Meeting/Event

Workshop on Interventions for Metabolic and Endocrine Complications of HIV/AIDS and Drug Abuse

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Meeting Summary

Introduction

The workshop was organized by Jag H. Khalsa, Ph.D., Paul Coulis, Ph.D., Sander Genser, M.D., M.P.H., and Henry (Skip) Francis, M.D. (Director) of the Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA), National Institute on Drug Abuse (NIDA). It was co-sponsored by the Office of Dietary Supplements (ODS), and the National Center for Complementary and Alternative Medicine (NCCAM), all parts of the National Institutes of Health (NIH). The group of nationally and internationally recognized clinicians and scientists reviewed the published research findings and presented new information on metabolic and endocrine complications of HIV/AIDS and drug abuse and various conventional and alternative (e.g., dietary supplements, exercise, herbal products) interventions. The topics included the underlying pathophysiology of metabolic complications (lipid disorders [lipodystrophy], bone disorder, insulin resistance, oxidative stress), role of mitochondria and nutrition in metabolic complications; opportunistic illnesses; endocrine complications and the use of growth hormone and other non-conventional interventions used for the treatment of HIV/AIDS complications. Finally, the group made recommendations for future research among HIV-infected individuals who may or may not be abusing drugs of abuse. Participants also agreed that the proceedings should be published in a professional scientific journal. A brief summary of the workshop that includes agenda, abstracts, recommendations for future research, and a list of participants follow.

Abstracts

Zinc Status in HIV Infection and Drug Abuse

Marianna Baum, Ph.D.
Florida International University

Dr. Baum is the Director of International Research at the College of Health and Urban Affairs and Professor at The Florida University in Miami. For 13 years, Dr. Baum has been the principal investigator of the Fogarty International Training Grant in AIDS. She has served as a Principal Investigator in a number of studies on nutritional status and metabolism in relationship to HIV-1 disease progression in various populations, including chronic drug users.

The trace element zinc has long been recognized as an important factor for maintaining a healthy immune system. Zinc deficiency reduces generation of T-cells, and depresses humoral and cell-mediated immunity. Additionally, through its alteration of cellular immunity, zinc deficiency can influence intracellular HIV-1 replication (1). Levels of zinc in ranges indicative of zinc deficiency are prevalent in HIV-1 infected men and women who abuse drugs (2), even among those administered highly active antiretroviral therapy (HAART), and are widespread in other HIV-1 infected cohorts (3,4). Moreover, such low plasma zinc levels have been shown to predict a three-fold increase in HIV-1 related mortality in drug users (5). Zinc has been used with impressive success as an immunostimulatory agent in malnutrition, obesity, sickle cell anemia, and in children, adolescents, and the elderly. Zinc supplementation delayed HIV-1 disease progression and decreased the rate of opportunistic infections in a cohort comprised mainly of drug users, as well as a cohort of HIV-1 infected HAART-treated subjects (6,7). Furthermore, normalization of plasma zinc in HIV-1 infected patients, who were zinc deficient, has been associated with a significantly slower disease progression (8). Zinc supplementation, in amounts above the RDA level, has been linked with faster disease progression and increased mortality (9, 10). Our studies, however, indicate that 86% of the HIV-1 infected drug users consume inadequate amounts of zinc and that zinc supplementation in nutritional doses, particularly to individuals with low plasma zinc levels, could be effective in modulating HIV-1 disease, without producing adverse side effects. As drug users are particularly susceptible to zinc deficiency, zinc therapy in HIV-1 infected drug users with low zinc levels, is both timely and warranted. We are initiating a randomized, double blind, placebo-controlled trial to determine whether zinc therapy can improve immune function and slow disease progression in HIV-1 infected male and female drug users with low levels of plasma zinc.

  • Edeas MA, Peltier E, Claise C, Khalfoun Y, Lindenbaum A. Immunocytochemical study of uptake of exogenous carrier-free copper-zinc superoxidase dismutase by peripheral blood lymphocytes. Cell Mol Biol 1996;42(8):1137-43
  • Baum MK, Shor-Posner G, Zhang G, Lai H, Quesada J, Miguez-Burbano M, Fletcher MA, Sauberlich H, Page JB. HIV-1 infection in women is associated with severe nutritional deficiencies. JAIDS 1997;16:272 –278
  • Beach RS, Mantero-Atienza E, Shor-Posner G, Javier JJ, Szapocznik J, Morgan R, Sauberlich HE, Cornwell PE, Eisdorfer C, Baum MK. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992;6:701-708
  • Campa A, Shor-Posner G, Indacocchea F, Scott G, Zhang G, Lai H, Deshratn A, Baum MK. Mortality risk in selenium deficient HIV+ children. J Acquir Immun Defic Syndr 1999;12:508-513
  • Baum MK, Shor-Posner G, Lai S, Zhang G, Lai H, Fletcher MA, Sauberlich H, Page JB. High risk of HIV-related mortality is associated with selenium deficiency. JAIDS 1997;15:370-374
  • Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. Int J Immunopharmacol 1995;17:719-727
  • Mocchegiani E, Muzzioli M, Gaetti R, Veccia S, Viticchi C, Scalise G. Contribution of zinc to reduce CD4+ risk factor for ‘severe’ infection relapse in aging: parallelism with HIV. Int J Immunopharmacol 1999;21:271-81
  • Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH. Micronutrients and HIV-1 disease progression. AIDS 1995;9:1051-1056
  • Tang AM, Graham NM, Kirby AJ, McCall LD, Willett WC, Saah AJ. Dietary micronutrient intake and risk of progression to acquired immunodeficiency syndrome (AIDS) in human deficiency virus type 1 (HIV-1)-infected homosexual men. Am J Epidemiol 1993;138(11):937-951
  • Tang AM, Graham NMH, Saah AJ. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. Am J Epidemiol1996;143:1244-1256.

Effects of Testosterone Administration on Regional Fat Distribution and Mechanisms of Anabolic Effects on the Muscle

Shalender Bhasin, M.D.
UCLA School of Medicine

Dr. Bhasin is Professor of Medicine at the University of California, Los Angeles School of Medicine and at the Charles R. Drew University of Medicine and Science in Los Angeles. Dr. Bhasin is an internationally recognized expert on androgen effects on the muscle and has published extensively on the effects of testosterone supplementation in androgen-deficiency states and in sarcopenia associated with chronic illness. 

Androgen deficiency is a common metabolic complication of HIV-infection in men, affecting 15-20% of HIV-infected men receiving highly active anti-retroviral drug therapy, and a higher proportion of patients with weight loss. There is agreement that replacement doses of testosterone administered to androgen-deficient men and supraphysiologic doses given to eugonadal men increase fat-free mass, maximal voluntary strength, and leg power. However, we do not know whether testosterone supplementation can improve physical function and reduce the risk of disability. The effects of testosterone on fat-free mass and muscle size are dose- and concentration-dependent, and conform to a log-linear dose-response curve. Testosterone administration of healthy, young men is associated with dose-dependent increase in muscle fiber cross-sectional area. Testosterone-induced increase in muscle fiber cross-sectional area is accompanied by a proportionate increase in myonuclear number. The absolute number of muscle fibers, and the relative proportion of type I and type II muscle fibers are not affected by testosterone. The mechanisms by which testosterone induces muscle fiber hypertrophy are not well understood, but might include upregulation of intramuscular IGF-1 and downregulation of myostatin gene expression. A number of epidemiological studies have reported that increased abdominal fat mass is associated with low testosterone levels and increased risk of cardiovascular disease and type 2 diabetes. Men with spontaneous as well as experimentally-induced androgen deficiency have higher fat mass than eugonadal men, and testosterone supplementation of healthy, androgen-deficient men decreases whole body fat mass (FM). Testosterone supplementation dose- and concentration-dependently decreases fat mass in healthy, young men in a region-specific manner; it predominantly decreases abdominal and intermuscular fat. Previous studies have shown that testosterone supplementation of middle-aged men with visceral obesity decreases visceral fat, improves insulin sensitivity and plasma glucose, and reduces blood pressure. Testosterone effects on cardiovascular risk appear to be curvilinear; in a castrated rat model, both castration and administration of supraphysiologic doses of testosterone induce insulin resistance, while physiologic testosterone replacement of castrated rats improves insulin sensitivity. In a mouse model of atherosclerosis, castration accelerates atherosclerosis progression, while testosterone replacement retards atherosclerosis progression. These observations collectively suggest that physiologic testosterone replacement men with low testosterone levels might reduce visceral and intermuscular fat, improve insulin sensitivity, and retard atherosclerosis progression; this hypothesis should be tested in prospective clinical trials.

  • Mauras N, Hayes V, Welch S, et al. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab 1998; 83:1886-92
  • Bhasin S, Woodhouse L, Casaburi R, et al 2001 Testosterone dose-response relationships in healthy, young men. Am J Physiol. Endocrinol Metab2001;281(6):E1172-81
  • Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S. The effects of varying doses of of testosterone on insulin sensitivity, plasma lipids, apolipoproteins, and c-reactive protein in healthy, young men. J Clin Endocrinol Metab 2001 (in press)
  • Arver S, Sinha-Hikim I, Beall G, Guerrero M, Shen R, Bhasin S. Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss. J Androl1999;20(5):611-8
  • Rietschel P, Corcoran C, Stanley T, Basgoz N, Klibanski A, Grinspoon S. Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 2000;31(5):1240-4
  • Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. International Journal of Obesity 1992; 16:991-997
  • Holmang A, Bjornthorp P. 1992. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand. 146: 505-510
  • Fairfield WP, Treat M, Rosenthal DI, Frontera W, Stanley T, Corcoran C, Costello M, Parlman K, Schoenfeld D, Klibanski A, Grinspoon S. Effects of testosterone and exercise on muscle leanness in eugonadal men with AIDS wasting. J Appl Physiol 2001;90(6):2166-71
  • Khaw KT, Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol 1992; 2:675-82
  • Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, Sannerstedt R. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 1990; 39:897-901.

Adrian Dobs, M.D.
Johns Hopkins University School of Medicine

Dr. Dobs is Professor of Medicine and Oncology, Vice Chair of the Department of Medicine for Clinical Research, and Director of the Clinical Trials Unit at The Johns Hopkins University School of Medicine. She is an active investigator in the field of male gonadal function and is interested in the development of new forms of male hormone replacement therapy. She recently was awarded an $8 million NIH grant to direct The Johns Hopkins Complementary and Alternative Cancer Center.

Endocrine abnormalities are frequently observed in individuals with HIV infection and/or injection drug use. Some of these abnormalities are a consequence of the disease itself, while other times it is a non-specific finding associated with malnutrition and chronic illness. I will present data from the Mulitcenter AIDS Cohort and our on-going study of metabolic abnormalities in drug users.

  • Wahlstrom J, Tang A, Cofrancesco J, Shah N, Dobs A. Gonadal hormone levels in injection drugs users: a subset of the ALIVE study. Drug and Alcohol Dependence, 60(3)11-3, 2000
  • Kingsley L, Smith E, Riddler S, Li R, Chmiel J, Palella F, Vischer B, Oishi J, Taylor E, Dobs A, Evans R. The prevalence of lipodystrophy and metabolic abnormalities in the multicenter AIDS cohort study (MACS). Submitted The International AIDS Meeting, January, 2000
  • Dobs AS, Brown T. Metabolic Abnormalities in HIV and Injection Drug Users. JAIDS. In press
  • Skolasky RL, Dobs AS, Calhoun BC, Visscher BR, Palella FJ, Jacobson LP. Changes in the incidence and predictors of HIV related wasting syndrome: 1987-1999. Submitted to AIDS, 2001.

Ellen Engelson, Ed.D.
Columbia University

Dr. Engelson is an Associate Research Scientist at Columbia University and St. Luke’s-Roosevelt Hospital Center. The major focus of her work is nutrition and HIV, with a special interest in women; her current research addresses the pathogenesis and treatment of HIV-associated fat redistribution and metabolic complications. An additional focus of her work is on the use of body composition measurements to assess nutritional status in a variety of clinical disorders.

One characteristic of recent HIV-associated body composition changes is accumulation of excess visceral adipose tissue (VAT), raising concern because of associations in HIV-uninfected people between excess VAT and negative clinical outcomes, including insulin resistance, diabetes, cardiovascular disease and stroke. A number of interventions have been reported to reduce VAT, usually in conjunction with total weight loss, and investigators frequently claim preferential loss of VAT compared with subcutaneous adipose tissue (SAT) loss. Smith and Zachwieja1 reviewed 23 of these studies performed in people without HIV. A direct comparison between % loss of VAT and % loss of body fat indicated greater loss of VAT than SAT. However, VAT loss is influenced by amount of VAT prior to weight loss and amount of weight lost, and controlling for these factors in a subset of studies indicated comparable results between diet, exercise and pharmacologic intervention (diet pills). HIV studies performed at St. Luke’s-Roosevelt have included a trial of recombinant human growth hormone (rhGH) for excess VAT2, a diet and exercise weight loss program for obese women with and without high VAT/SAT (unpublished), and a trial of progressive resistance exercise in malnourished HIV+ women3 . When these studies were compared with the Smith and Zachwieja results, only the weight loss program fit their model, perhaps because this was the only study group that began with similar body composition. Although rhGH treatment promoted significant loss of VAT, the ratio of VAT/SAT at baseline was nearly quadruple the highest ratio in the HIV-negatives, primarily because of the incidence of lipoatrophy in addition to VAT accumulation. And among the malnourished women, who began with normal VAT/SAT but a relatively small absolute amount of either, there was an insignificant gain of VAT despite a 7% loss of total body fat. It is unclear if HIV exerts an independent effect on VAT loss mediated by the metabolic changes associated with fat redistribution, if there is a direct effect of antiretrovirals, or if the interventions, especially rhGH, are actually different in their effects.

  • Smith SR, Zachwieja JJ. Visceral adipose tissue: a critical review of intervention strategies. Int J Obes Relat Metab Disord. 1999;23:329-35
  • Engelson ES, Glesby MJ, Mendez D, Albu JB, Wang J, Heymsfield SB, Kotler DP. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. Submitted
  • Agin D, Gallagher D, Wang J, Heymsfield SB, Pierson Jr RN, Kotler DP. Effects of whey protein and resistance exercise on body cell mass, muscle strength, and quality of life in women with HIV. AIDS 2001;15:2431-40.

Jerome Ernst, M.D.
Community Research Initiative on AIDS

Dr. Ernst is the Medical Director of the Community Research Initiative on AIDS, a nonprofit community-based HIV/AIDS research and treatment education organization. He is an Associate Professor of Medicine at the Albert Einstein College of Medicine. Dr. Ernst created and supervised the AIDS program at New York’s Bronx Lebanon Hospital.

Linda Richmond
New York Village Center for Care

Dr. Richmond is Associate Director of Research at the Village Center for Care in New York City. Her major research and practice interests are in the area of providing care to people with chronic physical and emotional problems.

Eisenberg has defined alternative medicine therapies as interventions that are neither taught widely in medical schools nor generally available in US hospitals. While almost $386 million were spent on patient visits to primary care providers in 1997, over $629 million were spent on visits to CAM providers that same year (Eisenberg). CRIA has performed several trails of treatments that may be considered CAM which are reported here. Also discussed is VidaCare, a health maintenance organization based in AIDS Day Care Programs in New York that offers a variety of CAM therapies. The role of these therapies within the programs and the ways they are integrated into the overall medical care of the patients is discussed.

Integrative medicine refers to a clinical approach that combines the strengths of conventional and alternative medicine. An approach to evaluating the effectiveness of integrative therapies that asks the questions, “How does it work?” and “What does it add?” in addition to “Does it work?” is also proposed.

  • Starr, P. The Social Transformation of American Medicine. Basic Books. 1982.
  • Eisenberg D.M., Davis R.B., Ettner S.L., et al. Trends in Alternative Medicine Use in the United States, 1990-1997. JAMA.1998; 280:1569-1575
  • Wootton J.C., Sparber A. Surveys of Complementary and Alternative Medicine: Part III. Use of Alternative and Complementary Therapies for HIV/AIDS. J. Altern Complement Med. 2001;Aug;7(4):371-7
  • Standish L.J., Greene K.B., Bain S., et al. Alternative Medicine Use in HIV-Positive Men and Women: Demographics, Utilization Patterns and Health Status. AIDS CARE 2001; 13(2): 197-208
  • Shlay J.C., Chaloner K., Max M.B., et al. Acupuncture and Amitriptyline for Pain Due to HIV-Related Peripheral Neuropathy. JAMA.1998; 280:1590-1595
  • Cole S.W., Naliboff B.D., Kameny M.E.. Impaired Response to HAART in HIV-Infected Individuals with High Autonomic Nervous System Activity. PNAS.2001; 98(22): 12695-12700
  • Weber R., Christen C., Loy M., et al. Randomized, Placebo-Controlled Trial of Chinese Herb Therapy for HIV-1-Infected Individuals. JAIDS. 1999; 22(1): 56-71
  • Sicher F., Targ E., Moore D., et al. A Randomized Double-Blind Study of the Effect of Distant Healing in a Population with Advanced AIDS: Report of a Small Scale Study. West. J. Med. 1998; Dec; 169(6): 356-363

Wafaie Fawzi, M.D.
Harvard University School of Public Health

Dr. Fawzi is an Associate Professor of International Nutrition and Epidemiology at Harvard School of Public Health. He studies the role of nutritional factors in the etiology of adverse health outcomes among populations in developing countries, with an emphasis on infectious and perinatal outcomes among mothers and children.

The dual burden of HIV infection and malnutrition in many developing countries is evident, particularly among women and children. Poor micronutrient status has been associated with higher risks of adverse health outcomes. Most of the evidence among HIV-infected individuals come from prospective observational studies that were carried out primarily in the United States. These studies suggest that low dietary intake of micronutrients, including the B vitamins and vitamins C and E, is associated with faster disease progression and mortality. In other studies, low plasma levels of these micronutrients have been related to disease progression. Low plasma vitamin A levels among HIV-infected women were reported to be associated with higher risks of HIV shedding in breast milk and vertical transmission of the virus. Observational studies are limited in ascertaining causality between micronutrient status and these outcomes. A few randomized controlled trials were carried out to examine the efficacy of micronutrient supplements on health outcomes in HIV infection. Status of the field in this area will be reviewed including results from a recently completed randomized trial in Tanzania.

Endocrine Disorders In AIDS Patients and Drug Abusers

Rosita Fontes, M.D., Ph.D.
Universidade Catolica do Rio de Janeiro

Dr. Fontes received her medical degree at the Universidade Federal do Espirito Santo in Brazil and completed her residency in endocrinology at the Instituto de Diabetes e Endocrinologia Luis Capriglione Rio de Janeiro. She also studied endocrinology and metabolism at Pontificia Universidade Católica do Rio de Janeiro, where she now serves as an Associate Professor of Endocrinology and Metabolism.

The course of human immunodeficiency virus infection and the acquired immunodeficiency syndrome can be complicated by a variety of endocrine and metabolic abnormalities secondary to direct cytopathic effect by HIV, opportunistic infections, neoplasms, infection complications or drugs used in the treatment. Patients with AIDS may exhibit abnormal results on endocrine function tests. To evaluate some of the manifestations of AIDS disease, we studied individuals of both sex, 20-55 years old, classified in four groups: Gr 1 - control group (HIV negative); group 2 - asymptomatics; group 3 - constitutional disease and group 4 - AIDS. No patients were on treatment with antiretroviral drugs. Abnormalities of adrenal gland: We measured morning cortisol before and after administration of 0,25 mg ACTH rapid infusion and aldosterone and renin after postural stimulation test. Basal cortisol levels were significantly higher in group 4. After stimulus, the cortisol response to ACTH was lower in groups of 3 and 4 and could represent marginal adrenal function. After 1 hour recumbent we measured aldosterone and renin values as well as responses to upright posture. The responses were not different in the groups. We present a case record of one patient who had adrenal insufficiency, presumably due to the HIV virus, opportunistic CMV infection or Ketoconazol treatment. Abnormalities of pancreatic function: We studied the functional aspect of beta cells by fasting glucose and glucose-insulin curve. Greater glucose and insulin levels were observed in group 2. Greater incidence of hypoglycemia of multifactorial cause and smaller value of insulin was observed in group 4. No cases of glucose intolerance or Diabetes mellitus were detected. We present a case record that developed insulin resistance, deslipidemia and diabetes mellitus after the treatment with PIs, and the response to GH and Metformin treatment. Abnormalities in thyroid function: We studied the basal concentrations of total and free T3, total and free T4, TSH and the response of TSH to TRH test. Results of group 2 were similar to group 1. Group 3 showed lower levels of TT4 and TT3 and slighted high levels of FT4 and FT3, but in the normal range. In group 4, 80% of the patients had similar results to group 3 and 20%, had different abnormalities depending of the severity of the disease, progressing to fall of TSH and T3 and T4. Substance abuse can cause some endocrine disorders and interference in endocrine function tests. We present some cases of difficult approach in alcohol abusers.

Marshall Glesby, M.D. , Ph.D.
Weill Medical College of Cornell University

Dr. Glesby is an Assistant Professor of Medicine at Weill Medical College of Cornell University and Co-Director of Cornell’s Clinical Trials Unit. His research interests include adverse effects of antiretroviral therapy, cardiovascular, and metabolic complications of HIV infection, and viral opportunistic infections.

Prior to the advent of potent antiretroviral therapy, the most common bone disorders in HIV-infected patients were complications of infections and malignancies. In the current HIV treatment era, increasing recognition is being given to osteoporosis and osteonecrosis. HIV-infected patients receiving potent antiretroviral therapy appear to have a high prevalence of reduced bone mineral density (BMD)1. However, patients who are antiretroviral naïve also appear to have a higher than expected prevalence of reduced BMD2, suggesting that HIV itself may be a contributing factor. The role of specific classes of antiretroviral agents in the pathogenesis of osteopenia/osteoporosis is uncertain, as is the contribution of other factors such as cytokines3, lipodystrophy4, and nutritional status5. The risk of fractures remains undefined in this population. Similarly, no data exist on interventions to increase BMD and possibly prevent fractures. Osteonecrosis, also known as avascular necrosis, has been reported in HIV-infected patients since 19906. The available data suggest that corticosteroid use and other established risk factors contribute significantly to its pathogenesis7,8. Although case reports have suggested that protease inhibitors may increase the risk of osteonecrosis, controlled data have not supported this contention. Potent antiretroviral therapy may indirectly increase the risk of osteonecrosis through prolongation of survival.

  • Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14:F63-F67
  • Nolan D, Upton R, McKinnon E, John M, James I, Adler B, et al. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 2001; 15:1275-1280
  • Aukrust P, Haug CJ, Ueland T, Lien E, Muller F, Espevik T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab 1999; 84:145-150
  • Huang JS, Rietschel P, Hadigan CM, Rosenthal DI, Grinspoon S. Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy. AIDS 2001; 15:975-982
  • Fairfield WP, Finkelstein JS, Klibanski A, Grinspoon SK. Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome. J Clin Endocrinol Metab 2001; 86:2020-2026
  • Goorney BP, Lacey H, Thurairajasingam S, Brown JDK. Avascular necrosis of the hip in a man with HIV infection. Genitourin.Med. 1990; 66:451-452
  • Glesby MJ, Hoover DR, Vaamonde CM. Osteonecrosis in patients infected with human immunodeficiency virus: a case-control study. J Infect Dis 2001; 184:519-523
  • Scribner AN, Troia-Cancio PV, Cox BA, Marcantonio D, Hamid F, Keiser P, et al. Osteonecrosis in HIV: A case-control study. J Acquir Immune Defic Syndr2000; 25:19-25

Sherwood Gorbach, M.D.
Tufts University School of Medicine

Dr. Gorbach is a Professor in the Department of Family Medicine and Community Health at Tufts University School of Medicine. He is the Principal Investigator on four NIH projects, including a program project grant on nutrition and HIV infection, a grant for studies of Hispanic drug abusers with HIV, and a program project grant on nutrition in simian immunodeficiency virus infection.

Since highly active antiretroviral therapy became available there have been many reports of changes in fat distribution and serum lipid levels among persons with HIV. These changes are referred to as the HIV-associated lipodystrophy syndrome. Most studies have examined the presence of these changes in association with disease related-factors such as antiretroviral therapy and viral load. Little is known about the influence of drug abuse on the presentation of the lipodystrophy syndrome. Here we report preliminary data from the baseline visit of a prospective cohort study of Hispanic men and women. The study is comprised of three groups: HIV-positive drug abusers, HIV-negative drug abusers, and HIV-positive non-drug abusers. We report data on body composition and fat distribution, measured by dual-energy X-ray absorptiometry, in relation to HIV status, the use of highly active anti-retroviral therapy (HAART) and drug abuse. A better understanding is needed of the relation of drug abuse to the manifestations of the HIV-lipodystrophy syndrome.

Steve Grinspoon, M.D.
Massachusetts General Hospital

Dr. Grinspoon is the Clinical Director of the Neuroendocrine Clinical Center and Director of Metabolism Research for the Massachusetts General Hospital/Brigham Center for AIDS Research. He also is an Assistant Professor of Medicine at Harvard Medical School and Assistant Program Director of the Massachusetts Institute of Technology Cancer Research Center. He has a longstanding interest in the metabolism of HIV disease.

Abnormalities of glucose homeostasis and lipid metabolism occur frequently in association with changes in body composition among HIV-infected patients receiving highly active antiretroviral therapy (HAART). Hyperinsulinemia and insulin resistance are central features of the HIV lipodystrophy syndrome. Among such patients, fasting glucose levels are most often normal, but impaired glucose tolerance is often seen on standard oGTT testing. Fasting hyperinsulinemia, inappropriate insulin responses to standard glucose challenge, and decreased glucose disposal rates have now been shown both in relationship to changes in body composition, e.g. loss of subcutaneous abdominal and extremity fat and increased abdominal visceral fat, and in response to specific antiviral therapies. In vitro evidence for an effect of protease inhibitors on Glut-4 mediated glucose transport and also in vivo among non HIV-infected patients have been demonstrated. Insulin resistance is associated with an atherogenic lipid profile and impaired thrombolysis in HIV-infected patients with the lipodystrophy syndrome and may contribute independently to an increased risk of cardiovascular disease, even among HIV-infected patients who do not have Type II diabetes mellitus. Recent data suggest that insulin-sensitizing agents may improve the metabolic abnormalities associated with the HIV lipodystrophy syndrome. The evidence, potential mechanisms, clinical consequences, and therapeutic strategies for insulin resistance in patients with HIV-lipodystrophy, will be reviewed in this presentation.

  • Carr A, Samaras K, Thorisdottir A, Kaufman GR, Chisolm DJ, and Cooper DA. 1999 Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor associated lipodystrophy, hyperlipidemia, and diabetes mellitus: a cohort study. Lancet 353:2093-99
  • Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving protease inhibitor therapy. AIDS 1998;12:F51-F58
  • Walli RK, Herfort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1 infected patients. AIDS 1998;12:F167-F173
  • Vigouroux C, Gharakhanian S, Salhi Y, et al. 1999 Diabetes, Insulin resistance and Dyslipidemia in Lipodystrophic HIV-Infected Patient on Highly Active Antiretroviral Therapy (HAART). Diabetes and Metabolism (Paris) 25:225-232
  • Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, and Grinspoon S. 1999 Fasting hyperinsulinemia and Changes in Regional Body Composition in HIV-Infected Women. J Clin Endocrinol Metab 84:1932-37
  • Hadigan C, Corcoran C, Stanley T, Piecuch S, Klibanski A, and Grinspoon S. 2000 Fasting hyperinsulinemia in HIV-infected men: relationship to body composition, gonadal function and protease-inhibitor use. J Clin Endocrinol Metab 85:35-41
  • Mynarcik DC, McNurlan MA, Steigbigel RT, et al. 2000 Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr25:312-21
  • Noor M, Lo J, Mulligan K, et al. 2000. Metabolic effects of indinavir in healthy HIV-seronegative subjects. Antiretroviral Therapy, 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Toronto. Suppl 5;8
  • Murata H, Hruz PW, Mueckler M. 2000 The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 275:20251-4
  • Hadigan C, Meigs JB, Corcoran C, et al., 2001 Characterization of metabolic abnormalities and cardiovascular disease risk factors in HIV-infected men and women with the lipodystrophy syndrome. Clin Inf Dis 32:130-139
  • Despres JP, Lamarche B, Mauriege P, et al. 1996 Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952-957
  • Johansson L, Jansson JH, Boman K et al. 2000. Tissue plasminogen activator, plasminogen activator inhibitor-1 and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of first stroke. Stroke 31:26-32
  • Hadigan C, Meigs J, Rabe J, D'Agostino RB, Wilson PWF, Lipinska I, Tofler GH, Grinspoon S. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. 2001 J Clin Endocrin Metab
  • Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, and Grinspoon S. 2000 Metformin in the Treatment of HIV Lipodystrophy. JAMA 284:472-7
  • Saint-Marc T and Touraine JL. 1999 Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy. AIDS 13:1000-2
  • Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, Lo JC, Schambelan M. 2000. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. JAIDS 23(1):35-43

Difficulties in Understanding the Changes in Fat Distribution and Metabolism in HIV Infection

Carl Grunfeld, M.D., Ph.D.
Veterans Affairs Medical Center, San Francisco

Dr. Grunfeld is a Professor of Medicine at the University of California, San Francisco, and Chief of the Metabolism and Endocrine sections at the Department of Veterans Affairs Medical Center in San Francisco. He has done extensive research in the areas of arthritis and in metabolic diseases and diabetes.

It is increasingly clear that he concept of a single syndrome of HV-associated lipodystrophy with peripheral fat wasting, central fat hypertrophy, hypertriglyceridemia, hypercholesterolemia and insulin resistance due to HIV protease inhibitors is an oversimplification. Rather, there are several metabolic processes that occur with distinct and overlapping etiologies. Failure to recognize these processes may lead to studies of selected populations that are not as applicable as presumed. Peripheral fat loss is the most dominant syndrome and has been reported both in patients who are on PI therapy and who are PI naïve. Although early data suggested that the NRTI lamivudine played a role, more recent data support a dominant role for stavudine. Because stavudine and lamivudine were introduced just before PI therapy, many smart clinicians started these drugs at the same time as the PI. There are data to support a synergy between stavudine and PI therapy. Studies of large groups of HIV-infected patients who report fat redistribution show on the average decreased truncal fat and low BMI. Thus a lower percentage of HIV-infected patients have absolute central hypertrophy. The results from studies selecting for patients with both peripheral fat wasting and obvious central hypertrophy cannot be extrapolated to the affected population as a whole. Furthermore, it is important to use the proper controls when such groups are selected. If patients selected for visceral obesity as well as peripheral wasting are compared to healthy normal or even BMI-matched controls, then the differences could be due to visceral obesity per se, unrelated to peripheral fat wasting and not unique to HIV. To understand the contributions of these changes in body composition, cohorts matched for visceral obesity must be compared. Measurement ore f the compartments is essential. PI drugs have been shown to induce metabolic changes independent of body composition changes. If cohorts are selected for PI-associated lipodystrophy, then metabolic changes directly due to the PI may be attributed to the lipodystrophy. Furthermore, not all PI’s are alike. Ritonavir induces more of an increase in triglycerides than other PI’s. Amprenivir may induce less insulin resistance. The insulin resistance of the PI indinavir is rapid in onset, appearing as soon as drugs reach therapeutic levels. As a consequence, if a drug is omitted during a fasting study or does not reach therapeutic levels (for example if it is normally taken with food), it is possible that an effect on glucose metabolism will be missed. Finally, it is not clear that all of the metabolic effects are directly due to the PI itself. An increase in LDL cholesterol is seen in HIV-infected patients who initiate PI therapy, but is not found in HIV-seronegative volunteers who are given PI drugs. The increase in LDL may represent restoration to health, as LDL is decreased in HIV infected patients.

Colleen Hadigan, MD, MPH
Massachusetts General Hospital

Dr. Hadigan is an Assistant Professor in Pediatrics at the Harvard Medical School. Her research interests include metabolic complications of HIV-infection and its treatment, and her recently published work has focused on the evaluation and treatment of insulin resistance and cardiovascular disease risk in patients with HIV-associated lipodystrophy.

Relatively little is known regarding the potential influence of dietary habits on the metabolic complications associated with HIV infection and lipodystrophy. Using food frequency questionnaires, Batterham and colleagues (AIDS, 2000, 14:1839-1843) investigated energy, fat and saturated fat intake between HIV infected patients with fat redistribution compared to patients without fat redistribution. No relationship was noted between saturated or total fat intake and the metabolic and body composition abnormalities associated with lipodystrophy. In a similar study (CID, 2001) we assessed the relationship between dietary intake, body composition and metabolic parameters in 85 consecutive HIV infected patients with fat redistribution (62 men and 23 women). Dietary history, fasting glucose, insulin, lipid levels, and an oral glucose tolerance test (OGTT) were obtained. Multivariate regression analysis was used to predict insulin area under the curve (AUC) following OGTT which included age, gender, BMI, waist-to-hip ratio, kilocalories, duration of protease inhibitor (PI), fat redistribution pattern, alcohol, dietary fiber and polyunsaturated- to -saturated (P:S) fat ratio. Age (p=0.004), PI duration (p=0.02), and P:S fat ratio (p=0.003) were positively associated with insulin AUC. Dietary fiber was inversely associated with insulin AUC (p=0.001). In a similar analysis, alcohol consumption was a significant positive predictor of LDL cholesterol. Polyunsaturated fats, fiber and alcohol are strongly associated with insulin resistance and hyperlipidemia in this population, and may be important targets for dietary modification.

  • Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284(4):472-77
  • Hadigan C, Jeste S, Anderson EJ, Tsay R, Cyr H, Grinspoon S. Modifiable dietary habits and their relation to metabolic abnormalities in men and women with HIV-infection and fat redistribution. Clin Inf Dis 2001; 33(5):710-7

Turnover of Adipocytes and Mitochondrial DNA in Humans: Direct Testing of Pathogenic Role in Lipodystrophy and Mitochondrial Toxicity Syndromes

Marc Hellerstein, M.D., Ph.D.
University of California Berkeley

Dr. Hellerstein is a Professor of Nutritional Sciences at the University of California, Berkeley, and an Associate Professor of Nutritional Sciences at the University of California, San Francisco. He has taught at these two institutions since 1987.

The theme of this presentation will be that hypotheses concerning the biochemical pathogenesis of disease can be directly tested in vivo in humans, using new techniques. Well-defined biochemical hypotheses have been proposed for two important metabolic disorders in HIV/AIDS: NRTI-associated complications (impaired replication of mitochondrial [mt]DNA) and lipoatrophy (altered turnover of triglyceride [TG] or adipocytes in adipose tissue). We will describe recently developed stable isotope-mass spectrometric techniques that allow measurement of relevant biochemical processes in vivo. In particular, measurement of DNA replication, and thus cell proliferation or mtDNA synthesis, by labeling the deoxyribose-moiety (with 2H2O for slow-turnover cells); and TG synthesis or de novo lipogenesis, by mass isotopomer distribution analysis (also with 2H2O, for adipose lipids). Kinetic studies of adipose tissue components will be presented. Several hypotheses have been addressed, including: is mesenteric TG more lipolytically active than S.C. fat? Does rosiglitazone have depot-specific effects on TG metabolism? Does rosiglitazone reduce lipolysis and thereby increase fat mass? Do TZD’s increase adipose mass and TG synthesis on either high-fat or low-fat diets? Are the effects of leptin different than energy restriction in ob/ob mice? Does resistin/ADSF expression correlate with adipose TG metabolism? Do adult humans exhibit turnover of adipocytes? Do protease inhibitors have direct effects on adipose TG metabolism in healthy subjects? Is lipoatrophy in HIV/AIDS due to reduced TG synthesis or increased lipolysis? Preliminary results to date for mtDNA synthesis and mitochondrial biogenesis will also be presented. Turnover of muscle mtDNA in rats has been measured; the effects of administration of NRTI in the diet is being investigated. Synthesis of mitochondrial phospholipids correlates with mtDNA. Human platelet mtDNA synthesis has also been measured, after 2H2O administration. In summary, powerful new tools are available for testing the metabolic pathogenesis of HIV/AIDS complications in humans. These tests also may have uses for diagnostics and treatment monitoring. We do not yet have definitive answers, however, regarding pathogenesis of mitochondrial or lipoatrophic syndromes.

  • Hellerstein MK, Christiansen M, Kaempfer S, Kletke C, Wu K, Reid JS, Hellerstein S, Shackleton CHL. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J Clin Invest, 87:1841-52, 1991
  • Hellerstein MK, Wu K, Kaempfer S, Kletke C, Shackleton CHL. Sampling the lipogenic hepatic acetyl-CoA pool in vivo in the rat. Comparison of xenobiotic probe to values predicted from isotopomeric distribution in circulating lipids and measurement of lipogenesis and acetyl-CoA dilution. J Biol Chem 266:10912-9, 1991
  • Blackham M, Cesar D, Park O-J, Wu K, Kaempfer S, Shackleton CHL, Hellerstein MK. Effects of recombinant monokines on hepatic pyruvate dehydrogenase (PDH), PDH kinase, de novo lipogenesis and plasma triglycerides. Abolition by prior fasting. Biochem J 284 (1):129-135, 1992
  • Hellerstein MK, Neese R. Mass isotopomer distribution analysis (MIDA): a statistical approach for measuring biosynthesis and turnover of polymers. Am J Physiol 263:E988-E1001, 1992
  • Neese R, Faix D, Kletke C, Wu K, Shackleton CHL, Hellerstein MK. Measurement of endogenous synthesis of serum cholesterol in vivo in rats and humans using mass isotopomer distribution analysis (MIDA). Am J Physiol 264:E136-E147, 1993
  • Hellerstein MK. Pathophysiology of lean tissue wasting in HIV infection: therapeutic implications. HIV: Advances in Research and Therapy 3(3):8-16, 1993
  • Hellerstein M, Grunfeld C, Wu K, Christiansen M, Kaempfer S, Kletke C, Shackleton CHL. Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab 76:559-565, 1993
  • Mulligan K, Grunfeld C, Hellerstein M, Neese R, Schambelan M. Anabolic effects of recombinant growth hor-mone in patients with weight loss associated with HIV infection. J Clin Endocrinol Metab 77:956-62, 1993
  • Hellerstein MK, Benowitz NL, Neese RA, Hoh R, Jacob P, Fong I, Hsieh J, Faix D. Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. J Clin Invest 93:265-272, 1994
  • Neese RA, Faix D, Schwarz J-M, Turner SM, Vu D, Hellerstein MK. Measurement of gluconeogenesis and rate of appearance of intrahepatic triose-phosphate and its regulation by substrates by mass isotopomer distribution analysis (MIDA). Testing of assumptions and potential problems. J Biol Chem270:14452-63, 1995
  • Schwarz J-M, Neese RA, Turner S, Dare D, Hellerstein MK. Short-term alterations in carbohydrate energy intake in humans: striking effects on hepatic glucose production, de novo lipogenesis, lipolysis and whole-body fuel selection. J Clin Invest 96:2735-2743, 1995
  • Hellerstein MK, Wu K, McGrath M, Faix D, George D, Shackleton CHL, Horn W, Hoh R, Neese RA. Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the Acquired Immune Deficiency Syndrome: relation to indices of cytokine production. Journal of Acquired Immunodeficiency Syndromes & Human Retrovirol 11(3):258-70, 1996

Fat Mass Protects HIV-Infected Women from HIV Progression, But Not Mortality

Clara Jones, M.D., M.P.H.
Tufts University School of Medicine

Dr. Jones is an Assistant Professor in Family Medicine and Community Health at Tufts University School of Medicine in Boston. Her research interests include evaluating the effect of overweight/obesity on HIV progression in HIV-positive women, the association of micronutrients and cervical dysplasia in HIV-positive women, and the correlation of EKG abnormalities and nutrition in HIV-positive patients.

Background: Several studies (1,2) report improved survival in overweight HIV+ persons. These did not include data on body composition, were largely pre-HAART, and had fewer women. We evaluate the relationship of fat mass with AIDS-defining conditions and CD4 count in HIV+ women. Methods: At baseline and six-month intervals, history, laboratory values, BIA and anthropometry were obtained on 190 HIV+ women. Longitudinal analysis of fat mass as a predictor of new AIDS diagnosis and change in CD4 count was performed. Results: Each kg of additional fat mass was associated with 4% decreased risk of a new AIDS diagnosis during the interval after adjusting for potential confounders. Intervals starting with CD4<200 cells/mm3 had a mean 4.2 cell higher ‘change in CD4’ for each 2.5 kg fat while in intervals starting with >200 CD4 cells, no significant ‘change in CD4’ was seen. Increased fat mass did not significantly improve survival. Summary: In the NFHL cohort, fat mass was inversely associated with probability of developing a new AIDS-defining condition, and was positively associated with ‘change in CD4’ in intervals with starting CD4<200. BMI was inversely associated with the probability of developing CD4<200 in the HERS cohort. Conclusion: Increased fat appears independently beneficial for HIV+ women in terms of HIV progression. No significant survival benefit was seen. Supporting data from the HERS cohort, and a potential biologic rationale are discussed.

  • Shor-Posner, G.; Campa, A.; Zhang, G.; Persaud, N.; Miguez-Burbano, M.; Quesada, J.; Fletcher, M.A.; Page, J.B.; Baum, M.K.; “When Obesity is Desirable: A Longitudinal Study of the Miami HIV-1-Infected Drug Abusers (MIDAS) Cohort”, Journal of Acquired Immune Deficiency Syndromes 23:81-88, 2000
  • Shuter, J.; Chang,C.J.; Klein,R.S. "Prevalence and Predictive Value of Overweight in an Urban HIV Care Clinic" Journal of Acquired Immune Deficiency Syndromes 26(3):291-297, 2001

Studies of Subcutaneous Adipose Tissue in HIV+ Subjects with Lipodystrophy

Don Kotler, M.D.
Columbia University College of Physicians and Surgeons
St. Luke’s – Roosevelt Hospital Center

Dr. Kotler is a Professor of Medicine at the Columbia University College of Physicians and Surgeons and Chief of Gastroenterology at St. Luke’s-Roosevelt Hospital Center in New York City. His research interests focus on nutrition and gastrointestinal disease.

The etiology of HIV-associated lipodystrophy (HIVL+) is multifactorial. In addition to antiretroviral (ARV) therapies, an inflammatory response occurring as a consequence of immune reconstitution has been proposed as an etiologic factor. We tested the hypothesis that lipoatrophy is associated with metabolic alterations in subcutaneous adipose tissue (SAT) obtained by aspiration. Studies were performed in 56 subjects, 27 with self-reported change in fat distribution, 17 HIV+ without such changes and 12 healthy volunteers. Aspirations were taken from buffalo humps in 7 subjects with lipodystrophy. Short-term (3-hr) cultures of tissue explants were performed, and the release of TNF, leptin, lactate, and glycerol into the medium were measured. In addition, 3 day incubations also were performed and the supernatant concentrated and assayed for C3a desArg, a complement component with homology to acylation stimulating protein (ASP), a cytokine ! that promotes lipid deposition. The patients with lipodytrophy had more visceral fat (VAT) and less SAT than healthy controls. Glycerol production, reflecting lipolysis, was elevated in both HIV+ groups compared to controls, and not different in patients with and without lipodystrophy. Lactate production also was elevated in both HIV+ groups. TNF secretion into the medium was significantly higher in HIV+ subjects with lipodystrophy compared to the other groups. Serum concentrations of a soluble TNF receptor also were elevated in the HIV-lipodystrophy group suggesting that the inflammatory influence was systemic in nature. In contrast, the release of leptin into the media was similar in all 3 groups (P>0.2). The secretion of glycerol, lactate, and TNF all were higher in SAT than in buffalo hump. The secretion of complement factor 3 into the media during a 3 day incubation was similar in all groups, while the production of C3! a desArg (ASP) was significantly lower in the lipodystrophy group, as compared to the other groups. These preliminary studies suggest that the metabolism of SAT may be altered in several ways in HIV+ patients with lipodystrophy. Elevations in lipolytic rates occur as a result of HIV infection or its treatment, while the secretion of the proinflammatory cytokine, TNF, is associated with lipodystrophy. The production of ASP was decreased in patients with lipodystrophy, an effect that could be related to TNF activity.

Metabolic Effects of Growth Hormone in Patients with HIV Infection

Kathleen Mulligan, Ph.D.
University of California, San Francisco

Dr. Mulligan is an Assistant Professor of Medicine at the University of California, San Francisco, and works in the Division of Endocrinology at San Francisco General Hospital. Her research group has implemented numerous NIH-funded studies of the effects of HIV infection and its therapies on body composition, energy metabolism, and endocrine function in men and women. These studies include evaluation of several pharmacologic interventions for classic wasting, as well as the metabolic complications seen in the current treatment era.

Recombinant human growth hormone (GH) is an approved treatment for HIV-associated wasting and is currently of interest as a potential therapy in HIV-infected subjects with syndromes of fat accumulation. For the former, the primary beneficial effect of pharmacologic GH treatment is augmentation of lean body mass, and for the latter, a reduction in fat mass, particularly in the dorsocervical and abdominal regions. The present report will summarize the results of metabolic ward studies of the effects of open-label GH treatment on glucose and carbohydrate metabolism both in patients with classic wasting and those with central fat accumulation. Glucose and lipid metabolism were assessed before and during pharmacologic GH treatment by oral glucose and intravenous fat tolerance testing, indirect calorimetry, stable isotope infusion studies, and euglycemic hyperinsulinemic clamp. In both patients with wasting and those with fat accumulation, GH treatment produced sustained increases in lipid oxidation, consistent with increases in whole-body lipolysis and decreases in body fat stores. In HIV-infected subjects with fat accumulation, GH improved lipid profiles but worsened both peripheral and hepatic glucose homeostasis during fasting and hyperinsulinemia. The combined implications of these positive and negative metabolic effects for cardiovascular disease risk in the current treatment era, as well as the metabolic effects of lower doses of GH, warrant further study.

Iron Deficiency Anemia in HIV-Infected and Drug Exposed Women and Children

Richard D. Semba, M.D., M.P.H.
Johns Hopkins University School of Medicine

Dr. Semba is an Associate Professor in the Department of Ophthalmology of The Johns Hopkins School of Medicine. Dr. Semba recently co-edited the textbook Nutrition and Heath in Developing Countries (Humana Press, 2001) and is now writing Nutrition and Eye Health with Debra Schaumberg, to be published 2002. He also is working on another academic text, A History of Vitamin A.

Anemia is the most common morbidity of HIV/AIDS. The consequences of anemia include fatigue, malaise, limited physical endurance, and decreased quality of life. Several studies have shown that anemia is associated with increased mortality during HIV infection. During HIV infection, most men and nearly all women develop anemia sometime during the course of the disease. HIV-infected women are at higher risk than men for the development of anemia. The causes of anemia during HIV infection are diverse and include chronic disease, drugs, and micronutrient deficiencies. Iron deficiency accounts for a large proportion of anemia among HIV-infected female injection drug users. Most HIV-infected injection drug users also have chronic hepatitis C (HCV) infection. Iron deficiency and iron deficiency anemia may contribute to the cycle of poverty among inner city injection drug users, as anemia and fatigue may limit the ability of women to work, receive further education, or maintain social interactions. During HIV and/or HCV infection, increased or excess iron stores have been associated with higher morbidity and mortality. Although the benefits of iron supplementation for reducing iron deficiency anemia and fatigue are known, recent studies suggest that iron supplementation needs to be approached with caution during HIV and/or HCV infection.

  • Semba RD, Gray GE. Pathogenesis of anemia during human immunodeficiency virus infection. J Investig Med 2001; 49:225-39
  • Volberding P. Consensus statement: anemia in HIV infection B current trends, treatment options, and practice strategies. Clin Ther 2000; 22:1004-20

Abby Shevitz, M.D., M.P.H.
Tufts University School of Medicine

Dr. Shevitz is an Assistant Professor of Internal Medicine at Tufts University School of Medicine and a member of the clinical staff at the Immunodeficiency Clinic at the New England Medical Center. Dr. Shevitz’s current area of research is HIV/AIDS wasting and lipodystrophy.

The benefits of androgen therapy and exercise for the treatment of HIV-associated wasting have not been evaluated in the setting of optimized dietary therapy, or in a heterogeneous population. We conducted a 3-arm randomized clinical trial of intensive nutrition alone (placebo-controlled), nutrition with oxandrolone (OX; 20 mg/day), and progressive resistance training (PRT) in 50 subjects. There were significant increases in most groups in energy intake (540 kcal/d, p<0.001; 400 kcal/d, p=0.16; and 710 kcal/d, p=0.005); in all groups in protein intake (39g/d, 32g/d, and 40g/d, all p<0.003); in CSMA in the OX (6.8cm2, p=0.02) and PRT (5.7cm2, p=0.04) groups, but only in PF in the PRT group (10 points/100, p=0.02). Strength increased with PRT group only; performance improved in all groups. Women demonstrated significant responses only to OX, whereas men had suggestive responses to all therapies, but strongest responses to PRT. Heavy alcohol use (> 3 drinks/day average) was reported by 21%, ongoing (non-IV) drug use by 42%, and a history of IVDU by 30%. CSMA responses to OX were consistently higher among non-abusers; PF in the OX group appeared to increase in all non-abusers and to decrease in abusers. Responses to PRT suggested better results among non-users, but findings were less consistent. These results may be due to dietary differences, differential compliance, metabolic effects of substance abuse, or the small size of subgroups.

Oxidative Stress and Antioxidant Status in HIV+ and HIV- Injections Drug Users

Alice Tang, Ph.D.
Tufts University School of Medicine

Dr. Tang is an Assistant Professor in the Department of Family Medicine and Community Health at Tufts University School of Medicine. Dr. Tang has served as Principal Investigator of three studies related to HIV infection in injection drug users—two funded by NIH and one by CDC. Dr. Tang has published several articles and two book chapters on the role of micronutrients in HIV infection.

It has been hypothesized that the low serum antioxidant levels observed in many HIV infected populations is largely due to an increase in oxidative stress. Oxidative stress is defined as a disturbance in the equilibrium status of pro-oxidant/antioxidant systems of intact cells (1). In HIV infection, oxidative stress may be caused by both overproduction of reactive oxygen intermediates (ROI’s) and a simultaneous deficiency of antioxidant defenses (2). Furthermore, injection drug use has been associated with increased levels of oxidative stress in animal models (3,4). Currently, there is widespread use of self-prescribed antioxidant supplementation among the HIV-infected population, and a prevailing belief that high dose supplementation is beneficial, or at the very least, not harmful. Data from our studies show that HIV-positive injection drug users (IDU’s) who are on antiretroviral combination therapies including a protease inhibitor have significantly higher mean serum levels of several antioxidants, independent of dietary and supplemental intake, compared with both HIV-negatives and HIV-positives not taking protease inhibitors(5). This suggests that oxidative stress may be reduced in patients taking protease inhibitors. Preliminary data on glutathione status and lipid peroxidation in this cohort of past and current injection drug users will be presented.

  • Thomas JA. Oxidative stress, oxidant defense, and dietary constituents. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. Eighth ed. Philadelphia: Lea & Febiger, 1994, p. 501-512
  • Greenspan HC and Aruoma OI. Oxidative stress and apoptosis in HIV infection: a role for plant-derived metabolites with synergistic antioxidant activity. Immunology Today 1994;15:209-213
  • Devi BG and Chan AWK. Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury. Life Sci1997;60:849-855
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  • Tang AM, Smit E, Semba RD, Lyles CM, Shah N, Li D, and Vlahov D. Improved antioxidant status among HIV-infected drug users on HAART. J Acquir Immune Defic Syndr 2000;23:321-326
  • Baruchel S and Wainberg MA. The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. J Leuk Biol 1992;52:111-114
  • Repetto M, Reides C, Gomez Carretro ML, et al. Oxidative stress in blood of HIV infected patients. Clin Chim Acta 1996;255:107-117

Christine Wanke, M.D.
Tufts University School of Medicine

Dr. Wanke is an Associate Professor of Medicine at Tufts University School of Medicine. She is the Director of the HIV Clinical Program at New England Medical Center and a staff physician in the Department of Infectious Disease at New England Medical Center. Her research interests include nutritional and metabolic aspects of HIV infection, intestinal function and diarrheal disease in HIV infection, and persistent diarrhea and nutrition in children in the developing world.

Objective: To re-evaluate the contribution of AIDS Defining Conditions (ADC) to HIV-associated wasting in the current era of Highly Active Antiretroviral Therapy (HAART).
Design: Longitudinal data analysis of the 671 patients in a prospective cohort designed to look at the interaction of nutrition and HIV. Methods: Data on ADC’s, height, and weight were collected at baseline and 6 month follow-up visits by trained study staff. Results: Few ADC’s occurred (39 in 1999; 2 in 2000). A history of more than one ADC was associated with currently dropping BMI to less than 20 kg/m2 (p=.026) but not the other definitions of wasting. A history of one ADC had no impact on current nutritional status. The development of a new ADI was associated with meeting any of one of the three wasting definitions used in the study: including first BMI <20 kg/m2, loss of 10% baseline weight, and loss of 5% weight over 6 months maintained over one or both of the next two study visits (p=.011). Conclusions: ADCs have decreased dramatically in frequency. When they do occur, ADCs cause acute weight loss. Based on the decrease in frequency, ADC’s cannot explain all of the weight loss that is still seen in HIV-infected adults.

  • Hellerstein MK, Kahn J, Mudie H, Viteri F: Current approach to the treatment of human immunodeficiency virus-associated weight loss: pathophysiologic considerations and emerging management strategies. Semin Oncol 1990, 17:17-33
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  • Wanke CA. Weight Loss and wasting remain common complications in individuals infected with Human Immunodeficiency Virus in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 2000, 31: 803-805
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  • Coodley GO, Loveless MO, Merill TM. The HIV wasting syndrome: a review. J Acquir Immune Defic Syndr 1994, 7:681-94
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  • Woods MN, Spiegelman D, Knox TA, Forrester JE, Connors JL, Skinner SC, Silva M, Kim JH, Gorbach SL. Nutrient intake and body weight in a large HIV Cohort that includes women and minorities (submitted for publication to JADA, 2000)
  • Knox TA, Spiegelman D, Skinner SC, Gorbach S. Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection. Amer Journal Gastroenterology 2000, 95: 3482- 3489
  • Nahlen BL, Chu SY, Nwanyanwu OC, Berkelman RL, Martinez SA, Rullan JU. HIV wasting syndrome in the United States. AIDS 1993, 7: 183-8

Recommendations

Areas Recommended for Future Research Emphasis

  1. Prevalence of specific nutritional/metabolic problems during lipodystrophy;
  2. Role of modified dietary practices for lipodystrophy;
  3. Diet/exercise in lipodystrophy;
  4. Influence of body composition on diabetes and atherosclerosis; linkage of treatment to outcomes;
  5. Role of prevention in glucose intolerance among drug users;
  6. Risks/benefits of micronutrient supplementation;
  7. Bone disease and associated issues;
  8. Surrogate markers of metabolic conditions such as bone disease and atherosclerosis;
  9. Pathophysiology of HIV- and hepatitis associated metabolic complications in drug abusers.
  10. Risk factors for the development of endocrine and metabolic disorders in HIV-infected and uninfected drug abusers worldwide, with emphasis on children and women.