Multivariate analyses of baseline covariates associated with the development of MS are summarized in Table 2. High baseline BMI, waist/hip ratio, diastolic blood pressure, or triglyceride and low baseline HDL cholesterol were all significantly associated with an increased risk of ATP-III-defined MS. In contrast, only high BMI, hip circumference, waist/hip ratio and triglyceride levels were significantly associated with IDF-defined MS.
Metabolic syndrome as a predictor of cardiovascular events
During follow-up, 21 CVD events were reported among 19 (2.2%) individuals. These events included 11 episodes of shock/heart failure, 6 episodes of angina/ischaemic heart disease, 2 episodes of arrhythmia and 1 episode for each of myocardial infarction and unspecified CVD. Factors associated with developing a CVD event are summarized in Table 3. IDF-defined MS at baseline showed a borderline, nonsignificant association with an increased risk of CVD [hazard ratio (HR), 2.89; 95% confidence interval (CI), 0.98–8.63; P = 0.058], whereas ATP-III-defined MS at baseline did not show a significant association (HR, 2.56; 95% CI, 0.86–7.60; P = 0.095). Progression to MS during follow-up by ATP-III and IDF definitions was significantly associated with an increased risk of developing cardiovascular events during follow-up (ATP-III: HR, 2.73; 95% CI, 1.07–6.96; P = 0.036; IDF: HR, 3.05; 95% CI, 1.20–7.275; P = 0.019). Of MS components, only waist circumference and systolic blood pressure were significantly associated with cardiovascular events during follow-up. Higher baseline Framingham score was not significantly associated with an increased risk of CVD (HR, 1.29 95% CI, 0.35–4.82; P = 0.7).
Metabolic syndrome as a predictor of type 2 diabetes
The incidence of T2DM during 3 years of follow-up was 5% (per 100 patient-years) derived from a total of 41 diagnoses. In total, 13 of these patients had more than one episode of casual plasma glucose > 11.1 mmol/l. Participants with ATP-III- or IDF-defined MS at baseline showed a significantly increased risk of developing T2DM during follow-up (ATP-III: HR, 4.34; 95% CI, 1.83–10.25; P = 0.001; IDF: HR, 3.33; 95% CI, 1.35–8.17; P = 0.009). Several individual components of MS (waist circumference, systolic blood pressure, triglycerides and glucose) were significant predictors of incident T2DM (Table 3). Progression to MS during follow-up according to both ATP-III and IDF definitions was associated with a significantly increased risk of developing T2DM (ATP-III: HR, 4.89; 95% CI, 2.22–10.78; P < 0.0001; IDF: HR, 4.84; 95% CI, 2.20–10.64; P < 0.0001). These relative risk values were higher than those for the individual risk factors. The baseline median glucose levels for patients who later developed T2DM were 5.4 mmol/l (IQR, 5.0–6.2) and 5.2 mmol/l (IQR, 5.0–6.1) for those with metabolic syndrome defined by ATP-III and IDF criteria, respectively. Higher baseline Framingham score did not predict risk of T2DM (HR, 1.10 95% CI, 0.42–2.67; P = 0.9).
In this study of 881 HIV-infected adults commencing combination ART and followed for 3 years, the baseline prevalence of MS was 8.5% assessed by ATP-III criteria and 7.8% assessed by IDF criteria. The presence of MS at baseline was associated with at least a 2.5-fold increase in risk for development of CVD (P = 0.095) and at least a 3.3-fold increase in risk of T2DM (P = 0.009). Incident MS was significantly associated with the development of CVD and T2DM. This findings, based on relatively few incident cases of CVD (21) or T2DM (41), is striking.
Our analyses showed that baseline and incident MS had greater predictive value than a baseline dichotomized Framingham Risk Score for subsequent CVD and T2DM. These results provide an evidential basis for the use of MS in risk determination. Previous investigations have indicated that the Framingham Risk Score underestimates myocardial infarction in HIV-infected patients treated with ART but overestimates myocardial infarction in HIV-infected patients who are not treated with ART . In both patient groups, the Framingham Risk Score was sensitive. In the present study, we employed a more extensive list of CVD events than myocardial infarction alone. These differences in endpoint definition might have contributed to the lack of prediction for CVD events provided by the Framingham Risk Score at baseline. It is also possible that the Framingham Risk Score lacks precision when assessed in a treatment-naive, HIV-infected subject (there are physiological features not included in the Framingham equation that are important and independent determinants of CVD risk). This would argue for assessment of CVD risk to include MS as well as the Framingham Risk Score. An additional benefit from this approach would be the assessment of risk for T2DM.
The prevalence of MS in the US general population exceeds 23% and is approximately 26% in British men [2,4]. The prevalence of MS in this HIV-infected cohort was substantially less than these HIV-negative populations. It was also lower than that reported elsewhere for HIV-positive populations, where prevalence ranged between 14 and 24% [14–18]. INITIO participants were young (mean age 38.7 years), recruited in diverse clinical settings (119 sites in 21 countries), and 21% were female. The relatively low baseline prevalence of MS may reflect the differing demographic characteristics of study participants. The influence of age and race on MS has been well described; the potential contribution of underlying HIV wasting in the absence at baseline of ART should also be considered. Uncontrolled HIV replication also affects serum lipid concentrations (reducing HDL and low density lipoprotein cholesterol but increasing triglycerides) [24–26]. These derangements in lipid metabolism would be expected to increase the prevalence of MS in the INITIO population at baseline, and particularly for the ATP-III definition. Although higher MS prevalence has been described in HIV-positive cohorts, these studies were cross-sectional and predominantly included individuals already taking ART [14–17,27,28]. The INITIO trial provided a unique opportunity to examine MS progression in HIV-infected, treatment-naive individuals. Importantly, the lower rates of MS in this population suggests that HIV infection per se probably does not contribute to MS or may perhaps confer protection from components of the syndrome. Whether ART-naive patients are at reduced risk of subsequent CVD or T2DM is unclear, particularly in light of emerging data from randomized trials and cohorts indicating rates of CVD are higher in people with HIV who are not treated with ART [29,30].
Despite low baseline prevalence, we observed substantial rates of progression to MS (12/100 patient-years by ATP-III and 8/100 patient-years by IDF) over the 3 years following initiation of ART. These estimates are substantially higher than those recently reported in the prospective follow up of a US cohort . It seems probable the difference arises because we assessed incidence in a truly treatment-naive cohort while only 25% (135) of the recently reported population were ART naive at baseline and it is not clear how many of these actually commenced ART during follow-up.
The most prevalent progression to MS was elevated triglycerides in association with increased blood pressure and glucose. In HIV-negative populations, the most common features associated with MS are obesity and hypertension. Elevated blood pressure and triglycerides were also reported as common components in the prospective follow up of a US HIV-positive cohort and the most frequent abnormalities that led to MS diagnosis in a cross-sectional HIV-infected cohort [18,31]. Prevention and management of MS in HIV-positive patients might need to be tailored accordingly.
This study found the risk of T2DM increased at least 3.3-fold in those with MS at baseline (ATP-III: HR, 4.34; 95% CI, 1.83–10.25; IDF: HR, 3.33; 95% CI, 1.35–8.17). In addition, incident MS was significantly associated both with a diagnosis of T2DM and with the development of CVD. These findings are consistent with observations made in the general populations studied to date . The adjusted HR values for MS were higher than those for the individual MS components. This finding is important, indicating a higher predictive value from MS than the predictive value of its individual components. The validity of MS has been under substantial international debate and this study is one of the first to use prospective data to support the multiplicative effects of the combined risk factors over the assessment of individual risk factors .
We did not observe any significant differences in rates of progression to MS between the randomized treatment groups in INITIO. This is despite the well-described impact of ART class or drugs on the components of MS [7,9–14,18,31–33]. There was departure from the protocol-defined initial regimens of therapy in INITIO . It is possible this dilution tended to mask any real differences arising from the different regimens in this study. Similarly, all patients received a common nucleoside reverse transcriptase inhibitor component in their ART regimen, didanosine and stavudine. This too, may have masked any contributions of either nelfinavir or efavirenz on progression to MS in this cohort.
There are some important caveats to this work. First, all of the analyses were post hoc and there was no adjustment for multiple analyses. There is a possibility of type I errors. Second, our CVD endpoints were assessed from spontaneous study site reports that were not subjected to any type of validation. It is also true that our analyses included only a limited number of defined clinical events (21 CVD and 41 T2DM), resulting in very limited overall power. Third, it should be noted that the INITIO regimens would no longer be recommended for initial therapy . Currently recommended initial ART would be expected to induce less dyslipidaemia and lipodystrophy. Fourth, we do not have reliable data on race or ethnicity and cannot comment on any racial differences within our cohort. Finally, we were not able to confirm that assessment of serum triglycerides or glucose was performed on blood drawn from fasted subjects for all but a minority of scheduled visits. We selected an applicable definition of T2DM and selected a CVD diagnosis that we felt to be clinically related to atherosclerosis and vascular disease. Collectively, we urge caution against overinterpretation of these findings.
Debate continues on the validity of MS for clinical management. We did not observe substantial differences between the ATP-III and IDF assessment of MS in this cohort. Because the IDF system now adjusts for race, we would propose that it is likely to be more applicable. Our data indicate that MS is less prevalent in HIV-infected individuals who are ART naive compared with that in the general population. We observed an incident rate of progression to MS in HIV-infected patients treated with combination ART somewhat higher than previously reported. The finding that MS possibly identifies those at increased risk of CVD and T2DM may be of value for selecting patients for risk assessment and possibly preventive strategies. This is particularly true given the need for lifelong ART in people with HIV-1 infection. The impact of preventive strategies would need evaluation.
We thank all the participants who joined the trial. We also thank the investigators and staff at the participating sites, which are listed in full in the main trial report (Lancet 2006; 368:287–98).
Sponsorship: The NCHECR is funded by the Australian Federal Department of Health and Ageing and is affiliated through the Faculty of Medicine with the University of New South Wales. The Federal Department of Health played no role in the design, collection, analysis or interpretation of data or in the decision to prepare a written report or submit for publication.
INITIO Trial International Coordinating Committee. D.A. Cooper (joint Chair NCHECR), P. Yeni (joint Chair Groupe Hospitalier Bichat). J.-P. Aboulker (INSERM SC10), F. Antunes (National Principal Investigator, Portugal), A. Babiker (MRC CTU), M. Becker (Roche), N. Boukli (INSERM SC10), F. Brun-Vezinet (joint chair Virology Group), D. Carey (NCHECR), D. Churchill (joint National Principal Investigator, UK), B. Conway (National Principal Investigator, Canada), C. Chazallon (INSERM SC10), J. Darbyshire (MRC CTU), S. De Wit (National Principal Investigator, Belgium), B. Dusak (Dupont), S. Emery (NCHECR), M. Flepp (National Principal Investigator, Switzerland), M. Floridia (ISS), J. Gatell (National Principal Investigator, Spain), P.-M. Girard (National Principal Investigator, France), R.L. Goodall (MRC CTU), R. Hemmer (National Principal Investigator, Luxembourg), M. Hooker (MRC CTU), M. Law (NCHECR), C. Loveday (joint chair Virology Group), J. Lundgren (National Principal Investigator, Denmark), D. Manion (Dupont), V. Meiffredy (INSERM SC10), A. Mijch (National Principal Investigator, Australia and New Zealand), F. Mulcahy (National Principal Investigator, Ireland), A. Orani (National Principal Investigator, Italy), C. Pharo (GSK), M. Ristola (National Principal Investigator, Finland), B. Salzberger (joint National Principal Investigator, Germany), E. Sandstrom (National Principal Investigator, Sweden), M. Schechter (National Principal Investigator, Brazil), S. Schnittman (Bristol Myers Squibb), M. Seligmann (Chair Immunology Group), S. Staszewski (joint National Principal Investigator, Germany), M. Stek (Merck), W. Verbiest (VIRCO), J. Weber (joint National Principal Investigator, UK).
Coordinating Trial Centres. Australia/New Zealand/Brazil: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney (D. Carey, S. Emery, W. Lee, S. Phipps, T. Sharkey); Canada: Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver (B. Conway, R. Dimayuga, M. Jones, S. Jutha, D. Kraus, B. Zastre); Denmark/Sweden/Finland: Copenhagen HIV Programme, Hvidovre (U. Dragsted, A. Grønholdt, K. Jensen, J. Lundgren, D. Mollerup, L. Skinnes); France/Belgium/Luxembourg/Spain/Portugal: INSERM SC10, Paris (J.-P. Aboulker, N. Boukli, C. Chazallon, B. Guillon, S. Kahi, L. Léger, V. Meiffrédy, A.-S. Rodier, Y. Saidi); UASP: Hospital Clinic, Barcelona (A. Cruceta); Germany: Coordinating Centre for Clinical Studies (KKS), Philipps University, Marburg (B. Lenz, J. Rochon, C. Schade-Brittinger, M. Wittenberg, H. Wolf); Italy: Laboratory of Virology and Department of Clinical Research and Evaluation, Istituto Superiore di Sanità, Rome (R. Bucciardini, M. Floridia, V. Fragola, C.M. Galluzzo, E. Germinario, M. Guidi, F. Innocenti, M. Massella, A. Mattei, M. Mirra, M.I. Paoloni, C. Polizzi, M. Pirillo, S. Vella); Switzerland: Clinic for Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich (M. Flepp, E. Gremlich, A. Mosimann); UK and Ireland: MRC Clinical Trials Unit, London (A. Babiker, J. Darbyshire, R. Goodall, M. Hooker, F. Hudson, D. Johnson, P. Kelleher, A. Poland, K. Taylor, J. Wait, R. Withnall); Overall coordination: MRC CTU (London); databases held and maintained: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; INSERM SC10, Paris, France; Coordinating Centre for Clinical Studies, Philipps University, Marburg, Germany; Laboratory of Virology and Department of Clinical Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy; MRC Clinical Trials Unit, London, UK.
1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third and final report
2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356–359.
3. Kahn R, Buse J, Ferrannini E, Stern M, for the American Diabetes Association European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28:2289–2304.
4. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005; 165:2644–2650.
5. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al
. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung and Blood Institute Statement. Circulation 2005; 112:2735–2752.
6. Alberti KG, Zimmet P, Shaw J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome: a new worldwide definition. Lancet 2005; 366:1059–1062.
7. 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–F58.
8. Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med 2005; 118(Suppl 2):23S–28S.
9. Sattler FR, Qian D, Louie S, Johnson D, Briggs W, DeQuattro V, Dube MP. Elevated blood pressure in subjects with lipodystrophy. AIDS 2001; 15:2001–2010.
10. Seaberg EC, Munoz A, Lu M, Detels R, Margolick JB, Riddler SA, et al
, for the Multicenter AIDS Cohort Study. Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003. AIDS 2005; 19:953–960.
11. Thiébaut R, El-Sadr WM, Friis-Moller N, Rickenbach M, Reiss P, Monforte AD, et al
, for the Data Collection of Adverse events of anti-HIV Drugs (D:A:D) Study Group. Predictors of hypertension and changes of blood pressure in HIV-infected patients. Antivir Ther 2005; 10:811–823.
12. Crane HM, Van Rompaey SE, Kitahata MM. Antiretroviral medications associated with elevated blood pressure among patients receiving highly active antiretroviral therapy. AIDS 2006; 20:1019–1026.
13. Friis-Møller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, et al
, for the Data Collection on Adverse Events of Anti-HIV Drugs Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
14. Jerico C, Knobel H, Montero M, Ordonez-Llanos J, Guelar A, Gimeno JL, et al
. Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors. Diabetes Care 2005; 28:132–137.
15. Mondy K, Overton E, Grubb J, Tong S, Segfreid W, Powderly W, et al
. Metabolic syndrome in HIV-infected patients from an urban, mid-western US outpatient population. Clin Infec Dis 2007; 44:726–734.
16. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003; 163:427–436.
17. 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. Diabetes Care 2007; 30:113–119.
18. Jacobson DL, Tang AM, Spiegelman D, Thomas AM, Skinner S, Gorbach S, et al
. 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 Def Syndr 2006; 43:458–466.
19. INITIO Trial International Co-ordinating Committee. Virological and immunological outcomes at three years following initiation of ART with regimens containing a NNRTI or PI or both: the INITIO trial
20. Eberly LE, Stamler J, Neaton JD, for the MrFIT Research Group. Relation of triglyceride levles, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Arch Intern Med 2003; 163:1077–1083.
21. American Diabetes Association. The Diagnosis and Classification of Diabetes Mellitus
. Diabetes Care
22. Anderson KM, Odell PM, Wilson PWF, Kammel WB. Cardiovascular disease risk profiles. Am Heart J 1990; 121:293–298.
23. Law MG, Friis-Moller N, El-Sadr WM, Weber R, Reiss P, D'Arminio-Monforte A, et al
. The use of the Framingham equation to rpedict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med 2006; 7:218–230.
24. Grunfeld C, Feingold KR. The role of cytokines, interferon alpha and tumour necrosis factor in te hypertriglyceridemia and wasting of AIDS. J Nutr 1992; 122:749–753.
25. Grunfeld C, Kotler DP, Shigenaga JK, Doerrler W, Tierney A, Wang J, et al
. Circulating interferon-alpha levels and hypertriglcyeridemia in the acquired immunodeficiency syndrome. Am J Med 1991; 90:154–162.
26. Shor-Posner G, Basit A, Lu Y, Cabrejos C, Chang J, Flectcher M, et al
. Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med 1993; 94:515–519.
27. Bonfanti P, Ricci E, de Socio G, Zeme D, Carradori S, Penco G, et al
. Metabolic syndrome: a real threat for HIV-positive patients? J Acquir Immun Defic Syndr 2006; 42:128–131.
28. 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.
29. The D:A:D Study Group. Combination antiretroviral therapy and the risk of myocardial infarction
. N Engl J Med
30. The SMART Study Group. CD4+ cell count guided antiretroviral treatment interruption and clinical outcomes among HIV infected individuals with CD4+ cell count > 350 cells/mm3: Primary results of the Strategies for Management of Antiretroviral Therapy (SMART) Trial
. N Engl J Med
31. Hadigan C, Meigs JB, Wilson PW, D'Agostino RB, Davis B, Basgoz N, et al
. Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution. Clin Infect Dis 2003; 36:909–916.
32. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999; 353:2093–2099.
33. Meigs JB. Metabolic syndrome: in search of a clinical role. Diabetes Care 2006; 27:2761–2763.
© 2007 Lippincott Williams & Wilkins, Inc.
34. US Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents
. Washington, DC: US Department of Health and Human Services; October 2006. http://aidsinfo.nih.gov
(accessed January 10, 2007).