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HIV and its relationship to insulin resistance and lipid abnormalities

Published:December 22, 2016DOI:https://doi.org/10.1016/j.trsl.2016.12.007
      Antiretroviral therapy has revolutionized the care of people with human immunodeficiency virus (HIV) by reducing morbidity and mortality from acquired immunodeficiency syndrome–related conditions. Despite longer life expectancy, however, HIV-infected individuals continue to have a higher risk of death compared with the general population. This has been attributed to the increasing incidence of noncommunicable diseases, in particular, atherosclerotic cardiovascular diseases. This is driven, in part, by the emergence of metabolic disorders, particularly dyslipidemia, insulin resistance, and lipodystrophy, in those on antiretroviral therapy. The pathogenesis of these metabolic derangements is complex and multifactorial, and could be a consequence of an interplay between traditional age-related risk factors, HIV infection, antiretroviral therapy effects, and the inflammatory state and immune activation in this population. Understanding the contributions of each of these factors could not just impact the current management of these individuals and help mitigate the risk for premature cardiovascular disease, but also shape the future direction of research in HIV.

      Abbreviations:

      ABCA1 (adenosine-triphosphate-binding cassette transporter A1), AIDS (acquired immunodeficiency syndrome), AMI (acute myocardial infarction), Apo-B (apolipoprotein B), cART (combined antiretroviral therapy), CRP (c-reactive protein), DM (diabetes mellitus), HDL-C (high-density lipoprotein-cholesterol), HIV (human immunodeficiency virus), HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A), HOMA-IR (homeostatic model assessment-IR), IL (interleukin), IR (insulin resistance), JNK (c-Jun N-terminal kinase), LDL-C (low-density lipoprotein-cholesterol), LRP1 (LDL receptor–related protein type 1), mtDNA (mitochondrial DNA), NNRTI (non-nucleoside reverse transcriptase inhibitors), NRTI (nucleoside reverse transcriptase inhibitors), PI (protease inhibitors), PPAR-γ (proliferator-activated receptors-gamma), SAT (subcutaneous adipose tissue), SREBP (sterol regulatory element–binding protein), TC (total cholesterol), TG (triglyceride), TNF-α (tumor necrosis factor-alpha), tNRTI (thymidine nucleoside reverse transcriptase inhibitors), VAT (visceral adipose tissue), VLDL (very low-density lipoprotein), Vpr (viral protein (of HIV))
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      References

        • Walensky R.P.
        • Paltiel A.D.
        • Losina E.
        • et al.
        The survival benefits of AIDS treatment in the United States.
        J Infect Dis. 2006; 194: 11-19
        • Lewden C.
        • Bouteloup V.
        • et al.
        • Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord
        All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration.
        Int J Epidemiol. 2012; 41: 433-445
        • Lohse N.
        • Hansen A.B.
        • Pedersen G.
        • et al.
        Survival of persons with and without HIV infection in Denmark, 1995-2005.
        Ann Intern Med. 2007; 146: 87-95
        • Sackoff J.E.
        • Hanna D.B.
        • Pfeiffer M.R.
        • Torian L.V.
        Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City.
        Ann Intern Med. 2006; 145: 397-406
        • Kim J.H.
        • Psevdos G.
        • Gonzalez E.
        • Singh S.
        • Kilayko M.C.
        • Sharp V.
        All-cause mortality in hospitalized HIV-infected patients at an acute tertiary care hospital with a comprehensive outpatient HIV care program in New York City in the era of highly active antiretroviral therapy (HAART).
        Infection. 2013; 41: 545-551
        • Cerrato E.
        • Calcagno A.
        • D'Ascenzo F.
        • et al.
        Cardiovascular disease in HIV patients: from bench to bedside and backwards.
        Open Heart. 2015; 2: e000174
        • Grunfeld C.
        • Pang M.
        • Doerrler W.
        • Shigenaga J.K.
        • Jensen P.
        • Feingold K.R.
        Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
        J Clin Endocrinol Metab. 1992; 74: 1045-1052
        • Anuurad E.
        • Semrad A.
        • Berglund L.
        Human immunodeficiency virus and highly active antiretroviral therapy-associated metabolic disorders and risk factors for cardiovascular disease.
        Metab Syndr Relat Disord. 2009; 7: 401-410
        • Lake J.E.
        • Currier J.S.
        Metabolic disease in HIV infection.
        Lancet Infect Dis. 2013; 13: 218-225
        • Grunfeld C.
        Dyslipidemia and its treatment in HIV infection.
        Top HIV Med. 2010; 18: 112-118
        • Tall A.R.
        • Yvan-Charvet L.
        Cholesterol, inflammation and innate immunity.
        Nat Rev Immunol. 2015; 15: 104-116
        • Samaras K.
        The burden of diabetes and hyperlipidemia in treated HIV infection and approaches for cardiometabolic care.
        Curr HIV/AIDS Rep. 2012; 9: 206-217
        • Constans J.
        • Pellegrin J.L.
        • Peuchant E.
        • et al.
        Plasma lipids in HIV-infected patients: a prospective study in 95 patients.
        Eur J Clin Invest. 1994; 24: 416-420
        • Rose H.
        • Woolley I.
        • Hoy J.
        • et al.
        HIV infection and high-density lipoprotein: the effect of the disease vs the effect of treatment.
        Metabolism. 2006; 55: 90-95
        • Zangerle R.
        • Sarcletti M.
        • Gallati H.
        • Reibnegger G.
        • Wachter H.
        • Fuchs D.
        Decreased plasma concentrations of HDL cholesterol in HIV-infected individuals are associated with immune activation.
        J Acquir Immune Defic Syndr. 1994; 7: 1149-1156
        • El-Sadr W.M.
        • Mullin C.M.
        • Carr A.
        • et al.
        Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort.
        HIV Med. 2005; 6: 114-121
        • Estrada V.
        • Martínez-Larrad M.T.
        • González-Sánchez J.L.
        • et al.
        Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy.
        Metabolism. 2006; 55: 940-945
        • Hadigan C.
        • Meigs J.B.
        • Corcoran C.
        • et al.
        Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.
        Clin Infect Dis. 2001; 32: 130-139
      1. WHO|Number of people (all ages) living with HIV. WHO. Published 2016. Available at: http://www.who.int/gho/hiv/epidemic_status/cases_all/en/. Accessed August 13, 2016.

      2. Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United States and dependent areas, 2014. HIV Surveill Report, 2014. 2015;26:1–123. Available at: http://www.cdc.gov/hiv/library/reports/surveillance/. Accessed July 5, 2016.

        • Friedman E.E.
        • Duffus W.A.
        Chronic health conditions in medicare beneficiaries 65 years and older with HIV infection.
        AIDS. 2016; 30: 2529-2536
        • Paisible A.L.
        • Chang C.C.
        • So-Armah K.A.
        • et al.
        HIV infection, cardiovascular disease risk factor profile, and risk for acute myocardial infarction.
        J Acquir Immune Defic Syndr. 2015; 68: 209-216
        • Womack J.A.
        • Chang C.C.
        • So-Armah K.A.
        • et al.
        HIV infection and cardiovascular disease in women.
        J Am Heart Assoc. 2014; 3: e001035
        • Currier J.S.
        • Taylor A.
        • Boyd F.
        • et al.
        Coronary heart disease in HIV-infected individuals.
        J Acquir Immune Defic Syndr. 2003; 33: 506-512
        • Shen Y.
        • Wang J.
        • Wang Z.
        • et al.
        Prevalence of dyslipidemia among antiretroviral-naive HIV-infected individuals in China.
        Medicine (Baltimore). 2015; 94: e2201
        • Armstrong C.
        • Liu E.
        • Okuma J.
        • et al.
        Dyslipidemia in an HIV-positive antiretroviral treatment-naive population in Dar es Salaam, Tanzania.
        J Acquir Immune Defic Syndr. 2011; 57: 141-145
        • Kuti M.A.
        • Adesina O.A.
        • Awolude O.A.
        • et al.
        Dyslipidemia in ART-naive HIV-infected persons in Nigeria–Implications for care.
        J Int Assoc Provid AIDS Care. 2015; 14: 355-359
        • Dave J.A.
        • Levitt N.S.
        • Ross I.L.
        • Lacerda M.
        • Maartens G.
        • Blom D.
        Anti-retroviral therapy increases the prevalence of dyslipidemia in South African HIV-infected patients.
        PLoS One. 2016; 11: e0151911
        • Ombeni W.
        • Kamuhabwa A.R.
        Lipid profile in HIV-infected patients using first-line antiretroviral drugs.
        J Int Assoc Provid AIDS Care. 2016; 15: 164-171
        • Nsagha D.S.
        • Weledji E.P.
        • Assob N.J.C.
        • et al.
        Highly active antiretroviral therapy and dyslipidemia in people living with HIV/AIDS in Fako Division, South West Region of Cameroon.
        BMC Cardiovasc Disord. 2015; 15: 95
        • Nduka C.
        • Sarki A.
        • Uthman O.
        • Stranges S.
        Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis.
        Int J Cardiol. 2015; 199: 307-318
        • Phillips A.N.
        • Carr A.
        • Neuhaus J.
        • et al.
        Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial.
        Antivir Ther. 2008; 13: 177-187
        • Jin C.
        • Ji S.
        • Xie T.
        • et al.
        Severe dyslipidemia and immune activation in HIV patients with dysglycemia.
        HIV Clin Trials. 2016; 17: 189-196
        • Walli R.
        • Herfort O.
        • Michl G.M.
        • 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
        • Hommes M.J.
        • Romijn J.A.
        • Endert E.
        • Eeftinck Schattenkerk J.K.
        • Sauerwein H.P.
        Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men.
        Metabolism. 1991; 40: 651-656
        • Nightingale S.L.
        From the Food and Drug Administration.
        JAMA. 1997; 278: 379
        • Aguilar M.
        • Bhuket T.
        • Torres S.
        • Liu B.
        • Wong R.J.
        Prevalence of the metabolic syndrome in the United States, 2003-2012.
        JAMA. 2015; 313: 1973-1974
        • Gazzaruso C.
        • Sacchi P.
        • Garzaniti A.
        • Fratino P.
        • Bruno R.
        • Filice G.
        Prevalence of metabolic syndrome among HIV patients.
        Diabetes Care. 2002; 25: 1253-1254
        • Bonfanti P.
        • Ricci E.
        • de Socio G.
        • et al.
        Metabolic syndrome: a real threat for HIV-positive patients?: Results from the SIMONE study.
        J Acquir Immune Defic Syndr. 2006; 42: 128-131
        • Mondy K.
        • Overton E.T.
        • Grubb J.
        • et al.
        Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population.
        Clin Infect Dis. 2007; 44: 726-734
        • Palacios R.
        • Santos J.
        • González M.
        • Ruiz J.
        • Márquez M.
        Incidence and prevalence of the metabolic syndrome in a cohort of naive HIV-infected patients: prospective analysis at 48 weeks of highly active antiretroviral therapy.
        Int J STD AIDS. 2007; 18: 184-187
        • Wand H.
        • Calmy A.
        • Carey D.L.
        • et al.
        Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection.
        AIDS. 2007; 21: 2445-2453
        • Amorosa V.
        • Synnestvedt M.
        • Gross R.
        • et al.
        A tale of 2 epidemics: the intersection between obesity and HIV infection in Philadelphia.
        J Acquir Immune Defic Syndr. 2005; 39: 557-561
        • Ogden C.L.
        • Carroll M.D.
        • Lawman H.G.
        • et al.
        Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014.
        JAMA. 2016; 315: 2292-2299
        • NCD Risk Factor Collaboration (NCD-RisC)
        Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.
        Lancet. 2016; 387: 1513-1530
        • Feeney E.R.
        • Mallon P.W.
        HIV and HAART-associated dyslipidemia.
        Open Cardiovasc Med J. 2011; 5: 49-63
        • Riddler S.A.
        Impact of HIV infection and HAART on serum lipids in men.
        JAMA. 2003; 289: 2978
        • Khera A.V.
        • Cuchel M.
        • de la Llera-Moya M.
        • et al.
        Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
        N Engl J Med. 2011; 364: 127-135
        • Fitzgerald M.L.
        • Mujawar Z.
        • Tamehiro N.
        ABC transporters, atherosclerosis and inflammation.
        Atherosclerosis. 2010; 211: 361-370
        • Mujawar Z.
        • Rose H.
        • Morrow M.P.
        • et al.
        Human immunodeficiency virus impairs reverse cholesterol transport from macrophages.
        PLoS Biol. 2006; 4: 1970-1983
        • Maisa A.
        • Hearps A.C.
        • Angelovich T.A.
        • et al.
        Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration.
        AIDS. 2015; 29: 1445-1457
        • Cui H.L.
        • Ditiatkovski M.
        • Kesani R.
        • et al.
        HIV protein Nef causes dyslipidemia and formation of foam cells in mouse models of atherosclerosis.
        FASEB J. 2014; 28: 2828-2839
        • Lo J.
        • Rosenberg E.S.
        • Fitzgerald M.L.
        • et al.
        High-density lipoprotein-mediated cholesterol efflux capacity is improved by treatment with antiretroviral therapy in acute human immunodeficiency virus infection.
        Open Forum Infect Dis. 2014; 1: ofu108
        • El Khoury P.
        • Ghislain M.
        • Villard E.F.
        • et al.
        Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART.
        J Lipid Res. 2015; 56: 692-702
        • Low H.
        • Cheng L.
        • Di Yacovo M.S.
        • et al.
        Lipid metabolism in patients infected with Nef-deficient HIV-1 strain.
        Atherosclerosis. 2016; 244: 22-28
        • Shrivastav S.
        • Kino T.
        • Cunningham T.
        • et al.
        Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy.
        Mol Endocrinol. 2008; 22: 234-247
        • Gavrilova O.
        • Haluzik M.
        • Matsusue K.
        • et al.
        Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass.
        J Biol Chem. 2003; 278: 34268-34276
        • Rasheed S.
        • Yan J.S.
        • Lau A.
        • Chan A.S.
        HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study.
        PLoS One. 2008; 3: e3003
        • Khovidhunkit W.
        • Kim M.S.
        • Memon R.A.
        • et al.
        Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.
        J Lipid Res. 2004; 45: 1169-1196
        • Shinohara E.
        • Yamashita S.
        • Kihara S.
        • et al.
        Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C.
        Hepatology. 1997; 25: 1502-1506
        • Haugaard S.B.
        • Andersen O.
        • Pedersen S.B.
        • et al.
        Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy.
        Metabolism. 2006; 55: 175-182
        • Hellerstein M.K.
        • Grunfeld C.
        • Wu K.
        • et al.
        Increased de novo hepatic lipogenesis in human immunodeficiency virus infection.
        J Clin Endocrinol Metab. 1993; 76: 559-565
        • McGillicuddy F.C.
        • de la Llera Moya M.
        • Hinkle C.C.
        • et al.
        Inflammation impairs reverse cholesterol transport in vivo.
        Circulation. 2009; 119: 1135-1145
        • Akerele O.A.
        • Cheema S.K.
        Fatty acyl composition of lysophosphatidylcholine is important in atherosclerosis.
        Med Hypotheses. 2015; 85: 754-760
        • Stewart C.R.
        • Stuart L.M.
        • Wilkinson K.
        • et al.
        CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.
        Nat Immunol. 2010; 11: 155-161
        • Sheedy F.J.
        • Grebe A.
        • Rayner K.J.
        • et al.
        CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
        Nat Immunol. 2013; 14: 812-820
        • Zidar D.A.
        • Juchnowski S.
        • Ferrari B.
        • et al.
        Oxidized LDL levels are increased in HIV infection and may drive monocyte activation.
        J Acquir Immune Defic Syndr. 2015; 69: 154-160
        • Romeo G.R.
        • Lee J.
        • Shoelson S.E.
        Metabolic syndrome, insulin resistance, and roles of inflammation–mechanisms and therapeutic targets.
        Arterioscler Thromb Vasc Biol. 2012; 32: 1771-1776
        • Lopes H.F.
        • Corrêa-Giannella M.L.
        • Consolim-Colombo F.M.
        • Egan B.M.
        Visceral adiposity syndrome.
        Diabetol Metab Syndr. 2016; 8: 40
        • Shulman G.I.
        Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease.
        N Engl J Med. 2014; 371: 2237-2238
        • Emery S.
        • Neuhaus J.A.
        • et al.
        • Strategies for Management of Antiretroviral Therapy (SMART) Study Group
        Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study.
        J Infect Dis. 2008; 197: 1133-1144
        • Baker J.V.
        • Neuhaus J.
        • Duprez D.
        • et al.
        Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy.
        AIDS. 2011; 25: 2133-2142
        • Lederman M.M.
        • Funderburg N.T.
        • Sekaly R.P.
        • Klatt N.R.
        • Hunt P.W.
        Residual immune dysregulation syndrome in treated HIV infection.
        Adv Immunol. 2013; 119: 51-83
        • Funderburg N.T.
        Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients.
        Curr Opin HIV AIDS. 2014; 9: 80-86
        • Angelovich T.A.
        • Hearps A.C.
        • Maisa A.
        • et al.
        Viremic and virologically suppressed HIV infection increases age-related changes to monocyte activation equivalent to 12 and 4 Years of aging, respectively.
        J Acquir Immune Defic Syndr. 2015; 69: 11-17
        • Munger A.M.
        • Chow D.C.
        • Playford M.P.
        • et al.
        Characterization of lipid composition and high-density lipoprotein function in HIV-infected individuals on stable antiretroviral regimens.
        AIDS Res Hum Retroviruses. 2015; 31: 221-228
        • van Wijk J.P.
        • Cabezas M.C.
        Hypertriglyceridemia, metabolic syndrome, and cardiovascular disease in HIV-infected patients: effects of antiretroviral therapy and adipose tissue distribution.
        Int J Vasc Med. 2012; 2012: 201027
        • Zilberman-Schapira G.
        • Zmora N.
        • Itav S.
        • Bashiardes S.
        • Elinav H.
        • Elinav E.
        The gut microbiome in human immunodeficiency virus infection.
        BMC Med. 2016; 14: 83
        • Pandiyan P.
        • Younes S.A.
        • Ribeiro S.P.
        • et al.
        Mucosal regulatory T Cells and T Helper 17 cells in HIV-associated immune activation.
        Front Immunol. 2016; 7: 228
        • Marchetti G.
        • Bellistrì G.M.
        • Borghi E.
        • et al.
        Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy.
        AIDS. 2008; 22: 2035-2038
        • Tincati C.
        • Douek D.C.
        • Marchetti G.
        Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection.
        AIDS Res Ther. 2016; 13: 19
        • Trøseid M.
        • Manner I.W.
        • Pedersen K.K.
        • Haissman J.M.
        • Kvale D.
        • Nielsen S.D.
        Microbial translocation and cardiometabolic risk factors in HIV infection.
        AIDS Res Hum Retroviruses. 2014; 30: 514-522
        • Srinivasa S.
        • Fitch K.V.
        • Lo J.
        • et al.
        Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine.
        AIDS. 2015; 29: 443-452
        • Koeth R.A.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
        Nat Med. 2013; 19: 576-585
        • Vujkovic-Cvijin I.
        • Dunham R.M.
        • Iwai S.
        • et al.
        Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism.
        Sci Transl Med. 2013; 5: 193ra91
        • Grinspoon S.
        • Carr A.
        Cardiovascular risk and body fat abnormalities in HIV-infected adults.
        N Engl J Med. 2005; 352: 48-62
        • Carr A.
        • Samaras K.
        • Thorisdottir A.
        • Kaufmann G.R.
        • Chisholm D.J.
        • Cooper D.A.
        Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.
        Lancet. 1999; 353: 2093-2099
        • Riddler S.A.
        • Li X.
        • Chu H.
        • et al.
        Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy.
        HIV Med. 2007; 8: 280-287
        • Currier J.
        • Scherzer R.
        • Bacchetti P.
        • et al.
        Regional adipose tissue and lipid and lipoprotein levels in HIV-infected women.
        J Acquir Immune Defic Syndr. 2008; 48: 35-43
        • Friis-Møller N.
        • Weber R.
        • Reiss P.
        • et al.
        Cardiovascular disease risk factors in HIV patients–association with antiretroviral therapy. Results from the DAD study.
        AIDS. 2003; 17: 1179-1193
        • Glass T.R.
        • Ungsedhapand C.
        • Wolbers M.
        • et al.
        Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort Study.
        HIV Med. 2006; 7: 404-410
        • Gervasoni C.
        • Ridolfo A.L.
        • Trifirò G.
        • et al.
        Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy.
        AIDS. 1999; 13: 465-471
        • Mulligan K.
        • Grunfeld C.
        • Tai V.W.
        • 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
        • Penzak S.R.
        • Chuck S.K.
        Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment.
        Scand J Infect Dis. 2000; 32: 111-123
        • Hiransuthikul N.
        • Hiransuthikul P.
        • Kanasook Y.
        Lipid profiles of Thai adult HIV-infected patients receiving protease inhibitors.
        Southeast Asian J Trop Med Public Health. 2007; 38: 69-77
        • D'Ascenzo F.
        • Cerrato E.
        • Biondi-Zoccai G.
        • et al.
        Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy.
        Eur Heart J. 2012; 33: 875-880
        • Coplan P.M.
        • Nikas A.
        • Japour A.
        • et al.
        Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors.
        AIDS Res Hum Retroviruses. 2003; 19: 449-455
        • Holmberg S.D.
        • Moorman A.C.
        • Williamson J.M.
        • et al.
        Protease inhibitors and cardiovascular outcomes in patients with HIV-1.
        Lancet. 2002; 360: 1747-1748
        • Calza L.
        • Colangeli V.
        • Manfredi R.
        • Bon I.
        • Re M.C.
        • Viale P.
        Clinical management of dyslipidaemia associated with combination antiretroviral therapy in HIV-infected patients.
        J Antimicrob Chemother. 2016; 71: 1451-1465
        • Young J.
        • Weber R.
        • Rickenbach M.
        • et al.
        Lipid profiles for antiretroviral-naive patients starting PI- and NNRTI-based therapy in the Swiss HIV cohort study.
        Antivir Ther. 2005; 10: 585-591
        • Randell P.A.
        • Jackson A.G.
        • Boffito M.
        • et al.
        Effect of boosted fosamprenavir or lopinavir-based combinations on whole-body insulin sensitivity and lipids in treatment-naive HIV-type-1-positive men.
        Antivir Ther. 2010; 15: 1125-1132
        • Overton E.T.
        • Arathoon E.
        • Baraldi E.
        • Tomaka F.
        Effect of darunavir on lipid profile in HIV-infected patients.
        HIV Clin Trials. 2012; 13: 256-270
        • Vrouenraets S.M.
        • Wit F.W.
        • Fernandez Garcia E.
        • et al.
        Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients.
        HIV Med. 2011; 12: 620-631
        • Kamara D.A.
        • Smith C.
        • Ryom L.
        • et al.
        Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study.
        Antivir Ther. 2016; 21: 495-506
        • Miserez A.R.
        • Muller P.Y.
        • Spaniol V.
        Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations.
        AIDS. 2002; 16: 1587-1594
        • Liang J.S.
        • Distler O.
        • Cooper D.A.
        • 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
        • Petit J.M.
        • Duong M.
        • Duvillard L.
        • et al.
        LDL-receptors expression in HIV-infected patients: relations to antiretroviral therapy, hormonal status, and presence of lipodystrophy.
        Eur J Clin Invest. 2002; 32: 354-359
        • Carr A.
        • Samaras K.
        • Chisholm D.J.
        • Cooper D.A.
        Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.
        Lancet. 1998; 351: 1881-1883
        • Zha B.S.
        • Wan X.
        • Zhang X.
        • et al.
        HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.
        PLoS One. 2013; 8: e59514
        • Gibellini L.
        • De Biasi S.
        • Pinti M.
        • et al.
        The protease inhibitor atazanavir triggers autophagy and mitophagy in human preadipocytes.
        AIDS. 2012; 26: 2017-2026
        • Murata H.
        • Hruz P.W.
        • Mueckler M.
        The mechanism of insulin resistance caused by HIV protease inhibitor therapy.
        J Biol Chem. 2000; 275: 20251-20254
        • Murata H.
        • Hruz P.W.
        • Mueckler M.
        Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations.
        AIDS. 2002; 16: 859-863
        • Hruz P.W.
        Molecular mechanisms for altered glucose homeostasis in HIV infection.
        Am J Infect Dis. 2006; 2: 187-192
        • 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
        • Noor M.A.
        • Flint O.P.
        • Maa J.F.
        • Parker R.A.
        Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically.
        AIDS. 2006; 20: 1813-1821
        • Yan Q.
        • Hruz P.W.
        Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal.
        J Acquir Immune Defic Syndr. 2005; 40: 398-403
        • Aberg J.A.
        • Tebas P.
        • Overton E.T.
        • et al.
        Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks.
        AIDS Res Hum Retroviruses. 2012; 28: 1184-1195
        • Overton E.T.
        • Tebas P.
        • Coate B.
        • et al.
        Effects of once-daily darunavir/ritonavir versus atazanavir/ritonavir on insulin sensitivity in HIV-infected persons over 48 weeks: results of an exploratory substudy of METABOLIK, a phase 4, randomized trial.
        HIV Clin Trials. 2016; 17: 72-77
        • Gallant J.E.
        • DeJesus E.
        • Arribas J.R.
        • et al.
        Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.
        N Engl J Med. 2006; 354: 251-260
        • Gallant J.E.
        Efficacy and Safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive Patients: A 3-year randomized trial.
        JAMA. 2004; 292: 191
        • Post F.A.
        • Tebas P.
        • Clarke A.
        • et al.
        Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected adults with renal impairment.
        J Acquir Immune Defic Syndr. 2017; 74: 180-184
        • Bacchetti P.
        • Gripshover B.
        • Grunfeld C.
        • et al.
        Fat distribution in men with HIV infection.
        J Acquir Immune Defic Syndr. 2005; 40: 121-131
        • Grunfeld C.
        • Saag M.
        • Cofrancesco J.
        • et al.
        Regional adipose tissue measured by MRI over 5 years in HIV-infected and control participants indicates persistence of HIV-associated lipoatrophy.
        AIDS. 2010; 24: 1717-1726
        • Grunfeld C.
        • Rimland D.
        • Gibert C.L.
        • et al.
        Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study.
        J Acquir Immune Defic Syndr. 2007; 46: 283-290
        • Lake J.E.
        • Wohl D.
        • Scherzer R.
        • et al.
        Regional fat deposition and cardiovascular risk in HIV infection: the FRAM study.
        AIDS Care. 2011; 23: 929-938
        • Tebas P.
        • Sension M.
        • Arribas J.
        • et al.
        Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials.
        Clin Infect Dis. 2014; 59: 425-434
        • Jemsek J.G.
        • Arathoon E.
        • Arlotti M.
        • et al.
        Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients.
        Clin Infect Dis. 2006; 42: 273-280
        • Gupta S.K.
        • Slaven J.E.
        • Kamendulis L.M.
        • Liu Z.
        A randomized, controlled trial of the effect of rilpivirine versus efavirenz on cardiovascular risk in healthy volunteers.
        J Antimicrob Chemother. 2015; 70: 2889-2893
        • Martínez E.
        • Conget I.
        • Lozano L.
        • Casamitjana R.
        • Gatell J.M.
        Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine.
        AIDS. 1999; 13: 805-810
        • De Wit S.
        • Sabin C.A.
        • Weber R.
        • et al.
        Incidence and risk factors for new-onset diabetes in HIV-infected patients: the data collection on adverse events of anti-HIV drugs (D: A:D) study.
        Diabetes Care. 2008; 31: 1224-1229
        • Quercia R.
        • Roberts J.
        • Martin-Carpenter L.
        • Zala C.
        Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks.
        Clin Drug Investig. 2015; 35: 211-219
        • Young L.
        • Wohl D.A.
        • Hyslop W.B.
        • Lee Y.Z.
        • Napravnik S.
        • Wilkin A.
        Effects of raltegravir combined with tenofovir/emtricitabine on body shape, bone density, and lipids in African-Americans initiating HIV therapy.
        HIV Clin Trials. 2015; 16: 163-169
        • Spinner C.D.
        • Kern K.E.
        • Zink A.
        • et al.
        Neither boosted elvitegravir nor darunavir with emtricitabine/tenofovir disoproxil fumarate increase insulin resistance in healthy volunteers: results from the STRIBILD-IR study.
        Antivir Ther. 2016; 21: 627-631
        • Bonjoch A.
        • Pou C.
        • Pérez-Álvarez N.
        • et al.
        Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial.
        J Antimicrob Chemother. 2013; 68: 1382-1387
        • Araujo S.
        • Banon S.
        • Machuca I.
        • Moreno A.
        • Perez-Elias M.J.
        • Casado J.L.
        Prevalence of insulin resistance and risk of diabetes mellitus in HIV-infected patients receiving current antiretroviral drugs.
        Eur J Endocrinol. 2014; 171: 545-554
        • Capeau J.
        • Bouteloup V.
        • Katlama C.
        • et al.
        Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment.
        AIDS. 2012; 26: 303-314
        • Brown T.T.
        • Cole S.R.
        • Li X.
        • et al.
        Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study.
        Arch Intern Med. 2005; 165: 1179-1184
        • Tien P.C.
        • Schneider M.F.
        • Cole S.R.
        • et al.
        Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study.
        AIDS. 2007; 21: 1739-1745
        • Tripathi A.
        • Liese A.D.
        • Jerrell J.M.
        • et al.
        Incidence of diabetes mellitus in a population-based cohort of HIV-infected and non-HIV-infected persons: the impact of clinical and therapeutic factors over time.
        Diabet Med. 2014; 31: 1185-1193
        • Butt A.A.
        • McGinnis K.
        • Rodriguez-Barradas M.C.
        • et al.
        HIV infection and the risk of diabetes mellitus.
        AIDS. 2009; 23: 1227-1234
        • Rasmussen L.D.
        • Mathiesen E.R.
        • Kronborg G.
        • Pedersen C.
        • Gerstoft J.
        • Obel N.
        Risk of diabetes mellitus in persons with and without HIV: a Danish nationwide population-based cohort study.
        PLoS One. 2012; 7: e44575
        • Galli L.
        • Salpietro S.
        • Pellicciotta G.
        • et al.
        Risk of type 2 diabetes among HIV-infected and healthy subjects in Italy.
        Eur J Epidemiol. 2012; 27: 657-665
        • Polsky S.
        • Floris-Moore M.
        • Schoenbaum E.E.
        • Klein R.S.
        • Arnsten J.H.
        • Howard A.A.
        Incident hyperglycaemia among older adults with or at-risk for HIV infection.
        Antivir Ther. 2011; 16: 181-188
        • Goulet J.L.
        • Fultz S.L.
        • Rimland D.
        • et al.
        Aging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity?.
        Clin Infect Dis. 2007; 45: 1593-1601
        • Justman J.E.
        • 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
        • Ledergerber B.
        • Furrer H.
        • Rickenbach M.
        • et al.
        Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV cohort study.
        Clin Infect Dis. 2007; 45: 111-119
        • Jain M.
        • Aragaki C.
        • Fischbach L.
        • et al.
        Hepatitis C is associated with type 2 diabetes mellitus in HIV-infected persons without traditional risk factors.
        HIV Med. 2007; 8: 491-497
        • Mehta S.H.
        • Moore R.D.
        • Thomas D.L.
        • Chaisson R.E.
        • Sulkowski M.S.
        The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons.
        J Acquir Immune Defic Syndr. 2003; 33: 577-584
        • Lo Y.C.
        • Chen M.Y.
        • Sheng W.H.
        • et al.
        Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study.
        HIV Med. 2009; 10: 302-309
        • Lang S.
        • Mary-Krause M.
        • Simon A.
        • et al.
        HIV replication and immune status are independent predictors of the risk of myocardial infarction in HIV-infected individuals.
        Clin Infect Dis. 2012; 55: 600-607
        • Silverberg M.J.
        • Leyden W.A.
        • Xu L.
        • et al.
        Immunodeficiency and risk of myocardial infarction among HIV-positive individuals with access to care.
        J Acquir Immune Defic Syndr. 2014; 65: 160-166
        • D'Ascenzo F.
        • Cerrato E.
        • Appleton D.
        • et al.
        Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.
        Thromb Res. 2014; 134: 558-564
        • Stone N.J.
        • Bilek S.
        • Rosenbaum S.
        Recent National cholesterol Education program adult treatment panel III update: adjustments and options.
        Am J Cardiol. 2005; 96: 53E-59E
        • Law M.G.
        • Friis-Møller N.
        • El-Sadr W.M.
        • et al.
        The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study.
        HIV Med. 2006; 7: 218-230
        • Monroe A.K.
        • Haberlen S.A.
        • Post W.S.
        • et al.
        Cardiovascular disease risk scores' relationship to subclinical cardiovascular disease among HIV-infected and HIV-uninfected men.
        AIDS. 2016; 30: 2075-2084
        • Herrera S.
        • Guelar A.
        • Sorlì L.
        • et al.
        The Framingham function overestimates the risk of ischemic heart disease in HIV-infected patients from Barcelona.
        HIV Clin Trials. 2016; 17: 131-139
        • Pirš M.
        • Jug B.
        • Eržen B.
        • et al.
        Cardiovascular risk assessment in HIV-infected male patients: a comparison of Framingham, SCORE, PROCAM and DAD risk equations.
        Acta Dermatovenerol Alp Pannonica Adriat. 2014; 23: 43-47
        • Markowicz S.
        • Delforge M.
        • Necsoi C.
        • De Wit S.
        Cardiovascular risk evaluation of HIV-positive patients in a case-control study: comparison of the D:A:D and Framingham equations.
        J Int AIDS Soc. 2014; 17: 19515
        • Salinas J.L.
        • Rentsch C.
        • Marconi V.C.
        • et al.
        Baseline, time-updated, and cumulative HIV care metrics for predicting acute myocardial infarction and all-cause mortality.
        Clin Infect Dis. 2016; 63: 1423-1430
        • Thompson-Paul A.M.
        • Lichtenstein K.A.
        • Armon C.
        • et al.
        Cardiovascular disease risk prediction in the HIV Outpatient Study.
        Clin Infect Dis. 2016; 63: 1508-1516
        • Raggi P.
        • De Francesco D.
        • Manicardi M.
        • et al.
        Prediction of hard cardiovascular events in HIV patients.
        J Antimicrob Chemother. 2016; 71: 3515-3518
        • Lloyd-Jones D.M.
        • Huffman M.D.
        • Karmali K.N.
        • et al.
        Estimating longitudinal risks and benefits from cardiovascular preventive therapies among medicare patients: The Million Hearts longitudinal ASCVD risk assessment tool.
        Circulation. 2016; ([Epub ahead of print])
        • Klein D.B.
        • Leyden W.A.
        • Xu L.
        • et al.
        Declining relative risk for myocardial infarction among HIV-positive compared with HIV-negative individuals with access to care.
        Clin Infect Dis. 2015; 60: 1278-1280
        • Clement M.E.
        • Park L.P.
        • Navar A.M.
        • et al.
        Statin utilization and recommendations among HIV- and HCV-infected veterans: a cohort study.
        Clin Infect Dis. 2016; 63: 407-413
        • Elsamadisi P.
        • Cha A.
        • Kim E.
        • Latif S.
        Statin use with the ATP III guidelines compared to the 2013 ACC/AHA guidelines in HIV primary care patients.
        J Pharm Pract. 2015; ([Epub ahead of print])https://doi.org/10.1177/0897190015611774
        • Hanson R.L.
        • Imperatore G.
        • Bennett P.H.
        • Knowler W.C.
        Components of the “metabolic syndrome” and incidence of type 2 diabetes.
        Diabetes. 2002; 51: 3120-3127
        • Gami A.S.
        • Witt B.J.
        • Howard D.E.
        • et al.
        Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies.
        J Am Coll Cardiol. 2007; 49: 403-414
        • McLaughlin T.
        • Abbasi F.
        • Lamendola C.
        • Reaven G.
        Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals: effect of differences in insulin sensitivity.
        Arch Intern Med. 2007; 167: 642-648
        • Hamaguchi M.
        • Kojima T.
        • Takeda N.
        • et al.
        The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.
        Ann Intern Med. 2005; 143: 722-728
        • Ip M.S.
        • Lam B.
        • Ng M.M.
        • Lam W.K.
        • Tsang K.W.
        • Lam K.S.
        Obstructive sleep apnea is independently associated with insulin resistance.
        Am J Respir Crit Care Med. 2002; 165: 670-676
        • Chen Q.
        • Zhang Y.
        • Ding D.
        • et al.
        Metabolic syndrome and its individual components with mortality among patients with coronary heart disease.
        Int J Cardiol. 2016; 224: 8-14
        • Wang J.
        • Ruotsalainen S.
        • Moilanen L.
        • Lepistö P.
        • Laakso M.
        • Kuusisto J.
        The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns.
        Eur Heart J. 2007; 28: 857-864
        • Meininger G.
        • Hadigan C.
        • Laposata M.
        • et al.
        Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution.
        Metabolism. 2002; 51: 260-266
        • Price J.
        • Hoy J.
        • Ridley E.
        • Nyulasi I.
        • Paul E.
        • Woolley I.
        Changes in the prevalence of lipodystrophy, metabolic syndrome and cardiovascular disease risk in HIV-infected men.
        Sex Health. 2015; 12: 240-248