Lactate Metabolism Study in HIV Infected Persons

January 12, 2016 updated by: Dr. Wendy Wobeser, Queen's University

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Kingston, Ontario, Canada, K7L 3N6
        • Queen's University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Health Services Research
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Thiamine: 50 mg po od; Riboflavin: 100 mg po od; L-carnitine: 990 mg po bid.
Other Names:
  • L-carnitine: Carnitor
Experimental: 2
Individuals living with HIV who are on an antiretroviral regimen including one of D4T/ddI/ddC/AZT
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Thiamine: 50 mg po od; Riboflavin: 100 mg po od; L-carnitine: 990 mg po bid.
Other Names:
  • L-carnitine: Carnitor
Experimental: 3
Individuals living with HIV who are on an antiretroviral regimen including one of D4T/ddI/ddC/AZT and have liver disease.
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Thiamine: 50 mg po od; Riboflavin: 100 mg po od; L-carnitine: 990 mg po bid.
Other Names:
  • L-carnitine: Carnitor
Experimental: 4
HIV negative control group
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine)
Thiamine: 50 mg po od; Riboflavin: 100 mg po od; L-carnitine: 990 mg po bid.
Other Names:
  • L-carnitine: Carnitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Changes in lactate clearance pre and post supplementation
Time Frame: two months
two months

Secondary Outcome Measures

Outcome Measure
Time Frame
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
six months
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)
two months (increased where necessary to cover any individual's entire study period should it exceed two months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Queen's University

Collaborators

Ontario HIV Treatment Network

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2002

Primary Completion (Actual)

October 1, 2008

Study Completion (Actual)

September 1, 2011

Study Registration Dates

First Submitted

September 13, 2005

First Submitted That Met QC Criteria

September 13, 2005

First Posted (Estimate)

September 20, 2005

Study Record Updates

Last Update Posted (Estimate)

January 13, 2016

Last Update Submitted That Met QC Criteria

January 12, 2016

Last Verified

January 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DMED-629-02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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