Lactate Metabolism Study in HIV Infected Persons
Lactate Metabolism Study in HIV Infected Persons
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.
Inclusion Criteria:

 -  Participants at least 18 years of age or older either:

 -  HIV negative, or

 -  HIV positive, not on antiretroviral therapy (for at least 6 months) or

 -  HIV positive, on D4T/ddC/ddI/AZT containing HAART or

 -  HIV positive, on D4T/ddC/ddI/AZT containing HAART, with hepatic steatosis/liver
 disease

 -  No evidence of acute illness on physical or laboratory examination

 -  Patients who have voluntarily consented to the study and signed the appropriate
 consent

 -  have not been supplementing with multi-vitamins, thiamine, riboflavin for at least 2
 months prior to inclusion

 Exclusion Criteria:

 -  Active AIDS defining illness

 -  Treatment with growth hormone

 -  Known poor adherence with therapy

 -  End stage renal disease

 -  Pregnancy