HIV Infections Clinical Trial
Official title:
Lactic Acid Metabolism in HIV-Infected Persons. Predicting Abnormalities in Lactate Production and Clearance Related to Treatment and Liver Disease and Measuring the Impact of Vitamin Supplementation.
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.
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.
;
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Health Services Research
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