Horm Metab Res 2003; 35(3): 129-136
DOI: 10.1055/s-2003-39072
Review
© Georg Thieme Verlag Stuttgart · New York

AIDS-Related Lipodystrophy/Insulin Resistance Syndrome

T.  Kino1 , M.  Mirani1 , S.  Alesci1 , G.  P.  Chrousos1
  • 1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Further Information

Publication History

Received 1 October 2002

Accepted after revision 15 November 2002

Publication Date:
07 May 2003 (online)

Abstract

The recent development and clinical use of three different types of highly effective anti-HIV-1 drugs, including nucleotide and non-nucleotide reverse transcriptase inhibitors (NRTIs) and non-peptidic viral protease inhibitors (PIs) and their combinations, termed highly active antiretroviral therapy (HAART), have dramatically reduced the infection-related mortality of AIDS patients in developed countries. However, the prolongation of the life expectancy of HIV-1-infected patients and/or long-term use of the above antiviral agents have generated a score of new problems and complications. Among them is the relatively common AIDS-related lipodystrophy/insulin resistance syndrome, which is associated with severe metabolic disturbances such as carbohydrate intolerance/diabetes mellitus and severe dyslipidemia, which influence the quality of life and threaten the life expectancies of HIV-1-infected patients by increasing the risk of atherosclerotic cardiovascular disease. The etiology of this syndrome appears to be multi-factorial; the classes of anti-viral drugs listed above, hypercytokinemia in AIDS patients, and the HIV-1 infection itself could induce the pathologic changes of this syndrome or increase the vulnerability of patients to the adverse effect of the therapeutic compounds. In this article, we review our current understanding of the pathogenesis of this severe AIDS-associated metabolic disorder.

References

  • 1 Pantaleo G, Graziosi C, Fauci A S. New concepts in the immunopathogenesis of human immunodeficiency virus infection.  N Engl J Med. 1993;  328 327-335
  • 2 Tashima K T, Flanigan T P. Antiretroviral therapy in the year 2000.  Infect Dis Clin North Am. 2000;  14 827-849
  • 3 Morris A B, Cu-Uvin S, Harwell J I, Garb J, Zorrilla C, Vajaranant M, Dobles A R, Jones T B, Carlan S, Allen D Y. Multicenter review of protease inhibitors in 89 pregnancies.  J Acquir Immune Defic Syndr. 2000;  25 306-311
  • 4 Kaufmann G R, Cooper D A. Antiretroviral therapy of HIV-1 infection: established treatment strategies and new therapeutic options.  Curr Opin Microbiol. 2000;  3 508-514
  • 5 Harrington M, Carpenter C C. Hit HIV-1 hard, but only when necessary.  Lancet. 2000;  355 2147-2152
  • 6 Vella S, Palmisano L. Antiretroviral therapy: state of the HAART.  Antiviral Res. 2000;  45 1-7
  • 7 de Luca A, Murri R, Damiano F, Ammassari A, Antinori A. “Buffalo hump” in HIV-1 infection.  Lancet. 1998;  352 320
  • 8 Miller K K, Daly P A, Sentochnik D, Doweiko J, Samore M, Basgoz N O, Grinspoon S K. Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients.  Clin Infect Dis. 1998;  27 68-72
  • 9 Lo J C, Mulligan K, Tai V W, Algren H, Schambelan M. “Buffalo hump” in men with HIV-1 infection.  Lancet. 1998;  351 867-870
  • 10 Stocker D N, Meier P J, Stoller R, Fattinger K E. “Buffalo hump” in HIV-1 infection.  Lancet. 1998;  352 320-321
  • 11 Saint-Marc T, Touraine J L. “Buffalo hump” in HIV-1 infection.  Lancet. 1998;  352 319-320
  • 12 Christeff N, Melchior J C, de Truchis P, Perronne C, Nunez E A, Gougeon M L. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations.  AIDS. 1999;  13 2251-2260
  • 13 Dornier C, Posth M, Granel F, Barbaud A, Schmutz J L. “Buffalo hump” related to indinavir treatment.  Ann Dermatol Venereol. 1999;  126 720-722
  • 14 Graham N M. Metabolic disorders among HIV-infected patients treated with protease inhibitors: a review.  J Acquir Immune Defic Syndr. 2000;  25 4-11
  • 15 Carr A, Cooper D A. Adverse effects of antiretroviral therapy.  Lancet. 2000;  356 1423-1430
  • 16 Behrens G M, Stoll M, Schmidt R E. Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?.  Drug Saf. 2000;  23 57-76
  • 17 Qaqish R B, Fisher E, Rublein J, Wohl D A. HIV-associated lipodystrophy syndrome.  Pharmacotherapy. 2000;  20 13-22
  • 18 Hadigan C, Meigs J B, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson P W, D'Agostino R B, Grinspoon S. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.  Clin Infect Dis. 2001;  32 130-139
  • 19 Jain R G, Furfine E S, Pedneault L, White A J, Lenhard J M. Metabolic complications associated with antiretroviral therapy.  Antiviral Res. 2001;  51 151-177
  • 20 Carr A, Samaras K, Chisholm D J, Cooper D A. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.  Lancet. 1998;  351 1881-1883
  • 21 Beisiegel U, Weber W, Ihrke G, Herz J, Stanley K K. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein.  Nature. 1989;  341 162-164
  • 22 Erkelens D W. Metabolic basis for hypertriglyceridaemia in familial combined hyperlipidaemia.  Eur Heart J. 1998;  19 Suppl H H23-26
  • 23 Chambon P. A decade of molecular biology of retinoic acid receptors.  FASEB J. 1996;  10 940-954
  • 24 Schutt M, Meier M, Meyer M, Klein J, Aries S P, Klein H H. The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells.  Diabetologia. 2000;  43 1145-1148
  • 25 Petit J M, Duong M, Duvillard L, Piroth L, Grappin M, Verges B, Chavanet P, Brun J M, Portier H. HIV-1 protease inhibitors induce an increase of triglyceride level in HIV-infected men without modification of insulin sensitivity: a longitudinal study.  Horm Metab Res. 2000;  32 367-372
  • 26 Lenhard J M, Weiel J E, Paulik M A, Furfine E S. Stimulation of vitamin A(1) acid signaling by the HIV protease inhibitor indinavir.  Biochem Pharmacol. 2000;  59 1063-1068
  • 27 Nguyen A T, Gagnon A, Angel J B, Sorisky A. Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis.  AIDS. 2000;  14 2467-2473
  • 28 Dowell P, Flexner C, Kwiterovich P O, Lane M D. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors.  J Biol Chem. 2000;  275 41 325-41 332
  • 29 Cossarizza A, Mussini C, Vigano A. Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders?.  BioEssays. 2001;  23 1070-1080
  • 30 Murata H, Hruz P W, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy.  J Biol Chem. 2000;  275 20 251-20 254
  • 31 Jiminez-Exposito M J, Paul A, Laville A, Masana L. Non-activity of hepatic lipase during a treatment with ritonavir. Proceedings of the 6th European Conference on Clinical Aspects and Treatment of HIV Infection. Hamberg, Germany; 1997
  • 32 Zhang B, MacNaul K, Szalkowski D, Li Z, Berger J, Moller D E. Inhibition of adipocyte differentiation by HIV protease inhibitors.  J Clin Endocrinol Metab. 1999;  84 4274-4277
  • 33 Lenhard J M, Furfine E S, Jain R G, Ittoop O, Orband-Miller L A, Blanchard S G, Paulik M A, Weiel J E. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro.  Antiviral Res. 2000;  47 121-129
  • 34 Wentworth J M, Burris T P, Chatterjee V K. HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer.  J Endocrinol. 2000;  164 R7-10
  • 35 Baldo A, Sniderman A D, St-Luce S, Avramoglu R K, Maslowska M, Hoang B, Monge J C, Bell A, Mulay S, Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis.  J Clin Invest. 1993;  92 1543-1547
  • 36 Liang J S, Distler O, Cooper D A, Jamil H, Deckelbaum R J, Ginsberg H N, Sturley S L. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia.  Nat Med. 2001;  7 1327-1331
  • 37 Behrens G, Schmidt H H, Stoll M, Schmidt R E. ApoE genotype and protease-inhibitor-associated hyperlipidaemia.  Lancet. 1999;  354 76
  • 38 Brinkman K, Smeitink J A, Romijn J A, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.  Lancet. 1999;  354 1112-1115
  • 39 Ujpal M, Nemeth Z S, Reichwein A, Szabo G Y. Long-term results following surgical treatment of benign symmetric lipomatosis (BSL).  Int J Oral Maxillofac Surg. 2001;  30 479-483
  • 40 Klopstock T, Naumann M, Seibel P, Shalke B, Reiners K, Reichmann H. Mitochondrial DNA mutations in multiple symmetric lipomatosis.  Mol Cell Biochem. 1997;  174 271-275
  • 41 Klopstock T, Naumann M, Schalke B, Bischof F, Seibel P, Kottlors M, Eckert P, Reiners K, Toyka K V, Reichmann H. Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.  Neurology. 1994;  44 862-866
  • 42 Brinkman K, ter Hofstede H J, Burger D M, Smeitink J A, Koopmans P P. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway.  AIDS. 1998;  12 1735-1744
  • 43 Dalakas M C, Illa I, Pezeshkpour G H, Laukaitis J P, Cohen B, Griffin J L. Mitochondrial myopathy caused by long-term zidovudine therapy.  N Engl J Med. 1990;  322 1098-1105
  • 44 Flomenbaum M, Soeiro R, Udem S A, Kress Y, Factor S M. Proliferative membranopathy and human immunodeficiency virus in AIDS hearts.  J Acquir Immune Defic Syndr. 1989;  2 129-135
  • 45 Yanovski J A, Miller K D, Kino T, Friedman T C, Chrousos G P, Tsigos C, Falloon J. Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.  J Clin Endocrinol Metab. 1999;  84 1925-1931
  • 46 Shikuma C, Hu N, Milne C, Yost F, Shimizu S, Shiramizu B. Analysis of subcutaneous adipose tissue mitochondrial DNA from individuals with HARRT-associated lipodystrophy. 8th Conference on Retroviruses and Opportunistic Infections. Chicago; 2001: 244
  • 47 Ledru E, Christeff N, Patey O, de 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 3191-3198
  • 48 Sethi J K, Hotamisligil G S. The role of TNF alpha in adipocyte metabolism.  Semin Cell Dev Biol. 1999;  10 19-29
  • 49 Chrousos G P. The stress response and immune function: clinical implications. The 1999 Novera H. Spector Lecture.  Ann N Y Acad Sci. 2000;  917 38-67
  • 50 Orban Z, Remaley A T, Sampson M, Trajanoski Z, Chrousos G P. The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man.  J Clin Endocrinol Metab. 1999;  84 2126-2133
  • 51 Vgontzas A N, Papanicolaou D A, Bixler E O, Hopper K, Lotsikas A, Lin H M, Kales A, Chrousos G P. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.  J Clin Endocrinol Metab. 2000;  85 1151-1158
  • 52 Christeff N, Melchior J C, de Truchis P, Perronne C, Gougeon M L. Increased serum interferon alpha in HIV-1 associated lipodystrophy syndrome.  Eur J Clin Invest. 2002;  32 43-50
  • 53 Feingold K R, Grunfeld C. Role of cytokines in inducing hyperlipidemia.  Diabetes. 1992;  41 Suppl. 2 97-101
  • 54 Grimble R F. Inflammatory status and insulin resistance.  Curr Opin Clin Nutr Metab Care. 2002;  5 551-559
  • 55 Graham N M. Metabolic disorders among HIV-infected patients treated with protease inhibitors: a review.  J Acquir Immune Defic Syndr. 2000;  25 S4-S11
  • 56 Moyle G. Mitochondrial toxicity hypothesis for lipoatrophy: a refutation.  AIDS. 2001;  15 413-415
  • 57 Diederich S, Grossmann C, Hanke B, Quinkler M, Herrmann M, Bahr V, Oelkers W. In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I.  Eur J Endocrinol. 2000;  142 200-207
  • 58 Seckl J R, Walker B R. Minireview: 11beta-hydroxysteroid dehydrogenase type 1 - a tissue-specific amplifier of glucocorticoid action.  Endocrinology. 2001;  142 1371-1376
  • 59 Tomlinson J W, Moore J, Cooper M S, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart P M. Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines.  Endocrinology. 2001;  142 1982-1989
  • 60 Escher G, Galli I, Vishwanath B S, Frey B M, Frey F J. Tumor necrosis factor alpha and interleukin 1beta enhance the cortisone/cortisol shuttle.  J Exp Med. 1997;  186 189-198
  • 61 Pavlakis G N. The molecular biology of HIV-1, AIDS: Diagnosis, Treatment and Prevention. DeVita VT, Hellman S, Rosenberg SA (eds) Philadelphia; Lippincott Raven 1996 4 Edition: 45-74
  • 62 Cohen E A, Subbramanian R A, Gottlinger H G. Role of auxiliary proteins in retroviral morphogenesis.  Curr Top Microbiol Immunol. 1996;  214 219-235
  • 63 Emerman M. HIV-1, Vpr and the cell cycle.  Curr Biol. 1996;  6 1096-1103
  • 64 Stewart S A, Poon B, Jowett J B, Xie Y, Chen I S. Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells.  Proc Natl Acad Sci U S A. 1999;  96 12 039-12 043
  • 65 Ayyavoo V, Mahalingam S, Rafaeli Y, Kudchodkar S, Chang D, Nagashunmugam T, Williams W V, Weiner D B. HIV-1 viral protein R (Vpr) regulates viral replication and cellular proliferation in T cells and monocytoid cells in vitro.  J Leukoc Biol. 1997;  62 93-99
  • 66 Goh W C, Rogel M E, Kinsey C M, Michael S F, Fultz P N, Nowak M A, Hahn B H, Emerman M. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo.  Nat Med. 1998;  4 65-71
  • 67 Gibbs J S, Lackner A A, Lang S M, Simon M A, Sehgal P K, Daniel M D, Desrosiers R C. Progression to AIDS in the absence of a gene for vpr or vpx.  J Virol. 1995;  69 2378-2383
  • 68 Sawaya B E, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome.  J Biol Chem. 2000;  275 35 209-35 214
  • 69 He J, Choe S, Walker R, di Marzio P, Morgan D O, Landau N R. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity.  J Virol. 1995;  69 6705-6711
  • 70 Jowett J B, Planelles V, Poon B, Shah N P, Chen M L, Chen I S. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle.  J Virol. 1995;  69 6304-6313
  • 71 Re F, Braaten D, Franke E K, Luban J. Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B.  J Virol. 1995;  69 6859-6864
  • 72 Heinzinger N K, Bukinsky M I, Haggerty S A, Ragland A M, Kewalramani V, Lee M A, Gendelman H E, Ratner L, Stevenson M, Emerman M. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells.  Proc Natl Acad Sci U S A. 1994;  91 7311-7315
  • 73 Vodicka M A, Koepp D M, Silver P A, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection.  Genes Dev. 1998;  12 175-185
  • 74 Popov S, Rexach M, Zybarth G, Reiling N, Lee M A, Ratner L, Lane C M, Moore M S, Blobel G, Bukrinsky M. Viral protein R regulates nuclear import of the HIV-1 pre-integration complex.  EMBO J. 1998;  17 909-917
  • 75 Levy D N, Refaeli Y, Weiner D B. Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency.  J Virol. 1995;  69 1243-1252
  • 76 Henklein P, Bruns K, Sherman M P, Tessmer U, Licha K, Kopp J, de Noronha C M, Greene W C, Wray V, Schubert U. Functional and structural characterization of synthetic HIV-1 vpr that transduces cells, localizes to the nucleus, and induces G2 cell cycle arrest.  J Biol Chem. 2000;  275 32 016-32 026
  • 77 Kino T, Gragerov A, Kopp J B, Stauber R H, Pavlakis G N, Chrousos G P. The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor.  J Exp Med. 1999;  189 51-62
  • 78 Kino T, Gragerov A, Slobodskaya O, Tsopanomichalou M, Chrousos G P, Pavlakis G N. Human immunodeficiency virus type-1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators.  J Virol. 2002;  76 9724-9734
  • 79 Wei P, Garber M E, Fang S M, Fischer W H, Jones K A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA.  Cell. 1998;  92 451-462
  • 80 Kino T, Slobodskaya O, Pavlakis G N, Chrousos G P. Nuclear receptor co-activator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex.  J Biol Chem. 2002;  277 2396-2405
  • 81 Fawell S, Seery J, Daikh Y, Moore C, Chen L L, Pepinsky B, Barsoum J. Tat-mediated delivery of heterologous proteins into cells.  Proc Natl Acad Sci U S A. 1994;  91 664-668
  • 82 Willson T M, Lambert M H, Kliewer S A. Peroxisome proliferator-activated receptor gamma and metabolic disease.  Annu Rev Biochem. 2001;  70 341-367
  • 83 Jacob S, Stumvoll M, Becker R, Koch M, Nielsen M, Loblein K, Maerker E, Volk A, Renn W, Balletshofer B, Machicao F, Rett K, Haring H U. The PPARgamma2 polymorphism pro12Ala is associated with better insulin sensitivity in the offspring of type 2 diabetic patients.  Horm Metab Res. 2000;  32 413-416
  • 84 Shrivastav S, Kino T, Chrousos G P, Kopp J B. HIV-1 Vpr binds and inhibits PPAR-g: Implications for HIV-associated Insulin resistance and lipodystrophy. 2000 International Meeting of the Institute of Human Virology. Baltimore, MA; 2000
  • 85 Kino T, Chrousos G P. Acquired immunodeficiency syndrome-related insulin resistance and lipodystrophy: a multifactorial viral and iatrogenic condition.  Endocr Pract. 2001;  7 480-484
  • 86 Kino T, Gragerov A, Pavlakis G N, Chrousos G P. HIV-1 accessory protein Vpr antagonizes insulin"s effect on the cytosolic translocation of FKHR and promotes its transcriptional activity: potential contribution of Vpr to insulin resistance of AIDS patients. . 83rd Endocrine Society Annual Meeting. Denver; 2001: 95
  • 87 Nakae J, Barr V, Accili D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR.  EMBO J. 2000;  19 989-996
  • 88 Brunet A, Bonni A, Zigmond M J, Lin M Z, Juo P, Hu L S, Anderson M J, Arden K C, Blenis J, Greenberg M E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.  Cell. 1999;  96 857-868
  • 89 Green M L. Evaluation and management of dyslipidemia in patients with HIV infection.  J Gen Intern Med. 2002;  17 797-810
  • 90 Negredo E, Ribalta J, Paredes R, Ferre R, Sirera G, Ruiz L, Salazar J, Reiss P, Masana L, Clotet B. Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine.  AIDS. 2002;  16 1383-1389
  • 91 Wensing A M, Reedijk M, Richter C, Boucher C A, Borleffs J C. Replacing ritonavir by nelfinavir or nelfinavir/saquinavir as part of highly active antiretroviral therapy leads to an improvement of triglyceride levels.  AIDS. 2001;  15 2191-2193
  • 92 Walli R K, Michl G M, Bogner J R, Goebel F D. Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir.  Eur J Med Res. 2001;  6 413-421
  • 93 Barreiro P, Soriano V, Blanco F, Casimiro C, de la Cruz J J, Gonzalez-Lahoz J. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy.  AIDS. 2000;  14 807-812
  • 94 Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J. Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities.  Lancet. 1998;  352 1031-1032
  • 95 Moyle G J, Lloyd M, Reynolds B, Baldwin C, Mandalia S, Gazzard B G. Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.  AIDS. 2001;  15 1503-1508
  • 96 Miller J, Brown D, Amin J, Kent-Hughes J, Law M, Kaldor J, Cooper D A, Carr A. A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia.  AIDS. 2002;  16 2195-2200
  • 97 Murillas J, Martin T, Ramos A, Portero J L. Atorvastatin for protease inhibitor-related hyperlipidaemia.  AIDS. 1999;  13 1424-1425
  • 98 Baldini F, di Giambenedetto S, Cingolani A, Murri R, Ammassari A, de Luca A. Efficacy and tolerability of pravastatin for the treatment of HIV-1 protease inhibitor-associated hyperlipidaemia: a pilot study.  AIDS. 2000;  14 1660-1662
  • 99 Fichtenbaum C J, Gerber J G. Interactions Between Antiretroviral Drugs and Drugs Used for the Therapy of the Metabolic Complications Encountered During HIV Infection.  Clin Pharmacokinet. 2002;  41 1195-1211
  • 100 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;  284 472-477
  • 101 Hadigan C, Meigs J B, Rabe J, D'Agostino R B, Wilson P W, Lipinska I, Tofler G H, Grinspoon S S. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance.  J Clin Endocrinol Metab. 2001;  86 939-943
  • 102 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 1932-1937
  • 103 Hadigan C, Rabe J, Grinspoon S. Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance.  J Clin Endocrinol Metab. 2002;  87 4611-4615
  • 104 Alessi M C, Morange P, Juhan-Vague I. Fat cell function and fibrinolysis.  Horm Metab Res. 2000;  32 504-508
  • 105 Gervasoni C, Ridolfo A L, Rovati L, Vaccarezza M, Cassana L, Galli M. Maintenance of breast size reduction after mastoplasty and switch to a protease inhibitor-sparing regimen in an HIV-positive woman with highly active antiretroviral therapy-associated massive breast enlargement.  AIDS Patient Care STDS. 2002;  16 307-311
  • 106 Talmor M, Hoffman L A, LaTrenta G S. Facial atrophy in HIV-related fat redistribution syndrome: anatomic evaluation and surgical reconstruction.  Ann Plast Surg. 2002;  49 11-17
  • 107 Walther R A. Facial lipodystrophy in patients with HIV infections troublesome to treat.  Lakartidningen. 2002;  99 3826-3829
  • 108 Oral E A, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner A J, DePaoli A M, Reitman M L, Taylor S I, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy.  N Engl J Med. 2002;  346 570-578
  • 109 Estrada V, Serrano-Rios M, Martinez L arrad, Villar N G, Gonzalez Lopez A, Tellez M J, Fernandez C. Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy.  J Acquir Immune Defic Syndr. 2002;  29 32-40
  • 110 Garg A. Lipodystrophies.  Am J Med. 2000;  108 143-152

T. Kino, M.D., Ph.D.

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development

Bldg. 10, Rm. 9D42 · 10 Center Drive MSC 1583 · Bethesda, MD 20892-1583 · USA

Phone: + 1 (301) 496-64 17

Fax: + 1 (301) 480-20 24

Email: kinot@mail.nih.gov