Lactate Metabolism Study in HIV Infected Persons
Summary
Lactic acidosis is a potentially life-threatening disease associated with the treatment of chronic HIV infection. Although acidosis is rare, hyperlactatemia is common and may have long term consequences yet to be recognized. Lactic acidosis is a manifestation of mitochondrial toxicity; consequences which have yet to be fully recognized and understood. In this study, we propose to look at lactate clearance and production by two methods, in four treatment groups, including HIV positive subjects on highly active antiretroviral therapy (HAART) treatment regimes and without HAART regimes, with liver steatosis and without, and compared with HIV negative controls. Supplementation with cofactors thiamine, niacin and L-carnitine, which may have a positive effect on lactate metabolism by facilitating mitochondrial function, will be studied as well.
Description
The management of chronic HIV infection is increasingly dependent upon the management of long term toxicities of therapy. Toxicities are often metabolic and include hyperlipidemia, hyperglycemia, osteopenia and lipodystrophy. While more rare, lactic acidosis may present also, and is associated with mortality. The consequences of chronic hyperlactatemia are not well understood, but it is known that the cause is likely related to mitochondrial toxicity of nucleoside analogues, which are the cornerstone class of HIV therapies.
No treatments for the syndrome of chronic lactic acidosis have been proven, but evidence exists which suggests that the utilization of cofactors such as thiamine, riboflavin and L-carnitine in the management of the acute syndrome; these factors may alleviate the mitochondrial compromise.
The mechanism underlying lactic acidemia may be a result of both increased production (as a result of mitochondrial dysfunction), and poor clearance of lactate by the liver which is the primary organ for clearance. Some of this liver dysfunction could also be attributable to mitochondrial toxicity.
In this study we propose to study lactate metabolism among persons with chronic HIV infection (both on treatment and treatment naive) and compare the results to uninfected control population. We will also study a subset of HIV infected persons with known underlying liver disease. Two methodologies will be used: a lactate challenge test and a forearm ischemia test. The effect of supplementation with cofactors which may have a positive effect on lactate metabolism by facilitating mitochondrial function will be studied as well. All persons enrolled for evaluation will have these tests repeated 4-6 weeks after supplementation with standardized doses of cofactors thiamine and L-carnitine between tests. Fat tissue samples and PBMC's will be collected and analyzed for quantity and function, and participants will have liver ultrasounds. Liver biopsies will be completed on those subjects where clinically indicated. The results of the study will provide important insights into the effects on lactate metabolism, nucleoside analogues, and HIV itself.
Our primary hypothesis is that persons on D4T/ddI/ddC/AZT containing highly active antiretroviral therapy (HAART) will demonstrate increased lactate production compared to HIV negative controls; that lactate metabolism will be normalized after treatment with cofactors (riboflavin, thiamine, L-carnitine); that persons with liver disease on therapy will demonstrate prolonged lactate clearance; and that persons changed to a non-D4T/ddI/ddC/AZT containing regime will demonstrate a decrease in lactate production from baseline.
Study Design
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Health Services Research
Conditions
HIV Infections
Intervention
cofactor supplementation (thiamine, riboflavin, L-carnitine)
Location
Queen's University
Kingston
Ontario
Canada
K7L 3N6
Status
Active, not recruiting
Source
Queen's University
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00202228
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Thiamine Pyrophosphatase
An enzyme that hydrolyzes thiamine pyrophosphate to thiamine monophosphate plus inorganic phosphate. EC 3.6.1.-.
Pyrithiamine
A thiamine antagonist due to its inhibition of thiamine pyrophosphorylation. It is used to produce thiamine deficiency.
Carnitine O-acetyltransferase
An enzyme that catalyzes the formation of O-acetylcarnitine from acetyl-CoA plus carnitine. EC 2.3.1.7.
Riboflavin Synthase
An enzyme that catalyzes the formation of riboflavin from two molecules of 6,7-dimethyl-8-ribityllumazine, utilizing a four-carbon fragment from one molecule which is transferred to the second molecule. EC 2.5.1.9.
Riboflavin Deficiency
A dietary deficiency of riboflavin causing a syndrome chiefly marked by cheilitis, angular stomatitis, glossitis associated with a purplish red or magenta-colored tongue that may show fissures, corneal vascularization, dyssebacia, and anemia. (Dorland, 27th ed)
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