and function will be determined by frequency of CD4+ T cells in LT using IHC. | 30 months | 
| Frequency TUNEL+CD3+CD8+ T Cells | Impact of losartan on immune reconstitution and function will be determined by frequency of TUNEL+CD3+CD8+ T cells in LT using IHC. | 30 months | 
| Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta | Impact of losartan on immune reconstitution and function will be determined by frequency of cells expressing TGF-beta and lymphotoxin-beta in LT using IHC. | 30 months | 
| Serum Concentration of IL-7 | Impact of losartan on immune reconstitution and function will be determine by serum concentrations of IL-7 measured with ELISA. | 30 months | 
| Serum Concentration of TGF-beta | Impact of losartan on immune reconstitution and function will be determine by serum concentrations of TGF-beta measured with ELISA. | 30 months | 
| Immune Response to HPV Vaccination | Impact of losartan on immune reconstitution and function will be determine by measuring the immune response to HPV vaccination using flow cytometry to identify cells stimulated by specific HPV peptides. | 30 months | 
| Frequency of Activated T-cell Populations - Immunofluorescent Staining | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the frequency of activated T-cell populations (specifically CD3+CD4+CD38+, CD3+,CD8+CD38+,CD4+Ki67+ and CD8+Ki67+ T cells) in LT using immunofluorescence staining | 30 months | 
| Percent of Activated T Cells in PBMCs - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated T cells in peripheral blood mononuclear cells (PBMCs) using flow cytometry. | 30 months | 
| Percent of Activated Macrophages in PBMCs - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated macrophages in peripheral blood mononuclear cells (PBMCs) using flow cytometry. | 30 months | 
| Percent of Activated Dendritic Cells in PBMCs - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated dendritic cells in peripheral blood mononuclear cells (PBMCs) using flow cytometry. | 30 months | 
| Percent of Activated T Cells in LT - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated T cells in lymphoid tissues (LT) using flow cytometry. | 30 months | 
| Percent of Activated Macrophages in LT - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated macrophages in lymphoid tissues (LT) using flow cytometry. | 30 months | 
| Percent of Activated Dendritic Cells in LT - Flow Cytometry | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the percentage of activated dendritic cells in lymphoid tissues (LT) using flow cytometry. | 30 months | 
| Intracellular Concentration of IL-17 in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-17 in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of IFNg in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IFNg in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of IL-2 in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-2 in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of TNF in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine TNF in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of IL-10 in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-10 in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of GM-CSF in PBMCs | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine GM-CSF in PBMCs using cytokine staining. | 30 months | 
| Intracellular Concentration of IL-17 in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-17 in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Intracellular Concentration of IFNg in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IFNg in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Intracellular Concentration of IL-2 in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-2 in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Intracellular Concentration of TNF in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine TNF in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Intracellular Concentration of IL-10 in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine IL-10 in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Intracellular Concentration of GM-CSF in LT | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the intracellular levels of the inflammatory cytokine GM-CSF in lymphoid tissue (LT) using cytokine staining. | 30 months | 
| Plasma Concentration of LPS | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of LPS by ELISA. | 30 months | 
| Plasma Concentration of sCD14 | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of sCD14 by limulus assay. | 30 months | 
| Plasma Concentration of I-FABP | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of I-FABP using ELISA. | 30 months | 
| Plasma Concentration of IL-1b | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-1b using ELISA. | 30 months | 
| Plasma Concentration of IL-1RA | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-1RA using ELISA. | 30 months | 
| Plasma Concentration of IL-6 | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of IL-6 using ELISA. | 30 months | 
| Plasma Concentration of TNF | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of TNF using ELISA. | 30 months | 
| Plasma Concentration of Amyloid A | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of amyloid A using ELISA. | 30 months | 
| Plasma Concentration of CRP | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of CRP using ELISA. | 30 months | 
| Plasma Concentration of D-dimer | The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of D-dimer using ELISA. | 30 months | 
| Frequency of HIV RNA+ and DNA+ Cells in LN - Radiolabeled ISH | The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN using radiolabeled in situ hybridization (ISH). | 30 months | 
| Frequency of HIV RNA+ and DNA+ Cells in LN - RNAscopeTM in Situ Technology | The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in LN using RNAscopeTM in situ technology. | 30 months | 
| Frequency of HIV RNA+ and DNA+ Cells in GALT - Radiolabeled in Situ Hybridization (ISH) | The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the 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 | The Potential for Losartan to Reduce the Size of the Viral Reservoir will be assessed by determining the frequency of HIV RNA+ and DNA+ cells in GALT using RNAscopeTM in situ technology. | 30 months | 
| Concentration of Losartan and Antiretrovirals (ARVs) | Potential Drug-drug Interactions Between Losartan and Antiretrovirals (ARVs) will be assessed by measuring levels of ARVs and losartan in plasma and peripheral blood mononuclear cells (PBMCs). | 30 months | 
| Intracellular Concentration of Losartan and Antiretrovirals (ARVs) | Potential Drug-drug Interactions Between Losartan and Antiretrovirals (ARVs) will be assessed by measuring intracellular concentration of losartan and ARVs in lympoidtissue. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibrosis, Infection, HIV 1, HIV, Losartan, Immune Activation, Immune Reconstitution