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

Reversibility of Mitochondrial Toxicity in HIV Lipoatrophy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00119379

Enrollment

Registered

2005-07-13

Start date

2005-04-30

Completion date

2008-10-31

Last updated

2017-06-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infections, Lipodystrophy, Metabolic Diseases, Nutrition Disorders

Keywords

lipoatrophy, mitochondria, HIV, treatment experienced

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.

Interventions

DRUGNucleomaxX

NucleomaxX 36 grams TID every other day

DRUGTenofovir Disoproxil Fumarate

Switch of thymidine nucleoside reverse transcriptase inhibitors to Tenofovir Disoproxil Fumarate

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

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

Secondary

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Uridine Supplementation NucleomaxX 36 grams TID every other day NucleomaxX: NucleomaxX 36 grams TID every other day	26
Switch to TDF Switch of AZT or d4T to tenofovir Tenofovir disoproxil fumarate: Switch thymidine NRTI to tenofovir	24
Total	50

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	1

Baseline characteristics

Characteristic	Switch to TDF	Uridine Supplementation	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	24 Participants	26 Participants	50 Participants
Age, Continuous	48 years	48 years	48 years
Region of Enrollment United States	24 Participants	26 Participants	50 Participants
Sex: Female, Male Female	3 Participants	4 Participants	7 Participants
Sex: Female, Male Male	21 Participants	22 Participants	43 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 26	0 / 24
other Total, other adverse events	18 / 26	13 / 24
serious Total, serious adverse events	8 / 26	6 / 24