Lactate Metabolism Study in HIV Infected Persons

This study has been completed.
Sponsor:
Collaborator:
Ontario HIV Treatment Network
Information provided by (Responsible Party):
Wendy Wobeser, Queen's University
ClinicalTrials.gov Identifier:
NCT00202228
First received: September 13, 2005
Last updated: October 4, 2011
Last verified: October 2011

September 13, 2005
October 4, 2011
July 2002
October 2008   (final data collection date for primary outcome measure)
Changes in lactate clearance pre and post supplementation [ Time Frame: two months ] [ Designated as safety issue: No ]
  • lactate clearance and production among HIV+ and HIV- groups,
  • l/c and prdtn between HAART/d4T/ddI/ddC/AZT and trtmt naive
  • l/c and prdtn between liver disease+ and liver disease-
Complete list of historical versions of study NCT00202228 on ClinicalTrials.gov Archive Site
  • to estimate the change in lactate metabolism and mitochondrial function after a change in antiretroviral therapy to a non D4t/ddC/ddI/AZT regime [ Time Frame: six months ] [ Designated as safety issue: No ]
  • Evidence of adverse response to supplements and/or antiretroviral medications [ Time Frame: two months (increased where necessary to cover any individual's entire study period should it exceed two months) ] [ Designated as safety issue: Yes ]
  • to measure and compare lactate metabolism and mitochondrial function using two methods among HIV+/HIV-
  • to estimate the change in lactate metabolism and mitochondrial function afther the introduction of putative modifying agents (supplementation)
  • to estimate the change in lactate metabolism and mitochondrial function after a change in antiretroviral therapy to a non D4t/ddC/ddI/AZT regime
Not Provided
Not Provided
 
Lactate Metabolism Study in HIV Infected Persons
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.

Interventional
Phase 4
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Health Services Research
  • HIV Infections
  • AIDS
  • Lactic Acidosis
  • Lipodystrophy
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Thiamine: 50 mg po od; Riboflavin: 100 mg po od; L-carnitine: 990 mg po bid.
Other Name: L-carnitine: Carnitor
  • Experimental: 1
    Individuals living with HIV who are naive to antiretroviral treatment, or who have been on a treatment interruption for at least six months
    Intervention: Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
  • Experimental: 2
    Individuals living with HIV who are on an antiretroviral regimen including one of D4T/ddI/ddC/AZT
    Intervention: Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
  • Experimental: 3
    Individuals living with HIV who are on an antiretroviral regimen including one of D4T/ddI/ddC/AZT and have liver disease.
    Intervention: Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
  • Experimental: 4
    HIV negative control group
    Intervention: Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
September 2011
October 2008   (final data collection date for primary outcome measure)

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
Both
18 Years and older
Yes
Contact information is only displayed when the study is recruiting subjects
Canada
 
NCT00202228
DMED-629-02
No
Wendy Wobeser, Queen's University
Queen's University
Ontario HIV Treatment Network
Principal Investigator: Wendy Wobeser, MD Queen's University
Queen's University
October 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP