- Open Access
Metabolic syndrome in HIV-infected individuals: underlying mechanisms and epidemiological aspects
AIDS Research and Therapy volume 10, Article number: 32 (2013)
The success of highly active antiretroviral therapy (HAART) has determined a dramatic decline in AIDS- and immunodeficiency-related causes of death in the HIV-infected population. As life-expectancy increases, such individuals have become gradually exposed not only to the effects of aging itself, but also to the influence of environmental risk factors, which are known to act in the general population. These features can lead to obesity, diabetes mellitus and ultimately cardiovascular diseases (CVD). Metabolic complications and abnormal fat distribution were frequently observed after a few years of antiretroviral therapy and, as the array of antiretroviral drugs became broader, long term metabolic alterations are becoming far more common worldwide. Nevertheless, the risk of not being on HAART is overwhelmingly greater than the metabolic adverse events in terms of morbidity and mortality events. HIV/HAART-induced metabolic unbalances overlap in some extent the components of Metabolic Syndrome (MetS) and its high rates in the HIV population place infected individuals in an elevated CVD risk category. MetS can explain at least in part the emergence of CVD as the major morbidity and mortality conditions in the HIV population. In this review we convey information on the underlying aspects of MetS during HIV infection, highlighting some physiopathological and epidemiological features of this comorbidity along with the role played by HIV itself and the synergy action of some antiretroviral drugs. Considerations on MetS management in the HIV population are also depicted.
The introduction and widespread use of highly active antiretroviral therapy (HAART) in the mid 1990’s, has led HIV-infected individuals to experience a dramatic decline in immunodeficiency-related events, including causes of death [1–3]. As a consequence, life-expectancy increased, which exposed them to the effects of aging itself, including the influence of the same environmental risk factors known to act in the general population and contributing to the occurrence of obesity, diabetes mellitus (DM), and cardiovascular diseases (CVD) [4, 5].
Metabolic syndrome (MetS) has been playing a major role as a marker for metabolic disorders . According to the Third National Health and Nutrition Examination Survey, prevalence of MetS in the general US population has been estimated in 25% and this number has been growing continuously over time . A recent British study on a cohort of middle-aged men reported the prevalence of MetS at 26% . The increasing prevalence of MetS relates to the growing tendencies verified for its underlying causes, such as unbalanced food intake, physical inactivity and obesity, which peaked in the developed world and have been suggested to be independent risk factors for the development of the syndrome .
MetS encompasses a cluster of risk factors leading to CVD as primary clinical outcome and contribute to higher risks of DM. Such factors include obesity (mainly central adiposity), defective glucose metabolism (DM, impaired glucose tolerance, or impaired fasting glycaemia), raised blood pressure, and elevated TG and low HDL-c levels. Notwithstanding the cardiovascular outcomes, individuals with MetS are thought to be more susceptible to a range of conditions including some cancers , polycystic ovary syndrome  and asthma .
Since its first comprehensive recognition in 1988, when Reaven described the relation between insulin resistance, plasma insulin levels, glucose intolerance and hypertension , MetS has been subject to a number of operational definitions. Despite the absence of a consensual definition to date, which dampers accurate prevalence estimates, the different working definitions for the syndrome converge to some extent. Four of the main MetS operational definitions and their differential and overlapping components can be seen in Table 1.
MetS in HIV infection
Despite the unquestionable success of HAART, prevalence of DM, insulin resistance, blood pressure fat redistribution and mainly dyslipidemia have substantially increased after its global scaling up . Though the actual numbers of MetS in HIV populations are still debatable, reported prevalences for MetS in the HIV population can be regarded as high, ranging from 11.2% up to 45.4% (Table 2). The high rates of MetS in the HIV-infected population place it in a CVD high-risk category, turning MetS into a major public health concern [18–20].
The natural course of HIV infection is associated with particular unbalances in lipid levels. The dynamics of HIV infection determine an initial decrease in HDL-c followed by a decrease in LDL-c levels. In more advanced stages, there is an increase in TG and in VLDL-c levels with a strong correlation between serum IFN-α levels and TG clearance time . Notwithstanding, there is evidence for different MetS pathways among HIV individuals under HAART treatment, since a recent report indicated an unbalanced relationship between HDL-c and TG in the presence of high TG levels or another component of MetS , which claims for an appropriate MetS definition in HIV infection.
Physiopathology of MetS in HIV-infected individuals
Since the description of abnormal fat distribution following a few years on HAART with Protease Inhibitors (PI), chiefly ritonavir plus saquinavir combination , metabolic changes in HIV individuals have been widely studied. The main features included dyslipidemia, insulin resistance, and lipodystrophy. Many of these phenotypic and metabolic changes fit MetS criteria  and therefore, there is growing concern that metabolic complications associated to HIV and HAART may lead to increased risk for cardiovascular events. Such reasoning can explain, at least partially, the emergence of CVD as causes of morbidity and death in the HIV population.
HIV infection is associated with deregulated inflammatory response, through suppressing genes necessary to extinguish inflammation. In such context, HIV-infected monocytic cells have downregulated expression of the tyrosine kinase RON, a negative regulator of the inflammatory process and HIV transcription as well, via ubiquitin-proteosome degradation . This long term inflammatory environment along with higher white blood cells count act as a metabolic risk factor in the pathogenesis of HIV .
While obesity is a central component of MetS, adipose tissue is a dynamic source of several proinflammatory cytokines, chemokines, growth factors and complement proteins, which can alter endothelial cells integrity and contribute to the atherosclerosic process . This constitutive low-grade inflammatory status is characterized by increased plasma levels of TNF-α and IL-6 and other mediators of inflammation . The interplay between HIV-triggered low-grade inflammatory injury, inbalances in lipid and glucose metabolism, and fat redistribution has already been described, with soluble urokinase plasminogen activator receptor (suPAR) emerging as a stronger predictor of dysmetabolism than TNF-α and IL-6 .
Insulin resistance is thought to determine excessive adipokine production yielding to endothelial dysfunction. As it progresses towards MetS and DM, the ongoing process of endothelial damage, along with inflammation, thrombosis and oxidation orchestrate at the vessel wall to produce atherosclerotic plaques . Accordingly, caloric restriction-induced weight loss contributes to the regulation of a wide variety of inflammation-related molecules adipose tissue and upregulated the expression of molecules with anti-inflammatory properties .
HIV-related risk factors
Inflammation is thought to be a major determinant in the pathogenesis of both DM and atherosclerosis. However, the key inflammatory molecules involved in atheroma and DM in HIV individuals on HAART are poorly understood . Epicardial and thoracic periaortic fat deposition have been associated to high levels of hsCRP, insulin resistance and subclinical atherosclerosis in virologically suppressed HIV-infected patients on HAART and both have been related to MetS [40, 41]. In fact, epicardial fat storage and some lipodystrophy phenotypes and well established risk factors for atherosclerosis seem to be associated .
A case–control study performed among HIV-infected ART-naïve Africans showed a high prevalence of MetS and increased arterial stiffness, considered an early marker of atherosclerosis. In this report, prevalence of impaired fasting glucose and DM, levels of fasting TG and the atherogenic dyslipidemia ratio were higher in HIV-individuals than in controls. Elevated blood pressure prevalence was high but comparable in both groups .
Although to a lesser degree than HAART, HIV infection act as an independent risk factor for atherosclerosis development and cardiovascular damage, been responsible for the increased prevalence of MetS and arterial function impairment . HIV-specific mechanisms include immune dysfunction and increased inflammatory response leading to increased thrombosis and changes in lipid levels and cholesterol metabolism, which are also responsible for MetS and cardiovascular risk in the general population. Tat, a key molecule in HIV replication and pathogenesis can affect both mesenchymal stem cells survival and differentiation by downregulating the expression of VEGF-induced endothelial markers and this might play an instrumental role in vessel damage and in the atherosclerotic lesions observed in HIV infection .
The pathogenesis of dyslipidemia in HIV-infected individuals has been associated with increased apolipoprotein levels, increased hepatic synthesis of VLDL-c, decreased clearance of TG  and also to the effects of viral infection itself, acute-phase proteins and increase in circulating cytokines such as IL-6 and IFN-α . In fact, lipid unbalances are common in art-naïve HIV-infected individuals even in the absence of major host-related risk factors for dyslipidemia, such as high blood pressure, DM and obesity .
HIV-1 infection itself is able to elicit adipose tissue alterations critical to lipodystrophy causation through adipose tissue gene expression alterations. Subcutaneous adipose tissue from infected individuals bears reduced mRNA levels of cytochrome c oxidase subunit II compared to non-infected individual. These concentrations decreased further in association with HAART .
Antiretroviral-related risk factors
HAART therapy has both positive and deleterious effects on cardiovascular risk. Cumulative evidence has pointed to the relation between different metabolic disorders and HAART use, including insulin resistance, hyperlipidaemia, and lipodystrophy , even though it remains controversial whether these effects can be directly ascribed to antiretroviral drugs . Antiretroviral-driven suppression of HIV replication seem to act as double-edged sword since it can reduce and also increase HIV-related cardiovascular risk through its toxicity .
Despite effective treatment with HAART, some degree of chronic immune activation may persist. In the SMART trial, participants bearing ≤400 copies/mL of HIV RNA also had elevated hsCRP and IL-6 levels in 38% and 60%, respectively, in comparison to normal individuals form cohorts for cardiovascular outcomes . HIV-infected individuals have higher blood levels of major inflammation markers such as IL-6, hsCRP and p-selectin, considered independently associated with increased cardiovascular risk . Interrupting ART use may further increase the risk of death by raising IL-6 and D-dimer levels .
HAART toxicity depends on the antiretroviral drug used and may include adverse lipoprotein changes, insulin resistance, inflammation, platelet dysfunction, and vascular injury. Studies performed in vitro have demonstrated that some HAART regimens, such as those including zidovudine, some NNRTI (e.g. efavirenz) and indinavir induce toxicity through induction of cardiomyocyte and endothelial cell apoptosis leading to endothelial dysfunction and vascular damage . Thus, compared to untreated HIV infection, the net effect of starting antiretroviral therapy on cardiovascular disease risk is unknown as it may increase or decrease the overall risk . Studies suggest that conventional risk factors will play major role in the development of CVD in HIV patients, as seen in the general population and such risk factors urge to be targeted by prevention strategies [56, 57].
The unbalances in glucose metabolism depend on the particular antiretroviral drug in use. Treatments with stavudine , zidovudine [59, 60], lamivudine  or didanosine , as well as indinavir [61, 62], or lopinavir/ritonavir , and efavirenz have [63, 64] been implicated in insulin resistance, glucose metabolism changes, and DM. The pathways underlying such alterations are not always know but an in vitro essay with PIs and NRTIs showed altered adipocyte functions and decreased adiponectin, a positive regulator of insulin sensitivity, due to an increased expression and secretion of pro-inflammatory cytokines . In another study, the PI indinavir has been implicated in inducing insulin resistance by acutely blocking transport of glucose by the insulin-sensitive glucose transporter GLUT4, a mechanism not found in non-HIV patients with DM .
Dyslipidemia in HIV population can result from both uncontrolled HIV disease and clinical restoration after HAART initiation. Individual, demographic and genetic traits besides the specific side effects of the antiretroviral combination contribute greatly to the type and degree of dyslipidemia seen in this population . According to the D:A:D, a consortium assessing adverse events of anti-HIV drugs, the risk associated to certain PI’s (indinavir, lopinavir/ritonavir, abacavir) was consistently lower than the one calculated to the annual increment in risk associated to advanced age and current smoking habit . The use of lopinavir/ritonavir , stavudine , efavirenz  and nelfinavir, zidovudine/lamivudine and didanosine/stavudine  have already been reported as causative of dyslipedemia by at least one of the following mechanisms (i) increased TG levels, (ii) increased LDL-c levels, and (iii) increased HDL-c levels.
Aside these specific cardiovascular risks, CVD have been reported as adverse effect with some ARV drugs, independently of metabolic disorders [71, 72]. A meta-analysis indicated an increased risk of myocardial infarction in patients exposed to abacavir (RR 1.92, 95% CI 1.51-2.42), and an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05-1.17) and lopinavir (RR 1.22, 95% CI 1.01-1.47) . A prospective observational study from the D:A:D consortium showed that combination antiretroviral therapy was independently associated with a relative increase 0f 1.26 times in the rate of myocardial infarction per year of exposure during the first four to six years of use . Despite these minor metabolic unbalances described for many antiretroviral drugs, it is important to keep in mind that the morbidity and mortality risks for HIV patients not on HAART are much higher than the risks seen with any antiretroviral drug or combination of drugs.
Targeting MetS risk factors in the HIV population
As aforementioned, the success of HAART implementation allowed HIV individuals to live longer and as a consequence they can accumulate the same cardiovascular risks exposure described for the general population, such as high blood pressure, DM, dyslipidemia, and smoking habit, which is known to be a more prevalent risk in the HIV infected than in general population . A French nationwide cohort of HIV+ adults on HAART showed that nearly half the patients were overweight or obese at HAART initiation and 20% of the patients gained excessive weight within 2 years of HAART initiation . Additionally, a retrospective cross-sectional study reported that, even though less common than among the general population, obesity and overweight were more prevalent in comparison to wasting in the HIV population .
In a recent cohort of HIV-infected patients receiving care in HIV clinics in US, 38.2% of patients were in either the moderately high-risk or high-risk categories, of whom 77.9% were current or past smokers, 74.2% had high blood pressure, 71.5% had elevated baseline LDL-c levels, 70.5% had low HDL-c levels, and 35.8% had MetS .
A recent study has suggested an exclusive map for estimating the correct risk of cardiovascular disease in these patients that should include, besides traditional risk factors, specific factors for HIV patients like viral factors, immune activation, chronic inflammation and side effects of antiretroviral therapy .
In managing hyperlipidemia, the decision to use lipid-lowering therapy or to switch antiretroviral therapy regimens should be individualized. Unfortunately, at least one-fifth of HIV-infected outpatients with high cardiovascular risk who were eligible for pharmacologic treatment did not received recommended interventions and so treatment goals could not be achieved . Effective management of dyslipidemia in HIV individuals is essential to reduce cardiovascular risk but presents multiple pitfalls due to interactions between HAART and lipid-lowering drugs . A primary effort in treating dyslipidemia in HIV patients is selecting lipid-lowering agents capable to work effectively to restore lipid metabolism while maintaining proper interactions with HAART .
Beyond their canonical activity in inhibiting HMG-CoA reductase, statins might attenuate inflammation associate to the low-level viremia which can lead to a higher risk of age-associated non-AIDS morbidity and mortality. In fact, there is evidence showing that patients who maintained virologic suppression on effective HAART obtained additional survival benefit from the use of a statin .
As for the general population, cigarette smoking is thought to be the most important cardiovascular risk factor among HIV patients. More than half of the subjects evaluated in a cross-sectional analysis were current or past cigarette smokers, and smoking conferred a 2.35 (95% CI = 1.92-2.87) risk for myocardial infarction . Cessation of smoking was more likely to reduce cardiovascular risk than either the choice of the ART regimen or the use of lipid-lowering drugs . When assessing carotid intima-media thickness as a surrogate marker of CVD in HIV cohort, only gender, age, BMI, hypertension and family history of CVD remained as significant factors associated with thickened carotid intima-media, suggesting that traditional CVD risk factors may play a major role in CVD among HIV population .
HIV individuals submitted to short-term exercise training can undergo reductions in the waist-to-hip ratio and in the amount of visceral fat, and reductions in the levels of cholesterol, triglyceride, and LDL-c and such changes may improve some of the adverse metabolic effects associated to HAART . The assessing of aerobic training in improving abdominal fat accumulation and metabolic disorders in HIV infection revealed that it reduced visceral fat, lipid disorders, basal blood lactate and coronary heart disease and may be particularly important for patients with marked dyslipidemia .
The current HAART-modified natural history of HIV infection has practically turned the disease into a manageable chronic condition. As such, special attention should be paid to both imperfect control of HIV replication and long-term adverse events linked to drugs used in the therapeutic scheme. Even though the benefits of HAART use are overwhelmingly greater than possible MetS and CVD risks, close management of those patients is called for, especially due to the fact that general population risk factors now overlap with specific ones in this population, even though the former are usually more prominent than the latter.
Thus, MetS in HIV populations ought to be closely monitored and controlled by programmatic and comprehensive public measures. These findings call for an integrated management strategy, including smoking cessation policies, diet modification, and regular physical activity planning. Finally, comprehensive educational measures are needed and further research is instrumental to assess the barriers to implement preconized interventions and to achieving recommended treatment goals that are singular to the HIV-population.
American heart association
Body mass index
A:D: Data collection on adverse events of anti-HIV drugs
European group for study of insulin resistance
High density lipoprotein cholesterol
High sensitivity C-reactive protein
International diabetes federation
Low density lipoprotein cholesterol
- NCEP/ATP III:
National cholesterol education program/adult treatment panel III
- NCEP/ATP III:
National heart, lung and blood institute
Non-nucleoside reverse transcriptase inhibitors
Nucleoside reverse transcriptase inhibitors
Strategies for management of anti-retroviral therapy
Tumor necrosis factor
Type 2 diabetes mellitus
Vascular endothelial growth factor
Very low density lipoprotein cholesterol.
Grinsztejn B, Luz PM, Pacheco AG, Santos DV, Velasque L, Moreira RI, Guimaraes MR, Nunes EP, Lemos AS, Ribeiro SR: Changing mortality profile among HIV-infected patients in Rio de Janeiro, Brazil: Shifting from AIDS to non-AIDS related conditions in the HAART era. PLoS One. 2013, 8: e59768- 10.1371/journal.pone.0059768
Krentz HB, Kliewer G, Gill MJ: Changing mortality rates and causes of death for HIV-infected individuals living in Southern Alberta, Canada from 1984 to 2003. HIV Med. 2005, 6: 99-106. 10.1111/j.1468-1293.2005.00271.x
Pacheco AG, Tuboi SH, May SB, Moreira LF, Ramadas L, Nunes EP, Mercon M, Faulhaber JC, Harrison LH, Schechter M: Temporal changes in causes of death among HIV-infected patients in the HAART era in Rio de Janeiro, Brazil. J Acquir Immune Defic Syndr. 2009, 51: 624-630. 10.1097/QAI.0b013e3181a4ecf5
Pacheco AG, Tuboi SH, Faulhaber JC, Harrison LH, Schechter M: Increase in non-AIDS related conditions as causes of death among HIV-infected individuals in the HAART era in Brazil. PLoS One. 2008, 3: e1531- 10.1371/journal.pone.0001531
Tate T, Willig AL, Willig JH, Raper JL, Moneyham L, Kempf MC, Saag MS, Mugavero MJ: HIV infection and obesity: Where did all the wasting go?. Antivir Ther. 2012, 17: 1281-1289. 10.3851/IMP2348
Rosolova H, Nussbaumerova B: Cardio-metabolic risk prediction should be superior to cardiovascular risk assessment in primary prevention of cardiovascular diseases. EPMA J. 2011, 2: 15-26. 10.1007/s13167-011-0066-1
Mozumdar A, Liguori G: Persistent increase of prevalence of metabolic syndrome among U.S. adults: NHANES III to NHANES 1999–2006. Diabetes Care. 2011, 34: 216-219. 10.2337/dc10-0879
Wannamethee SG: The metabolic syndrome and cardiovascular risk in the British Regional Heart Study. Int J Obes. 2008, 32 (Suppl 2): S25-S29.
Westley RL, May FE: A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Int J Endocrinol. 2013, 2013: 632461-
Teede H, Deeks A, Moran L: Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010, 8: 41- 10.1186/1741-7015-8-41
Brumpton BM, Camargo CA, Romundstad PR, Langhammer A, Chen Y, Mai XM: Metabolic syndrome and incidence of asthma in adults: The HUNT study. Eur Respir J. 2013
Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988, 37: 1595-1607. 10.2337/diab.37.12.1595
Balkau B, Charles MA: Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med. 1999, 16: 442-443.
Expert Panel on Detection E, Treatment of High Blood Cholesterol in A : 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. 10.1001/jama.285.19.2486
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol. 2005, 4: 198-203. 10.1097/00132577-200512000-00018
Alberti KG, Zimmet P, Shaw J: Group IDFETFC: The metabolic syndrome–a new worldwide definition. Lancet. 2005, 366: 1059-1062. 10.1016/S0140-6736(05)67402-8
Barbaro G: Metabolic and cardiovascular complications of highly active antiretroviral therapy for HIV infection. Curr HIV Res. 2006, 4: 79-85. 10.2174/157016206775197664
Biron A, Bobin-Dubigeon C, Volteau C, Piroth L, Perre P, Leport C, Prazuck T, Jovelin T, Billard M, Sebille V: Metabolic syndrome in French HIV-infected patients: Prevalence and predictive factors after 3 years of antiretroviral therapy. AIDS Res Hum Retroviruses. 2012, 28: 1672-1678. 10.1089/aid.2012.0048
Feleke Y, Fekade D, Mezegebu Y: Prevalence of highly active antiretroviral therapy associated metabolic abnormalities and lipodystrophy in HIV infected patients. Ethiop Med J. 2012, 50: 221-230.
Jacobson DL, Tang AM, Spiegelman D, Thomas AM, Skinner S, Gorbach SL, Wanke C: Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr. 2006, 43: 458-466. 10.1097/01.qai.0000243093.34652.41
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. 10.2337/diacare.25.7.1253
Jerico C, Knobel H, Montero M, Ordonez-Llanos J, Guelar A, Gimeno JL, Saballs P, Lopez-Colomes JL, Pedro-Botet J: Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors. Diabetes Care. 2005, 28: 132-137. 10.2337/diacare.28.1.132
Bonfanti P, Ricci E, De Socio G, Zeme D, Carradori S, Penco G, Parruti G, Grosso C, Madeddu G, Vichi F: Metabolic syndrome: A real threat for HIV-positive patients?: Results from the SIMONE study. J Acquir Immune Defic Syndr. 2006, 42: 128-131. 10.1097/01.qai.0000219775.20174.2d
Estrada V, Martinez-Larrad MT, Gonzalez-Sanchez JL, De Villar NG, Zabena C, Fernandez C, Serrano-Rios M: Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy. Metabolism. 2006, 55: 940-945. 10.1016/j.metabol.2006.02.024
Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A: Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: Associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia. Diabetes Care. 2007, 30: 113-119. 10.2337/dc06-1075
Mondy K, Overton ET, Grubb J, Tong S, Seyfried W, Powderly W, Yarasheski K: Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population. Clin Infect Dis. 2007, 44: 726-734. 10.1086/511679
Bruno R, Gazzaruso C, Sacchi P, Zocchetti C, Giordanetti S, Garzaniti A, Ciappina V, Maffezzini E, Maserati R, Filice G: High prevalence of metabolic syndrome among HIV-infected patients: Link with the cardiovascular risk. J Acquir Immune Defic Syndr. 2002, 31: 363-365. 10.1097/00126334-200211010-00015
Gazzaruso C, Bruno R, Garzaniti A, Giordanetti S, Fratino P, Sacchi P, Filice G: Hypertension among HIV patients: Prevalence and relationships to insulin resistance and metabolic syndrome. J Hypertens. 2003, 21: 1377-1382. 10.1097/00004872-200307000-00028
Bernal E, Masia M, Padilla S, Martin-Hidalgo A, Gutierrez F: Prevalence and characteristics of metabolic syndrome among HIV-infected patients from a Mediterranean cohort. Med Clin. 2007, 128: 172-175. 10.1157/13098391. quiz 171 p following 200
Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR: Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992, 74: 1045-1052. 10.1210/jc.74.5.1045
Vu CN, Ruiz-Esponda R, Yang E, Chang E, Gillard B, Pownall HJ, Hoogeveen RC, Coraza I, Balasubramanyam A: Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: Further evidence for a unique form of metabolic syndrome in HIV patients. Metabolism. 2013, 62: 1014-1020. 10.1016/j.metabol.2013.01.020
Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998, 12: F51-58. 10.1097/00002030-199807000-00003
Kalantari P, Harandi OF, Hankey PA, Henderson AJ: HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation. J Immunol. 2008, 181: 1548-1555.
Farhangi MA, Keshavarz SA, Eshraghian M, Ostadrahimi A, Saboor-Yaraghi AA: White blood cell count in women: Relation to inflammatory biomarkers, haematological profiles, visceral adiposity, and other cardiovascular risk factors. J Health Popul Nutr. 2013, 31: 58-64.
Lyon CJ, Law RE, Hsueh WA: Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003, 144: 2195-2200. 10.1210/en.2003-0285
Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B: Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006, 17: 4-12.
Andersen O, Eugen-Olsen J, Kofoed K, Iversen J, Haugaard SB: Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected patients receiving highly active antiretroviral therapy. J Med Virol. 2008, 80: 209-216. 10.1002/jmv.21114
Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD: Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004, 18: 1657-1669. 10.1096/fj.04-2204com
De Lorenzo F, Collot-Teixeira S, Boffito M, Feher M, Gazzard B, McGregor JL: Metabolic-inflammatory changes, and accelerated atherosclerosis in HIV patients: Rationale for preventative measures. Curr Med Chem. 2008, 15: 2991-2999. 10.2174/092986708786848668
Longenecker CT, Jiang Y, Yun CH, Debanne S, Funderburg NT, Lederman MM, Storer N, Labbato DE, Bezerra HG, McComsey GA: Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy. Int J Cardiol. 2013, 13: 414-425.
Yerramasu A, Dey D, Venuraju S, Anand DV, Atwal S, Corder R, Berman DS, Lahiri A: Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis. Atherosclerosis. 2012, 220: 223-230. 10.1016/j.atherosclerosis.2011.09.041
Sacks HS, Fain JN: Human epicardial adipose tissue: A review. Am Heart J. 2007, 153: 907-917. 10.1016/j.ahj.2007.03.019
Ngatchou W, Lemogoum D, Ndobo P, Yagnigni E, Tiogou E, Nga E, Kouanfack C, Van de Borne P, Hermans MP: Increased burden and severity of metabolic syndrome and arterial stiffness in treatment-naive HIV + patients from Cameroon. Vasc Health Risk Manag. 2013, 9: 509-516.
Maloberti A, Giannattasio C, Dozio D, Betelli M, Villa P, Nava S, Cesana F, Facchetti R, Giupponi L, Castagna F: Metabolic Syndrome in Human Immunodeficiency Virus-Positive Subjects: Prevalence, Phenotype, and Related Alterations in Arterial Structure and Function. Metab Syndr Relat Disord. 2013, 3: 214-219.
Gibellini D, Miserocchi A, Tazzari PL, Ricci F, Clo A, Morini S, Ponti C, Pasquinelli G, Bon I, Pagliaro P: Analysis of the effects of HIV-1 Tat on the survival and differentiation of vessel wall-derived mesenchymal stem cells. J Cell Biochem. 2012, 113: 1132-1141. 10.1002/jcb.23446
Daniyam C, Iroezindu M: Lipid Profile of Anti-Retroviral Treatment-Naive HIV-Infected Patients in Jos, Nigeria. Ann Med Health Sci Res. 2013, 3: 26-30. 10.4103/2141-9248.109468
Crowe SM, Westhorpe CL, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M: The macrophage: The intersection between HIV infection and atherosclerosis. J Leukoc Biol. 2010, 87: 589-598. 10.1189/jlb.0809580
Giralt M, Domingo P, Guallar JP, De la Concepcion ML R, Alegre M, Domingo JC, Villarroya F: HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV- 1/HAART-associated lipodystrophy. Antivir Ther. 2006, 11: 729-740.
Wand H, Calmy A, Carey DL, Samaras K, Carr A, Law MG, Cooper DA, Emery S, Committee ITIC: Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS. 2007, 21: 2445-2453. 10.1097/QAD.0b013e3282efad32
Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD: Investigators HIVOS: Mortality in the highly active antiretroviral therapy era: Changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006, 43: 27-34. 10.1097/01.qai.0000233310.90484.16
Neuhaus J, Jacobs DR, Baker JV, Calmy A, Duprez D, La Rosa A, Kuller LH, Pett SL, Ristola M, Ross MJ: Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010, 201: 1788-1795. 10.1086/652749
De Luca A, De Gaetano Donati K, Colafigli M, Cozzi-Lepri A, De Curtis A, Gori A, Sighinolfi L, Giacometti A, Capobianchi MR ADA: The association of high-sensitivity c-reactive protein and other biomarkers with cardiovascular disease in patients treated for HIV: a nested case--control study. BMC Infect Dis. 2013, 13: 414- 10.1186/1471-2334-13-414
Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D: Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008, 5: e203- 10.1371/journal.pmed.0050203
Fiala M, Murphy T, MacDougall J, Yang W, Luque A, Iruela-Arispe L, Cashman J, Buga G, Byrns RE, Barbaro G, Arthos J: HAART drugs induce mitochondrial damage and intercellular gaps and gp120 causes apoptosis. Cardiovasc Toxicol. 2004, 4: 327-337. 10.1385/CT:4:4:327
Baker JV, Lundgren JD: Cardiovascular implications from untreated human immunodeficiency virus infection. Eur Heart J. 2011, 32: 945-951. 10.1093/eurheartj/ehq483
Sabin CA, Worm SW: Conventional cardiovascular risk factors in HIV infection: How conventional are they?. Curr Opin HIV AIDS. 2008, 3: 214-219. 10.1097/COH.0b013e3282f6a613
Pacheco AGFGB, Fonseca MDJ, Moreira RI, Veloso VG, Friedman RK, Cardoso SW, Falcão M, Mil JG, Bensenor I, Lotufo P, Chor D: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Carotid intima-media thickness (cIMT) in HIV-infected patients in Rio de Janeiro, Brazil: Overall and gender analysis. 2013, Kuala Lumpur; Birmingham, AL, USA
Capeau J, Bouteloup V, Katlama C, Bastard JP, Guiyedi V, Salmon-Ceron D, Protopopescu C, Leport C, Raffi F, Chene G: Group ACA-CCS: Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment. AIDS. 2012, 26: 303-314. 10.1097/QAD.0b013e32834e8776
Blumer RM, Van Vonderen MG, Sutinen J, Hassink E, Ackermans M, Van Agtmael MA, Yki-Jarvinen H, Danner SA, Reiss P, Sauerwein HP: Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy. AIDS. 2008, 22: 227-236. 10.1097/QAD.0b013e3282f33557
Van Vonderen MG, Blumer RM, Hassink EA, Sutinen J, Ackermans MT, Van Agtmael MA, Yki-Jarvinen H, Danner SA, Serlie MJ, Sauerwein HP, Reiss P: Insulin sensitivity in multiple pathways is differently affected during zidovudine/lamivudine-containing compared with NRTI-sparing combination antiretroviral therapy. J Acquir Immune Defic Syndr. 2010, 53: 186-193. 10.1097/QAI.0b013e3181c190f4
Palacios R, Merchante N, Macias J, Gonzalez M, Castillo J, Ruiz J, Marquez M, Gomez-Mateos J, Pineda JA, Santos J: Incidence of and risk factors for insulin resistance in treatment-naive HIV-infected patients 48 weeks after starting highly active antiretroviral therapy. Antivir Ther. 2006, 11: 529-535.
Murata H, Hruz PW, Mueckler M: The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem. 2000, 275: 20251-20254. 10.1074/jbc.C000228200
Dave JA, Lambert EV, Badri M, West S, Maartens G, Levitt NS: Effect of nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy on dysglycemia and insulin sensitivity in South African HIV-infected patients. J Acquir Immune Defic Syndr. 2011, 57: 284-289. 10.1097/QAI.0b013e318221863f
Rosenkranz SL, Yarasheski KE, Para MF, Reichman RC, Morse GD: Antiretroviral drug levels and interactions affect lipid, lipoprotein, and glucose metabolism in HIV-1 seronegative subjects: A pharmacokinetic-pharmacodynamic analysis. Metab Syndr Relat Disord. 2007, 5: 163-173. 10.1089/met.2006.0034
Lagathu C, Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, Caron M, Bastard JP: HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo. Biochimie. 2005, 87: 65-71. 10.1016/j.biochi.2004.12.007
Moog AM, Becker W: Management of dyslipidemia in HIV-infected patients. MMW Fortschr Med. 2012, 154 (Suppl 1): 34-36.
Friis-Moller N, Thiebaut R, Reiss P, Weber R, Monforte AD, De Wit S, El-Sadr W, Fontas E, Worm S, Kirk O: Predicting the risk of cardiovascular disease in HIV-infected patients: The data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil. 2010, 17: 491-501. 10.1097/HJR.0b013e328336a150
Pinto Neto LF, Das Neves MB, Ribeiro-Rodrigues R, Page K, Miranda AE: Dyslipidemia and fasting glucose impairment among HIV patients three years after the first antiretroviral regimen in a Brazilian AIDS outpatient clinic. Braz J Infect Dis. 2013, 17: 438-443. 10.1016/j.bjid.2012.12.006
Gotti D, Cesana BM, Albini L, Calabresi A, Izzo I, Foca E, Motta D, Bellagamba R, Fezza R, Narciso P: Increase in standard cholesterol and large HDL particle subclasses in antiretroviral-naive patients prescribed efavirenz compared to atazanavir/ritonavir. HIV Clin Trials. 2012, 13: 245-255. 10.1310/hct1305-245
Dube MP, Parker RA, Tebas P, Grinspoon SK, Zackin RA, Robbins GK, Roubenoff R, Shafer RW, Wininger DA, Meyer WA: Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS. 2005, 19: 1807-1818. 10.1097/01.aids.0000183629.20041.bb
Souza SJ, Luzia LA, Santos SS, Rondo PH: Lipid profile of HIV-infected patients in relation to antiretroviral therapy: A review. Rev Assoc Med Bras. 2013, 59: 186-198. 10.1016/j.ramb.2012.11.003
Bavinger C, Bendavid E, Niehaus K, Olshen RA, Olkin I, Sundaram V, Wein N, Holodniy M, Hou N, Owens DK, Desai M: Risk of cardiovascular disease from antiretroviral therapy for HIV: A systematic review. PloS One. 2013, 8: e59551- 10.1371/journal.pone.0059551
Vidrine DJ: Cigarette smoking and HIV/AIDS: Health implications, smoker characteristics and cessation strategies. AIDS Educ Prev. 2009, 21: 3-13.
Amorosa V, Synnestvedt M, Gross R, Friedman H, MacGregor RR, Gudonis D, Frank I, Tebas P: A tale of 2 epidemics: The intersection between obesity and HIV infection in Philadelphia. J Acquir Immune Defic Syndr. 2005, 39: 557-561.
Lichtenstein KA, Armon C, Buchacz K, Chmiel JS, Buckner K, Tedaldi E, Wood K, Holmberg SD, Brooks JT, Investigators H: Provider compliance with guidelines for management of cardiovascular risk in HIV-infected patients. Prev Chronic Dis. 2013, 10: E10-
Malvestutto CD, Aberg JA: Management of dyslipidemia in HIV-infected patients. Clin Lipidol. 2011, 6: 447-462. 10.2217/clp.11.25
Moore RD, Bartlett JG, Gallant JE: Association between use of HMG CoA reductase inhibitors and mortality in HIV-infected patients. PLoS One. 2011, 6: e21843- 10.1371/journal.pone.0021843
Friis-Moller N, Weber R, Reiss P, Thiebaut R, Kirk O, D’Arminio Monforte A, Pradier C, Morfeldt L, Mateu S, Law M: Cardiovascular disease risk factors in HIV patients--association with antiretroviral therapy. Results from the DAD study. AIDS. 2003, 17: 1179-1193. 10.1097/00002030-200305230-00010
Grinspoon S, Carr A: Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005, 352: 48-62. 10.1056/NEJMra041811
Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M: Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy. AIDS. 2001, 15: 2049-2051. 10.1097/00002030-200110190-00021
Thoni GJ, Fedou C, Brun JF, Fabre J, Renard E, Reynes J, Varray A, Mercier J: Reduction of fat accumulation and lipid disorders by individualized light aerobic training in human immunodeficiency virus infected patients with lipodystrophy and/or dyslipidemia. Diabetes Metab. 2002, 28: 397-404.
This study has been partially funded by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (Capes).
The authors declare that they have no competing interest.
AAP: drafted the manuscript; MCNF: drafted the manuscript; AGP: conceived and drafted the manuscript. All authors read and approved the final manuscript.
About this article
Cite this article
Paula, A.A., Falcão, M.C. & Pacheco, A.G. Metabolic syndrome in HIV-infected individuals: underlying mechanisms and epidemiological aspects. AIDS Res Ther 10, 32 (2013). https://0-doi-org.brum.beds.ac.uk/10.1186/1742-6405-10-32
- Metabolic syndrome
- Cardiovascular risk