Lactate Metabolism Study in HIV Infected Persons

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Brief Title

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.

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.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Changes in lactate clearance pre and post supplementation

Secondary Outcome

 to estimate the change in lactate metabolism and mitochondrial function after a change in antiretroviral therapy to a non D4t/ddC/ddI/AZT regime

Condition

HIV Infections

Intervention

cofactor supplementation (thiamine, riboflavin, L-carnitine)

Study Arms / Comparison Groups

 1
Description:  Individuals living with HIV who are naive to antiretroviral treatment, or who have been on a treatment interruption for at least six months

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

July 2002

Completion Date

September 2011

Primary Completion Date

October 2008

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Wendy Wobeser, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT00202228

Organization ID

DMED-629-02


Responsible Party

Principal Investigator

Study Sponsor

Queen's University

Collaborators

 Ontario HIV Treatment Network

Study Sponsor

Wendy Wobeser, MD, Principal Investigator, Queen's University


Verification Date

January 2016