Relationship Between Fatigue and Mitochondrial Damage in Patients With HIV/AIDS

Overview

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.

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.