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Metabolic Abnormalities
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Background
Reports of metabolic abnormalities among people with HIV disease, many of who are taking HIV anti-viral therapy, have increased dramatically over the past few years. The signs and symptoms of these abnormalities include:
- abnormal lipid levels
- insulin resistance
- peripheral wasting
- truncal obesity
- breast enlargement and
- the development of "buffalo hump."
The cause of these abnormalities is not clear. The syndrome(s) may be associated with HIV disease progression, related to HIV anti-viral therapies, or caused by the return to health subsequent to successful suppression of viral replication. Also, it is not clear which of these various signs and symptoms are related to each other. The absence of a clear definition of metabolic consequences of HIV disease and treatment is reflected in the wide range of prevalence rates, from <1% to 64%, reported by various researchers.
Defining the Problem and Looking for Answers
In September 1997, the Forum held the very first meeting of researchers, government and industry representatives, health care providers and patients to discuss the anecdotal reports of body changes and lipid abnormalities in people with HIV on HAART. No published reports or conference abstracts were available at this time. Meeting participants shared what information they had and discussed methods to gather more data about the prevalence, nature, cause, and effect of these signs and symptoms. The report from that meeting is the first publication to discuss what is now widely known as HIV-related lipodistrophy.
In October 1998, the Forum sponsored a second meeting of relevant stakeholders to discuss reported metabolic abnormalities in HIV disease and treatment. The focus of the meeting was to:
- develop an interim "case definition" of the metabolically-associated reported syndrome(s) and
- discuss the need for and the design and implementation of a cross-sectional prevalence study.
As a result of that meeting, one participant designed a large cross-sectional prevalence study, which will examine the extent of these symptoms in HIV-infected people, both on and off therapy. This 16 site, 1200 patient, state-of-the art study was funded by the National Institutes of Health and is currently enrolling patients. The following materials related to the Forum meeting on Metabolic Abnormalities in HIV Disease are available
- Meeting Agenda
- Meeting Summary
- "The Syndrome"
- Table of Fat Maldistribution Variables
- Meeting Participant List
- Metabolic Abnormalities in HIV Disease and Treatment: a report based on the proceedings of the meeting
- Metabolic Consequences of HIV Disease and Treatment: a report discussing the many, disparate metabolic symptoms reported and the various theories on their cause, and related research and reports presented prior to the 12th World AIDS Conference in 1998.
Focusing on Specific Abnormalities
In 2000 the Forum continued its investigation of HIV-related metabolic abnormalities with a series of three small workshops on mitochondrial toxicities, adipocyte biology and bone metabolism and HIV disease. Invited representatives from Europe, Australia, and the United States included basic scientists with expertise in these three areas, clinical scientists with expertise in HIV disease, representatives from regulatory agencies, the pharmaceutical industry, and the patient advocacy community. Workshop participants identified gaps in research related to the pathogenesis and treatment of these metabolic abnormalities in people with HIV disease and also made recommendations for further investigation. The findings from the meetings were presented at the 2nd International Workshop on HIV-related Lipodystrophy, September 14-15, 2000 in Toronto, Canada.
Mitochondrial Toxicity and HIV Disease
Mitochondrial toxicity associated with anti-viral drugs is an emerging issue in HIV disease. Many aspects of this toxicity are not well understood and could pose a major threat to the long-term success of HIV therapy. Presentations and discussions at the Forum-convened meeting included the pathophysiology, prevalence, clinical manifestations, and management of mitochondrial toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs). The following questions were addressed:
- What is the role of NRTIs and/or HIV in the pathogenesis of mitochondrial toxicity?
- What are the clinical and pathological indicators of mitochondrial dysfunction in HIV-infected individuals?
- Is mitochondrial toxicity linked to the lipodystrophy syndrome seen in patients receiving HIV therapy?
- What is the relationship between lactic acidosis and mitochondrial toxicity?
- What is the impact of lactic acidosis from mitochondrial toxicity to morbidity and mortality in HIV disease?
- What is the impact of in utero exposure to anti-viral agents on both infected and uninfected infants?
- What are the appropriate diagnostic measures (clinical, biochemical and molecular) for mitochondrial dysfunction in HIV infected individuals?
- What, if any, therapeutic options are available for treatment of mitochondrial toxicity in HIV disease?
Adipocyte Biology and HIV Disease
Metabolic abnormalities associated with lipodystropy and lipoatrophy continue to be a concern with the long-term success of HIV therapy. There is an urgent need to develop a better understanding of the pathophysiology and treatment of these conditions. The Forum's meeting provided an opportunity to discuss the biology of the adipocyte and how dysfunction is related to HIV disease and treatment. Invited speakers reviewed genetic and acquired syndromes of lipodystrophy, brown and white fat metabolism, syndrome X, obesity, adipocyte differentiation, PPARg, mouse obesity models, TNFalpha, and leptin. Questions for discussion included:
- What are the clinical and pathological indicators of metabolic dysfunction in HIV infected individuals?
- What is the role of protease inhibitors, NRTIs, and/or HIV in the pathogenesis of lipoatrophy/lipodystrophy? Of insulin resistance? Of lipid abnormalities?
- How many of the above effects might be attributable to the adipocyte?
- What is the relationship between lipodystrophy and insulin resistance?
- What is known about the contribution of cytokines to the HIV lipodystrophy/insulin resistance/metabolic dysfunction?
- Are there relevant animal (mouse) models?
- What are the appropriate diagnostic measures (clinical, biochemical and molecular) for insulin resistance/metabolic dysfunction in HIV infected individuals?
- What, if any, therapeutic options are available for treatment of insulin resistance/metabolic dysfunction in HIV disease? Should treatment be started for insulin resistance, or should one wait for overt diabetes?
- Are there treatments specifically aimed at the adipocyte?
Bone Metabolism and HIV Disease
Abnormalities associated with bone metabolism in HIV disease are beginning to be seen with the long-term success of HIV therapy. The relationship between bone disorders and HIV is not well understood. The Forum's meeting on Bone Metabolism and HIV Disease focused on the pathophysiology of bone metabolism and the prevalence of bone dysfunction in HIV disease. Speakers reviewed osteoblast and osteoclast differentiation, regulation of bone cell development and activity by inflammatory cytokines, bone breakdown in AIDS patients, and the role of immune cells in bone metabolism. Questions for discussion included:
- What are the clinical and pathological indicators of bone dysfunction in HIV-infected individuals?
- What are the appropriate diagnostic measures (clinical, biochemical and molecular) for bone abnormalities in HIV-infected individuals?
- What is known about the contribution of cytokines to the bone dysfunction seen in HIV?
- What roles are played by osteoblasts, osteoclasts, immune cells in bone abnormalities seen in HIV?
- What, if any, therapeutic options are available for treatment of bone dysfunction in HIV disease?
- Are there treatments specifically aimed at the osteoclast? At the osteoblast?
Forum for Collaborative HIV Research
Department of Prevention and Community Health
School of Public Health and Health Services2175 K St NW Ste 700
Washington, DC 20037
Phone: 202 530-2370
Fax: 202 530-3923
info@hivforum.org