Fish Oil for HIV-Related Inflamm-aging and Immune Senescence
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      HIV infection is associated with premature aging of the immune system. It is believe that the
      persistent inflammation that accompanies HIV infection is a major contributor to premature
      immune aging. Fish oil has well-documented anti-inflammatory properties. In this randomized,
      clinical trial, we're testing whether a 12-week course of fish oil supplementation will
      reverse premature aging in HIV-infected older adults.
    

Detailed description: 
      Due to treatment advances, the number of persons > 50 years old who are living with HIV/AIDS
      in the United States (US) has steadily increased. African Americans (AA) represent a
      disproportionate number of HIV/AIDS cases in this age group, with infection rates 12 times
      higher than among whites (51.7 per 100,000 compared to 4.2 per 100,000). Limited data suggest
      that older HIV+ AA are characterized by health status disparities. One cohort study of older,
      largely minority HIV+ persons (N=121, AA=83%;mean age=54), found that 34% had metabolic
      syndrome and 50% had a Framingham Cardiac Risk score > 10%. HIV+ older adults of all races
      show a premature onset of other age-associated co-morbidities, such as osteoporosis, non-AIDS
      malignancies, and cardiovascular disease (CVD). These co-morbidities have been linked to
      persistent inflammation and persistently elevated serum levels of proinflammatory cytokines
      that mimic an aging phenotype known as "inflamm-aging." In both middle-aged HIV+ persons and
      older HIV seronegative adults, inflamm-aging is associated with more limited T cell
      repertoires and increased risk for morbidities and mortality. In HIV infection, inflamm-aging
      is postulated to be maintained (a) by the constant antigen burden imposed by HIV and other
      chronic viral co-pathogens, such as cytomegalovirus (CMV), and (b) by HIV-induced disruption
      of intestinal epithelial integrity with subsequent translocation of gut microflora into the
      systemic circulation. Our hypothesis is that inflamm-aging is responsible for the premature
      immune senescence associated with HIV infection in aging individuals. Immune senescence,
      characterized by diminished replicative capacity, has been observed in middle-aged persons
      treated with highly active antiretroviral therapy (HAART) who achieve immune reconstitution
      and undetectable viral loads. Senescent cells are characterized by the absence of the surface
      marker CD28, and in advanced senescence express CD57 (CD28-/CD57+ phenotype). Because
      premature senescence leads to loss of anti-HIV cell-mediated immune responses and accelerated
      HIV disease progression,there is an urgent need to test new treatment strategies to reduce
      inflamm-aging and subsequent immune senescence.

      Fish oil may be an effective treatment option for reducing HIV-related inflamm-aging. Cold
      water fish are rich in the omega-3 highly unsaturated fatty acids (HUFA) eicosapentaenoic
      acid (EPA) and docosahexaenoic acid (DHA), which have anti-inflammatory effects. When
      consumed as fish or fish oil supplements, EPA and DHA replace arachidonic acid in cell
      membranes and inhibit the synthesis of proinflammatory arachidonic acid metabolites, such as
      prostaglandins and leukotrienes. Moreover, animal and in vitro studies have shown that EPA
      and DHA stimulate regeneration of intestinal mucosa damaged by methotrexate,16 IL-4, and
      experimental ulcerative colitis. Yet, to date, no studies have been conducted on the effects
      of fish oil for reducing HIV-related inflamm-aging and reversing immune senescence.

      The purpose of this study is to explore the safety and estimate the effect size of fish oil
      to modulate parameters of inflamm-aging and immune senescence in HIV+ older adults.
      Participants will receive either 1.6 grams of omega-3 fatty acids (800 mg of EPA, 600 mg DHA,
      200 mg other omega-3 fatty acids) or placebo for 12 weeks. We expect to find a reduction in
      inflammatory markers and the percentage of CD8+ and CD4+ T lymphocytes that exhibit a
      senescent phenotype in the fish oil condition, but not in the control condition, at 12 weeks.
      We expect to find no difference between the conditions on the safety parameters at 4 and 12
      weeks.

      The specific aims are:

      Aim 1. To assess the safety of the fish oil condition by comparing it to the control
      condition at 4 and 12 weeks, controlling for covariates (demographics, lifestyle, medications
      including HAART, fish oil supplement adherence, intercurrent illnesses), on

        1. HIV disease parameters (CD4+ T cell counts and HIV RNA levels)

        2. Drug toxicity (liver function tests and serum creatinine)

        3. Adverse events (e.g., diarrhea, vomiting)

      Aim 2. To estimate the effect size of the fish oil condition at 12 weeks, controlling for
      covariates, by comparing the following cell surface molecules and intracellular and soluble
      inflammatory markers before and after fish oil

        1. Markers of immune senescence on CD8+ T lymphocytes: percentage of CD8+/CD28- T
           lymphocytes, a phenotype of immune senescence (primary outcome); percentage of
           CD8+/CD28-/CD57- T lymphocytes (an intermediate senescent phenotype); percentage of
           CD8+/CD28-/CD57+ T lymphocytes (a terminally differentiated senescent phenotype)

        2. Markers of immune senescence on CD4+ T lymphocytes: percentage of CD4+/CD28- T
           lymphocytes; percentage of CD4+/CD28-/CD57- T lymphocytes; percentage of
           CD4+/CD28-/CD57+ T lymphocytes

        3. Markers of inflammation: plasma hsCRP and intracellular concentrations of TNF-alpha,
           IL-6, and gamma IFN

      Aim 3: To estimate the effect size of the fish oil condition at 12 weeks on gut permeability,
      controlling for covariates, by comparing the following indirect markers of gut permeability
      before and after fish oil

        1. Endotoxin

        2. Soluble mouse CD14

        3. Endotoxin binding antibody

        4. Lipopolysaccharide binding protein
    

Intervention name(s): Fish oil that contains omega-3 fatty acids; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Fish oil gelcaps that contain 800 mg of EPA, 600 mg of DHA, 200 mg other omega-3 fatty acids; Gelcaps that contain 1 gram of oleic sunflower oil
Other intervention name(s): Carlson Brand fish oil
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants were randomized to one of two arms:
Intervention arm = fish oil Control arm = placebo.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: African Americans; Older Adults