Lactate Metabolism Study in HIV Infected Persons
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
HIV Infections AIDS Lactic Acidosis Lipodystrophy |
Drug: cofactor supplementation (thiamine, riboflavin, L-carnitine) |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Health Services Research |
| 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. |
- Changes in lactate clearance pre and post supplementation [ Time Frame: two months ] [ Designated as safety issue: No ]
- 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 ]
| Enrollment: | 30 |
| Study Start Date: | July 2002 |
| Study Completion Date: | September 2011 |
| Primary Completion Date: | October 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 Name: 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 Name: 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 Name: 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 Name: L-carnitine: Carnitor
|
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| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
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
Contacts and Locations| Canada, Ontario | |
| Queen's University | |
| Kingston, Ontario, Canada, K7L 3N6 | |
| Principal Investigator: | Wendy Wobeser, MD | Queen's University |
More Information
No publications provided
| Responsible Party: | Wendy Wobeser, Doctor, Queen's University |
| ClinicalTrials.gov Identifier: | NCT00202228 History of Changes |
| Other Study ID Numbers: | DMED-629-02 |
| Study First Received: | September 13, 2005 |
| Last Updated: | October 4, 2011 |
| Health Authority: | Canada: Ethics Review Committee |
Keywords provided by Queen's University:
|
HIV HIV/AIDS Lactic Acidosis Supplementation |
Lactate Clearance Mitochondrial Toxicity HAART |
Additional relevant MeSH terms:
|
Acidosis Acidosis, Lactic Acquired Immunodeficiency Syndrome HIV Infections Lipodystrophy Acid-Base Imbalance Metabolic Diseases Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Slow Virus Diseases Immunologic Deficiency Syndromes |
Immune System Diseases Skin Diseases, Metabolic Skin Diseases Lipid Metabolism Disorders Carnitine Riboflavin Thiamine Vitamin B Complex Vitamins Micronutrients Growth Substances Physiological Effects of Drugs Pharmacologic Actions Photosensitizing Agents Radiation-Sensitizing Agents |
ClinicalTrials.gov processed this record on March 07, 2013
