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.

Further Study Details: 

Expected Total Enrollment:  150

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.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Men and women, ages 18-55 years, will be considered as potential candidates for this study.
Persons older than 55 years of age are excluded because of age related declines in mitochondrial number that may confound study results.
Ability to understand and provide informed consent.
Willing and able to comply with study requirements and procedures including storage of blood, muscle and adipose tissue samples for use in future studies of HIV, AIDS, immune function, muscle or adipose tissue diseases or other related diseases.
No or currently controlled depression.
Negative serum pregnancy test for females at screening and within one week prior to muscle and adipose tissue biopsy.
Specific lab criteria:
Absolute neutrophil count greater than 1000/mm(3).
PT/INR 1.5, PTT less than 45 sec.
Platelets greater than 75,000/mm(3).
Hemoglobin greater than 10.0mg/dl.
Serum creatinine greater than or equal to 1.5mg/dl.
AST and ALT less than 2 times the upper limit of normal.
Thyroid stimulating hormone and free thyroxine within normal limits.
Serum testosterone within normal limits or on adequate replacement.
Willing to avoid aspirin-containing medications or the non-steroidal anti-inflammatory drug piroxicam (Feldene) for 10 days prior to muscle and adipose tissue biopsy and willing to discontinue other nonsteroidal anti-inflammatory drugs 24 hours prior to biopsy.
For HIV negative volunteers:
Negative HIV-1 antibody testing.
For HIV positive volunteers:
Established HIV diagnosis (documentation of HIV-1 infection by licensed ELISA testing and confirmed by Western Blot).
HIV infection present greater than or equal to 1 year.
For patients in the antiretroviral treated group, stable antiretroviral treatment regimen for at least 3 months and currently receiving a two class antiretroviral regimen containing two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI).
For patients in the non-ART group, no antiretroviral treatment for at least one year.
Under the care of a primary care physician.
EXCLUSION CRITERIA:
Unable to provide informed consent.
Unable to understand protocol required questionnaires including inability to comprehend English (the fatigue questionnaires have not been validated in languages other than English).
Pregnant or breast-feeding.
Current treatment with an ARV regimen containing a protease inhibitor.
Active opportunistic infection or neoplasm.
History of myopathy or myositis.
Untreated or uncontrolled depression by clinical history or as indicated by a score on the Beck's Depression Inventory of greater than or equal to 19.
Severe psychiatric disorder that would interfere with adherence to protocol requirements.
Severe sleep disturbance.
Current alcohol or substance abuse.
Diabetes mellitus requiring drug therapy.
Decompensated cardiac or pulmonary disease.
Current use or a history of treatment with interleukin-2, interferon-alpha or other investigational agent(s) within 6 months of protocol screening.
Corticosteroid, immunosuppressive or cytotoxic agent use within 90 days of trial screening.
Any medical condition for which the principal investigator feels muscle and adipose tissue biopsy may be contraindicated.
Allergy to lidocaine.

Maryland
      Warren G. Magnuson Clinical Center (CC), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050127; 05-CC-0127
Record last reviewed:  March 17, 2005
Last Updated:  March 30, 2005
Record first received:  March 30, 2005
ClinicalTrials.gov Identifier:  NCT00106795
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08