Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV Infection
• Intervention / Treatment: Drug: Losartan; Drug: Placebo

Detailed Description

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
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Division of Infectious Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar Pill	Drug: Placebo; one tablet by mouth daily
Experimental: Losartan	Drug: Losartan; 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.; Other Names: Cozaar

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Dendritic Cell and CD4 T Cell Interactions With the FRCn	As an exploratory endpoint, we will determine the impact of losartan on frequency of dendritic cell and CD4 T cell interactions with the FRCn. This will be determined using two-photon microscopy in sections on LN obtained from study subjects. Given that this is an exploratory endpoint, these assays will be performed in a subset of subjects (5 losartan treated, 2 placebo treated and 5 HIV uninfected controls).	30 months

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Timothy Schacker, M.D., University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): July 16, 2019
• Study Completion (Actual): July 16, 2019

Study Registration Dates

• First Submitted: February 20, 2012
• First Submitted That Met QC Criteria: May 9, 2013
• First Posted (Estimate): May 14, 2013

Study Record Updates

• Last Update Posted (Actual): December 11, 2020
• Last Update Submitted That Met QC Criteria: November 16, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Fibrosis; Infection; HIV; Immune Reconstitution; Losartan; Immune Activation; HIV 1
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; Fibrosis; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 1111M06585; 13-3613 (Other Identifier: Hennepin County Medical Center); U01AI105872 (U.S. NIH Grant/Contract)