Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
Condition: HIV Infection; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Fibrosis
Intervention: Losartan; Placebo
Intervention description: 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.; one tablet by mouth daily
Intervention MeSH terms: Losartan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Infection; HIV 1; HIV; Losartan; Fibrosis; Immune Activation; Immune Reconstitution

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.
    

Eligibility criteria:

        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.