The introduction of protease inhibitors (PIs) has revolutionized the treatment of human immunodeficiency virus (HIV)– positive patients. The consequences of potential long-term metabolic complications have led to the use of PI-sparing regimens. As HIV treatment with PIs is associated with lipodystrophy (fat redistribution, hyperlipidemia, and glucose intolerance), it is essential to effectively manage these long-term toxicities. The impact of PI-induced glucose intolerance hasresulted in studies investigating both pathogenesis andmanagement of this side effect. The action of PIs on the glucose transporter, GLUT4, may explain themechanismof action of PI use on glucose tolerance. Insulin-sensitizing agents, such as metformin and thiazolidinediones, may improve glucose intolerance, insulin resistance, and lipodystrophy caused by PI therapy.
Get full access to this article
View all access options for this article.
References
1.
1. Electronic orange book approved drug products with therapeutic equivalence evaluations. Food and Drug AdministrationWeb site. Retrieved September 1, 2003, from http://www.fda.gov/cder/ob/default.htm.
2.
2. Palella FJ, DelaneyKM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection . N Engl J Med. 1998;338: 853-860 .
3.
3. Lumpkin MM. Reports of Diabetes and Hyperglycemia in Patients Receiving Protease Inhibitors for the Treatment of Human Immunodeficiency Virus (HIV).FDA Public Health Advisory. Washington, DC: US Food and Drug Administration ; 1977.
4.
4. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection . AIDS. 1999;13: 2493-2505 .
5.
5. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors . AIDS. 1998;12: F51-F58 .
6.
6. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Rockville, MD: US Department of Health and Human Services ; July 14, 2003.
7.
7. 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 .
8.
8. Gharakhanian S, Salhi Y, Nguyen TH, et al. Frequency of lipodystrophy and factors associated with glucose/lipid abnormalities in a cohort of 650 patients treated by protease inhibitors [Abstract 642] . 6th Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago.
9.
9. Saves M, Chene G, Dellamonica P, et al. Incidence of lipodystrophy and glucose and lipid abnormalities during the follow-up of a cohort ofHIV infected patents started on a protease inhibitor (PI) containing regimen [Abstract 682] . 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, WA.
10.
10. Basic Diabetes Information. American Diabetes Association Web site. Retrieved September 1, 2003, from http://www.diabetes.org.
11.
11. Currier JS, Boyd F, Kawabata H, Dezii C, Burtcel B, Hodder S. Diabetes mellitus in HIV-infected individuals [Abstract 677] . 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, WA.
12.
12. Walli RK, Michl GM, Segerer S, et al. Dyslipidemia and insulin resistance in HIV-infected patients treated with reverse transcriptase inhibitors alone and in combination with protease inhibitors [Abstract 645] . 6th Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago.
13.
13. Lee GA, Seneviratne T, Noor MA, et al. Metabolic effects of lopinavir/ritonavir (Kaletra) in healthy HIV-seronegative men [Abstract 748] . 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston.
14.
14. Dubé MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus . Clin Infect Dis. 2000;31: 1467-1475 .
15.
15. Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance in HIV protease inhibitor–associated diabetes . J Acquir Immune Defic Syndr. 1999;21: 209-216 .
16.
16. Dubé MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor–associated hyperglycaemia . Lancet. 1997;350: 713-714 .
17.
17. Murata H, Hruz PW, MuecklerM. The mechanism of insulin resistance caused by HIV protease inhibitor therapy . J Biol Chem. 2000;275: 20251-20251 .
18.
18. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults withhumanimmunodeficiency virus infection and lipodystrophy . Clin Infect Dis. 2001;32: 130-139 .
19.
19. Saint Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy . AIDS. 1999;13: 1659-1667 .
20.
20.Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection . AIDS. 2000;14: 1309-1316 .
21.
21. NoorMA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men . AIDS. 2001;15: F11-F18 .
22.
22. NoorMA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study . AIDS. 2002;16: F1-F8 .
24. 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 .
25.
25. Palacios R, Santos J, Ruiz J, Gonzalez M, Marquez M. Factors associated with the development of diabetes mellitus in HIVinfected patients on antiretroviral therapy: a case-control study . AIDS. 2003;17: 933-935 .
26.
26. van derValkM, Bisschop PH, Romijn JA, et al. Lipodystrophy in HIV-1 positive patients is associated with insulin resistance in multiple metabolic pathways . AIDS. 2001;15: 2093-2100 .
27.
27. PanditMK, Burke J, Gustafson AB, Minocha A, Peiris AN. Druginduced disorders of glucose tolerance . Ann Intern Med. 1993; 118: 529-539 .
28.
28. Bouchard P, Sai P, Reach G, Caubarrere I, Ganeval D, AssanR. Diabetes mellitus following pentamidine-induced hypoglycemia in humans . Diabetes. 1982;31: 40-45 .
29.
29. Assan R, Perronne C, Assan D, et al. Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. Astudy of 128 patients . Diabetes Care. 1995;18: 47-55 .
30.
30. Albrecht H, Stellbrink HJ, Araseth K. Didanosine induced disorders of glucose tolerance . Ann Intern Med. 1993;119: 1050-1050 .
31.
31. SchambelanM, 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 .
32.
32. American Diabetes Association. Clinical practice recommendations 2003 . Diabetes Care. 2003;26: S1-S156 .
33.
33. Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy . AIDS. 1999;13: 1000-1002 .
34.
34. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome . JAMA. 2000;284: 472-477 .
35.
35. 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 .
36.
36. Hadigan C, Meigs JB, Rabe J, et al. 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 .
37.
37. Center for Drug Evaluation and Research. 2000 report to the nation. Food and Drug AdministrationWeb site. US Department of Health and Human Services. Retrieved September 5, 2003, from http://www.fda.gov/cder/reports/rtn2000/RTN2000.PDF
38.
38. Walli RK, MichlGM, Bogner JR, Goebel FD. Effects of the PPAR-. activator troglitazone on protease inhibitor associated peripheral insulin resistance [Abstract 673] . 6th Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago.
39.
39. 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: 263-274 .
40.
40. Gelato MC, Mynarcik DC, Quick JL, et al. Improvement of insulin sensitivity with rosiglitazone . J Acquir Immune Defic Syndr. 2002;31: 163-170 .
41.
41. Sutinen J, Hakkinen AM, Westerbacka J, et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy—a randomized double-blind placebo-controlled study . Antivir Ther. 2003;8: 199-207 .
42.
42. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine . AIDS. 1999;13: 805-810 .
43.
43. Martinez E, Garcia-ViejoMA, Bianco JL, et al. Impact of switching from human immunodeficiency virus type I protease inhibitors to efavirenz in successfully treated adults with lipodystrophy . Clin Infect Dis. 2000;31: 1266-1273 .
44.
44. Walli RK, Michl GM, Bogner JR, Goebel FD. Improvement of HAART-associated insulin resistance and dyslipidemia after replacementof protease inhibitors with abacavir . Eur J Med Res. 2001;6: 413-421 .
45.
45. Bristol Myers Squibb Virology and Oncology. Atazanavir (Reyataz®) [package insert]. New York, NY: Bristol Myers Squibb ; 2003.
