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13 - Metabolic complications of antiretroviral therapy in children

Published online by Cambridge University Press:  23 December 2009

Carol J. Worrell
Affiliation:
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD
Steven L. Zeichner
Affiliation:
National Cancer Institute, Bethesda, Maryland
Jennifer S. Read
Affiliation:
National Institutes of Health, Bethesda, Maryland
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Summary

Introduction

The introduction of highly active antiretroviral therapy (HAART) has revolutionized the care of HIV-1 infected children and adults in the developed world, However, unforeseen toxicities attributable to the use of HAART continue to emerge. Pediatricians who care for HIV-infected children and adolescents increasingly face a population that has had extensive and prolonged exposure to HAART. These toxicities have been described extensively in the adult literature yet the definitions of particular syndromes, their etiology, prevalence, diagnosis, and management remain unclear. The consequences of these changes for the overall health of the patients are also uncertain. The pediatric data are quite limited. The available information suggests that the manifestations of these toxicities in HIV-infected children can be subtle and may vary with developmental stage. Younger children may have different presentations than adults. Metabolic complications have been reported in association with the use of nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have not been directly implicated. There may be significant intraclass variability, with respect to individual drug effects. The complications discussed in this chapter will include the fat redistribution syndrome, abnormalities in lipid and glucose metabolism, and hyperlactatemia and lactic acidosis.

Fat redistribution syndrome, lipid abnormalities, and insulin resistance

Background

This constellation of clinical and laboratory abnormalities is often referred to as the lipodystrophy syndrome, but a uniform case definition of lipodystrophy in the context of HIV infection does not yet exist.

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Publisher: Cambridge University Press
Print publication year: 2006

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References

John, M., Nolan, D., Mallal, S.Antiretroviral therapy and the lipodystrophy syndrome. Antiviral Ther. 2001;6(1):9–20.Google ScholarPubMed
Mallal, S. A., John, M., Moore, C. B., James, I. R., McKinnon, E. J.Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with human immunodeficiency virus infection. acquired immune deficiency syndrome 2000;14(10):1309–1316.Google Scholar
Chene, G., Angelini, E., Cotte, L.et al.Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin. Infect. Dis. 2002;34(5):649–657.CrossRefGoogle ScholarPubMed
Gervasoni, C., Ridolfo, A. L., Trifiro, G.et al.Redistribution of body fat in human immunodeficiency virus-infected women undergoing combined antiretroviral therapy. acquired immune deficiency syndrome 1999;13(4):465–471.Google Scholar
Hadigan, C., Miller, K., Corcoran, C., Anderson, E., Basgoz, N., Grinspoon, S.Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J. Clin. Endocrinol. Metab. 1999;84(6):1932–1937.Google ScholarPubMed
Ledru, E., Christeff, N., Patey, O., Truchis, P., Melchior, J. C., Gougeon, M. L.Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood 2000;95(10):3191–3198.Google ScholarPubMed
Kotler, D. P., Rosenbaum, K., Wang, J., Pierson, R. N.Studies of body composition and fat distribution in human immunodeficiency virus-infected and control subjects. J. Acquir Immune. Defic. Syndr. Hum. Retrovirol. 1999;20(3):228–237.CrossRefGoogle Scholar
Grunfeld, C., Pang, M., Doerrler, W., Shigenaga, J. K., Jensen, P., Feingold, K. R.Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J. Clin. Endocrinol. Metab. 1992;74(5):1045–1052.Google ScholarPubMed
Saint-Marc, T., Partisani, M., Poizot-Martin, I.et al.A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. acquired immune deficiency syndrome 1999;13(13):1659–1667.Google ScholarPubMed
Hadigan, C., Corcoran, C., Stanley, T., Piecuch, S., Klibanski, A., Grinspoon, S.Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use. J. Clin. Endocrinol. Metab. 2000;85(1):35–41.Google ScholarPubMed
Jain, R. G., Furfine, E. S., Pedneault, L., White, A. J., Lenhard, J. M.Metabolic complications associated with antiretroviral therapy. Antiviral Res. 2001;51(3):151–177.CrossRefGoogle ScholarPubMed
Valk, M., Gisolf, E. H., Reiss, P.et al.Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of human immunodeficiency virus-1 infection. acquired immune deficiency syndrome 2001;15(7):847–855.Google Scholar
Dong, K. L., Bausserman, L. L., Flynn, M. M.et al.Changes in body habitus and serum lipid abnormalities in human immunodeficiency virus-positive women on highly active antiretroviral therapy (highly active antiretroviral therapy). J. Acquir. Immune Defic. Syndr. 1999;21(2):107–113.Google Scholar
Carr, A., Samaras, K., Burton, S.et al.A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving human immunodeficiency virus protease inhibitors. acquired immune deficiency syndrome 1998;12(7):F51–F58.Google Scholar
Carr, A., Samaras, K., Thorisdottir, A., Kaufmann, G. R., Chisholm, D. J., Cooper, D. A.Diagnosis, prediction, and natural course of human immunodeficiency virus-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353(9170):2093–2999.CrossRefGoogle ScholarPubMed
Herman, J., Easterbrook, P.The metabolic toxicities of antiretroviral therapy. Int. J. STD acquired immune deficiency syndrome 2001;12:555–564.Google ScholarPubMed
Qaqish, R., Rublein, J., Wohl, D.human immunodeficiency virus-associated lipodystrophy syndrome. Pharmacotherapy 2000;20(1):13–22.CrossRefGoogle Scholar
Wanke, C. A., Falutz, J. M., Shevitz, A., Phair, J. P., Kotler, D. P.Clinical evaluation and management of metabolic and morphologic abnormalities associated with human immunodeficiency virus. Clin. Infect. Dis. 2002;34(2):248–259.CrossRefGoogle ScholarPubMed
Amaya, R., Kozinetz, C., McMeans, A., Schwarzwald, H., Kline, M.Lipodystrophy syndrome in human imunnodeficiency virus-infected children. Pediatr. Infect. Dis. J. 2002;21(5):405–410.CrossRefGoogle Scholar
Arpadi, S. M., Cuff, P. A., Horlick, M., Wang, J., Kotler, D. P.Lipodystrophy in human immunodeficiency virus-infected children is associated with high viral load and low cluster of differentiation4+ -lymphocyte count and cluster of differentiation4+ -lymphocyte percentage at baseline and use of protease inhibitors and stavudine. J. Acquir. Immune Defic. Syndr. 2001;27(1):30–34.CrossRefGoogle Scholar
Jaquet, D., Levine, M., Ortega-Rodriguez, E.et al.Clinical and metabolic presentation of the lipodystrophic syndrome in human immunodeficiency virus-infected children. acquired immune deficiency syndrome 2000;14(14):2123–2128.Google Scholar
Meneilly, G., Forbes, J., Peabody, D., Remple, V., Burdge, D. Metabolic and body composition changes in human immunodeficiency virus-infected children on antiretroviral therapy. In Eighth Conference on Retroviruses and Opportunistic Infections; 2001; February 4–8, 2001; Chicago, Illinois.Google Scholar
Brambilla, P., Bricalli, D., Sala, N.et al.Highly active antiretroviral-treated human immunodeficiency virus-infected children show fat distribution changes even in absence of lipodystrophy. acquired immune deficiency syndrome 2001;15(18):2415–2422.Google Scholar
Savage, D. B.Leptin: a novel therapeutic role in lipodystrophy. J. Clin. Invest. 2002;109:1285–1286.CrossRefGoogle ScholarPubMed
Montague, C. T., O'Rahilly, S.The perils of portliness: causes and consequences of visceral adiposity. Diabetes 2000;49(6):883–888.CrossRefGoogle ScholarPubMed
Flier, J. Obesity. In Braunwald, E.et al., ed. Harrison's Principles of Internal Medicine. 15th edn. McGraw-Hill Companies, 2001.Google Scholar
Powderly, W. G., Long-term exposure to lifelong therapies. J. Acquir. Immune Defic. Syndr. 2002;29 Suppl 1:S28–S40.CrossRefGoogle ScholarPubMed
Mulligan, K., Grunfeld, C., Tai, V. W.et al.Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with human immunodeficiency virus infection. J. Acquir. Immune Defic. Syndr. 2000;23(1):35–43.CrossRefGoogle Scholar
Melvin, A. J., Lennon, S., Mohan, K. M., Purnell, J. Q.Metabolic abnormalities in human immunodeficiency virus type 1-infected children treated and not treated with protease inhibitors. acquired immune deficiency syndrome Res. Hum. Retroviruses 2001;17(12):1117–1123.Google Scholar
Arpadi, S. M., Cuff, P. A., Horlick, M., Kotler, D. P.Visceral obesity, hypertriglyceridemia and hypercortisolism in a boy with perinatally acquired human immunodeficiency virus infection receiving protease inhibitor-containing antiviral treatment. acquired immune deficiency syndrome 1999;13(16):2312–2313.Google Scholar
Tsiodras, S., Mantzoros, C., Hammer, S., Samore, M.Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch. Intern. Med. 2000;160(13):2050–2056.CrossRefGoogle ScholarPubMed
Cheseaux, J. J., Jotterand, V., Aebi, C.et al.Hyperlipidemia in human immunodeficiency virus-infected children treated with protease inhibitors: relevance for cardiovascular diseases. J. Acquir. Immune Defic. Syndr. 2002;30(3):288–293.CrossRefGoogle Scholar
Carr, A., Samaras, K., Chisholm, D. J., Cooper, D. A.Pathogenesis of human immunodeficiency virus-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998;351(9119):1881–1883.CrossRefGoogle Scholar
Brinkman, K., Hofstede, H. J., Burger, D. M., Smeitink, J. A., Koopmans, P. P.Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. acquired immune deficiency syndrome 1998;12(14):1735–17244.Google ScholarPubMed
Kakuda, T. N., Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin. Ther. 2000;22(6):685–708.CrossRefGoogle ScholarPubMed
Dube, M. P., Sprecher, D., Henry, W. K.et al.Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult acquired immune deficiency syndrome Clinical Trial Group Cardiovascular Disease Focus Group. Clin. Infect. Dis. 2000;31(5):1216–1224.Google ScholarPubMed
The Adult acquired immune deficiency syndrome Clinical Trials Group. AACTG Metabolic Complications Guides. Adult acquired immune deficiency syndrome Clinical Trials Group; 2002.
Roubenoff, R., Weiss, L., McDermott, A.et al.A pilot study of exercise training to reduce trunk fat in adults with human immunodeficiency virus-associated fat redistribution. acquired immune deficiency syndrome 1999;13(11):1373–1375.Google Scholar
Jones, S. P., Doran, D. A., Leatt, P. B., Maher, B., Pirmohamed, M.Short-term exercise training improves body composition and hyperlipidaemia in human immunodeficiency virus-positive individuals with lipodystrophy. acquired immune deficiency syndrome 2001;15(15):2049–2051.Google Scholar
American Academy of Pediatrics. Committee on Nutrition. “Cholesterol in childhood”. Pediatrics 1998;101(1 Pt 1):141–147.CrossRef
Wedekind, C. A., Pugatch, D.Lipodystrophy syndrome in children infected with human immunodeficiency virus. Pharmacotherapy 2001;21(7):861–866.CrossRefGoogle ScholarPubMed
Barreiro, P., Soriano, V., Blanco, F., Casimiro, C., Cruz, J. J., Gonzalez-Lahoz, J.Risks and benefits of replacing protease inhibitors by nevirapine in human immunodeficiency virus-infected subjects under long-term successful triple combination therapy. acquired immune deficiency syndrome 2000;14(7):807–812.Google Scholar
Martinez, E., Conget, I., Lozano, L., Casamitjana, R., Gatell, J. M.Reversion of metabolic abnormalities after switching from human immunodeficiency virus-1 protease inhibitors to nevirapine. acquired immune deficiency syndrome 1999;13(7):805–810.Google ScholarPubMed
Carr, A., Workman, C., Smith, D. E.et al.Abacavir substitution for nucleoside analogs in patients with human immunodeficiency virus lipoatrophy: a randomized trial. J. Am. Med. Assoc. 2002;288(2):207–215.CrossRefGoogle ScholarPubMed
Currier, J. S., Metabolic complications of Antiretroviral Therapy and human immunodeficiency virus Infection. In Medscape human immunodeficiency virus/acquired immune deficiency syndrome Annual Update 2001 edn. Medscape; 2001.
John, M., Mallal, S. A.Hyperlactatemia syndromes in people with human immunodeficiency virus infection. Curr. Opin. Infect. Dis. 2002;15:23–29.CrossRefGoogle Scholar
Haas, R. H., A comparison of genetic mitochondrial disease and nucleoside analogue toxicity. Does fetal nucleoside toxicity underlie reports of mitochondrial disease in infants born to women treated for human immunodeficiency virus infection?Ann. N. Y. Acad. Sci. 2000;918:247–261.CrossRefGoogle Scholar
Vu, T. H., Sciacco, M., Tanji, K.et al.Clinical manifestations of mitochondrial deoxyribonucleic acid depletion. Neurology 1998;50(6):1783–1790.CrossRefGoogle Scholar
John, M., Moore, C. B., James, I. R.et al.Chronic hyperlactatemia in human immunodeficiency virus-infected patients taking antiretroviral therapy. acquired immune deficiency syndrome 2001;15(6):717–723.Google Scholar
Boubaker, K., Flepp, M., Sudre, P.et al.Hyperlactatemia and antiretroviral therapy: the Swiss human immunodeficiency virus Cohort Study. Clin. Infect. Dis. 2001;33(11):1931–1937.CrossRefGoogle ScholarPubMed
Brinkman, K., Management of hyperlactatemia: no need for routine lactate measurements. acquired immune deficiency syndrome 2001;15(6):795–797.Google ScholarPubMed
Giaquinto, C., Romeo, A., Giacomet, V.et al.Lactic acid levels in children perinatally treated with antiretroviral agents to prevent human immunodeficiency virus transmission. acquired immune deficiency syndrome 2001;15(8):1074–1075.Google Scholar
Gerard, Y., Maulin, L., Yazdanpanah, Y.et al.Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. acquired immune deficiency syndrome 2000;14(17):2723–2730.Google ScholarPubMed
Lonergan, J. T., Behling, C., Pfander, H., Hassanein, T. I., Mathews, W. C.Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin. Infect. Dis. 2000;31(1):162–166.CrossRefGoogle ScholarPubMed
Scalfaro, P., Chesaux, J. J., Buchwalder, P. A., Biollaz, J., Micheli, J. L.Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment. Intens. Care Med. 1998;24(3):247–250.CrossRefGoogle ScholarPubMed
Miller, K. D., Cameron, M., Wood, L. V., Dalakas, M. C., Kovacs, J. A.Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann. Intern. Med. 2000;133(3):192–196.CrossRefGoogle ScholarPubMed
Church, J. A., Mitchell, W. G., Gonzalez-Gomez, I.et al.Mitochondrial deoxyribonucleic acid depletion, near-fatal metabolic acidosis, and liver failure in an human immunodeficiency virus-infected child treated with combination antiretroviral therapy. J. Pediatr. 2001;138(5):748–751.CrossRefGoogle Scholar
Blanche, S., Tardieu, M., Rustin, P.et al.Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354(9184):1084–1089.CrossRefGoogle ScholarPubMed
Mandelbrot, L., Landreau-Mascaro, A., Rekacewicz, C.et al.Lamivudine-zidovudine combination for prevention of maternal–infant transmission of human immunodeficiency virus-1. J. Am. Mid. Assoc. 2001;285(16):2083–2093.CrossRefGoogle Scholar
The Perinatal Safety Review Working Group. Nucleoside exposure in the children of human immunodeficiency virus-infected women receiving antiretroviral drugs: abscence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J. Acquir. Immune Defic. Syndr. 2000;25:261–268.CrossRef

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