Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

Phase 2

Completed

Conditions: HIV Infections
HIV Infection

Interventions: Drug: Placebo
Drug: Losartan

Registration Number: NCT01852942

Lead Sponsor: University of Minnesota

Brief Summary: 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.

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sugar Pill	Placebo	-
Losartan	Losartan	-

Primary Outcome Measures

Name	Time	Method
Integrity of the Fibroblastic Reticular Cell Network (FRCn)	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	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.

Secondary Outcome Measures

Name	Time	Method
Intracellular Concentration of IL-17 in PBMCs	30 months	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.
Frequency TUNEL+CD3+CD8+ T Cells	30 months	Impact of losartan on immune reconstitution and function will be determined by frequency of TUNEL+CD3+CD8+ T cells in LT using IHC.
Serum Concentration of TGF-beta	30 months	Impact of losartan on immune reconstitution and function will be determine by serum concentrations of TGF-beta measured with ELISA.
Percent of Activated Macrophages in PBMCs - Flow Cytometry	30 months	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.
Intracellular Concentration of IFNg in PBMCs	30 months	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.
Immune Response to HPV Vaccination	30 months	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.
Frequency of Activated T-cell Populations - Immunofluorescent Staining	30 months	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
Intracellular Concentration of IFNg in LT	30 months	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.
Intracellular Concentration of GM-CSF in LT	30 months	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.
Plasma Concentration of IL-1RA	30 months	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.
Concentration of Losartan and Antiretrovirals (ARVs)	30 months	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).
Frequency of CD4+ T Cells	30 months	Impact of losartan on immune reconstitution and function will be determined by frequency of CD4+ T cells in LT using IHC.
Frequency of Cells Expressing TGF-beta and Lymphotoxin-beta	30 months	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.
Percent of Activated Dendritic Cells in PBMCs - Flow Cytometry	30 months	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.
Percent of Activated T Cells in LT - Flow Cytometry	30 months	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.
Percent of Activated Macrophages in LT - Flow Cytometry	30 months	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.
Intracellular Concentration of IL-10 in PBMCs	30 months	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.
Intracellular Concentration of GM-CSF in PBMCs	30 months	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.
Serum Concentration of IL-7	30 months	Impact of losartan on immune reconstitution and function will be determine by serum concentrations of IL-7 measured with ELISA.
Percent of Activated T Cells in PBMCs - Flow Cytometry	30 months	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.
Percent of Activated Dendritic Cells in LT - Flow Cytometry	30 months	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.
Intracellular Concentration of IL-2 in PBMCs	30 months	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.
Intracellular Concentration of IL-10 in LT	30 months	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.
Plasma Concentration of IL-6	30 months	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.
Intracellular Concentration of TNF in PBMCs	30 months	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.
Intracellular Concentration of TNF in LT	30 months	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.
Plasma Concentration of IL-1b	30 months	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.
Plasma Concentration of TNF	30 months	The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of TNF using ELISA.
Plasma Concentration of Amyloid A	30 months	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.
Frequency of HIV RNA+ and DNA+ Cells in GALT - Radiolabeled in Situ Hybridization (ISH)	30 months	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).
Frequency of HIV RNA+ and DNA+ Cells in GALT - RNAscopeTM in Situ Technology	30 months	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.
Intracellular Concentration of Losartan and Antiretrovirals (ARVs)	30 months	Potential Drug-drug Interactions Between Losartan and Antiretrovirals (ARVs) will be assessed by measuring intracellular concentration of losartan and ARVs in lympoidtissue.
Intracellular Concentration of IL-17 in LT	30 months	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.
Intracellular Concentration of IL-2 in LT	30 months	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.
Plasma Concentration of LPS	30 months	The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of LPS by ELISA.
Plasma Concentration of sCD14	30 months	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.
Plasma Concentration of CRP	30 months	The Impact of Losartan on Immune Activation in HIV Infected, Treated Individuals will be determined by measuring the plasma concentration of CRP using ELISA.
Plasma Concentration of D-dimer	30 months	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.
Plasma Concentration of I-FABP	30 months	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.
Frequency of HIV RNA+ and DNA+ Cells in LN - Radiolabeled ISH	30 months	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).
Frequency of HIV RNA+ and DNA+ Cells in LN - RNAscopeTM in Situ Technology	30 months	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.