Chronic complications of human immunodeficiency virus (HIV) and highly active retroviral therapy have become increasingly relevant as life expectancy for HIV patients has improved and the affected population ages. HIV-associated lipodystrophy syndrome is characterised by an abnormal fat distribution syndrome associated with metabolic disturbances including insulin resistance, and deranged glucose and lipid metabolism. It is associated with increased risks of progression to type 2 diabetes and cardiovascular disease.
Lipodystrophy is a clinical diagnosis and mostly subjective as standardised diagnostic criteria have not yet been defined. Several therapeutic interventions have been investigated including lifestyle therapy, vitamin supplements, switching antiretroviral therapy and specific therapies for insulin resistance and hyperlipidaemia. Current management options for HIV associated lipodystrophy are limited and are mostly based on avoidance of risk factors and switching of antiretroviral drugs. Therapies to improve insulin resistance have been tried but they are frequently ineffective as are lipid-lowering drugs. Interest in anabolic agents has been resurrected and new clinical data suggest that HIV-associated lipodystrophy growth hormone releasing factor therapy may have a beneficial role in the treatment of HIV-associated lipodystrophy. However, there still remains a need for robust prospective cohort studies and well designed intervention trials to resolve the aetiology and define the best treatment for this complication of HIV disease and its treatment.
Lohse N., Hansen AB, Pedersen G. et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med2007;146:87-95.
2.
Bozzette SA, Ake CF, Tam HK et al. Cardiovascular Rand cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med2003;348:702-10.
3.
World Health Organisation and Joint United Nations Programme on HIV/AIDS.Treating 3 million by 2005: making it happen, the WHO strategy. Geneva: World Health Organisation; 2003.
4.
Carr A., Samaras K., Chisholm DJ et al. Pathogen ( esis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet1998;351:1881-3.
5.
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. Lancet1999;353:2093-9.
6.
Mallon PW, Cooper DA, Carr A.HIV-associated lipodystrophy. HIV Med2001 ;2:166-73.
7.
Wierzbicki AS , Purdon SD, Hardman TC et al. HIV lipodystrophy and its metabolic consequences: implications for clinical practice. Curr Med Res Opin2008;24:609-24.
8.
Milinkovic A. , Martinez E.Current perspectives on HIV-associated lipodystrophy syndrome. J Antimicrob Chemother2005;56:6-9.
9.
Grunfeld C., Tien P.Difficulties in understanding the metabolic complications of acquired immune deficiency syndrome. Clin Infect Dis2003;37(suppl 2):S43-S46.
10.
Carr A., Samaras K., Burton S. et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS1998;12:F51-F58.
11.
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 . AIDS1999;13:1659-67.
12.
Behrens GM, Stoll M., Schmidt RELipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?Drug Saf2000;23(1):57-76.
13.
Hakeem L., Campbell IW, Bhattacharyya DPHIV-associated lipodystrophy - a new metabolic syndrome. Br J Diabetes Vasc Dis2008; 8:129-34.
14.
Wanke CA, Falutz JM, Shevitz A. et al. Clinical evaluation and management of metabolic and morphologic abnormalities associated with human immunodeficiency virus. Clin Infect Dis2002;34:248-59.
15.
Justman JE, Benning L., Danoff A. et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr2003;32:298-302.
16.
Paparizos VA , Kyriakis KP, Botsis C. et al. Protease inhibitor therapy-associated lipodystrophy, hypertriglyceridaemia and diabetes mellitus . AIDS2000;14:903-05.
17.
Sharp M.Metabolic complications associated with HIV disease. Posit Aware2003;14(2):32-6.
18.
Kulasegaram R., Peters BS, Wierzbicki ASDyslipidaemia and cardiovascular risk in HIV infection. Curr Med Res Opin2005 ;21:1717-25.
19.
Executive Summary of The 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). JAMA2001;285:2486-97.
20.
Mondy K., Overton ET, Grubb J. et al. Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population. Clin Infect Dis2007;44:726-34.
Heath KV, Hogg RS, Chan KJ et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS2001;15:231-9.
23.
Galli M., Ridolfo AL, Adorni F. et al. Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr2002 ;29(1):21-31.
24.
Heath KV, Hogg RS, Singer J. et al. Antiretroviral treatment patterns and incident HIV-associated morphologic and lipid abnormalities in a populatio-based chort. J Acquir Immune Defic Syndr2002;30:440-7.
25.
Grinspoon SKMetabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med2005;118 (suppl 2):S23-S28.
26.
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. Lancet1999;353:2093-9.
27.
Kotler DP, Thea DM, Heo M. et al. Relative influences of sex, race, environment, and HIV infection on body composition in adults. Am J Clin Nutr1999;69:432-9.
28.
Jaya G., Lutchman N., Crowther N.Metabolic Complications of ART in Black South Africans. 14th Conference on Retrovirus' and Opportunistic Infections Los Angeles USA2007 Abstract 796
29.
Saves M., Raffi F., Capeau J. et al. Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis2002 ;34:1396-405.
30.
Maisonneuve C., Igoudjil A., Begriche K. et al. Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting. Antivir Ther2004 ;9:801-10.
31.
Haubrich RH, Riddler S., diRienzo G. et al. Metabolic outcomes of ACTG 5142: a prospective, randomised, phase III trial of NRTI-, PI-, and NNRTI-sparing regimes for initial treatment of HIV-1 infection2007.
32.
Cameron DW, da Silva B., Arribas J. et al. Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction followed by LPV/r monotherapy compared with EFV/3TC. 2007.
33.
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 Metab1992;74:1045-52.
34.
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. AIDS2003;17:772-4.
35.
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 . Circulation2001;104:257-62.
36.
Lafeuillade A. , Alessi MC, Poizot-Martin I. et al. Endothelial cell dysfunction in HIV infection. J Acquir Immune Defic Syndr1992 ;5:127-31.
37.
Seminari E., Pan A., Voltini G. et al. Assessment of atherosclerosis using carotid ultrasonography in a cohort of HIV-positive patients treated with protease inhibitors. Atherosclerosis2002;162:433-8.
38.
Mercie P., Thiebaut R., Lavignolle V. et al. Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement. Ann Med2002;34(1):55-63.
39.
Purnell JQ, Zambon A., Knopp RH et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS2000;14(1):51-7.
40.
Atazanavir demonstrates antiviral efficacy and a favorable lipid profile at 48 weeks. J Assoc Nurses AIDS Care2002;13(2):86-7.
41.
Noor MA, Parker RA, O'Mara E. et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIVseronegative healthy adults. AIDS2004;18:2137-44.
42.
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 Antiretroviral-Naive Subjects. J Acquir Immune Defic Syndr2003 ;32(1):18-29.
43.
Penzak SR, Chuck SKHyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. Scand J Infect Dis2000;32:111-23.
44.
Martinez E. , Garcia-Viejo MA, Blanco JL et al. Impact of switching from HIV type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy . Clin Infect Dis2000;31:1266-73.
45.
Piketty C., Peytavin G., Trylezinski A. et al. Low increase in serum lipids in patients receiving a combination of ritonavir, saquinavir and efavirenz. HIV Med2002;3:287-9.
46.
Martinez E. , Arnaiz JA, Podzamczer D. et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with huma immunodeficiency virus infection. N Engl J Med2003;349:1036-46.
47.
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. AIDS1999;13:F63-F70.
48.
Murata H., Hruz PW, Mueckler M.The mechanism of insulin resistance caused by HIV protease inhibitor therapy . J Biol Chem2000;275:20251-4.
49.
Carpentier A., Patterson BW, Uffelman KD et al. Mechanism of highly active antiretroviral therapy-induced hyperlipidemia in HIV-infected individuals. Atherosclerosis2005;178:165-72.
50.
Lucas GM, Chaisson RE, Moore RDSurvival in an urban HIV-1 clinic in the era of highly active antiretroviral therapy: a 5-year cohort study. J Acquir Immune Defic Syndr2003:33:321-8.
51.
Brambilla AM , Novati R., Calori G. et al. Stavudine or indinavir-containing regimens are associated with an increased risk of diabetes mellitus in HIV-infected individuals. AIDS2003;17:1993-5.
52.
Zimmet P.Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders. Am J Med2005;118(suppl 2):3S-8S.
53.
Gerschenson M., Brinkman K.Mitochondrial dysfunction in AIDS and its treatment. Mitochondrion2004;4:763-77.
54.
Fleischman A. , Johnsen S., Systrom D. et al. Effects of NRTI, stavudine, on insulin sensitivity and mitochondrial function in muscle of healthy adults. 14th Conference on Retrovirus' and Opportunistic Infections Los Angeles USA2007 Abstract 43.
55.
Birkus G., Hitchcock MJ, Cihlar T.Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother2002;46:716-23.
56.
Lee H., Hanes J., Johnson KAToxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry2003;42:14711-19.
57.
Lewis W., Dalakas MCMitochondrial toxicity of antiviral drugs. Nat Med1995;1:417-22.
58.
Lichtenstein KARedefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr2005;39:395-400.
59.
Carr A., Law M.An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score. J Acquir Immune Defic Syndr2003;33:571-6.
60.
Sheridan S. , Pignone M., Mulrow C.Framingham-based tools to calculate the global risk of coronary heart disease: a systematic review of tools for clinicians . J Gen Intern Med2003;18:1039-52.
61.
Hippisley-Cox J., Coupland C., Vinogradova Y. et al. Derivatioon and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study. BMJ2007;335:136.
62.
Hanley AJ, Karter AJ, Williams K. et al. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation2005; 112:3713-21.
63.
Wilson PW, Meigs JB, Sullivan L. et al. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med2007;167:1068-74.
64.
Roubenoff R. , Schmitz H., Bairos L. et al. Reduction of abdominal obesity in lipodystrophy associated with human immunodeficiency virus infection by means of diet and exercise: case report and proof of principle . Clin Infect Dis2002;34:390-3.
65.
Orchard TJ, Temprosa M., Goldberg R. et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial . Ann Intern Med2005;142:611-19.
66.
Wierzbicki ASLow HDL-cholesterol: Common and under-treated, but which drug to use?Int J Clin Pract2006 ;60:1149-53.
67.
Brinkman K. , ter Hofstede HJ, Burger DM et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway . AIDS1998;12:1735-44.
68.
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. AIDS2000;14(1):37-49.
69.
Safrin S., Grunfeld C.Fat distribution and metabolic changes in patients with HIV infection . AIDS1999;13:2493-505.
70.
Martinez E. , Conget I., Lozano L. et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS1999;13:805-10.
71.
Opravil M., Hirschel B., Lazzarin A. et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. J Infect Dis2002;185:1251-60.
72.
Sattler F.Body habitus changes related to lipodystrophy. Clin Infect Dis2003;36(Suppl 2):S84-S90.
73.
Lindström J. , Ilanne-Parikka P., Peltonen M. et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet2006;368:1673-9.
74.
Hadigan C., Corcoran C., Basgoz N. et al. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA2000;284:472-7.
75.
Blazes DL, Decker CFSymptomatic hyperlactataemia precipitated by the addition of tetracycline to combination antiretroviral therapy. Lancet Infect Dis2006;6:249-52.
76.
Gavrila A., Hsu W., Tsiodras S. et al. Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2 x 2 factorial, randomised, double-blinded, placebo-controlled trial. Clin Infect Dis2005;40:745-9.
77.
Prasithsirikul W., Bunnag P.Improvement of fat redistribution, insulin resistance and hepatic fatty infiltration in HIV-associated lipodystrophy syndrome by pioglitazone: a case report. J Med Assoc Thai2004;87:166-72.
78.
Sutinen J., Hakkinen AM, Westerbacka J. et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy - a randomized double-blind placebo-controlled study. Antivir Ther2003;8:199-207.
79.
Sheffield CA , Kane MP, Busch RSOff-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection. Pharmacotherapy2007;27:1449-55.
80.
Fichtenbaum CJ, Gerber JGInteractions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet2002 ;41:1195-211.
81.
Mallon PW, Miller J., Kovacic JC et al. Effect of pravastatin on body composition and markers of cardiovascular disease in HIV-infected men -a randomized, placebo-controlled study. AIDS2006;20:1003-10.
82.
Badiou S., Merle De BC, Dupuy AM et al. Fenofibrate improves the atherogenic lipid profile and enhances LDL resistance to oxidation in HIV-positive adults. Atherosclerosis2004;172:273-9.
83.
Nystrom T., Bratt G., Sjoholm A.Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance. J Intern Med2002;252:570-4.
84.
Dube MP, Wu JW, Aberg JA et al. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. Antivir Ther2006;11:1081-9.
85.
Samson SL, Pownall HJ, Scott LW et al. Heart positive: design of a randomized controlled clinical trial of intensive lifestyle intervention, niacin and fenofibrate for HIV lipodystrophy/dyslipidemia . Contemp Clin Trials2006;27:518-30.
86.
Lee JH, Chan JL, Sourlas E. et al. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy . J Clin Endocrinol Metab2006;91:2605-11.
87.
Benavides S. , Nahata MCPharmacologic therapy for HIV-associated lipodystrophy . Ann Pharmacother2004;38:448-57.
88.
Mulligan K. , Grunfeld C., Hellerstein MK et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab1993 ;77:956-62.
89.
Wanke C., Gerrior J., Kantaros J. et al. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS1999;13:2099-103.
90.
Schwarz JM, Mulligan K., Lee J. et al. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation . J Clin Endocrinol Metab2002;87:942.
91.
Falutz J., Allas S., Blot K. et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med2007;357:2359-70.
