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Metabolic Complications Associated with HIV Protease Inhibitor Therapy

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Abstract

HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.

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References

  1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60

    Article  PubMed  Google Scholar 

  2. Massip P, Marchou B, Bonnet E, et al. Lipodystrophia with protease inhibitors in HIV patients. Therapie 1997; 52(6): 615

    PubMed  CAS  Google Scholar 

  3. Viraben R, Aquilina C. Indinavir-associated lipodystrophy. AIDS 1998; 12(6): 37F-9F

    Article  Google Scholar 

  4. Hengal RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease inhibitors [letter]. Lancet 1997; 350: 1596

    Article  Google Scholar 

  5. Herry I, Bernard L, de Truchis P, et al. Hypertrophy of the breasts in a patient treated with indinavir. Clin Infect Dis 1997; 25(4): 937–8

    Article  PubMed  CAS  Google Scholar 

  6. Lui A, Karter D, Turett G. Another case of breast hypertrophy in a patient treated with indinavir [letter]. Clin Infect Dis 1998; 26: 1482

    Article  PubMed  CAS  Google Scholar 

  7. Lo JC, Mulligan K, Tai VW, et al. ‘Buffalo hump’ in men with HIV-1 infection. Lancet 1998; 351(9106): 867–70

    Article  PubMed  CAS  Google Scholar 

  8. Wurtz R. Abnormal fat distribution and use of protease inhibitors [letter]. Lancet 1998; 351(9117): 1735–6

    Article  PubMed  CAS  Google Scholar 

  9. Roth VR, Kravcik S, Angel JB. Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 1998; 27(1): 65–7

    Article  PubMed  CAS  Google Scholar 

  10. Striker R, Conlin D, Marz M, et al. Localised adipose tissue hypertrophy in patients receiving human immunodeficiency virus protease inhibitors. Clin Infect Dis 1998; 27(1): 218–20

    Article  PubMed  CAS  Google Scholar 

  11. Ho TT, Chan KC, Wong KH, et al. Abnormal fat distribution and use of protease inhibitors. Lancet 1998; 351(9117): 1736–7

    Article  PubMed  CAS  Google Scholar 

  12. Shaw AJ, McLean KA, Evans BA. Disorders of fat distribution in HIV infection. Int J STD AIDS 1998; 9(10): 595–9

    Article  PubMed  CAS  Google Scholar 

  13. Miller KK, Daly PA, Sentochnik D, et al. Pseudo-Cushing’s syndrome in human immunodeficiency virus infected patients. Clin Infect Dis 1998; 27(1): 68–72

    Article  PubMed  CAS  Google Scholar 

  14. Saint Marc T, Touraine JL. ‘Buffalo hump’ in HIV-1 infection. Lancet 1998; 352(9124): 319–20

    Article  PubMed  CAS  Google Scholar 

  15. Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351(9106): 871–5

    Article  PubMed  CAS  Google Scholar 

  16. Stricker RB, Goldberg B. Fat accumulation and HIV-1 protease inhibitors [letter]. Lancet 1998; 352(9137): 1392

    Article  PubMed  CAS  Google Scholar 

  17. Carr A, Cooper DA. Images in clinical medicine: lipodystrophy associated with an HIV-protease inhibitor. N Engl J Med 1998; 339(18): 1296

    Article  PubMed  CAS  Google Scholar 

  18. Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society — USA panel. J Acquir Immune Defic Syndr 2002; 31: 257–75

    Article  PubMed  Google Scholar 

  19. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of change in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 2000; 23: 35–43

    PubMed  CAS  Google Scholar 

  20. Sullivan AK, Nelson MR. Marked hyperlipidemia on ritonavir therapy. AIDS 1997; 11(7): 938–9

    PubMed  CAS  Google Scholar 

  21. Churchill DR, Pym AS, Babiker AG, et al. Hyperlipidemia following treatment with protease inhibitors in patients with HIV-1 infection. Br J Clin Pharmacol 1998; 46(5): 518–9

    PubMed  CAS  Google Scholar 

  22. Meyer L, Rabaud C, Ziegler O, et al. Protease inhibitors, diabetes mellitus and blood lipids. Diabetes Metab 1998; 24(6): 547–9

    PubMed  CAS  Google Scholar 

  23. Dong KL, Bausserman LL, Flynn MM, et al. Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr 1999; 21(2): 107–13

    PubMed  CAS  Google Scholar 

  24. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 1999; 13(10): F63–70

    Article  PubMed  CAS  Google Scholar 

  25. Schmidt HH-J, Behrens G, Genschel J. Lipid evaluation in HIV-1 positive patients treated with protease inhibitors. Antivir Ther 1999; 4: 163–70

    PubMed  CAS  Google Scholar 

  26. Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 1999; 33(7–8): 859–63

    Article  PubMed  CAS  Google Scholar 

  27. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV infected individuals treated with protease inhibitors. Circulation 1999; 100(7): 700–5

    Article  PubMed  CAS  Google Scholar 

  28. Segerer S, Bogner JR, Walli R, et al. Hyperlipidemia under treatment with proteinase inhibitors. Infection 1999; 27(2): 77–81

    Article  PubMed  CAS  Google Scholar 

  29. Berthold HK, Parhofer KG, Ritter MM, et al. Influence of protease inhibitor therapy on lipoprotein metabolism. J Intern Med 1999; 246(6): 567–75

    Article  PubMed  CAS  Google Scholar 

  30. Tsiodras S, Mantzoros C, Hammer S, et al. Effects of protease inhibitors on hyperglyceamia, hyperlipidaemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000; 160(13): 2050–6

    Article  PubMed  CAS  Google Scholar 

  31. Dube MP, Johnson DL, Currier JS, et al. Protease inhibitor associated hyperglycemia. Lancet 1997; 350(9079): 713–4

    Article  PubMed  CAS  Google Scholar 

  32. Eastone JA, Decker CP. New-onset diabetes mellitus associated with use of a protease inhibitor [letter]. Ann Intern Med 1997; 127: 948

    PubMed  CAS  Google Scholar 

  33. Visnegarwala F, Krause KL, Musher DM. Severe diabetes associated with protease inhibitor therapy [letter]. Ann Intern Med 1997; 127: 947

    PubMed  CAS  Google Scholar 

  34. Martinez E, Casamitjana R, Conget I, et al. Protease inhibitor-associated hyperinsulinaemia [letter]. AIDS 1998; 12(15): 2077–9

    Article  PubMed  CAS  Google Scholar 

  35. Walli R, 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(15): F167–73

    Article  PubMed  CAS  Google Scholar 

  36. Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance and HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr 1999; 21(3): 209–16

    Article  PubMed  CAS  Google Scholar 

  37. Carr A, Samsaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving protease inhibitors. AIDS 1998; 12(7): F51–8

    Article  PubMed  CAS  Google Scholar 

  38. Carr A, Samsaras K, Chisholm DJ, et al. Pathogenesis of HIV-1 protease inhibitor associated peripheral lipodystrophy, hyperlipidemia and insulin resistance. Lancet 1998; 351(9119): 1881

    Article  PubMed  CAS  Google Scholar 

  39. Carr A, Samsaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease inhibitor associated lipodystrophy, hyperlipidemia and diabetes mellitus: a cohort study. Lancet 1999; 353(9170): 2093–9

    Article  PubMed  CAS  Google Scholar 

  40. Ford ES, Giles WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care 2003; 26: 575–81

    Article  PubMed  Google Scholar 

  41. National Cholesterol Education Program. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): the guidelines [online]. Available from URL: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm [Accessed 2003 Sep 10]

  42. Dube MP, Zackin R, Tebas P, et al. Prospective study of regional body composition in antiretroviral-naive subjects randomized to receive zidovudine+lamivudine or didanosine+stavudine combined with nelfinavir, efavirenz, or both: A5005s, a susbstudy of ACTG 384 [abstract no. 27]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  43. Chene G, Angelini E, Cotte L, et al. Role of long-term nucleo-side-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis 2002; 34: 649–57

    Article  PubMed  CAS  Google Scholar 

  44. Joly V, Flandre P, Meiffredy S, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002; 16: 2447–54

    Article  PubMed  CAS  Google Scholar 

  45. Law M, Emery S, French M, et al. Lipodystrophy and metabolic abnormalities in a cross-sectional study of participants in randomized controlled studies of combination antiretroviral therapy [abstract no. O28]. 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy; 2000 Sep 13–15; Toronto (ON)

  46. Dreschler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis 2002; 35: 1219–30

    Article  Google Scholar 

  47. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356–9

    Article  PubMed  Google Scholar 

  48. Frayn KN. Insulin resistance, impaired postprandial lipid metabolism and abdominal obesity: a deadly triad. Med Princ Pract 2002; 11 Suppl. 2: 31–40

    Article  PubMed  Google Scholar 

  49. McGarry JD. Banting Lecture 2001. Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002; 51: 7–18

    Article  PubMed  CAS  Google Scholar 

  50. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32: 130–9

    Article  PubMed  CAS  Google Scholar 

  51. Christeff N, Melchior J-C, de Truchis P, et al. 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: 2251–60

    Article  PubMed  CAS  Google Scholar 

  52. Bonnet E, Ruidavets J-B, Tuech J, et al. 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 2001; 86: 296–302

    Article  PubMed  CAS  Google Scholar 

  53. Vigouroux C, Gharakanian S, Salhi Y, et al. Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diab Metab (Paris) 1999; 25: 225–32

    CAS  Google Scholar 

  54. Saint-Marc T, Partisani M, Poizot-Martin I, et al. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000; 14(1): 37–49

    Article  PubMed  CAS  Google Scholar 

  55. Van der Valk M, Bisschop PH, Romijn JA, et al. Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS 2001; 15: 2093–100

    Article  PubMed  Google Scholar 

  56. Sekhar RV, Jahoor F, White AC, et al. Metabolic basis of HIV-lipodystrophy syndrome. Am J Physiol Endocrinol Metab 2002; 283: E332–7

    PubMed  CAS  Google Scholar 

  57. Nolan D, John M, Mallal S. Antiretoviral therapy and the lipodystrophy syndrome, part 2: concepts in aetiopathogenesis. Antivir Ther 2001 Sep; 6(3): 145–60

    PubMed  CAS  Google Scholar 

  58. Merwood MA, Sosman JM, Bellehumeur JL, et al. Increased levels of post-prandial triglyceride-rich lipoproteins in patients taking HIV protease inhibitors [abstract no. 51]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  59. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104(3): 257–62

    Article  PubMed  CAS  Google Scholar 

  60. Krauss RM. Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol 1998; 81: 13B-7B

    Article  Google Scholar 

  61. Sniderman AD, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapoB: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Ann Intern Med 2001; 135: 447–59

    PubMed  CAS  Google Scholar 

  62. Hadigan C, Borgonha S, Rabe J, et al. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. Metabolism 2002; 51: 1143–7

    Article  PubMed  CAS  Google Scholar 

  63. Hadigan C, Rabe J, Meininger G, et al. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution. Am J Clin Nutr 2003; 77: 490–4

    PubMed  CAS  Google Scholar 

  64. Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2001; 16(5): F1–8

    Article  Google Scholar 

  65. Gan SK, Samaras K, Thompson CH, et al. Altered myocellular and abdominal fat partitioning predict disturbance in insulin action in HIV protease inhibitor-related lipodystrophy. Diabetes 2002; 51: 3163–9

    Article  PubMed  CAS  Google Scholar 

  66. Behrens GMN, Boerner A-R, Weber K, et al. Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy. J Clin Invest 2002; 110: 1319–27

    PubMed  CAS  Google Scholar 

  67. Kosmiski LA, Kuritzkes DR, Lichtenstein KA, et al. Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 2001; 15: 1993–2000

    Article  PubMed  CAS  Google Scholar 

  68. Dube MP, Edmonson-Melancon H, Qian D, et al. Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquir Immune Defic Syndr 2001; 27: 130–4

    PubMed  CAS  Google Scholar 

  69. Sutinen J, Hakkinen A-M, Westerbacka J, et al. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 2002; 16: 2183–93

    Article  PubMed  CAS  Google Scholar 

  70. Meininger G, Hadigan C, Laposata M, et al. Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution. Metabolism 2002; 51: 260–6

    Article  PubMed  CAS  Google Scholar 

  71. Worm D, Kirk O, Andersen O, et al. Clinical lipoatrophy in HIV-1 patients on HAART is not associated with increased abdominal girth, hyperlipidaemia or glucose intolerance. HIV Med 2002; 3: 239–46

    Article  PubMed  CAS  Google Scholar 

  72. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and post-heparin lipase in normal subjects. AIDS 2000; 14: 51–7

    Article  PubMed  CAS  Google Scholar 

  73. Lee GA, Senviratne T, Noor MA, et al. Metabolic effects of lopinavir/ritonavir (Kaletra) in healthy HIV-seronegative men [abstract no. 748]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)

  74. Despres J-P, Couillard C, Gagnon J, et al. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the health, risk factors, exercise training, and genetics (HERITAGE) family study. Arterioscler Thromb Vasc Biol 2000; 20: 1932–8

    Article  PubMed  CAS  Google Scholar 

  75. Mynarcik DC, McNurlan MA, Steigbigel RT, et al. 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 Syndr 2000; 25: 312–21

    Article  PubMed  CAS  Google Scholar 

  76. Reiss P. New insights in the clinical management of HIV-1 associated metabolic complications: putting guidelines into perspective [abstract no. 163]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)

  77. Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med 2003; 349: 1036–46

    Article  PubMed  CAS  Google Scholar 

  78. Fajas L, Schoonjans K, German L, et al. Regulation of peroxisome proliferator-activated receptor γ expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol Cell Biol 1999; 19: 5495–503

    PubMed  CAS  Google Scholar 

  79. Flier JS, Hollenberg AN. ADD-1 provides new insight into the mechanisms of insulin action. Proc Natl Acad Sci U S A 1999; 96: 14191–2

    Article  PubMed  CAS  Google Scholar 

  80. Osborne TF. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 2000; 275: 32379–82

    Article  PubMed  CAS  Google Scholar 

  81. Caron M, Auclair M, Vigoureux C, et al. The HIV-protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 2001; 50: 1378–88

    Article  PubMed  CAS  Google Scholar 

  82. Bastard JP, Caron M, Vidal H, et al. 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 2002; 359: 1026–31

    Article  PubMed  CAS  Google Scholar 

  83. Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterolregulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations. AIDS 2002; 16: 1587–94

    Article  PubMed  CAS  Google Scholar 

  84. Rudich A, Vanounou S, Reisenberg K, et al. The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes 2001; 50: 1425–31

    Article  PubMed  CAS  Google Scholar 

  85. Stevens GJ, Lankford AC, Chen M, et al. Inhibition of adipocyte differentiation in HIV-1 protease inhibitors: potential mechanisms based on changes in gene expression [abstract]. Antivir Ther 2000; 5 Suppl. 5: 26

    Google Scholar 

  86. Hegele RA. Molecular basis of partial lipodystrophy and prospects for therapy. Trends Mol Med 2001; 7: 121–6

    Article  PubMed  CAS  Google Scholar 

  87. Caron M, Auclair M, Kornprobst M, et al. Differential in vitro effects of indinavir, nelfinavir and amprenavir on cell differentiation, insulin sensitivity and apoptosis in an adapted adipose cell model: preventive impact of rosiglitazone [abstract no. 24]. 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2001 Oct 23–26; Athens

  88. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275: 20251–4

    Article  PubMed  CAS  Google Scholar 

  89. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002; 16: 859–63

    Article  PubMed  CAS  Google Scholar 

  90. Hruz PW, Murata H, Qiu H, et al. Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes 2002; 51: 937–42

    Article  PubMed  CAS  Google Scholar 

  91. Ben-Romano R, Rudich A, Torok D, et al. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS 2003; 17: 23–32

    Article  PubMed  CAS  Google Scholar 

  92. Andre P, Groettrup M, Klenerman P, et al. An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Natl Acad Sci U S A 1998; 95: 13120–4

    Article  PubMed  CAS  Google Scholar 

  93. Nguyen AT, Gagnon A, Angel JB, et al. Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis. AIDS 2000; 14: 2467–73

    Article  PubMed  CAS  Google Scholar 

  94. Riddle TM, Kuhel DG, Woollett LA, et al. HIV protease inhibitor therapy increases hepatic lipoprotein production via stabilisation of activated Sterol Regulatory Element-Binding Protein-1 (SREBP-1) in the nucleus [abstract no. 659]. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago (IL)

  95. Liang JS, Distler O, Cooper DA, et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 2001 Dec; 7(12): 1327–31

    Article  PubMed  CAS  Google Scholar 

  96. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001; 15: F11–8

    Article  PubMed  CAS  Google Scholar 

  97. Murphy R, Thiry A, Mancini M, et al. Twelve weeks of atazanavir treatment reverses nelfinavir-associated hyperlipidaemia: results from BMS AI424-044 [abstract no. 15]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  98. Wang S, Mulvrey R, Laing N, et al. Differentiation of atazanavir from other HIV-protease inhibitors in preclinical models of glucose uptake, lipogenesis and proteasome function [abstract no. 10]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  99. Dube MP, Qian D, Edmondson-Melancon H, et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis 2002; 35: 475–81

    Article  PubMed  CAS  Google Scholar 

  100. Thompson M, Tashima K, Schooley R, et al. Different impact on metabolic parameters of amprenavir/ritonavir regimens with tenofovir versus efavirenz [abstract no. 45]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  101. Costa A, Pulido F, Rubio R, et al. Lipid changes in HIV-infected patients who started rescue therapy with an amrenavir/ ritonavir-based highly active antiretroviral therapy. AIDS 2002; 16: 1983–4

    Article  PubMed  Google Scholar 

  102. Davignon J, Genest Jr J. Genetics of lipoprotein disorders. Endocrinol Metab Clin North Am 1998; 27(3): 521–50

    Article  PubMed  CAS  Google Scholar 

  103. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025. Diabetes Care 1998; 21: 1414–31

    Article  PubMed  CAS  Google Scholar 

  104. National Cholesterol Education Program. Risk assessment tool for estimating 10-year risk of developing hard CHD (myocardial infarction and coronary death) [online]. Available from URL: http://hin.nhlbi.nih.gov/atpiii/calculator.asp/ [Accessed 2003 Sep 10]

  105. New Zealand Guidelines Group. Estimation of cardiovascular risk in men and women [online]. Available from URL: http://www.nzgg.org.nz/library/gl_complete/bloodpressure/tablel.cfm [Accessed 2003 Sep 10]

  106. Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74: 1045–52

    Article  PubMed  CAS  Google Scholar 

  107. Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors [letter]. Lancet 1998; 351: 1328

    Article  PubMed  CAS  Google Scholar 

  108. Behrens G, Schmidt H, Meyer D, et al. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998; 351: 1958

    Article  PubMed  CAS  Google Scholar 

  109. Gallet B, Pulik M, Genet P, et al. Vascular complications associated with use of HIV protease inhibitors. Lancet. 1998; 351: 1958–9

    Article  PubMed  CAS  Google Scholar 

  110. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998; 351: 1959

    Article  PubMed  CAS  Google Scholar 

  111. Laurence J. Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet 1998; 351: 1960

    Article  PubMed  CAS  Google Scholar 

  112. SoRelle R. Vascular and lipid syndromes in selected HIV-infected patients. Circulation 1998; 98: 829–30

    Article  PubMed  CAS  Google Scholar 

  113. Eriksson U, Opravil M, Amann FW, et al. Is treatment with ritonavir a risk factor for myocardial infarction in HIV-infected patients? AIDS 1998; 12: 2079–80

    Article  PubMed  CAS  Google Scholar 

  114. Sullivan AK, Nelson MR, Moyle GJ. Coronary artery disease occurring with protease inhibitor therapy. Int J STD AIDS 1998; 9: 711–2

    Article  PubMed  CAS  Google Scholar 

  115. Jutte A, Schwenk A, Franzen C, et al. Increasing morbidity from myocardial infarction during HIV protease inhibitor treatment? AIDS 1999; 13: 1796–7

    Article  PubMed  CAS  Google Scholar 

  116. Flynn TE, Bricker LA. Myocardial infarction in HIV-infected men receiving protease inhibitors. Ann Intern Med 1999; 131: 548

    PubMed  CAS  Google Scholar 

  117. Mary-Krause M, Cotte L, Partisani M, et al. Impact of treatment with protease inhibitors on myocardial infarction occurrence in HIV-infected men [abstract no. 657]. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago (IL)

  118. Holmberg S, Moorman A, Tong T, et al. Protease inhibitor use and adverse cardiovascular outcomes in ambulatory HIV patients [abstract no. 698]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle (WA)

  119. Currier J, Taylor A, Boyd F, et al. Coronary heart disease in HIV-infected individuals: associations with antiretroviral therapy [abstract no. 54]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  120. Bozzette SA, Carpenter A, Bommakanty U, et al. Cardio- and cerebrovascular outcomes with changing process of anti-HIV therapy in 36,776 US veterans [abstract no. LB9]. 9th Conference on Retroviruses and Opportunistic Infections; 2002 Feb 24–28; Seattle (WA)

  121. Klein D, Hurley LB, Quesenberry CP, et al. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr 2002; 30: 471–7

    Article  PubMed  CAS  Google Scholar 

  122. Grunfeld C, Kotier DP, Hamadeh R, et al. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1989; 86: 27–31

    Article  PubMed  CAS  Google Scholar 

  123. Shor-Posner G, Basit A, Lu Y, et al. Hypercholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med 1993; 94: 515–9

    Article  PubMed  CAS  Google Scholar 

  124. Hansson GK. Cell-mediated immunity in atherosclerosis. Curr Opin Lipidol 1997; 8: 301–11

    Article  PubMed  CAS  Google Scholar 

  125. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–26

    Article  PubMed  CAS  Google Scholar 

  126. Frostegard J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of proinflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145: 33–43

    Article  PubMed  CAS  Google Scholar 

  127. Stemme S, Faber B, Holm J, et al. T lymphocytes from human atherosclerotic plaques recognize oxidised LDL. Proc Natl Acad Sci U S A 1995; 92: 3893–7

    Article  PubMed  CAS  Google Scholar 

  128. Stemme S, Holm J, Hansson G. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb 1992; 12: 206–11

    Article  PubMed  CAS  Google Scholar 

  129. Austin MA, King M-C, Vranizan KM, et al. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease. Circulation 1990; 82: 495–506

    Article  PubMed  CAS  Google Scholar 

  130. Hodis HN, Mack WJ, Krauss RM, et al. Pathophysiology of triglyceride-rich lipoproteins in atherothrombosis: clinical aspects. Clin Cardiol 1999; 22 (6 Suppl.): II15–20

    Article  PubMed  CAS  Google Scholar 

  131. Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation 1993; 88: 2762–70

    Article  PubMed  CAS  Google Scholar 

  132. Weber T-J, Bengel F, Bogner J-R, et al. Cardiovascular dysregulation in HIV-infected individuals treated with HAART [abstract no. O26]. Program and abstracts of the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2000 Sep 13–15; Toronto (ON)

  133. Talwani R, Falusi OM, Mendes de Leon CF, et al. Electron beam computed tomography for assessment of coronary artery disease in HIV-infected men receiving antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 30: 191–5

    PubMed  Google Scholar 

  134. Heart Protection Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised, placebo-controlled trial. Lancet 2002; 360: 7–22

    Article  Google Scholar 

  135. Stein JH, Merwood MA, Bellehumeur JL, et al. Effects of pravastatin on lipids and lipoprotein sub-fractions in patients receiving HIV protease inhibitors [abstract no. 50]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  136. Doser N, Kubli S, Telenti A, et al. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients. AIDS 2002; 16: 1982–3

    Article  PubMed  Google Scholar 

  137. Visnegarwala F, Sajja P, Rodriguez-Barraddas MC, et al. Inconsistent effects of lipid-lowering drugs in the management of HIV-associated dyslipidemias [abstract no. 30]. 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2001 Oct 23–26; Athens

  138. Aberg JA, Zackin R, Evans S, et al. A prospective multicenter randomized trial comparing the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities [abstract no. 26]. ACTG 5087. 40th Annual Meeting of the Infectious Diseases of America; 2002 Oct 24–27; Chicago (IL)

  139. Iloeje UH, Yu-Isenberg KS, Ventura EP, et al. Treatment of HIV-associated dyslipidemia: a time trend analysis 1998–2001 [abstract no. 42]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  140. Iloeje UH, Kawabata H, Wu Y. Age and gender differences in treatment of antiretroviral treatment-associated dyslipidemia among HIV/AIDS patients [abstract no. 43]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  141. Van Der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001; 15: 2407–14

    Article  PubMed  Google Scholar 

  142. Simon GL, Liappis AP, Granger SL, et al. Antiretroviral therapy-induced changes in lipoprotein subclass phenotype: comparison of protease inhibitor and non-nucleoside reverse transcriptase inhibitor regimens [abstract no. 14]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  143. Mann JI. Diet and risk of coronary artery disease and type 2 diabetes. Lancet 2002; 360: 783–9

    Article  PubMed  CAS  Google Scholar 

  144. Barrios A, Blanco F, Garcia-Benayas T, et al. Effect of dietary intervention on highly active antiretroviral therapy-associated dyslipidemia. AIDS 2002; 16: 2079–81

    Article  PubMed  Google Scholar 

  145. Raghavan S, Iqbal S, Levine K, et al. Effectiveness of supervised exercise programme on fat accumulation and metabolic levels in HIV-infected African Americans and Latinos [abstract no. 60]. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2002 Sep 22–25; San Diego (CA)

  146. American Diabetes Association. Standards of medical care of patients with diabetes mellitus. Diabetes Care 2000; 23 Suppl. 1: S32–42

    Google Scholar 

  147. Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133: 263–74

    PubMed  CAS  Google Scholar 

  148. Gelato M, Mynarcik DC, Quick JL, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone. J Acquir Immune Defic Syndr 2002; 31: 163–70

    Article  PubMed  CAS  Google Scholar 

  149. Walli R, Michl GM, Muhlbayer D, et al. Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. Res Exp Med (Berl) 2000; 199: 253–62

    Article  CAS  Google Scholar 

  150. Saint-Marc T, Touraine J-L. Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy. AIDS 1999; 13: 1000–2

    Article  PubMed  CAS  Google Scholar 

  151. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome. JAMA 2000; 284: 472–7

    Article  PubMed  CAS  Google Scholar 

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Nolan, D. Metabolic Complications Associated with HIV Protease Inhibitor Therapy. Drugs 63, 2555–2574 (2003). https://doi.org/10.2165/00003495-200363230-00001

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