Purpose of Review
This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART).
IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naïve individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor.
The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted.
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Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999;354(9184):1112–5.
Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990;322(16):1098–105.
Finkle HI. Hepatic mitochondrial toxicity from nucleoside analog therapy. Arch Pathol Lab Med. 1999;123(3):189.
Le Bras P, D'Oiron R, Quertainmont Y, Halfon P, Caquet R. Metabolic, hepatic and muscular changes during zidovudine therapy: a drug-induced mitochondrial disease? AIDS. 1994;8(5):716–7.
Nolan D. Metabolic complications associated with HIV protease inhibitor therapy. Drugs. 2003;63(23):2555–74.
Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351(9119):1881–3. https://doi.org/10.1016/s0140-6736(98)03391-1.
Gan SK, Samaras K, Carr A, Chisholm D. Anti-retroviral therapy, insulin resistance and lipodystrophy. Diabetes Obes Metab. 2001;3(2):67–71.
Nolan D, Mallal S. Getting to the HAART of insulin resistance. AIDS. 2001;15(15):2037–41.
Lake JE, Currier JS. Metabolic disease in HIV infection. Lancet Infect Dis. 2013;13(11):964–75. https://doi.org/10.1016/s1473-3099(13)70271-8.
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Meigs JB, et al. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck study. Diabetes Care. 2007;30(2):318–24. https://doi.org/10.2337/dc06-0919.
•• Brener MI, Post WS, Haberlen SA, Zhang L, Palella FJ Jr, Jacobson LP, et al. Comparison of insulin resistance to coronary atherosclerosis in human immunodeficiency virus infected and uninfected men (from the multicenter AIDS cohort study). Am J Cardiol. 2016;117(6):993–1000. https://doi.org/10.1016/j.amjcard.2015.12.037. Important analysis of IR in MACS affirms higher HOMA-IR in men with HIV than those without, and associations between HOMA-IR and coronary stenosis.
Valcour V, Rubin LH, Tien P, Anastos K, Young M, Mack W, et al. Human immunodeficiency virus (HIV) modulates the associations between insulin resistance and cognition in the current combination antiretroviral therapy (cART) era: a study of the Women’s Interagency HIV Study (WIHS). J Neuro-Oncol. 2015;21(4):415–21. https://doi.org/10.1007/s13365-015-0330-6.
• Non LR, Escota GV, Powderly WG. HIV and its relationship to insulin resistance and lipid abnormalities. Transl Res. 2017;183:41–56. https://doi.org/10.1016/j.trsl.2016.12.007. Thorough current review covering epidemiology, pathogenesis, and evidence for direct HIV effects on IR; an extensive bibliography.
• Willig AL, Overton ET. Metabolic Complications and Glucose metabolism in HIV infection: a review of the evidence. Curr HIV/AIDS Rep. 2016;13(5):289–96. https://doi.org/10.1007/s11904-016-0330-z. Another current review; succinct, accessible, and clinically relevant.
Soumaya K. Molecular mechanisms of insulin resistance in diabetes. Adv Exp Med Biol. 2012;771:240–51.
Yazici D, Sezer H. Insulin resistance, obesity and lipotoxicity. Adv Exp Med Biol. 2017;960:277–304. https://doi.org/10.1007/978-3-319-48382-5_12.
Feeney ER, Mallon PW. Insulin resistance in treated HIV infection. Best Pract Res Clin Endocrinol Metab. 2011;25(3):443–58. https://doi.org/10.1016/j.beem.2010.11.002.
Blazquez D, Ramos-Amador JT, Sainz T, Mellado MJ, Garcia-Ascaso M, De Jose MI, et al. Lipid and glucose alterations in perinatally-acquired HIV-infected adolescents and young adults. BMC Infect Dis. 2015;15:119. https://doi.org/10.1186/s12879-015-0853-8.
Dejkhamron P, Unachak K, Aurpibul L, Sirisanthana V. Insulin resistance and lipid profiles in HIV-infected Thai children receiving lopinavir/ritonavir-based highly active antiretroviral therapy. J Pediatr Endocrinol Metab. 2014;27(5–6):403–12. https://doi.org/10.1515/jpem-2013-0253.
Hazra R, Hance LF, Monteiro JP, Ruz NP, Machado DM, Saavedra M, et al. Insulin resistance and glucose and lipid concentrations in a cohort of perinatally HIV-infected Latin American children. Pediatr Infect Dis J. 2013;32(7):757–9. https://doi.org/10.1097/INF.0b013e318286c774.
Innes S, Abdullah KL, Haubrich R, Cotton MF, Browne SH. High prevalence of dyslipidemia and insulin resistance in HIV-infected prepubertal African children on antiretroviral therapy. Pediatr Infect Dis J. 2016;35(1):e1–7. https://doi.org/10.1097/inf.0000000000000927.
Sharma TS, Jacobson DL, Anderson L, Gerschenson M, Van Dyke RB, McFarland EJ, et al. Short communication: the relationship between mitochondrial dysfunction and insulin resistance in HIV-infected children receiving antiretroviral therapy. AIDS Res Hum Retrovir. 2013;29(9):1211–7. https://doi.org/10.1089/aid.2012.0354.
Takemoto JK, Miller TL, Wang J, Jacobson DL, Geffner ME, Van Dyke RB, et al. Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration. AIDS. 2017;31(1):15–23. https://doi.org/10.1097/qad.0000000000001299.
Hostalek U, Gwilt M, Hildemann S. Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs. 2015;75(10):1071–94. https://doi.org/10.1007/s40265-015-0416-8.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Phys. 1979;237(3):E214–23. https://doi.org/10.1152/ajpendo.1979.237.3.E214.
Otten J, Ahren B, Olsson T. Surrogate measures of insulin sensitivity vs the hyperinsulinaemic-euglycaemic clamp: a meta-analysis. Diabetologia. 2014;57(9):1781–8. https://doi.org/10.1007/s00125-014-3285-x.
Hommes MJ, Romijn JA, Endert E, Eeftinck Schattenkerk JK, Sauerwein HP. Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism. 1991;40(6):651–6.
Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr. 2000;25(4):312–21.
Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001;15(7):F11–8.
van der Valk M, Bisschop PH, Romijn JA, Ackermans MT, Lange JM, Endert E, et al. Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS. 2001;15(16):2093–100.
Gelato MC, Mynarcik DC, Quick JL, Steigbigel RT, Fuhrer J, Brathwaite CE, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr. 2002;31(2):163–70.
Lo JC, Mulligan K, Noor MA, Schwarz JM, Halvorsen RA, Grunfeld C, et al. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab. 2001;86(8):3480–7. https://doi.org/10.1210/jcem.86.8.7785.
Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002;16(5):F1–8.
Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23(1):57–63.
Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402–10. https://doi.org/10.1210/jcem.85.7.6661.
Randell PA, Jackson AG, Boffito M, Back DJ, Tjia JF, Taylor J, 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(8):1125–32. https://doi.org/10.3851/imp1675.
Woerle HJ, Mariuz PR, Meyer C, Reichman RC, Popa EM, Dostou JM, et al. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes. 2003;52(4):918–25.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.
Kim SR, Lerman LO. Diagnostic imaging in the management of patients with metabolic syndrome. Transl Res. 2017;194:1–18. https://doi.org/10.1016/j.trsl.2017.10.009.
Ng JM, Bertoldo A, Minhas DS, Helbling NL, Coen PM, Price JC, et al. Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance. J Clin Endocrinol Metab. 2014;99(1):E102–E6. https://doi.org/10.1210/jc.2013-2095.
Johansson E, Lubberink M, Heurling K, Eriksson JW, Skrtic S, Ahlström H, et al. Whole-body imaging of tissue-specific insulin sensitivity and body composition by using an integrated PET/MR system: a feasibility study. Radiology. 2018;286(1):271–8. https://doi.org/10.1148/radiol.2017162949.
Cade WT, Reeds DN, Overton ET, Herrero P, Waggoner AD, Laciny E, et al. Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials. 2013;14(6):303–12. https://doi.org/10.1310/hct1406-303.
Ghotb A, Noworolski SM, Madden E, Scherzer R, Qayyum A, Pannell J, et al. Adipose tissue and metabolic factors associated with steatosis in HIV/HCV coinfection: histology versus magnetic resonance spectroscopy. J Acquir Immune Defic Syndr. 2010;55(2):228–31. https://doi.org/10.1097/QAI.0b013e3181e1d963.
Price JC, Dodge JL, Ma Y, Scherzer R, Korn N, Tillinghast K, et al. Controlled attenuation parameter and magnetic resonance spectroscopy-measured liver steatosis are discordant in obese HIV-infected adults. AIDS. 2017;31(15):2119–25. https://doi.org/10.1097/qad.0000000000001601.
Sathekge M, Maes A, Kgomo M, Stolz A, Ankrah A, Van de Wiele C. Evaluation of glucose uptake by skeletal muscle tissue and subcutaneous fat in HIV-infected patients with and without lipodystrophy using FDG-PET. Nucl Med Commun. 2010;31(4):311–4. https://doi.org/10.1097/MNM.0b013e3283359058.
Torriani M, Zanni MV, Fitch K, Stavrou E, Bredella MA, Lim R, et al. Increased FDG uptake in association with reduced extremity fat in HIV patients. Antivir Ther. 2013;18(2):243–8. https://doi.org/10.3851/imp2420.
Ioannou GN, Bryson CL, Boyko EJ. Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes. J Diabetes Complicat. 2007;21(6):363–70. https://doi.org/10.1016/j.jdiacomp.2006.07.005.
Araujo S, Banon S, Machuca I, Moreno A, Perez-Elias MJ, Casado JL. Prevalence of insulin resistance and risk of diabetes mellitus in HIV-infected patients receiving current antiretroviral drugs. Eur J Endocrinol. 2014;171(5):545–54. https://doi.org/10.1530/eje-14-0337.
Schulte-Hermann K, Schalk H, Haider B, Hutterer J, Gmeinhart B, Pichler K, et al. Impaired lipid profile and insulin resistance in a cohort of Austrian HIV patients. J Infect Chemother. 2016;22(4):248–53. https://doi.org/10.1016/j.jiac.2016.01.007.
•• Nansseu JR, Bigna JJ, Kaze AD, Noubiap JJ. Incidence and risk factors for prediabetes and diabetes mellitus among HIV infected adults on antiretroviral therapy: systematic review and meta-analysis. Epidemiology. 2018. https://doi.org/10.1097/EDE.0000000000000815. Extensive review of incidence and risk factors; very detailed supplemental tables of individual study results are valuable resource.
• McMahon CN, Petoumenos K, Hesse K, Carr A, Cooper DA, Samaras K. High rates of incident diabetes and prediabetes are evident in men with treated HIV followed for 11 years. AIDS. 2018;32(4):451–9. https://doi.org/10.1097/QAD.0000000000001709. Small study, but longest known follow-up of a single cohort with OGTT capturing transitions to pre-diabetes and diabetes.
• Koethe JR. Adipose tissue in HIV infection. Compr Physiol. 2017;7(4):1339–57. https://doi.org/10.1002/cphy.c160028. Exhaustive review of biological relevance of adipose tissue in metabolic complications of HIV infection and treatment.
Koethe JR, Hulgan T, Niswender K. Adipose tissue and immune function: a review of evidence relevant to HIV infection. J Infect Dis. 2013;208(8):1194–201. https://doi.org/10.1093/infdis/jit324.
Lake JE. The fat of the matter: obesity and visceral adiposity in treated HIV infection. Curr HIV/AIDS Rep. 2017;14(6):211–9. https://doi.org/10.1007/s11904-017-0368-6.
Byrne CD, Targher G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol. 2014;34(6):1155–61. https://doi.org/10.1161/atvbaha.114.303034.
Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(12):1131–41. https://doi.org/10.1056/NEJMra1011035.
• Longenecker CT, Margevicius S, Liu Y, Schluchter MD, Yun CH, Bezerra HG, et al. Effect of pericardial fat volume and density on markers of insulin resistance and inflammation in patients with human immunodeficiency virus infection. Am J Cardiol. 2017;120(8):1427–33. https://doi.org/10.1016/j.amjcard.2017.07.019. Longitudinal analysis demonstrating independent associations between pericardial fat measured by computed tomography and HOMA-IR in persons with HIV.
Kaji H. Adipose tissue-derived plasminogen activator Inhibitor-1 function and regulation. Compr Physiol. 2016;6(4):1873–96. https://doi.org/10.1002/cphy.c160004.
Wirunsawanya K, Belyea L, Shikuma C, Watanabe RM, Kohorn L, Shiramizu B, et al. Plasminogen activator Inhibitor-1 predicts negative alterations in whole-body insulin sensitivity in chronic HIV infection. AIDS Res Hum Retrovir. 2017;33(7):723–7. https://doi.org/10.1089/aid.2016.0292.
Shikuma CM, Chow DC, Gangcuangco LM, Zhang G, Keating SM, Norris PJ, et al. Monocytes expand with immune dysregulation and is associated with insulin resistance in older individuals with chronic HIV. PLoS One. 2014;9(2):e90330. https://doi.org/10.1371/journal.pone.0090330.
Hessol NA, Ameli N, Cohen MH, Urwin S, Weber KM, Tien PC. The association between diet and physical activity on insulin resistance in the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr. 2013;62(1):74–80. https://doi.org/10.1097/QAI.0b013e318275d6a4.
Monroe AK, Brown TT, Cox C, Reynolds SM, Wiley DJ, Palella FJ, et al. Physical activity and its association with insulin resistance in multicenter AIDS cohort study men. AIDS Res Hum Retrovir. 2015;31(12):1250–6. https://doi.org/10.1089/aid.2015.0027.
Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Nutr Metab Cardiovasc Dis. 2017;27(5):396–406. https://doi.org/10.1016/j.numecd.2017.03.001.
Muscogiuri G, Sarno G, Gastaldelli A, Savastano S, Ascione A, Colao A, et al. The good and bad effects of statins on insulin sensitivity and secretion. Endocr Res. 2014;39(4):137–43. https://doi.org/10.3109/07435800.2014.952018.
Erlandson KM, Jiang Y, Debanne SM, McComsey GA. Rosuvastatin worsens insulin resistance in HIV-infected adults on antiretroviral therapy. Clin Infect Dis. 2015;61(10):1566–72. https://doi.org/10.1093/cid/civ554.
Krishnan S, Wilson EM, Sheikh V, Rupert A, Mendoza D, Yang J, et al. Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis. 2014;209(6):931–9. https://doi.org/10.1093/infdis/jit581.
Hunt PW, Lee SA, Siedner MJ. Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infect Dis. 2016;214(Suppl 2):S44–50. https://doi.org/10.1093/infdis/jiw275.
Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol. 2012;8(12):709–16. https://doi.org/10.1038/nrendo.2012.114.
Koethe JR, Grome H, Jenkins CA, Kalams SA, Sterling TR. The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy. AIDS. 2016;30(1):83–91. https://doi.org/10.1097/QAD.0000000000000893.
Srinivasa S, Fitch KV, Wong K, Torriani M, Mayhew C, Stanley T, et al. RAAS activation is associated with visceral adiposity and insulin resistance among HIV-infected patients. J Clin Endocrinol Metab. 2015;100(8):2873–82. https://doi.org/10.1210/jc.2015-1461.
Tincati C, Douek DC, Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther. 2016;13:19. https://doi.org/10.1186/s12981-016-0103-1.
Klatt NR, Funderburg NT, Brenchley JM. Microbial translocation, immune activation, and HIV disease. Trends Microbiol. 2013;21(1):6–13. https://doi.org/10.1016/j.tim.2012.09.001.
O'Malley TK, Burdo TH, Robinson JA, Fitch KV, Grinspoon SK, Srinivasa S. Acute hyperinsulinemia effects on systemic markers of immune activation in HIV. AIDS. 2017;31(12):1771–3. https://doi.org/10.1097/QAD.0000000000001545.
Pedersen KK, Pedersen M, Troseid M, Gaardbo JC, Lund TT, Thomsen C, et al. Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction. J Acquir Immune Defic Syndr. 2013;64(5):425–33. https://doi.org/10.1097/QAI.0b013e31829f919d.
Moreno-Perez O, Giner L, Reus S, Boix V, Alfayate R, Frances R, et al. Impact of circulating bacterial DNA in long-term glucose homeostasis in non-diabetic patients with HIV infection: cohort study. Eur J Clin Microbiol Infect Dis. 2018;37(2):313–8. https://doi.org/10.1007/s10096-017-3134-1.
Brown AE, Walker M. Genetics of insulin resistance and the metabolic syndrome. Curr Cardiol Rep. 2016;18(8):75. https://doi.org/10.1007/s11886-016-0755-4.
Jimenez-Sousa MA, Berenguer J, Fernandez-Rodriguez A, Micheloud D, Guzman-Fulgencio M, Miralles P, et al. IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients. J Viral Hepat. 2014;21(3):189–97. https://doi.org/10.1111/jvh.12130.
Pineda-Tenor D, Berenguer J, Jimenez-Sousa MA, Garcia-Alvarez M, Aldamiz-Echevarria T, Carrero A, et al. FTO rs9939609 polymorphism is associated with metabolic disturbances and response to HCV therapy in HIV/HCV-coinfected patients. BMC Med. 2014;12:198. https://doi.org/10.1186/s12916-014-0198-y.
Gonzalez-Franquesa A, Patti ME. Insulin resistance and mitochondrial dysfunction. Adv Exp Med Biol. 2017;982:465–520. https://doi.org/10.1007/978-3-319-55330-6_25.
Wang CH, Wei YH. Role of mitochondrial dysfunction and dysregulation of Ca(2+) homeostasis in the pathophysiology of insulin resistance and type 2 diabetes. J Biomed Sci. 2017;24(1):70. https://doi.org/10.1186/s12929-017-0375-3.
Shikuma CM, Day LJ, Gerschenson M. Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord. 2005;5(3):255–62.
Hart AB, Samuels DC, Hulgan T. The other genome: a systematic review of studies of mitochondrial DNA haplogroups and outcomes of HIV infection and antiretroviral therapy. AIDS Rev. 2013;15(4):213–20.
Micheloud D, Berenguer J, Guzman-Fulgencio M, Campos Y, Garcia-Alvarez M, Catalan P, et al. European mitochondrial DNA haplogroups and metabolic disorders in HIV/HCV coinfected patients on highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2011;58:371–8. https://doi.org/10.1097/QAI.0b013e31822d2629.
Hulgan T, Stein JH, Cotter BR, Murdock DG, Ritchie MD, Dube MP, et al. Mitochondrial DNA variation and changes in adiponectin and endothelial function in HIV-infected adults after antiretroviral therapy initiation. AIDS Res Hum Retrovir. 2013;29(10):1293–9. https://doi.org/10.1089/aid.2013.0079.
Hulgan T, Ramsey B, Koethe JR, Samuels DC, Gerschenson M, Libutti D et al. Adipose mitochondrial function, adiponectin, and insulin resistance in ACTG A5224S. Conference on Retroviruses and Opportunistic Infections; February 13–16; Boston, MA, USA; 2017.
Haubrich RH, Riddler SA, DiRienzo AG, Komarow L, Powderly WG, Klingman K, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009;23(9):1109–18. https://doi.org/10.1097/QAD.0b013e32832b4377.
McComsey GA, Daar ES, O'Riordan M, Collier AC, Kosmiski L, Santana JL, et al. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis. 2013;207(4):604–11. https://doi.org/10.1093/infdis/jis720.
McComsey GA, Kitch D, Sax PE, Tebas P, Tierney C, Jahed NC, et al. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG study A5224s. Clin Infect Dis. 2011;53(2):185–96. https://doi.org/10.1093/cid/cir324.
Erlandson KM, Kitch D, Tierney C, Sax PE, Daar ES, Melbourne KM, et al. Impact of randomized antiretroviral therapy initiation on glucose metabolism. AIDS. 2014;28(10):1451–61. https://doi.org/10.1097/QAD.0000000000000266.
Ryom L, Lundgren J, El-Sadr WM, Reiss P, Phillips A, Kirk O et al. Association between cardiovascular disease & contemporarily used protease inhibitors. Conference on Retroviruses and Opportunistic Infections; February 13–16; Boston, MA, USA; 2017.
• Lundgren J, Mocroft A, Ryom L. Contemporary protease inhibitors and cardiovascular risk. Curr Opin Infect Dis. 2018;31(1):8–13. https://doi.org/10.1097/QCO.0000000000000425. Important review of evidence for associations between newer PI, including atazanavir and darunavir, and cardiovascular effects.
Overton ET, Tebas P, Coate B, Ryan R, Perniciaro A, Dayaram YK, 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(2):72–7. https://doi.org/10.1080/15284336.2016.1141468.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 3 Feb 2018.
Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796–806. https://doi.org/10.1016/s0140-6736(09)60918-1.
DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429–38. https://doi.org/10.1016/s0140-6736(12)60918-0.
Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439–48. https://doi.org/10.1016/s0140-6736(12)60917-9.
Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735–43. https://doi.org/10.1016/s0140-6736(12)61853-4.
Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–18. https://doi.org/10.1056/NEJMoa1215541.
McComsey GA, Moser C, Currier J, Ribaudo HJ, Paczuski P, Dube MP, et al. Body composition changes after initiation of raltegravir or protease inhibitors: ACTG A5260s. Clin Infect Dis. 2016;62(7):853–62. https://doi.org/10.1093/cid/ciw017.
•• Dirajlal-Fargo S, Moser C, Brown TT, Kelesidis T, Dube MP, Stein JH, et al. Changes in insulin resistance after initiation of raltegravir or protease inhibitors with tenofovir-emtricitabine: AIDS Clinical Trials Group A5260s. Open Forum Infect Dis. 2016;3(3):ofw174. https://doi.org/10.1093/ofid/ofw174. Unique targeted analysis of HOMA-IR in a clinical trial of contemporary ART regimens in treatment-naïve persons; HOMA-IR increased rapidly after starting either boosted PI or RAL-containing ART.
Zanni MV, Burdo TH, Makimura H, Williams KC, Grinspoon SK. Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects. Clin Endocrinol. 2012;77(3):385–90. https://doi.org/10.1111/j.1365-2265.2011.04284.x.
Fong PS, Flynn DM, Evans CD, Korthuis PT. Integrase strand transfer inhibitor-associated diabetes mellitus: a case report. Int J STD AIDS. 2017;28(6):626–8. https://doi.org/10.1177/0956462416675107.
Spinner CD, Kern KE, Zink A, Wolf E, Balogh A, Noe S, 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(7):627–31. https://doi.org/10.3851/imp3049.
Raffi F, Esser S, Nunnari G, Perez-Valero I, Waters L. Switching regimens in virologically suppressed HIV-1-infected patients: evidence base and rationale for integrase strand transfer inhibitor (INSTI)-containing regimens. HIV Med. 2016;17(Suppl 5):3–16. https://doi.org/10.1111/hiv.12440.
Menard A, Meddeb L, Tissot-Dupont H, Ravaux I, Dhiver C, Mokhtari S, et al. Dolutegravir and weight gain: an unexpected bothering side effect? AIDS. 2017;31(10):1499–500. https://doi.org/10.1097/QAD.0000000000001495.
Norwood J, Turner M, Bofill C, Rebeiro P, Shepherd B, Bebawy S, et al. Brief report: weight gain in persons with HIV switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. J Acquir Immune Defic Syndr. 2017;76(5):527–31. https://doi.org/10.1097/QAI.0000000000001525.
McLaughlin M, Walsh S, Galvin S. Dolutegravir-induced hyperglycaemia in a patient living with HIV. J Antimicrob Chemother. 2018;73(1):258–60. https://doi.org/10.1093/jac/dkx365.
Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014;210(3):354–62. https://doi.org/10.1093/infdis/jiu051.
Dolutegravir (Tivicay) [Package Insert]. Research Triangle Park, NC, USA: ViiV Healthcare, 2017. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tivicay/pdf/TIVICAY-PI-PIL.PDF. Accessed 6 Feb 2018.
Sax PE, DeJesus E, Crofoot G, Ward D, Benson P, Dretler R, et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. The Lancet HIV. 2017;4(4):e154–e60. https://doi.org/10.1016/S2352-3018(17)30016-4.
Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–72. https://doi.org/10.1016/S0140-6736(17)32299-7.
Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink H-J, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073–82. https://doi.org/10.1016/S0140-6736(17)32340-1.
Minami R, Yamamoto M, Takahama S, Ando H, Miyamura T, Suematsu E. Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir. J Infect Chemother. 2011;17(2):183–8. https://doi.org/10.1007/s10156-010-0101-5.
Moure R, Domingo P, Gallego-Escuredo JM, Villarroya J, Gutierrez Mdel M, Mateo MG, et al. Impact of elvitegravir on human adipocytes: alterations in differentiation, gene expression and release of adipokines and cytokines. Antivir Res. 2016;132:59–65. https://doi.org/10.1016/j.antiviral.2016.05.013.
Perez-Matute P, Perez-Martinez L, Blanco JR, Oteo JA. Neutral actions of raltegravir on adipogenesis, glucose metabolism and lipolysis in 3T3-L1 adipocytes. Curr HIV Res. 2011;9(3):174–9.
Masich A, Badowski ME, Liedtke MD, Fulco PP. Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus-infected patients. Int J STD AIDS. 2017;28(12):1229–33. https://doi.org/10.1177/0956462417695995.
Song IH, Zong J, Borland J, Jerva F, Wynne B, Zamek-Gliszczynski MJ, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr. 2016;72(4):400–7. https://doi.org/10.1097/qai.0000000000000983.
The author is supported by NIH/NIDDK (R21 DK101342), the NIH-funded Tennessee Center for AIDS Research (P30 AI110527), and the Tennessee Valley Veterans Health System. The author would like to acknowledge John Koethe, MD, MSCI, for reviewing a draft of this manuscript, and the providers, staff, and patients of the Vanderbilt Comprehensive Care Clinic and the Tennessee Valley/Nashville VA ID Clinics for always learning and teaching.
Conflict of Interest
The author declares that he has no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Complications of Antiretroviral Therapy
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Hulgan, T. Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update. Curr HIV/AIDS Rep 15, 223–232 (2018). https://doi.org/10.1007/s11904-018-0399-7
- Antiretroviral therapy
- Insulin resistance
- Integrase inhibitors