Conclusion
Taken as a whole, ART-related metabolic syndrome could result from the combination of factors found in the metabolic syndrome observed in the general population and it could also result from factors related to the treatment, the infection, and the immune status specific to HIV infection.
These factors will favor a proinflammatory, procoagulant, and proatherogenic state, which will worsen the situation (Fig. 9) leading to an increased occurrence of cardiovascular complications [83]. This is a major concern in patients who require continuous antiretroviral treatment to control viral infection and who can now expect prolonged life duration.References
1. Grundy S, Cleeman JI, Daniels SR et al (2005) Diagnosis and management of the metabolic syndrome: an American heart association/national heart, lung, and blood institute scientific statement. Circulation 112:2735-2752
2. Day C (2007) Metabolic syndrome, or What you will: definitions and epidemiology. Diab Vasc Dis Res 4:32-38
3. Mondy K, Overton ET, Grubb J et al (2007) Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population. Clin Infect Dis 44:726-734
4. Jacobson DL, Tang AM, Spiegelman D et al (2006) Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr 43:458-466
5. Bonfanti P, Ricci E, de Socio G et al; CISAI Study Group (2006) Metabolic syndrome: a real threat for HIV-positive patients?: results from the SIMONE study. J Acquir Immune Defic Syndr 42:128-131
6. Estrada V, Martinez-Larrad MT, Gonzalez- Sanchez JL et al (2006) Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy. Metabolism 55:940-945
7. Samaras K, Wand H, Law M et al (2007) Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reac- tive protein, and hypoadiponectinemia.
Diabetes Care 30:113-1198. Leow MK, Addy CL, Mantzoros CS (2003) Clinical review 159: Human immunodeficiency virus/highly active antiretroviral therapy-associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies. J Clin Endocrinol Metab 88:1961-1976
9. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806
10. Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785-789
11. Perseghin G, Petersen K, Shulman GI (2003) Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord 27(Suppl 3):S6-11
12. Fasshauer M, Paschke R (2003) Regulation of adipocytokines and insulin resistance. Dia- betologia 46:1594-1603
13. Mattison RE, Jensen M (2003) The adipocyte as an endocrine cell. Curr Opin Endocrinol Diabetes 10317-10321
14. Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847-453
15. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (2004) Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 24:29-33
16. Yamauchi T, Nio Y, Maki T et al (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332-339
17. Ouchi N, Kihara S, Funahashi T et al (2003) Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 14:561-566
18. Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447-455
19. Lagathu C, Bastard JP, Auclair M et al (2003) Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglita- zone. Biochem Biophys Res Commun 311:372-379
20.
Montague CT, O’Rahilly S (2000) The perils of portliness: causes and consequences of visceral adiposity. Diabetes 49:883-88821. Lafontan M, Berlan M (2003) Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 24:276-283
22. Stulnig TM, Waldhausl W (2004) 11beta-hydrox- ysteroid dehydrogenase type 1 in obesity and type 2 diabetes. Diabetologia 47:1-11
23. Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23:201-229
24. Gan SK, Kriketos AD, Poynten AM et al (2003) Insulin action, regional fat, and myocyte lipid: altered relationships with increased adiposity. Obes Res 11:1295-1305
25. Schaffer JE (2003) Lipotoxicity: when tissues overeat. Curr Opin Lipidol 14:281-287
26. Wellen KE, Hotamisligil GS (2003) Obesity- induced inflammatory changes in adipose tissue. J Clin Invest 112:1785-1788
27. Weisberg SP, McCann D, Desai M et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796-1808
28. Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821-1830
29. Cancello R, Tordjman J, Poitou C et al (2006) Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55:1554-1561
30. Fernandez-Real JM, Ricart W (2003) Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 24:278-301
31. Moyle G (2007) Metabolic issues associated with protease inhibitors. J Acquir Immune Defic Syndr 45(Suppl 1):S19-26
32. Perret B, Ferrand C, Bonnet E et al (2003) Lipoprotein metabolism in HIV-positive patients. Eur J Med Res 8(Suppl II):6
33. Grinspoon SK (2005) Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus.
Am J Med 118(Suppl 2):23S-28S34. Saves M, Raffi F, Capeau J et al (2002) Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis 34:1396-1405
35. Noor MA, Flint OP, Maa J et al (2006) Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake on insulin sensitivity: demonstrable differences in vitro and clinically. AIDS 20:1813-1821
36. Van der Valk M, Kastelein JJ, Murphy RL et al (2001) Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an antiatherogenic lipid profile. AIDS 15:2407-2414
37. Carr A, Samaras K, Thorisdottir A et al (1999) Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353:2093-2099
38. Liang JS, Distler O, Cooper DA et al (2001) HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 7:1327-1331
39. Lenhard JM, Croom DK et al (2000) HIV protease inhibitors stimulate hepatic triglyceride synthesis. Arterioscler Thromb Vasc Biol 20:2625-2629
40. Riddle TM, Kuhel DG, Woollett LA et al (2001) HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem 276:37514-37519
41. Bonnet E, Ruidavets JB, Tuech J et al (2001) Apoprotein c-III and E-containing lipoparticles are markedly increased in HIV-infected patients treated with protease inhibitors: association with the development of lipodystrophy. J Clin Endocrinol Metab 86:296-302
42. Lihn AS, Richelsen B, Pedersen SB et al (2003) Increased expression of TNF-alpha, IL-6, and IL- 8 in HALS: implications for reduced adiponectin expression and plasma levels.
Am J Physiol Endocrinol Metab 285:E1072-108043. Vigouroux C, Maachi M, Nguyen TH et al (2003) Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS 17:1503-1511
44. Bastard JP, Pereira E, Reynes J et al (2007) Follow-up of lipodystrophy and metabolic alterations in the ANRS APROCO-COPILOTE studying HIV-infected patients initiated with protease inhibitors in 1997 and 1998: relation to adiponectin, leptin and triglycerides levels and to TNF polymorphisms. Antivir Ther L30, P-16 (abstract)
45. Ledergerber B, Furrer H, Rickenbach M et al (2007) Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis 45:111-119
46. Brown TT, Cole SR, Li X et al (2005) Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 1651179-1651184
47. Florescu D, Kotler DP (2007) Insulin resistance, glucose intolerance and diabetes mellitus in HIV-infected patients. Antivir Ther 12:149-162
48. Noor MA, Lo JC, Mulligan K et al (2001) Metabolic effects of indinavir in healthy HIV- seronegative men. AIDS 15:F11-18
49. Noor MA, Seneviratne T, Aweeka FT et al (2002) Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 29:F1-8
50. Bacchetti P, Gripshover B, Grunfeld C et al (2005) Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr 40:121-131
51. Martin A, Smith DE, Carr A et al (2004) Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 18:1029-1036
52. Jemsek JG, Arathoon E, Arlotti M et al (2006) Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients.
Clin Infect Dis 42:273-28053. Johnson M, Grinsztejn B, Rodriguez C et al (2006) 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 20:711-718
54. Fisac C, Fumero E, Crespo M et al (2005) Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS 19:917-925
55. McComsey GA, Paulsen DM, Lonergan JT et al (2005) Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 19:15-23
56. Moyle GJ, Sabin CA, Cartledge J et al (2006) A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 20:2043-2050
57. Cherry CL, Lal L, Thompson KA et al (2005) Increased adipocyte apoptosis in lipoatrophy improves within 48 weeks of switching patient therapy from Stavudine to abacavir or zidovudine. J Acquir Immune Defic Syndr 38:263-267
58. Mallal SA, John M, Moore CB et al (2000) Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 14:1309-1316
59. Miller J, Carr A, Emery S et al (2003) HIV lipodystrophy: prevalence, severity and corre-
lates of risk in Australia. HIV Med 4:293-301
60. Gougeon M-L, Penicaud L, Fromenty B et al (2004) Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Antivir Ther 9:161-177
61. Caron M, Auclair M, Vigouroux C et al (2001) The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadi-pocyte differentiation, and induces insulin resistance. Diabetes 50:1378-1388
62. Caron M, Auclair M, Sterlingot H et al (2003) Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation. AIDS 17:2437-2444
63. Caron M, Auclair M, Donadille B et al (2007) Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death Differ (in press)
64. Krimm I, Ostlund C, Gilquin B et al (2002)The Ig-like structure of the C-terminal domain of lamin A/C, mutated in muscular dystrophies, cardiomyopathy, and partial lipodystrophy. Structure (Camb) 10:811-823
65. Lloyd DJ, Trembath RC, Shackleton S (2002) A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Hum Mol Genet 11:769-777
66. Vigouroux C, Auclair M, Dubosclard E et al (2001) Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene. J Cell Sci 114:4459-4468
67. Jones SP, Janneh O, Back DJ et al (2005) Altered adipokine response in murine 3T3-F442A adipocytes treated with protease inhibitors and nucleoside reverse transcriptase inhibitors. Antivir Ther 10:207-213
68. Lagathu C, Bastard JP, Auclair M et al (2004) Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammato- ry cytokines and adiponectin in vitro. Antivir Ther 9:911-920
69. Lagathu C, Eustace B, Prot M et al (2007) Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12:489-500
70. Caron M, Auclair M, Lagathu C et al (2004) The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 18:2127-2136
71. Bastard JP, Caron M,Vidal H et al (2002) Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 359:1026-1031
72. Domingo P, Matias-Guiu X, Pujol RM et al (1999) Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 13:2261-2267
73. Nolan D, Hammond E, Martin A et al (2003) Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 17:1329-1338
74. Lloreta J, Domingo P, Pujol RM et al (2002) Ultrastructural features of highly active antiretroviral therapy-associated partial lipodystrophy. Virchows Arch 441:599-604
75. Jan V, Cervera P, Maachi M et al (2004) Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1- infected lipodystrophic patients. Antivir Ther 9:555-564
76. Sutinen J, Korsheninnikova E, Funahashi T et al (2003) Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy. J Clin Endocrinol Metab 88:1907-1910
77. Domingo P, Matias-Guiu X, Pujol RM et al (2001) Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apoptosis in patients with highly active antiretroviral therapy-associated lipodystrophy. J Infect Dis 184:1197-1201
78. Kim M et al (2007) A six-month interruption of antiretroviral therapy improves adipose tissue function in HIV-infected patients: the ANRS EP29 Lipostrop Study. Antivir Ther 12:1273-1283
79. Ledru E, Christeff N, Patey O et al (2000) 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 95:3191-3198
80. Rietschel P, Hadigan C, Corcoran C et al (2001) Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab 86:504-510
81. Lo JC, Mulligan K, Noor MA et al (2001) The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 86:3480-3487
82. Luzi L, Meneghini E, Oggionni S et al (2005) GH treatment reduces trunkal adiposity in HIV- infected patients with lipodystrophy: a randomized placebo-controlled study. Eur J Endocrinol 153:781-789
83. Friis-Moller N, Reiss P, Sabin CA et al; DAD Study Group (2007) Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 356:1723-1735