Clinical trial NCT00202228: Lactate Metabolism Study in HIV Infected Persons
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
AIDS
Lactic Acidosis
Lipodystrophy
Keywords: HIV
HIV/AIDS
Lactic Acidosis
Supplementation
Lactate Clearance
Mitochondrial Toxicity
HAART
Lead sponsor: Queen's University
Sponsor class: OTHER
Collaborators: name: Ontario HIV Treatment Network
First posted: 2005-09-20
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in lactate clearance pre and post supplementation
timeFrame: two months
Secondary outcomes:
measure: to estimate the change in lactate metabolism and mitochondrial function after a change in antiretroviral therapy to a non D4t/ddC/ddI/AZT regime
timeFrame: six months
measure: Evidence of adverse response to supplements and/or antiretroviral medications
timeFrame: two months (increased where necessary to cover any individual's entire study period should it exceed two months)
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Queen's University
state: Ontario
Study officials:
affiliation: Queen's University
name: Wendy Wobeser, MD
role: PRINCIPAL_INVESTIGATOR
References: