Abstract
Although noted early in the HIV epidemic, metabolic abnormalities came to prominence when potent combination antiretroviral therapy was introduced. Complications associated with HIV infection and antiretroviral therapy include cardiovascular disease, lipid disorders, glucose metabolism disorders, adipose tissue disorders, bone metabolism disorders, and lactic acidosis. Metabolic complications have driven the discovery of new agents and classes of antiretrovirals, and have shaped guidelines for the management of HIV infection. However, significant uncertainty remains about pathogenesis and management. Substantial complexity exists in the treatment of these disorders, illustrated by the complex drugdrug interactions between lipid-lowering agents and antiretroviral regimens. Several important new developments include the association of a higher risk of cardiovascular events with the discontinuation of antiretroviral therapy or use of specific drugs like abacavir and didanosine. This article reviews the current understanding of metabolic abnormalities associated with HIV and its treatment.
Similar content being viewed by others
References and Recommended Reading
US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents: January 29, 2008. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed August 27, 2008.
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.
DA Wohl, McComsey G, Tebas P, et al.: Current concepts in the diagnosis and management of metabolic complications of HIV and its therapy. Clin Infect Dis 2006, 43:645–653.
Henry K, Melroe H, Huebusch J, et al.: Severe premature coronary artery disease with protease inhibitors [letter]. Lancet 1998, 351:1328.
Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group: Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003, 349:1993–2003.
Mary-Krause M, Cotte L, Simon A, et al.; and the Clinical Epidemiology Group from the French Hospital Database: Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003, 17:2479–2486.
Klein D, Hurley L, Queensbury C, Sidney S: Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr 2002, 30:471–477.
Bozzette SA, Ake CF, Tam HK, et al.: Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2008, 47:338–341.
D:A:D Study Group: Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008, 371:1417–1426.
Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al.: CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006, 355:2283–2296.
Grinspoon SK, Grunfeld C, Kotler DP, et al.: State of the Science Conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation 2008, 118:198–210.
Grinspoon S, Carr A: Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005, 352:48–62.
Sax PE, Kumar P: Tolerability and safety of HIV protease inhibitors in adults. J Acquir Immune Def Syndr 2004, 37:1111–1124.
van Leth F, Phanuphak P, Stroes E, et al.: Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med 2004, 1:e19.
Gallant JE, Staszewski S, Pozniak AL, et al.: Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004, 292:191–201.
Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults: 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, 285:2486–2497.
Drechsler H, Powderly WG: Switching effective antiretroviral therapy: a review. Clin Infect Dis 2002, 35:1219–1230.
Mobius U, Lubach-Ruitman M, Castro-Frenzel B, et al.: Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia. J Acquir Immune Defic Syndr 2005, 39:174–180.
Aberg JA, Zackin RA, Brobst SW, et al.: A prospective, multicenter, randomized trial comparing the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group Study 5087. AIDS Res Human Retroviruses 2005, 21:757–767.
Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al.: Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002, 16:569–577.
Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al.: Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS clinical trials group 5108 study. J Acquir Immune Defic Syndr 2005, 39:307–312.
Sekar VJ, Spinosa-Guzman S, Mariën K, et al.: Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin [abstract 54]. Presented at the 8th International Workshop on Clinical Pharmacology of HIV Therapy. Budapest, Hungary: April 16–18, 2007.
Kiser JJ, Gerber JG, Predhomme JA, et al.: Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 2008, 47:570–578.
Standards of medical care in diabetes. Diabetes Care 2005, 28(Suppl 1):S4–S36.
Brown TT, Li X, Cole SR, et al.: Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 2005, 19:1375–1383.
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.
Noor A, Flint OP, Mae JF, Parker RA: Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically. AIDS 2006, 20:1813–1821.
Kratz M, Purnell JQ, Breen PA, et al.: Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy. J Clin Endocrinol Metab 2008, 93:959–966.
Lichtenstein KA, Ward DJ, Morman AC, et al.: Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 2001, 15:1389–1398.
Hulgan T, Tebas P, Canter JA, et al.: Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis 2008, 197:858–866.
Dube MP, Parker RA, Tebas P, et al.: Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS 2005, 19:1807–1818.
van der Valk M, Gisolf EH, Reiss P, et al.: Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 2001, 15:847–855.
Haubrich RH, Riddler S, DiRienzo G, et al.: Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection [abstract 38]. Presented at the 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, CA; February 25–28, 2007.
Brinkman K, Smeitink JA, Romijn JA, et al.: Mitochondrial toxicity induced by nucleoside analogue reverse transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral therapy lipodystrophy. Lancet 1999, 354:1112–1115.
Lee H, Hanes J, Johnson KA: Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 2003, 42:14711–14719.
Carr A, Workman C, Smith DE, et al.: Abacavir substitution for thymidine nucleoside analogues in HIV-infected patients with lipoatrophy: a randomized controlled open-label multicenter 24 week study. JAMA 2002, 288:207–215.
McComsey GA, Ward DJ, Hessenthaler SM, et al.: Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virusinfected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clin Infect Dis 2004, 38:263–270.
Carr A, Workman C, Carey D, et al.: No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomized, double-blind, placebo-controlled trial. Lancet 2004, 363:429–438.
Sutinen J, Walker UA, Häkkinen AM, et al.: Uridine for the treatment of HAART-associated lipodystrophy: a randomized, double-blind, placebo-controlled trial. Antivir Ther 2007, 12:97–105.
Bacchetti P, Gripshover B, Grunfeld C, et al.: Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr 2005, 40:121–131.
Roubenoff R, Weiss L, McDermott A, et al.: A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution. AIDS 1999, 13:1373–1375.
Hadigan C, Corcoran C, Basgoz N, et al.: Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000, 284:472–477.
Falutz J, Allas S, Kotler D, et al.: A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS 2005, 19:1279–1287.
Cazanave C, Dupon M, Lavignolle-Aurillac V, et al.: Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS 2008, 22:395–402.
Prior J, Burdge D, Maan E, et al.: Fragility fractures and bone mineral density in HIV positive women: a case-control population-based study. Osteoporos Int 2007, 18:1345–1353.
Mondy K, Yarasheski K, Powderly WG, et al.: Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis 2003, 36:482–490.
McComsey GA, Kendall MA, Tebas P, et al.: Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007, 21:2473–2482.
Wohl DA, Pilcher CD, Evans S, et al.: Absence of sustained hyperlactatemia in HIV-infected patients with risk factors for mitochondrial toxicity. J Acquir Immune Defic Syndr 2004, 35:274–278.
Brinkman K, Smeitink JA, Romijn JA, et al.: Mitochondrial toxicity induced by nucleoside analogue reverse transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral therapy lipodystrophy. Lancet 1999, 354:1112–1115.
Wester C, Okezie OA, Thomas AM, et al.: Higher-thanexpected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial. J Acquir Immune Defic Syndr 2007, 46:318–22.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fichtenbaum, C.J. Metabolic abnormalities associated with HIV infection and antiretroviral therapy. Curr Infect Dis Rep 11, 84–92 (2009). https://doi.org/10.1007/s11908-009-0012-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11908-009-0012-8