Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

University of Minnesota52 enrolled

Overview

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: 1. reverse existing lymphoid tissue fibrosis, 2. restore lymphoid tissue architecture, 3. increase the number and improve the function of peripheral and lymphatic CD4 T cells, 4. decrease levels of systemic immune activation (IA), 5. decrease size of the HIV reservoir, and 6. be safe and well tolerated.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

HIV Infection HIV Infections

Interventions

LosartanDRUG

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.

PlaceboDRUG

one tablet by mouth daily

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

HIV infected participants: 1. 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. 2. 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: 1. 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. 2. 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.

Locations (1)

University of Minnesota, Division of Infectious Diseases

Minneapolis, Minnesota, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 30 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 30 months

Data from ClinicalTrials.gov

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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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 30 months

Intracellular Concentration of IL-17 in LT

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 30 months

Intracellular Concentration of IL-10 in LT

Time frame: 30 months

Intracellular Concentration of GM-CSF in LT

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 30 months