Clinical trial NCT00119379: Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults
Official title: Reversibility of Mitochondrial Toxicity in HIV Lipoatrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lipodystrophy
Metabolic Diseases
Nutrition Disorders
Keywords: lipoatrophy
mitochondria
HIV
treatment experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2005-07-13
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: HIV lipoatrophy is a condition marked by fat loss; it occurs in many patients taking antiretroviral (ARV) therapy that includes nucleoside reverse transcriptase inhibitors (NRTIs). Lipoatrophy may be related to mitochondrial toxicity, a condition that can damage the heart, nerves, muscles, kidneys, and liver, and can affect the body's ability to produce energy. NucleomaxX is a food supplement consisting of a sugar cane extract high in nucleosides, which are building blocks that may counteract the negative effects of NRTIs. Tenofovir disoproxil fumarate (TDF) is an NRTI that may cause less lipoatrophy than other drugs in its class, such as zidovudine (ZDV) or stavudine (d4T). The purpose of this study is to determine whether nucleoside supplementation with NucleomaxX and substitution of TDF for ZDV or d4T in an ARV regimen can reverse fat loss caused by mitochondrial toxicity in HIV infected adults.

Study hypotheses: 1) The substitution of TDF for d4T or ZDV in patients with HIV lipoatrophy will result in an increase in mitochondrial DNA content in fat, skeletal muscle, and peripheral blood mononuclear cells (PBMCs), which in turn will lead to an improvement in mitochondrial function as assessed by electron transport chain (ETC) and oxidative phosphorylation pathway (OXPHOS) activity. The latter should lead to a decrease in fat apoptosis and in mitochondrial and lipid oxidative damage biomarkers. 2) Supplementation with uridine (via NucleomaxX) will increase mtDNA content in adipose tissue and increase body fat content.

Detailed description: NRTIs are an important part of many ARV regimens used to treat HIV infected patients; however, the relationship between NRTI-induced mitochondrial dysfunction and lipoatrophy is still unclear and requires additional research. Additionally, the relationship between the gain in dual-energy x-ray absorptiometry (DEXA)-measured limb fat and mitochondrial DNA (mtDNA) content, mitochondrial function, fat apoptosis, and oxidative damage will also be examined in this study.

Patients will participate in this study for 48 weeks. Participants will be randomly assigned to one of two groups. Group 1 patients will receive NucleomaxX every other day. Group 2 patients will substitute TDF for ZDV or d4T every day in their current stable NRTI-containing ARV regimen. NucleomaxX will be provided to Group 1 patients, but TDF or any other ARV will not be provided by this study.

There will be 10 study visits, which will occur at study entry and Weeks 2, 4, 8, 12, 18, 24, 30, 36, and 48. Blood collection will occur at all visits. Additionally, urine collection, DEXA scans, and fat biopsies will be done at study entry and Weeks 24 and 48.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of HIV lipoatrophy
* Receiving a stable stavudine- or zidovudine-containing ARV regimen
* HIV-1 RNA viral load less than 50 copies/ml

Exclusion Criteria:

* Coagulopathies or other bleeding disorders
* Diabetes requiring medication
* Creatinine clearance less than 50 ml/min
* Pregnancy or breastfeeding

Primary outcomes:
measure: Change in Fat mtDNA Content
timeFrame: Baseline to Week 48
measure: Change in PBMC mtDNA
timeFrame: Baseline to Week 48
Secondary outcomes:
measure: Change in Limb Fat
timeFrame: Baseline to Week 48
measure: Change in Trunk Fat
timeFrame: Baseline to Week 48
measure: Change in Lumbar Spine Bone Mineral Density (BMD)
timeFrame: Baseline to Week 48
measure: Change in Hip Bone Mineral Density (BMD)
timeFrame: Baseline to Week 48
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
Study officials:
affiliation: Case Western Reserve University
name: Grace A. McComsey, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McComsey GA, O'Riordan M, Setzer B, Lebrecht D, Baron E, Walker UA. Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices. Eur J Clin Nutr. 2008 Aug;62(8):1031-7. doi: 10.1038/sj.ejcn.1602793. Epub 2007 May 30.
citation: McComsey GA, O'Riordan M, Choi J, Libutti D, Rowe D, Storer N, Harrill D, Gerschenson M. Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir. Antivir Ther. 2012;17(2):347-53. doi: 10.3851/IMP1928. Epub 2011 Oct 13.