Relationship Between Fatigue and Mitochondrial Damage in Patients With HIV/AIDS
Condition: HIV Infections; Fatigue; HIV Positive; AIDS; Healthy Volunteer; HV
MeSH terms: HIV Seropositivity; Fatigue
Study type: Observational

Summary: 
      This study will examine abnormalities in mitochondria (energy-producing machinery of cells)
      and in genes related to mitochondria in the blood cells, muscle, and fat of HIV-positive
      patients who are taking nucleoside reverse transcriptase inhibitors (NRTIs) and in patients
      not currently taking HIV medications, and compare the results to healthy volunteers. Many
      patients with HIV infection take NRTIs to help control the infection. These medications may
      damage cell mitochondria, possibly causing side effects such as fatigue. This study will
      explore the relationship between changes in mitochondria and related genes and patient
      reports of energy level, mood and quality of life.

      Healthy volunteers and HIV-infected patients between 18 and 55 years of age may be eligible
      for this study. Healthy volunteers must test negative for the HIV antibody. HIV-positive
      patients must have been diagnosed positive for at least 1 year. Patients who are taking
      antiretroviral therapy must have been taking the same drug regimen (with at least two NTRIs
      and no protease inhibitors) for at least 3 months. HIV positive patients not taking
      antiretroviral medication must not have had antiretroviral therapy for at least 1 year.
      Candidates are screened with a medical history, brief physical examination, blood and urine
      tests, and questionnaires related to mood and energy.

      Qualified volunteers will undergo the following procedures during three or four study visits:

      Visit 1

      Complete history and physical examination, blood tests, and questionnaires about energy
      level, mood, and quality of life.

      Visit 2

      Muscle and fat biopsy: Before the biopsy, blood is drawn to check blood counts and to test
      for pregnancy in women who can become pregnant. The biopsy is done on an outpatient basis in
      the operating room. The site of the biopsy (an area on the upper arm or upper leg) is numbed
      with an injection under the skin. A 1-inch incision is made over the muscle to be biopsied
      and a small sample of muscle tissue and small sample of fat are removed. The incision is then
      closed and bandaged. Following the biopsy, you will be monitored for about 4 hours in the
      clinic. Strenuous physical activity should be restricted in the week following biopsy to
      allow healing.

      Visit 3

      Examination of biopsy site and possible apheresis: The biopsy site is examined for healing.
      Apheresis may be scheduled for this visit or for an extra visit between the biopsy and the
      final visit. This procedure for obtaining white blood cells for study is optional. For
      apheresis, blood is withdrawn from a needle placed in a vein in the arm and the white cells
      are separated from the rest of the blood. The white cells are extracted and the red cells and
      plasma are then returned to the body through a second needle.
    

Detailed description: 
      Both HIV infection and antiretroviral nucleoside analogues (nucleoside reverse transcriptase
      inhibitors or NRTIs) are known to affect mitochondrial DNA content and mitochondrial
      function. A number of important clinical syndromes observed in HIV-infected persons relate to
      mitochondrial dysfunction including lactic acidosis, myopathy, cardiomyopathy, pancreatitis,
      peripheral neuropathy, and possibly lipodystrophy. Fatigue, one of the most prevalent
      complaints among persons with HIV infection, may also be the result of mitochondrial
      toxicity, though this has not been clearly established.

      Availability of minimally invasive tests to assess mitochondrial toxicity would greatly
      facilitate understanding of the contribution of mitochondrial dysfunction to clinical
      syndromes. Mitochondrial dysfunction ultimately results in lactic acidosis; however, venous
      lactate measurements are neither adequately sensitive nor specific for identification of
      early mitochondrial dysfunction. Muscle and liver biopsies are currently considered to be the
      reference standards for the evaluation and diagnosis of mitochondrial toxicity in muscle and
      liver, but these invasive tests are impractical for routine and repeated evaluations. The
      recent development of a real-time polymerase chain reaction (PCR) assay to accurately
      quantify the mtDNA copy numbers per cell in peripheral blood mononuclear cells (PBMCs) may
      allow non-invasive assessment of mitochondrial toxicity. This technique has been applied in a
      limited fashion to muscle, adipose tissue and liver samples as well.

      This pilot study seeks to examine the relationship between fatigue and other clinical
      parameters and markers of mitochondrial dysfunction. The goals of this study are threefold:
      1) to investigate the relationship between subjective fatigue ratings and mitochondrial
      dysfunction through measurements of mtDNA depletion in skeletal muscle 2) to determine
      whether there is a relationship between evidence of mitochondrial dysfunction in muscle and
      evidence of mitochondrial dysfunction in lymphocytes or adipose tissue suggesting that
      examination of lymphocytes or adipose tissue may be adequate for the accurate diagnosis of
      mitochondrial dysfunction and 3) to identify genes and proteins as potential biomarkers for
      fatigue and mitochondrial toxicity. For this cross-sectional study, three groups of
      participants will be enrolled: HIV positive patients on NRTI-containing and
      protease-inhibitor sparing regimens (n=30), HIV patients currently taking no antiretroviral
      medications (n=30) and healthy controls (n=15). HIV patients on NRTIs will be stratified
      according to their fatigue level (0-3, 4-7 or 8-10). Participants will complete a battery of
      questionnaires regarding fatigue and undergo muscle and adipose tissue biopsy.
    

Keywords: Antiretrovirals; Adipocytes; Skeletal Muscle; Fatigue; HIV; AIDS; Lymphocytes; Lipodystrophy; HIV Positive; Healthy Volunteer; HV