Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reversibility of Mitochondrial Toxicity in HIV Lipoatrophy

Conditions
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HIV Infections, Lipodystrophy, Metabolic Diseases, Nutrition Disorders

Intervention / Treatment
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* Drug: NucleomaxX
* Drug: Tenofovir Disoproxil Fumarate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: uridine supplementation<br>NucleomaxX 36 grams TID every other day | Drug: NucleomaxX<br>* NucleomaxX 36 grams TID every other day<br>* Other names: uridine;|
| Active Comparator: Switch to Tenofovir<br>Switch of AZT or d4T to Tenofovir Disoproxil Fumarate | Drug: Tenofovir Disoproxil Fumarate<br>* Switch of thymidine nucleoside reverse transcriptase inhibitors to Tenofovir Disoproxil Fumarate<br>* Other names: TDF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fat mtDNA Content | Subcutaneous abdominal fat mitochondrial DNA (mtDNA) | Baseline to Week 48 | 
| Change in PBMC mtDNA | Peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA), measured in copies/cell | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Limb Fat | Change in limb fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 | 
| Change in Trunk Fat | Change in trunk fat as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 | 
| Change in Lumbar Spine Bone Mineral Density (BMD) | Change in lumbar spine bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 | 
| Change in Hip Bone Mineral Density (BMD) | Change in hip bone mineral density (BMD) as measured by dual-energy x-ray absorbtiometry (DEXA) scan | Baseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lipoatrophy, mitochondria, HIV, treatment experienced