HIV InfectionsNCT00106795
Relationship Between Fatigue and Mitochondrial Damage in Patients With HIV/AIDS
An observational study of HIV Infections and Fatigue, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- HIV Infections, Fatigue, HIV Positive
- How many people
- 82 participants
- Where
- 1 siteUnited States
- Study dates
- 22 Mar 2005to 10 Apr 2014
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
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- Specific lab criteria:
- Absolute neutrophil count greater than 1000/mm(3).
- PT/INR less than or equal to 1.5, PTT less than 45 sec.
- Platelets greater than 75,000/mm(3).
- Hemoglobin greater than or equal to 10.0mg/dl.
- Serum creatinine less than or equal to 1.8mg/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, on a stable combination antiretroviral treatment regimen not containing a protease inhibitor for at least 3 months prior to protocol screening.
- For patients in the non-ART group, no antiretroviral treatment for at least one year.
- Under the care of a primary care physician.
Who cannot join
- 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.
- Opportunistic infection requiring treatment.
- Concurrent malignancy requiring cytotoxic chemotherapy or radiation therapy.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Assessing the Relationship Between Fatigue and Mitochondrial Toxicity in Patients With HIV/AIDS
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.
Read more
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.
Read the 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.
- Conditions
- HIV Infections, Fatigue, HIV Positive, AIDS, Healthy Volunteer, HV
- Keywords
- Antiretrovirals, Adipocytes, Skeletal Muscle, Fatigue, HIV, AIDS, Lymphocytes, Lipodystrophy, HIV Positive, Healthy Volunteer, HV
- Medical subject headings
- HIV Infections, Fatigue, HIV Seropositivity, Acquired Immunodeficiency Syndrome, Lipodystrophy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Mar 2005 (estimated)
- Study start22 Mar 2005
- Study completion10 Apr 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 82 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- Caryn G Morse, M.D., Principal investigator, National Institutes of Health Clinical Center (CC)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00106795
- Sponsor's protocol ID
- 050127
- Other IDs
- 05-I-0127
- Status last verified
- 10 Apr 2014
- First submitted
- 30 Mar 2005
- Last updated
- 6 Oct 2017
- Results posted
- No
Publications
Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998 Oct 1;12(14):1735-44. doi: 10.1097/00002030-199814000-00004. No abstract available.
PubMed 9792373Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995 May;1(5):417-22. doi: 10.1038/nm0595-417.
PubMed 7585087John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, Mallal SA. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001 Apr 13;15(6):717-23. doi: 10.1097/00002030-200104130-00007.
PubMed 11371686
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessing the Relationship Between Fatigue and Mitochondrial Toxicity in Patients With HIV/AIDS
- ClinicalTrials.gov ID
- NCT00106795
- Acronym / sponsor ID
- 050127
- Conditions
- HIV Infections, Fatigue, HIV Positive, AIDS, Healthy Volunteer, HV
- Keywords
- Antiretrovirals, Adipocytes, Skeletal Muscle, Fatigue, HIV, AIDS, Lymphocytes, Lipodystrophy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 82 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 22 Mar 2005
- Study completion
- 10 Apr 2014
- First posted
- 31 Mar 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (24 listed)
- 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.
Key exclusion criteria (17 listed)
- 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.
- Opportunistic infection requiring treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2017.
- Background: PubMed 9792373Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998 Oct 1;12(14):1735-44. doi: 10.1097/00002030-199814000-00004. No abstract available.
- Background: PubMed 7585087Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995 May;1(5):417-22. doi: 10.1038/nm0595-417.
- Background: PubMed 11371686John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, Mallal SA. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001 Apr 13;15(6):717-23. doi: 10.1097/00002030-200104130-00007.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Caryn G Morse, M.D. principal investigator
National Institutes of Health Clinical Center (CC)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV Infections and Fatigue, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00106795, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2017.