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The effects of HIV protease inhibitors on carbohydrate and lipid metabolism

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Abstract

Since the introduction of HIV protease inhibitors (PIs), disorders of glucose and lipid metabolism have emerged. In dissecting out the direct effect on lipid and glucose metabolism, it has become apparent that individual PIs have different effects on metabolism. Some PIs such as indinavir acutely induce insulin resistance. PIs have also been shown to cause other disorders of glucose metabolism, including impairment of insulin secretion and increased endogenous glucose production. Individual PIs also have different effects on lipid metabolism. Ritonavir predominantly increases triglyceride and very low-density lipoprotein cholesterol levels. Limited studies in HIV-negative volunteers suggest that several of the PIs do not increase low-density lipoprotein cholesterol levels. This review examines the direct effects of PIs on glucose and lipid metabolism by assessing prospective studies of HIV-infected and healthy normal volunteers, and in vitro studies.

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References and Recommended Reading

  1. Ferrannini E, Mari A: How to measure insulin sensitivity. J Hypertens 1998, 16:895–906.

    Article  PubMed  CAS  Google Scholar 

  2. Haugaard SB, Andersen O, Storgaard H, et al.: Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of non-glucose secretagogues and insulin resistance of beta-cells. Am J Physiol Endocrinol Metab 2004, 287:E677–685.

    Article  PubMed  CAS  Google Scholar 

  3. Woerle HJ, Mariuz PR, Meyer C, et al.: Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 2003, 52:918–925. This paper demonstrated that insulin secretion was impaired in HIVinfected patients on certain PIs.

    Article  PubMed  CAS  Google Scholar 

  4. Hommes MJ, Romijn JA, Endert E, et al.: Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism 1991, 40:651–656.

    Article  PubMed  CAS  Google Scholar 

  5. 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:F167-F173.

    Article  PubMed  CAS  Google Scholar 

  6. Silva M, Skolnik PR, Gorbach SL, et al.: The effect of protease inhibitors on weight and body composition in HIV-infected patients. AIDS 1998, 12:1645–1651.

    Article  PubMed  CAS  Google Scholar 

  7. Visnegarwala F, Krause KL, Musher DM: Severe diabetes associated with protease inhibitor therapy. Ann Intern Med 1997, 127:947.

    PubMed  CAS  Google Scholar 

  8. Dube MP, Johnson DL, Currier JS, Leedom JM: Protease inhibitorassociated hyperglycaemia. Lancet 1997, 350:713–714.

    Article  PubMed  CAS  Google Scholar 

  9. 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:F63-F70.

    Article  PubMed  CAS  Google Scholar 

  10. Carr A, Samaras K, Thorisdottir A, et al.: Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999, 353:2093–2099.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  12. Dube MP, Edmondson-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, 27:130–134.

    PubMed  CAS  Google Scholar 

  13. 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, 35:475–481.

    Article  PubMed  CAS  Google Scholar 

  14. Fisac C, Virgili N, Ferrer E, et al.: A comparison of the effects of nevirapine and nelfinavir on metabolism and body habitus in antiretroviral-naive human immunodeficiency virus-infected patients: a randomized controlled study. J Clin Endocrinol Metab 2003, 88:5186–5192.

    Article  PubMed  CAS  Google Scholar 

  15. Noor MA, Lo JC, Mulligan K, et al.: Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001, 15:F11-F18. In this study, 4 weeks of indinavir induced insulin resistance in healthy normal volunteers, suggesting a direct effect of PIs on insulin resistance.

    Article  PubMed  CAS  Google Scholar 

  16. Lee GA, Seneviratne T, Noor MA, et al.: The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 2004, 18:641–649. In this study, 4 weeks of lopinavir/ritonavir in healthy normal volunteers increased triglyceride, VLDL cholesterol, and free fatty acid levels with no significant induction of insulin resistance during the euglycemic hyperinsulinemic clamp.

    Article  PubMed  CAS  Google Scholar 

  17. Murata H, Hruz PW, Mueckler M: The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000, 275:20251–20254. In this study, direct blockade of the glucose transporter GLUT4 by PIs was shown to acutely induce insulin resistance in vitro.

    Article  PubMed  CAS  Google Scholar 

  18. Noor MA, Seneviratne T, Aweeka FT: Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002, 16:F1-F8.

    Article  PubMed  Google Scholar 

  19. Noor MA: The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  20. Shankar SS, Considine RV, Dube MP, Steinberg HO: Indinavir increases serum adiponectin in healthy HIV-negative men. Paper presented at the 63rd Scientific Sessions of the American Diabetes Association. New Orleans, LA; June 13–17, 2003.

  21. Lee GA, Mafong DD, Noor MA, et al.: HIV protease inhibitors increase adiponectin levels in HIV-negative men. J Acquir Immune Defic Syndr 2004, 36:645–647.

    Article  PubMed  Google Scholar 

  22. Kinlaw WB, Marsh B: Adiponectin and HIV-lipodystrophy: taking HAART. Endocrinology 2004, 145:484–486.

    Article  PubMed  CAS  Google Scholar 

  23. Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R: Adipocytederived hormone levels in HIV lipodystrophy. Antivir Ther 2003, 8:9–15.

    PubMed  CAS  Google Scholar 

  24. Sutinen J, Korsheninnikova E, Funahashi T, et al.: Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy. J Clin Endocrinol Metab 2003, 88:1907–1910.

    Article  PubMed  CAS  Google Scholar 

  25. Tong Q, Sankale JL, Hadigan CM, et al.: Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab 2003, 88:1559–1564.

    Article  PubMed  CAS  Google Scholar 

  26. Addy CL, Gavrila A, Tsiodras S, et al.: Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virusinfected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab 2003, 88:627–636.

    Article  PubMed  CAS  Google Scholar 

  27. Mynarcik DC, Combs T, McNurlan MA, et al.: Adiponectin and leptin levels in HIV-infected subjects with insulin resistance and body fat redistribution. J Acquir Immune Defic Syndr 2002, 31:514–520.

    PubMed  CAS  Google Scholar 

  28. Hadigan C, Yawetz S, Thomas A, et al.: Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial. Ann Intern Med 2004, 140:786–794.

    PubMed  CAS  Google Scholar 

  29. Xu A, Yin S, Wong L, et al.: Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice. Endocrinology 2004, 145:487–494.

    Article  PubMed  CAS  Google Scholar 

  30. Nolte LA, Yarasheski KE, Kawanaka K, et al.: The HIV protease inhibitor indinavir decreases insulin-and contractionstimulated glucose transport in skeletal muscle. Diabetes 2001, 50:1397–1401.

    Article  PubMed  CAS  Google Scholar 

  31. Murata H, Hruz PW, Mueckler M: Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002, 16:859–863.

    Article  PubMed  CAS  Google Scholar 

  32. Murata H, Hruz PW, Qiu H, Mueckler M: Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes 2002, 51:937–942.

    Article  PubMed  Google Scholar 

  33. Rudich A, Vanounou S, Riesenberg K, et al.: The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes 2001, 50:1425–1431.

    Article  PubMed  CAS  Google Scholar 

  34. Ranganathan S, Kern PA: The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes. J Endocrinol 2002, 172:155–162.

    Article  PubMed  CAS  Google Scholar 

  35. Koster JC, Remedi MS, Qiu H, et al.: HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes 2003, 52:1695–1700.

    Article  PubMed  CAS  Google Scholar 

  36. Dufer M, Neye Y, Krippeit-Drews P, Drews G: Direct interference of HIV protease inhibitors with pancreatic beta-cell function. Naunyn Schmiedebergs Arch Pharmacol 2004, 369:583–590.

    Article  PubMed  CAS  Google Scholar 

  37. Schwarz JM, Lee GA, Park S, et al.: Indinavir increases glucose production in healthy HIV-negative men. AIDS 2004, 18:1852–1854.

    Article  PubMed  Google Scholar 

  38. 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, 31:257–275.

    PubMed  Google Scholar 

  39. Gelato MC, Mynarcik DC, Quick JL, et al.: Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr 2002, 31:163–170.

    PubMed  CAS  Google Scholar 

  40. Carr A, Workman C, Carey D, et al.: No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, doubleblind, placebo-controlled trial. Lancet 2004, 363:429–438.

    Article  PubMed  CAS  Google Scholar 

  41. Mafong DD, Lee GA, Yu S, et al.: Development of multiplelipomas during treatment with rosiglitazone in a patient with HIV-associated lipoatrophy. AIDS 2004, 18:1742–1744.

    Article  PubMed  Google Scholar 

  42. Driscoll SD, Meininger GE, Lareau MT, et al.: Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients. AIDS 2004, 18:465–473.

    Article  PubMed  CAS  Google Scholar 

  43. Saint-Marc T, Touraine JL: Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy [letter]. AIDS 1999, 13:1000–1002.

    Article  PubMed  CAS  Google Scholar 

  44. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002, 106:3143–3421.

  45. 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, 74:1045–1052.

    Article  PubMed  CAS  Google Scholar 

  46. Constans J, Pellegrin JL, Peuchant E, et al.: Plasma lipids in HIV-infected patients: a prospective study in 95 patients. Eur J Clin Invest 1994, 24:416–420.

    Article  PubMed  CAS  Google Scholar 

  47. Feingold KR, Krauss RM, Pang M, et al.: The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab 1993, 76:1423–1427.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Hellerstein MK, Grunfeld C, Wu K, et al.: Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab 1993, 76:559–565.

    Article  PubMed  CAS  Google Scholar 

  50. Grunfeld C, Kotler DP, Shigenaga JK, et al.: Circulating interferonalpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1991, 90:154–162.

    PubMed  CAS  Google Scholar 

  51. Purnell JQ, Zambon A, Knopp RH, et al.: Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000, 14:51–57. In this study, ritonavir administered to healthy normal volunteers increased triglyceride and VLDL cholesterol levels.

    Article  PubMed  CAS  Google Scholar 

  52. Sadler BM, Piliero PJ, Preston SL, et al.: Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers. AIDS 2001, 15:1009–1018.

    Article  PubMed  CAS  Google Scholar 

  53. Petit JM, Duong M, Florentin E, et al.: Increased VLDL-apoB and IDL-apoB production rates in nonlipodystrophic HIVinfected patients on a protease inhibitor-containing regimen: a stable isotope kinetic study. J Lipid Res 2003, 44:1692–1697.

    Article  PubMed  CAS  Google Scholar 

  54. Reeds DN, Mittendorfer B, Patterson BW, et al.: Alterations in lipid kinetics in men with HIV-dyslipidemia. Am J Physiol Endocrinol Metab 2003, 285:E490-E497.

    PubMed  CAS  Google Scholar 

  55. 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, 7:1327–1331.

    Article  PubMed  CAS  Google Scholar 

  56. Riddle TM, Kuhel DG, Woollett LA, et al.: 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 2001, 276:37514–37519.

    Article  PubMed  CAS  Google Scholar 

  57. Young B, Fischl MA, Wilson HM, et al.: Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in protease inhibitor-naive HIV-infected adults. J Acquir Immune Defic Syndr 2002, 31:478–482.

    PubMed  CAS  Google Scholar 

  58. Voigt E, Wasmuth JC, Vogel M, et al.: Safety, efficacy and development of resistance under the new protease inhibitor lopinavir/ ritonavir: 48-week results. Infection 2004, 32:82–88.

    Article  PubMed  CAS  Google Scholar 

  59. Badiou S, De Boever CM, Dupuy AM, et al.: Small dense LDL and atherogenic lipid profile in HIV-positive adults: influence of lopinavir/ritonavir-containing regimen. AIDS 2003, 17:772–774.

    Article  PubMed  Google Scholar 

  60. Torti C, Quiros-Roldan E, Regazzi-Bonora M, et al.: Lipid abnormalities in HIV-infected patients are not correlated with lopinavir plasma concentrations. J Acquir Immune Defic Syndr 2004, 35:324–326.

    PubMed  Google Scholar 

  61. Murphy RL, Sanne I, Cahn P, et al.: Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS 2003, 17:2603–2614.

    Article  PubMed  CAS  Google Scholar 

  62. Sanne I, Piliero P, Squires K, et al.: Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviralnaive subjects. J Acquir Immune Defic Syndr 2003, 32:18–29.

    PubMed  CAS  Google Scholar 

  63. Squires K, Lazzarin A, Gatell JM, et al.: Comparison of oncedaily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004, 36:1011–1019.

    Article  PubMed  CAS  Google Scholar 

  64. van der Valk M, Kastelein JJ, Murphy RL, et al.: Nevirapinecontaining antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001, 15:2407–2414.

    Article  PubMed  Google Scholar 

  65. Periard D, Telenti A, Sudre P, et al.: Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999, 100:700–705.

    PubMed  CAS  Google Scholar 

  66. Martinez E, Domingo P, Galindo MJ, et al.: Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clin Infect Dis 2004, 38:1017–1023.

    Article  PubMed  CAS  Google Scholar 

  67. Grunfeld C, Doerrler W, Pang M, et al.: Abnormalities of apolipoprotein E in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1997, 82:3734–3740.

    Article  PubMed  CAS  Google Scholar 

  68. Schmidt HH, Behrens G, Genschel J, et al.: Lipid evaluation in HIV-1-positive patients treated with protease inhibitors. Antivir Ther 1999, 4:163–170.

    PubMed  CAS  Google Scholar 

  69. Behrens G, Schmidt HH, Stoll M, Schmidt RE: ApoE genotype and protease-inhibitor-associated hyperlipidaemia. Lancet 1999, 354:76.

    Article  PubMed  CAS  Google Scholar 

  70. Lister RK, Youle M, Nair DR, et al.: Latent dysbetalipoproteinaemia precipitated by HIV-protease inhibitors. Lancet 1999, 353:1678.

    Article  PubMed  CAS  Google Scholar 

  71. Fauvel J, Bonnet E, Ruidavets JB, et al.: An interaction between apo C-III variants and protease inhibitors contributes to high triglyceride/low HDL levels in treated HIV patients. AIDS 2001, 15:2397–2406.

    Article  PubMed  CAS  Google Scholar 

  72. Miller J, Brown D, Amin J, et al.: A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitorassociated hypertriglyceridaemia. AIDS 2002, 16:2195–2200.

    Article  PubMed  CAS  Google Scholar 

  73. Badiou S, Merle De Boever C, Dupuy AM, et al.: Fenofibrate improves the atherogenic lipid profile and enhances LDL resistance to oxidation in HIV-positive adults. Atherosclerosis 2004, 172:273–279.

    Article  PubMed  CAS  Google Scholar 

  74. Dube MP, Stein JH, Aberg JA, et al.: Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003, 37:613–627.

    Article  PubMed  Google Scholar 

  75. Fichtenbaum CJ, Gerber JG: Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002, 41:1195–1211.

    Article  PubMed  CAS  Google Scholar 

  76. Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al.: Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001, 45:3445–3450.

    Article  PubMed  CAS  Google Scholar 

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Lee, G.A., Rao, M.N. & Grunfeld, C. The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Rep 6, 471–482 (2004). https://doi.org/10.1007/s11908-004-0067-5

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