Clinical Aspects of the Management of HIV Lipodystrophy

[Guest guest]

Clinical Aspects of the Management of HIV Lipodystrophy

S Wierzbicki; D Purdon; C Hardman; Ranjababu Kulasegaram; Barry S s Br J Diabetes Vasc Dis. 2008;8(3):113-119. ©2008 Sherborne Gibbs Ltd.

Posted 07/16/2008 http://www.medscape.com/viewarticle/576618_print

Abstract and Introduction

Abstract

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.

Introduction

Life expectancy for HIV positive patients has improved from 20 years for those diagnosed at age 25–33 years (versus 51 years for non-HIV infected)1 and is still improving. Patients are now offered a wide variety of combination drug regimens HAART based on viral load and lymphocyte CD4 count.[2] New treatment classes are being introduced and unprecedented numbers of people are being treated world wide as part of the ‘3 by 5 initiative'.[3] As infection-related prognosis improves, this patient group is becoming susceptible to all the chronic diseases of the non-HIV population with the added risk of complications due to the HIV infection or its treatment. Of particular concern has been the occurrence of an abnormal fat distribution syndrome, termed the HIV-associated lipodystrophy syndrome.[4-6] Several reviews have addressed this subject in detail and this article provides a clinical summary of one.[7]

Clinical Presentation of HIV-associated Lipodystrophy

There is no standard case definition for HIV-associated lipodystrophy,[8] and its incidence ranges from 2–84% depending on the definition.[9] HIV-associated lipodystrophy involves fat redistribution (lipodystrophy or lipoatrophy), fat loss from the face, buttocks and extremities (lipoatrophy), and mixed fat disturbances (lipodystrophy and lipoatrophy).[4,10-13] The difficulties faced in defining HIV-associated lipodystrophy are further compounded by factors such as age, race, gender, environmental factors and disease status, all of which influence body composition.[14,15] Patients with HIV-associated lipodystrophy often have insulin resistance, type 2 diabetes and elevated plasma lipid concentrations.[16-18] The combination of hyperlipidaemia, insulin resistance and visceral fat accumulation resembles the cluster of abnormalities described in the 'metabolic syndrome' which is associated with increases in cardiovascular risk and a large increase for developing diabetes.[19] Metabolic syndrome rates between HIV-positive and HIV-negative patients are similar, but the phenotype often differs, with HIV-infected persons with significant peripheral lipoatrophy often having insulin resistance and an elevated waist-to-hip ratio.[20] Non-overweight HAART-treated patients show more NCEP-ATP III defined metabolic syndrome (15% vs. 2%; p<0.001) and increased insulin resistance (39% vs. 19%; p =0.01) compared to HIV negative subjects and only 2% of the HAART-naEFve patients.[19] However, the long-term consequences of HIV-associated lipodystrophy have not been studied extensively in HIV-infected patients in formal comparisons with HIV negative patients.

Risk Factors for HIV-associated Lipodystrophy

There are several apparent risk factors for HIV-associated lipodystrophy. Duration of exposure, both to protease inhibitors and NRTIs, is the most obvious risk factor for changes in fat distribution.[21-23] Other risk factors include age and gender – although it may be hard to isolate the effects of lifestyle and demographic factors and background differences in risk of non-HIV-associated cardiovascular disease from the underlying pathology responsible for expression of these apparent risk factors.[22,24] Finally, duration of HIV infection, more advanced infection and a greater degree of viral suppression all appear to be related to the risk of HIV-associated lipodystrophy.[25-27]

Men are more likely than women to report fat depletion; especially in the face (57% of men vs. 22% of women), buttocks (60% of men vs. 45% of women) and limbs (68% of men vs. 53% of women).[26] Conversely, women appear to report a greater incidence of fat accumulation; especially in the abdomen (98% women vs. 70% men) and breasts (74% women vs. 31% men). In black Africans, lipodystrophy occurs in 39% after 18 months with a stavudine (d4T), lamivudine (3TC) and efavirenz regimen in patients with greater central obesity independent of increases in body mass index, LDL-C and HDL-C.[28] Stavudine (d4T) is associated with a higher incidence of lipoatrophy than zidovudine (ZDV).[29,30] Also, regimens involving lower use of the NNRTI efavirenz are associated with lower risk of lipoatrophy either on induction31 or in maintenance therapy on a protease inhibitor background.[32]

Pathological Changes in HIV-associated Lipodystrophy

Disturbances in Lipid Metabolism

Infection with HIV is associated with subtle changes in lipid metabolism. Slight reductions in HDL-C occur early in the course of the infection.[33] This is followed by an increase in the number of small, dense, type B LDL particles and apo B.[34] Later on, as patients begin to develop symptomatic HIV disease, plasma triglyceride levels may also rise.[35]

Initiation of antiretroviral therapy also affects lipid metabolism, and protease inhibitors appear to further worsen the patients' atherogenic profile.[34,35] The treatment-associated increase in plasma triglycerides, total cholesterol and LDL-C, have raised concern over the long-term cardiovascular consequences of chronic therapy.[18] Evidence from studies that compare treatment-naEFve HIV-infected patients treated with protease inhibitors indicates a treatment-related loss of endothelial function and an increase in carotid intima media thickness.[36-38] Most currently available protease inhibitors induce dyslipidaemia but the most marked changes are seen with ritonavir. Even in healthy volunteers ritonavir increases triglycerides, VLDL-cholesterol and apo B in two weeks.[39] Second generation protease inhibitors e.g. atazanavir, show less atherogenic profiles, however, long-term data are required to confirm their benefits on HIV-associated lipodystrophy.[40-42] In contrast to the deleterious effects that many protease inhibitors have on lipid metabolism, some antiretroviral drugs may improve the plasma profile. The NRTI, nevirapine, can increase HDL-C by up to 50% compared with a protease inhibitor-based regimen.[43] Similarly, favourable changes in lipid profiles and insulin resistance have been with the NNRTIs efavirenz44,[45] and abacavir.[46]

Insulin Resistance

HIV infection per se is not associated with marked changes in glucose homeostasis. Secondary infections, however, are associated with an increase in insulin resistance and dyslipidaemia. Several studies have demonstrated treatment-induced insulin resistance in HIV-1 positive patients with lipodystrophy10 and 30–40% of patients taking protease inhibitors show IGT.[47] Insulin resistance in HIV-associated lipodystrophy is multifactorial involving reduced peripheral glucose uptake, increased endogenous glucose production in the liver and kidney, as well as effects on lipolysis and protein catabolism48,[49] (figure 1). The long-term consequence of impaired insulin sensitivity appears to be an increase in type 2 diabetes, as there is a two-fold increase in risk over one to two years of HAART therapy.[50-52]

Figure 1. A summary of the possible mechanisms linking hyperlipidaemia, insulin resistance and lipodystrophy in HIV. Key: GLUT = glucose transporter; HIV = human immunodeficiency virus; IR = Insulin resistance; NRTI = nucleoside reverse transcriptase inhibitor;PI = protease inhibitor

Changes in lipid and glucose metabolism are features of NRTI-related mitochondrial toxicity.[53] Stavudine (d4T) therapy leads to increased insulin resistance on euglycaemic clamp.[54] There is a hierarchy to toxicity ranging from zalcidine (ddC) to tenofovir and abacavir.[55,56] The mechanism is proposed to involve DNA polymerase gamma as phosphorylated NRTIs can inhibit this enzyme.[57] It is likely that NRTIs, NNRTIs and protease inhibitor all contribute to body habitus and metabolic changes. A study of nine trials58 showed that the risk factors for lipoatrophy were exposure to and duration of thymidine analogues, most commonly stavudine (d4T), age, presence of markers of disease severity (CD4, HIV RNA), duration of therapy and white race. Similarly, a review of lipohypertrophy studies suggested that multiple risk factors are involved.[58,59]

Clinical Assessment of Lipodystrophy

Patients with lipodystrophy should have any areas of lipoatrophy/hypertrophy documented (or photographed) and undergo baseline anthropometry including measurement of waist circumference and ideally arm and thigh circumferences, as well as assessment of fat distribution by bioimpedance or DEXA scanning. A metabolic profile including electrolytes, calculation of glomerular filtration rate, transaminases, gamma-glutamyltransferase, fasting lipids, glucose, insulin (or C-peptide) and assessment of microalbuminuria should be performed. Ideally risk of cardiovascular disease60, 61 and diabetes[62,63] should be calculated with the understanding that current risk algorithms[60,61] are based on non-HIV individuals prior to initiation of treatment. Patients should then be re-assessed at regular intervals (figure 2).

Figure 2. Clinical algorithm for investigation and management of CV and diabetes complications associated with HIV and antiretroviral therapy. Key: CV = cardiovascular; FG = fasting glucose; HIV = human immunodeficiency virus

Management of Lipodystrophy

Studies investigating the use of diet and exercise intervention have demonstrated improvements in truncal obesity but sometimes at the expense of highlighting lipoatrophy.[64] Data from non-HIV patients with IGT suggests that lifestyle measures are superior to frequently used oral antidiabetic drugs (e.g. metformin).[65] However, substantial confusion exists as to which therapies would be best for the metabolic syndrome in non-HIV patients as many affect only portions of the whole syndrome.[66] Few analogous studies of sufficient rigour and size have been performed as yet in populations with HIV-associated lipodystrophy. Theoretical reasons have been advanced that vitamin supplements may be beneficial on mitochondrial toxicity and hence HIV-associated lipodystrophy. However, the role of vitamin supplements is unclear as mitochondrial support therapy, utilising thiamine, riboflavin, ubiquinone and acetyl-carnitine have shown mixed results.[67]

Switching HAART

Given the relationship of lipodystrophy with drug regimes several interventions have been assessed. Studies of the effects of stavudine (d4T) cessation show improvements in peripheral fat wasting.[11,68] A study utilising a switch design reported improvements in lipodystrophy as early as 12 weeks after ten patients were switched from stavudine (d4T) and didanosine (plus a protease inhibitor) combination therapy to zidovudine (ZDV) and lamivudine (3TC) (plus a protease inhibitor).[69] Conversely, many studies while demonstrating virological control following switch and some improvement in metabolic parameters, there were no noted improvements in body habitus following treatment intervention by switching the protease inhibitor component of a therapy regimen.[60-72] The main criticism of switch studies is that the majority are small cohort studies with limited follow-up, often poorly randomised and analysed with a perplexing variety of anthropometric and metabolic variables and confounded by an inability to account for the impact of prior therapy.

Oral Antidiabetic Intervention

Based on data from patients without HIV, strategies should be instituted early in order to prevent development of overt diabetes. Yet there is no good randomised trial data of similar interventions in patients with HIV-associated lipodystrophy to compare with the Diabetes Prevention Program.[65,73] Trials of metformin alone show improvements in hyperinsulinemia, visceral and subcutaneous abdominal adipose tissue and minimal rates of lactic acidosis except in combination with NRTIs and other precipitants e.g. tetracyclines.[74,75] Similarly, TZDs reduce hyperinsulinemia and visceral adipose tissue without significant side-effects.[76] Unfortunately, despite the beneficial effects of TZDs on insulin resistance in HIV and early good reports77 they seem to have little effect on lipodystrophy and may have adverse effects on triglycerides and cholesterol.[78] There are anecdotal reports of insulin therapy and there may be theoretical benefits to using incretin analogues for patients with lipodystrophy and diabetes.[79]

Lipid Lowering Interventions

Though lipid lowering drugs may affect one part of the HIV-associated lipodystrophy complex of metabolic abnormalities there is little to suggest that they affect the whole syndrome. The interaction of protease inhibitors with many statins limits their potential use.[18,80] However, in one study of 33 patients pravastatin therapy improved LDL-C and subcutaneous fat.[81] Fibrates and niacin may benefit metabolic syndrome components in HIV but do not affect the degree of lipodystrophy.[82-84] Large scale trials of lipid-lowering drugs in HIV lipodystrophy are underway.[85]

Hormone Therapy Intervention

Hormone therapies in the treatment of lipodystrophy have also been explored. Leptin injections have improved insulin resistance and increased truncal fat mass but seem to have little effect on isolated lipodystrophy.[86] Anabolic steroids and androgens may be effective in increasing muscle mass but have little effect on lipodystrophy.[87] In contrast, growth hormone therapy has been associated with improvements in lipodystrophy[88,89] decreases in abdominal visceral fat and in improvements in lipid profiles in patients with lipodystrophy.[90] Tesamorelin, a GHRF, in a placebo-controlled trial in 412 patients with HIV, metabolic syndrome and truncal lipodystrophy showed a 20% reduction in abdominal visceral fat on DEXA scanning and an 18% reduction in triglycerides with no hyperglycaemia.[91] Thus, it seems that a specific therapy for HIV-associated lipodystrophy may exist, though the long-term consequences of GHRF therapy on virological metabolic and clinical outcomes remain to be confirmed.

Conclusion

Patients with HIV infection, especially those in the advanced stage of AIDS, may use as many as 8–10 drugs concomitantly and the possibility of drug interactions and drug toxicities are considerable. Adverse metabolic changes complicate adherence strategies and successful HAART therapy. There is debate about the clinical as opposed to psychological significance of lipodystrophy, and whether its treatment especially with switch strategies results in benefits on outcomes for long-term metabolic as opposed to virological control. It may well be that newer antiretroviral agents will be selected to show lesser adipose side-effect profiles and indeed this evolution already seems to be occurring with regard to hyperlipidaemia with protease inhibitors. However, the main need is for robust prospective cohort studies and randomised controlled trials to determine the aetiology and prognosis of lipodystrophy and to evaluate therapeutic interventions for this consequence of HAART. Until such time as those studies are undertaken it will not be clear which regimens patients should initiate and what clinical intervention strategies should be utilised upon occurrence of lipodystrophy.

References

Lohse N, Hansen AB, Pedersen G et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007;146:87-95. Bozzette SA, Ake CF, Tam HK et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;348:702-10. 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. Carr A, Samaras K, Chisholm DJ et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998;351:1881-3. 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;353:2093-9. Mallon PW, DA, Carr A. HIV-associated lipodystrophy. HIV Med 2001;2:166-73. Wierzbicki AS, Purdon SD, Hardman TC et al. HIV lipodystrophy and its metabolic consequences: implications for clinical practice. Curr Med Res Opin 2008;24:609-24. Milinkovic A, ez E. Current perspectives on HIV-associated lipodystrophy syndrome. J Antimicrob Chemother 2005;56:6-9. Grunfeld C, Tien P. Difficulties in understanding the metabolic complications of acquired immune deficiency syndrome. Clin Infect Dis 2003;37(suppl 2):S43-S46. 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. Saint-Marc T, Partisani M, Poizot- I et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999;13:1659-67. Behrens GM, Stoll M, Schmidt RE. Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed? Drug Saf 2000;23(1):57-76. Hakeem L, IW, Bhattacharyya DP. HIV-associated lipodystrophy – a new metabolic syndrome. Br J Diabetes Vasc Dis 2008; 8:129-34. Wanke CA, Falutz JM, Shevitz A et al. Clinical evaluation and management of metabolic and morphologic abnormalities associated with human immunodeficiency virus. Clin Infect Dis 2002;34:248-59. 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 Syndr 2003;32:298-302. Paparizos VA, Kyriakis KP, Botsis C et al. Protease inhibitor therapy-associated lipodystrophy, hypertriglyceridaemia and diabetes mellitus. AIDS 2000;14:903-05. Sharp M. Metabolic complications associated with HIV disease. Posit Aware 2003;14(2):32-6. Kulasegaram R, s BS, Wierzbicki AS. Dyslipidaemia and cardiovascular risk in HIV infection. Curr Med Res Opin 2005;21:1717-25. 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). JAMA 2001;285:2486-97. Mondy K, Overton ET, Grubb J et al. Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population. Clin Infect Dis 2007;44:726-34. Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis 2000;30 Suppl 2:S135-S142. Heath KV, Hogg RS, Chan KJ et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS 2001;15:231-9. 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 Syndr 2002;29(1):21-31. Heath KV, Hogg RS, Singer J et al. Antiretroviral treatment patterns and incident HIV-associated morphologic and lipid abnormalities in a population-based chort. J Acquir Immune Defic Syndr 2002;30:440-7. Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med 2005;118 (suppl 2):S23-S28. 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;353:2093-9. 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 Nutr 1999;69:432-9. Jaya G, Lutchman N, Crowther N. Metabolic Complications of ART in Black South Africans. 14th Conference on Retrovirus' and Opportunistic Infections Los Angeles USA 2007 Abstract 796 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 Dis 2002;34:1396-405. 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 Ther 2004;9:801-10. 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 infection 2007. 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. 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. 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;17:772-4. 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;104:257-62. Lafeuillade A, Alessi MC, Poizot- I et al. Endothelial cell dysfunction in HIV infection. J Acquir Immune Defic Syndr 1992;5:127-31. 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. Atherosclerosis 2002;162:433-8. 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 Med 2002;34(1):55-63. Purnell JQ, Zambon A, Knopp RH et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000;14(1):51-7. Atazanavir demonstrates antiviral efficacy and a favorable lipid profile at 48 weeks. J Assoc Nurses AIDS Care 2002;13(2):86-7. Noor MA, RA, O'Mara E et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS 2004;18:2137-44. 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 Syndr 2003;32(1):18-29. Penzak SR, Chuck SK. Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. Scand J Infect Dis 2000;32:111-23. ez E, -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 Dis 2000;31:1266-73. Piketty C, Peytavin G, Trylezinski A et al. Low increase in serum lipids in patients receiving a combination of ritonavir, saquinavir and efavirenz. HIV Med 2002;3:287-9. ez 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. 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. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000;275:20251-4. Carpentier A, BW, Uffelman KD et al. Mechanism of highly active antiretroviral therapy-induced hyperlipidemia in HIV-infected individuals. Atherosclerosis 2005;178:165-72. Lucas GM, Chaisson RE, RD. Survival in an urban HIV-1 clinic in the era of highly active antiretroviral therapy: a 5-year cohort study. J Acquir Immune Defic Syndr 2003;33:321-8. 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. AIDS 2003;17:1993-5. Zimmet P. Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders. Am J Med 2005;118(suppl 2):3S-8S. Gerschenson M, Brinkman K. Mitochondrial dysfunction in AIDS and its treatment. Mitochondrion 2004;4:763-77. Fleischman A, sen 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 USA 2007 Abstract 43. 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 Chemother 2002;46:716-23. Lee H, Hanes J, KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 2003;42:14711-19. W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995;1:417-22. Lichtenstein KA. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr 2005;39:395-400. Carr A, Law M. An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score. J Acquir Immune Defic Syndr 2003;33:571-6. 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 Med 2003;18:1039-52. Hippisley- 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. BMJ 2007;335:136. Hanley AJ, Karter AJ, K et al. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation 2005; 112:3713-21. PW, Meigs JB, Sullivan L et al. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med 2007;167:1068-74. 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 Dis 2002;34:390-3. 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 Med 2005;142:611-19. Wierzbicki AS. Low HDL-cholesterol: Common and under-treated, but which drug to use? Int J Clin Pract 2006;60:1149-53. Brinkman K, ter Hofstede HJ, Burger DM et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998;12:1735-44. Saint-Marc T, Partisani M, Poizot- 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. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999;13:2493-505. ez E, Conget I, Lozano L et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999;13:805-10. 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 Dis 2002;185:1251-60. Sattler F. Body habitus changes related to lipodystrophy. Clin Infect Dis 2003;36(Suppl 2):S84-S90. LindstrF6m 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. Lancet 2006;368:1673-9. Hadigan C, Corcoran C, Basgoz N et al. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284:472-7. Blazes DL, Decker CF. Symptomatic hyperlactataemia precipitated by the addition of tetracycline to combination antiretroviral therapy. Lancet Infect Dis 2006;6:249-52. 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 Dis 2005;40:745-9. 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 Thai 2004;87:166-72. 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. Sheffield CA, Kane MP, Busch RS. Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection. Pharmacotherapy 2007;27:1449-55. 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;41:1195-211. Mallon PW, 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. AIDS 2006;20:1003-10. 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. Atherosclerosis 2004;172:273-9. Nystrom T, Bratt G, Sjoholm A. Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance. J Intern Med 2002;252:570-4. 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 Ther 2006;11:1081-9. Samson SL, Pownall HJ, 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 Trials 2006;27:518-30. 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 Metab 2006;91:2605-11. Benavides S, Nahata MC. Pharmacologic therapy for HIV-associated lipodystrophy. Ann Pharmacother 2004;38:448-57. 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 Metab 1993;77:956-62. Wanke C, Gerrior J, Kantaros J et al. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS 1999;13:2099-103. 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 Metab 2002;87:942. Falutz J, Allas S, Blot K et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med 2007;357:2359-70.

Sidebar: Key Messages

Metabolic complications of HIV include lipodystrophy cardiovascular disease and diabetes

HIV lipodystrophy is a clinical diagnosis

HIV lipodystrophy is best managed by preventive lifestyle modification

Pharmacological options for management of lipodystrophy start by switching highly active antiretroviral therapy regimes

Classical cardiovascular and diabetes therapies have roles in preventing complications of established HIV lipodystrophy

The most promising new therapy for lipodystrophy is a growth hormone releasing factor

Regards, VergelDirectorProgram for Wellness Restorationpowerusa dot orgGet fantasy football with free live scoring. Sign up for FanHouse Fantasy Football today.