UCLA UCLA Previously Published Works Title Coronary Artery Disease in Patients with HIV Infection Permalink https://escholarship.org/uc/item/6qr2s3d9 Journal American Journal of Cardiovascular Drugs, 15(2) ISSN 1175-3277 Authors Patel, AA Budoff, MJ Publication Date 2015-04-01 DOI 10.1007/s40256-015-0105-8 Peer reviewed eScholarship.org Powered by the California Digital Library University of California https://escholarship.org/uc/item/6qr2s3d9 https://escholarship.org http://www.cdlib.org/ 1 23 American Journal of Cardiovascular Drugs ISSN 1175-3277 Volume 15 Number 2 Am J Cardiovasc Drugs (2015) 15:81-87 DOI 10.1007/s40256-015-0105-8 Coronary Artery Disease in Patients with HIV Infection Amish A. Patel & Matthew J. Budoff 1 23 Your article is protected by copyright and all rights are held exclusively by Springer International Publishing Switzerland. This e- offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. L E A D I N G A R T I C L E Coronary Artery Disease in Patients with HIV Infection Amish A. Patel • Matthew J. Budoff Published online: 12 February 2015 � Springer International Publishing Switzerland 2015 Abstract HIV-infected patients are known to be at risk for premature coronary artery disease. This emerging paradigm is a rising concern for clinicians. Due to advances in the treatment of HIV, this once fatal infection has been trans- formed into a chronic illness. Traditional risk factors paired with the long-term use of antiretroviral therapy (ART) and chronic inflammation leads to premature atherosclerosis, particularly progression of atherosclerotic plaque. This population of patients requires early recognition of sub- clinical atherosclerosis, as well aggressive primary and sec- ondary prevention strategies among the multi-disciplinary team of physicians caring for them. We sought to present a comprehensive review of the available literature related to HIV and atherosclerosis and cardiovascular risk. Key Points Recognize non-traditional and emerging risk factors for coronary artery disease (CAD) in the HIV population. The benefit of continuous antiretroviral therapy remains the standard in CAD reduction. Statins are suggested in the HIV population to reduce CAD but caution must be taken due to drug–drug interactions. Due to possible underestimation of CAD in the HIV population, consider computed tomography and coronary angioplasty for preventative and therapeutic guidance, respectively. 1 Introduction Cardiovascular disease (CVD) has emerged as a significant threat to the HIV-infected population, in large part due to the effectiveness of antiretroviral therapy (ART) in treating HIV infection and extending life expectancy [1]. Currently, CVD is the second most frequent cause of death among HIV patients, with the first being cancer [2]. The sub- clinical makers of atherosclerosis, such as carotid, femoral, or iliac intima-media thickness are consistently greater and progress earlier among the HIV-positive population than among the general population [3, 4]. The D:A:D (Data Collection in Adverse Effects of Anti- HIV Drugs) study showed that risk for cardiovascular event was statistically increased by such traditional risk factors as age, male sex, greater body mass index (BMI), family history of CVD, and smoking [5]. This is exacerbated by HIV-specific risk factors such as low CD4 T-lymphocyte cell (CD4) count, co-infection with hepatitis C virus, and certain ARTs (Table 1). D:A:D showed that the dys- metabolic effects of HIV protease inhibitors (PI) increased the risk of diabetes mellitus, hypertension, and dyslipi- demia [5]. In HIV-infected patients, the risk of myocardial infarction (MI) is approximately twofold [10], and the risk of sudden cardiac death is approximately fourfold [11] compared with the general population. The MACS (Multicenter AIDS Cohort Study), initiated in 1983, is an on-going multicenter prospective, observa- tional cohort study. It continues to conduct studies and publish key papers on the natural history of untreated and treated HIV infection [12]. A number of significant results a found that HIV-infected men had a greater extent of non- calcified coronary artery plaque (NCAP) [13]. In another study also using computed tomography coronary A. A. Patel � M. J. Budoff (&) Los Angeles Biomedical Research Institute at Harbor-UCLA, 1124 W Carson St, Torrance, CA 90502, USA e-mail: MBudoff@labiomed.org Am J Cardiovasc Drugs (2015) 15:81–87 DOI 10.1007/s40256-015-0105-8 Author's personal copy angiography (coronary CTA), an increased prevalence of vulnerable plaque features among relatively young HIV- infected men was found [14]. These findings are not only limited to the male HIV-infected population. A study that focused on the female HIV population found that young, asymptomatic HIV-infected women also demonstrate in- creased NCAP [15]. This has led to a surge in interest in the association between HIV infection and CVD, specifically NCAP due to the increase of major adverse cardiac events (MACE) associated with it [16]. It should be pointed out that the coronary plaque analysis from the MACS database was concluded using cross-sectional studies. This leaves the possibility that HIV-infected indi- viduals have an overall greater risk profile than non-in- fected individuals. The MACS cohort is currently undergoing a second CTA at 5 years to evaluate for plaque progression in the HIV group using different retroviral therapies. 2 Pathophysiology of Coronary Artery Disease in Patients with HIV Infection HIV acts by mainly targeting the CD4? T cells and, to a lesser extent, macrophages and dendritic cells, which all play an essential role in immunity. The infection and massive depletion of CD4? T cells represents the funda- mental pathogenesis of HIV infection [17]. The patho- physiology of coronary artery disease (CAD) in HIV- infected patients is multifactorial and complex, combining traditional and non-traditional risk factors in addition to emerging risk factors. To date, factors associated with CAD in HIV have been determined indirectly or by asso- ciation, which makes our understanding of the overall process limited. Prospective studies evaluating long-term CAD outcomes are needed. CAD is the result of chronic inflammation of the arterial wall, which is lined by endothelial cells (ECs) and smooth- muscle cells [18]. HIV infection is associated with an in- crease in systemic inflammation and damage to the vascular endothelium [19]. This leads to HIV-positive in- dividuals being prone to premature atherosclerosis. In atherosclerosis, the activation of ECs in response to an inflammatory state leads to the expression and release of cytokines and chemokines, specifically interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1. These have been suggested to play the key role in the initial phase of atherosclerosis [20–22]. An increase in IL-6 levels has been associated with an increase in cardiovascular mor- tality in HIV-infected individuals [20], and MCP-1 has been shown to play a part in the attraction, migration, and activation of monocytes [23]. When using mice deficient in MCP-1 or its receptor, C-C chemokine receptor (CCR)-2, to examine atherosclerosis, it was demonstrated that, in the absence of MCP-1 or its receptor, CCR-2, there was a substantial reduction in atherosclerosis [24]. Proinflammatory monocytes CD14? CD16? have also been implicated in the atherosclerosis disease process [25]. In a large study involving more than 200 patients with CAD, increased percentages of the CD14? CD16? monocytes were seen in the patient cohort [26]. A recent study analyzing coronary artery calcium (CAC) and in- flammatory markers found that higher frequencies of CD16? monocytes (lacking CD14 expression) predicted greater CAC progression [27]. CAC progression has been shown to be associated with increased cardiovascular morbidity and all-cause mortality [28, 29]. CAC has also been proven as an independent predictor of future risk of CVD events [30]. In HIV-in- fected patients, the disease process is thought to begin with an inflammatory state. Inflammation initiates the recruit- ment of monocytes; monocytes then migrate to the en- dothelium and differentiate to macrophages and foam cells. Foam cells transform and undergo apoptosis because of calcium-dependent endoplasmic reticulum stress, thus leading to atherosclerosis [31]. Excessive death of foam cells overloaded with cholesterol eventually forms the plaques in the arteries, induces further inflammation, and exacerbates metabolic dysregulation [32]. It is speculated that the HIV virus, which activates inflammation and lipid- markers, also triggers endoplasmic reticulum (ER) stress through its interaction with host genes that result in an imbalance of calcium [33]. Histopathologically, the vas- cular changes associated with HIV infection include ec- centric atheromatous plaques composed of fibrous tissue, lipid, and calcium, with variable degrees of chronic in- flammation and accelerated atherosclerosis [34]. A post- mortem study observed an unusual pattern of dystrophic vascular calcification in HIV? patients who were treated with ART from all major class for a mean ± standard deviation (SD) duration in years of 4.6 ± 3.5, speculating that the metabolic derangements in HIV? patients re- ceiving ART may predispose them to this type of Table 1 Cardiovascular risk factors in HIV [5–9] Traditional Nontraditional Age Low CD4 count Sex Lidodystrophy syndrome Greater body mass index Hepatitis C co-infection Family history of premature heart disease Metabolic syndrome Smoking End-stage renal disease Diabetes Antiretroviral therapy Dyslipidemia Hypertension 82 A. A. Patel, M. J. Budoff Author's personal copy atherosclerosis [35]. ART essentially acts to suppress the HIV viral load and is recommended for all HIV-infected individuals to reduce the risk of disease progression. Current data on the effect of CD4 count and viral load on cardiovascular mortality have not been entirely consis- tent. The D:A:D study found there was no association be- tween either the nadir CD4? lymphocyte count or peak HIV-1 RNA level and the risk of MI [36]. In the prospectively recorded FHDH (French Hospital Database on HIV) study, lower nadir CD4 cell count and higher plasma viral load were associated with a statistically sig- nificant increased rate of MI, independent of exposure to ART and presence of traditional risk factors [37]. There- fore, it appears that age-related changes in combination with HIV infection and long-term ART therapy all likely contribute in a cumulative effect on the arterial walls to produce atherosclerosis. 3 Diagnosis The first step in diagnosis of CVD in the HIV population begins with a thorough medical history, which would in- clude a complete history of prior antiretroviral exposure. A further detailed assessment of CAD risk factors is then to be performed, including smoking history, family history of CAD, and fasting determinations of total cholesterol, high- density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, Framingham Risk Score (FRS) or the atherosclerotic cardiovascular disease (ASCVD) risk assessment. As mentioned, recent analysis has suggested that chronic inflammation can partially at- tribute to the increased cardiovascular risk correlated with HIV infection [38, 39]. The underlying mechanism of this disease process is currently being studied and remains unclear. However, the atherosclerotic byproduct of this process can be detected with current cardiac imaging modalities, particularly cardiac CT. Cardiac CT estimates CAC, which provides a noninva- sive assessment of subclinical atherosclerosis that also correlates with the extent of histologically confirmed NACP [40, 41]. Additionally, CAC progression is inde- pendently associated with future risk of CVD events and all-cause mortality [28, 29]. The risk classification for CAD or stroke significantly improves by adding CAC assessment along with traditional risk factors [28, 42, 43]. However, in the HIV population, the generalized use of only CAC scoring could be deceptive. Recently demon- strated among an HIV population receiving ART therapy for at least 8 years, the extent of calcification was sig- nificantly reduced compared with HIV-seronegative con- trols [44]. In a study using coronary CTA, HIV-infected men were found to have a greater extent of non-calcified plaque after CAD risk factor adjustment [13]. Only a small number of studies have characterized the degree of both CAC plaque and NCAP in HIV-infected adults [45, 46]. One study found an increased NCAP volume in HIV-in- fected men compared with uninfected controls with a trend toward higher Agatston calcium scores among those pa- tients with HIV. Within the HIV-infected group, plaque volume was associated with traditional markers of CVD risk and HIV-specific risk factors [45]. In another study, the data found an increased prevalence of vulnerable plaque features among a relatively young population of HIV-in- fected patients [14]. Though the routine use of coronary CTA to assess the degree of coronary atherosclerosis is still debated, it can provide preventive and therapeutic guidance in this high- risk population. Furthermore, specific risk factors identified in HIV-related atherosclerosis, such as chronic inflamma- tion, immune activation, and effects of ART are not cal- culated with available risk scores. This can lead to underestimation of true cardiovascular risk in the HIV-in- fected population. 4 Prevention The most important preventive measure for a high-risk population is lifestyle modification and statin use. A study analyzing data from MACS and the WIHS (Women’s In- teragency HIV Study) found HIV-infected individuals to have a higher prevalence of smoking (up to 40 %) and to meet criteria for being overweight or obese (BMI [ 25), which increased predicted cardiovascular risk [47], thereby giving clinicians an opportunity to intervene on modifiable risk factors. The first of these is smoking cessation, as smoking is a well-known cardiovascular risk factor. The American Heart Association has set forth guidelines for lifestyle management to reduce cardiovascular risk in the general population and these shouldalso be applied to this sub- group. These include improved diet and increased physical activity, both of which contribute to weight loss, lowering blood pressure, reduction in insulin resistance, and blood lipid modification [48]. Due to the increased risk of premature atherosclerosis associated with HIV infection, an aggressive implementa- tion of cardiovascular therapies is required soon after di- agnosis. As mentioned earlier, ART remains the first-line treatment for HIV infection. Combination ART is currently defined as any combination of three antiretroviral drugs, usually two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus a PI or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus an integrase inhibitor [49]. Effec- tive ART reduces viral load, which is thought to decrease CAD in HIV 83 Author's personal copy the inflammatory effects of HIV and therefore reduce atherosclerosis [50]. The D:A:D study indicated that cumulative exposure to specific PIs (lopinavir–ritonavir and indinavir) and two NRTI drugs (abacavir and didanosine) was associated with an increased risk of MI [5, 51]. As the duration of exposure to PIs increases, the risk for MI also increases, as seen in the FHDH and D:A:D cohorts [37, 51]. The cumulative exposure to all studied PIs was associated with a higher risk of MI, with an odds ratio (OR) of 2.23 per 10 years of exposure [95 % confidence interval (CI) 1.17–4.24] [37]. However, the PI risk–benefit ratio continues to remain positive, as the increase in life expectancy in PI-based ART outweighs the risk of MI [52]. Neither of these cohorts found any significant association between the development of MI and cumulative exposure to an NNRTI [37, 51]. Of the NRTIs, the only significant association between MI risk and cumulative exposure was with abacavir [rela- tive risk (RR) 1.07 (95 % CI 1.00–1.14)]; recent exposure (less than 6 months) to abacavir [RR 1.70 (95 % CI 1.17–2.47)] or didanosine [RR 1.41 (95 % CI 1.09–1.82)] were both associated with an increased risk of MI. There were no significant associations between MI risk and recent exposure to any of the other NRTIs, particularly tenofovir [51]. The SMART (Strategies for Management of Anti- Retroviral Therapy) study reported that the current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical MI or major CVD were 4.3 (95 % CI 1.4–13.0) and 1.8 (95 % CI 1.0–3.1), respectively [53]. A Canadian study also found an increased risk of MI with any exposure to abacavir [OR 1.79 (95 % CI 1.16–2.76)] [54]. In contrast, a retrospective study using the US Veterans Administration’s Clinical Case Registry showed no sig- nificant association between abacavir use and MI risk [55]. The prospective FHDH study did not find any causal re- lationship, as the observed association with recent exposure to abacavir or didanosine was unstable in sensitivity ana- lysis [37]. Three meta-analyses also showed no significant association between abacavir use and MI [56–58]. In a study analyzing the MACS and Women’s Interagency HIV Study cohorts found abacavir use was not independently associated with elevated inflammatory markers (high sen- sitivity C-reactive protein, IL-6, or D-dimer) at 6 months after initiation [59]. The differences in these studies can be explained by the presence of confounding factors, such as smoking, kidney disease, cocaine and/or intravenous drug use, and potential for selection biases. Therefore, it is not currently possible to draw any conclusions regarding a causal relationship between treatment with abacavir and the risk for develop- ing an MI [60]. This should be taken into account when considering specific ART therapy. The recommendations to initiate medications for pri- mary prevention do not differ from those for the general population. Statins are recommended for the increased risk of CVD in the HIV infection [61], although caution needs to be taken due to possible drug interactions. For instance, certain HMG-CoA reductase inhibitors are contraindicated in combination with PIs [62]. Lower-dose fluvastatin, ro- suvastatin, pravastatin, and atorvastatin are recommended to avoid the increase of drug concentration induced by cytochrome P450 (CYP)-3A4 inhibition by PIs (Table 2). Evidence is clear that ART therapy significantly decreases the overall mortality associated with HIV infection. De- spite concern that certain ART agents might be associated with cardiovascular risks, the discontinuation of HIV-sup- pressive therapy may result in an even greater risk of dis- ease. A potential explanation for this finding is that HIV suppression in itself is cardioprotective by reducing proinflammatory cytokines (i.e., IL-6), which play a role in arterial inflammation [20]. The SMART study found that patients receiving episodic ART were at greater risk for cardiovascular events than were those receiving continuous therapy [64]. Therefore, the prevention of CVD should be focused on continuous ART, lifestyle modification, and consideration of lipid-lowering agents. 5 Conclusion The life expectancy of the HIV-infected population con- tinues to improve with ART therapy and nearly matches the general population when viral load is controlled [1]. Mortality from AIDS-related illnesses is steadily decreas- ing, while age-related disease such as CVD continues to increase in this population [65]. More profound is the evidence to suggest that subclinical atherosclerosis is being Table 2 Antiretroviral drug combinations to avoid [48, 63] Protease inhibitor HMG-CoA reductase inhibitors to avoid Ritonavir (RTV) Lovastatin, simvastatin Atazanavir (ATV)/RTV Lovastatin, simvastatin Darunavir (DRV)/RTV Lovastatin, simvastatin Fosamprenavir (FPV)/RTV Lovastatin, simvastatin Lopinavir/ritonavir (LPV/ RTV) Lovastatin, simvastatin Saquinavir (SQV)/RTV Lovastatin, simvastatin Tipranavir (TPV)/RTV Atorvastatin, lovastatin, simvastatin Alternative recommendations: use pravastatin or fluvastatin, which have the least potential for drug–drug interactions (except for pravastatin with DRV/RTV, which needs careful monitoring). May use atorvastatin or rosuvastatin with caution (start with the lower possible dose and titrate based on tolerance and lipid-lowering effi- cacy). Avoid atorvastatin with TPV 84 A. A. Patel, M. J. Budoff Author's personal copy found in relatively young HIV-infected patients [14, 15]. HIV suppression remains the standard in CVD reduction, as studies have suggested that higher CD4 cell counts and lower HIV RNA levels are associated with a decrease in MI risk [37, 64]. Opportunities for risk factor reduction such as lifestyle modification are required, and the imple- mentation of pharmacologic therapy such as statins can be considered. Once primary and secondary preventions have been exhausted and further risk stratification is needed, we suggest the novel use of coronary CTA to assess atherosclerotic plaque morphology among HIV-infected patients. The ability to compare plaque morphology be- tween HIV-infected patients and non-HIV-infected patients with similar traditional cardiovascular risk factors can be a useful tool not only in epidemiological studies but also in clinical applications. Finally, we hope continued interest remains to verify current data and associations with prospective studies involving coronary plaque analysis. Conflict of interest M. J. Budoff is a consultant for General Electric. A. A. Patel has no conflict of interest to declare. References 1. Wada N, Jacobson LP, Cohen M, French A, Phair J, Munoz A. Cause-specific life expectancies after 35 years of age for human immunodeficiency syndrome-infected and human immunodefi- ciency syndrome-negative individuals followed simultaneously in long-term cohort studies, 1984-2008. Am J Epidemiol. 2013;177:116e125. 2. Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis. 2008;47:542–53. 3. Periard D, Cavassini M, Taffé P, Chevalley M, Senn L, Chapuis- Taillard C, de Vallière S, Hayoz D, Tarr PE, Swiss HIV Cohort Study. High prevalence of peripheral arterial disease in HIV- infected persons. Clin Infect Dis. 2008;46:761–7. 4. Mercié P, Thiébaut R, Aurillac-Lavignolle V, Pellegrin JL, Yvorra-Vives MC, Cipriano C, Neau D, Morlat P, Ragnaud JM, Dupon M, Bonnet F, Lawson-Ayayi S, Malvy D, Roudaut R, Dabis F, Groupe d’Epidemiologie Clinique du Sida en Aquitaine (GECSA). Carotid intima-media thickness is slightly increased over time in HIV-1-infected patients. HIV Med. 2005;6:380–7. 5. Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, Monforte Ad, Kirk O, Friis-Moller N, Phillips A, Reiss P, El Sadr W, Pradier C, Worm SW, Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS. 2010;24(10):1537–48. 6. Gillis J, Smieja M, Cescon A, Rourke SB, Burchell AN, Cooper C, Raboud JM, OHTN Cohort Study Group. Risk of cardiovas- cular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals. Antivir Ther. 2014;19(3):309–17. 7. Lichtenstein KA, Armon C, Buchacz K, Chmiel JS, Buckner K, Tedaldi EM, et al. Low CD4R T cell count is a risk factor for cardiovascular disease events in the HIV Outpatient study. Clin Infect Dis. 2010;51:435–47. 8. Urbanus AT, van de Laar TJ, Stolte IG, Schinkel J, Heijman T, Coutinho RA, et al. Hepatitis C virus infections among HIV- infected men who have sex with men: an expanding epidemic. AIDS. 2009;23:F1–7. 9. Friis-Møller N, Sabin CA, Weber R, d’Arminio Monforte A, El- Sadr WM, Reiss P, Thiébaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD, Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of my- ocardial infarction. N Engl J Med. 2003;349(21):1993–2003. 10. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92:2506–12. 11. Tseng ZH, Secemsky EA, Dowdy D, Vittinghoff E, Moyers B, Wong JK, et al. Sudden cardiac death in patients with human immunodeficiency virus infection. J Am Coll Cardiol. 2012;59:1891–6. 12. Detels R, Jacobson L, Margolick J, Martinez-Maza O, Muñoz A, Phair J, Rinaldo C, Wolinsky S. The multicenter AIDS Cohort Study, 1983 to…. Public Health. 2012;126(3):196–8. 13. Post WS, Budoff M, Kingsley L, Palella FJ Jr, Witt MD, Li X, George RT, Brown TT, Jacobson LP. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med. 2014;160(7):458–67. 14. Zanni MV, Abbara S, Lo J, Wai B, Hark D, Marmarelis E, Grinspoon SK. Increased coronary atherosclerotic plaque vul- nerability by coronary computed tomography angiography in HIV-infected men. AIDS. 2013;27(8):1263–72. 15. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, Lo J, Grinspoon SK. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208(11):1737–46. 16. Nance JW Jr, Schlett CL, Schoepf UJ, Oberoi S, Leisy HB, Barraza JM Jr, Headden GF, Nikolaou K, Bamberg F. Incre- mental prognostic value of different components of coronary atherosclerotic plaque at cardiac CT angiography beyond coro- nary calcification in patients with acute chest pain. Radiology. 2012;264(3):679–90. 17. Siliciano JD, Siliciano RF. Latency and viral persistence in HIV- 1 infection. J Clin Invest. 2000;106:823–5. 18. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95. 19. Alonso-Villaverde C, Coll B, Parra S, Montero M, Calvo N, Tous M, Joven J, Masana L. Atherosclerosis in patients infected with HIV is influenced by a mutant monocyte chemoattractant protein- 1 allele. Circulation. 2004;110:2204–9. 20. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD, INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV in- fection. PLoS Med. 2008;5:e203. 21. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–81. 22. Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macro- phages. Nat Immunol. 2000;1(6):510–4. 23. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. Interferon Cytokine Res. 2009;29(6):313–26. 24. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion for- mation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394(6696):894–7. CAD in HIV 85 Author's personal copy 25. Ziegler-Heitbrock L. The CD14R CD16R blood monocytes: their role in infection and inflammation. J Leuk Biol. 2007;81:584–92. 26. Schlitt A, Heine GH, Blankenberg S, Espinola-Klein C, Dopheide JF, Bickel C, Lackner KJ, Iz M, Meyer J, Darius H, Rupprecht HJ. CD14?CD16? monocytes in coronary artery disease and their relationship to serum TNF levels. Thromb Haemost. 2004;92:419–24. 27. Baker JV, Hullsiek KH, Singh A, Wilson E, Henry K, Lichten- stein K, Onen N, Kojic E, Patel P, Brooks JT, Hodis HN, Budoff M, Sereti I, CDC SUN Study Investigators. Immunologic pre- dictors of coronary artery calcium progression in a contemporary HIV cohort. AIDS. 2014;28(6):831–40. 28. Budoff MJ, Young R, Lopez VA, Kronmal RA, Nasir K, Blu- menthal RS, Detrano RC, Bild DE, Guerci AD, Liu K, Shea S, Szklo M, Post W, Lima J, Bertoni A, Wong ND. Progression of coronary calcium and incident coronary heart disease events: MESA (MultiEthnic Study of Atherosclerosis). J Am Coll Car- diol. 2013;61:12319. 29. Budoff MJ, Hokanson JE, Nasir K, Shaw LJ, Kinney GL, Chow D, et al. Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovasc Imaging. 2010;3:1229–36. 30. Criqui MH, Denenberg JO, Ix JH, McClelland RL, Wassel CL, Rifkin DE, Carr JJ, Budoff MJ, Allison MA. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014;311(3):271–8. 31. Oh J, Riek AE, Weng S, Petty M, Kim D, Colonna M, Cella M, Bernal-Mizrachi C. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem. 2012;287(15):11629–41. 32. Tabas I. The role of endoplasmic reticulum stress in the pro- gression of atherosclerosis. Circ Res. 2010;107:839–50. 33. Shrestha S, Irvin MR, Grunfeld C, Arnett DK. HIV, inflamma- tion, and calcium in atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34(2):244–50. 34. Restrepo CS, Diethelm L, Lemos JA, et al. Cardiovascular complications of human immunodeficiency virus infection. Ra- diographics. 2006;26:213–31. 35. Micheletti RG, Fishbein GA, Fishbein MC, et al. Coronary atherosclerotic lesions in human immunodeficiency virus-infect- ed patients: a histopathologic study. Cardiovasc Pathol. 2009;18(1):28–36. 36. Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte Ad, El- Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17):1723–35. 37. Lang S, Mary-Krause M, Simon A, Partisani M, Gilquin J, Cotte L, Boccara F. Costagliola D; French Hospital Database on HIV (FHDH)–ANRS CO4. HIV replication and immune status are independent predictors of the risk of myocardial infarction in HIV-infected individuals. Clin Infect Dis. 2012;55(4):600–7. 38. Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One. 2012;7:e44454. 39. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268–73. 40. Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radio- logy and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation. 2006;114:1761–91. 41. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area, A histopathologic correlative study. Circulation. 1995;92:2157–62. 42. Raggi P, Cooil B, Shaw LJ, Aboulhson J, Takasu J, Budoff M, et al. Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myo- cardial infarction. Am J Cardiol. 2003;92:827–9. 43. Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA. 2010;303:1610–6. 44. Kingsley LA, Cuervo-Rojas J, Muñoz A, Palella FJ, Post W, Witt MD, Budoff M, Kuller L. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Co- hort Study. AIDS. 2008;22(13):1589–99. 45. Lo J, Abbara S, Shturman L, Soni A, Wei J, Rocha-Filho JA, Nasir K, Grinspoon SK. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomog- raphy angiography in HIV-infected men. AIDS. 2010;24:243–53. 46. Lai S, Bartlett J, Lai H, Moore R, Cofrancesco J Jr, Pannu H, Tong W, Meng W, Sun H, Fishman EK. Long-term combination antiretroviral therapy is associated with the risk of coronary plaques in African Americans with HIV infection. AIDS Patient Care STDS. 2009;23:815–24. 47. Kaplan RC, Kingsley LA, Sharrett AR, Li X, Lazar J, Tien PC, Mack WJ, Cohen MH, Jacobson L, Gange SJ. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis. 2007;45(8):1074–81 (Epub 2007 Sep 12). 48. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr, Svetkey LP, Wadden TA, Yanovski SZ, Kendall KA, Morgan LC, Trisolini MG, Velasco G, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 AHA/ACC guideline on lifestyle manage- ment to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S76–99. 49. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, Department of Health and Human Ser- vices, pp. 1–166. 2014. http://www.aidsinfo.nih.gov/ ContentFiles/AdultandAdolescentGL.pdf. Accessed November 21, 2014. 50. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R, Burman WJ, Williams I, Drummond F, Duprez D, Belloso WH, Goebel FD, Grund B, Hatzakis A, Vera J, Lundgren JD. Inter- ruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther. 2008;13(2):177–87. 51. Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study. J Infect Dis. 2010;210:3108–30. 52. Law M, Friis-Moller N, Weber R, et al. Modelling the 3-year risk of myocardial infarction among participants in the Data Collec- tion on Adverse Events of Anti-HIV Drugs (DAD) study. HIV Med. 2003;4:1–10. 53. Lundgren JD, Neuhaus J, Babiker A, Cooper D, Duprez D, El- Sadr W, Emery S, Gordin F, Kowalska J, Phillips A, Prineas RJ, Reiss P, Sabin C, Tracy R, Weber R, Grund B, Neaton JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. Strategies for Management of 86 A. A. Patel, M. J. Budoff Author's personal copy http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf Anti-Retroviral Therapy/INSIGHT1; DAD Study Groups. AIDS. 2008;22(14):F17–24. 54. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Asso- ciation between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec’s public health insurance database. J Acquir Immune Defic Syndr. 2011;57:245–53. 55. Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P. Abacavir use and risk of acute myocardial infarction and cere- brovas- cular events in the highly active antiretroviral therapy era. Clin Infect Dis. 2011;53:84–91. 56. Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment con- taining abacavir: short and long-term results from ACTG A5001/ ALLRT. Clin Infect Dis. 2011;52:929–40. 57. Cruciani M, Zanichelli V, Serpelloni G, et al. ABACAVIR use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS. 2011;25:1993–2004. 58. Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012;61:441–7. 59. Palella FJ Jr, Gange SJ, Benning L, Jacobson L, Kaplan RC, Landay AL, Tracy RP, Elion R. Inflammatory biomarkers and abacavir use in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS. 2010;24(11):1657–65. 60. Costagliola D, Lang S, Mary-Krause M, Boccara F. Abacavir and cardiovascular risk: reviewing the evidence. Curr HIV/AIDS Rep. 2010;7:127–33. 61. Moore RD, Bartlett JG, Gallant JE. Association between use of HMG CoA reductase inhibitors and mortality in HIV-infected patients. PLoS One. 2011;6(7):e21843. 62. Hare CB, Vu MP, Grunfeld C, Lampiris HW. Simvastatin-nelfi- navir interaction implicated in rhabdomyolysis and death. Clin Infect Dis. 2002;35(10):e111–2 (Epub 2002 Oct 25). 63. Dubé MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, Henry WK, Currier JS, Sprecher D, Glesby MJ, Adult AIDS Clinical Trials Group Cardiovascular Subcommittee, HIV Medical Association of the Infectious Disease Society of America. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37(5):613–27. 64. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4? count- guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–96. 65. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD, HIV Outpatient Study Investigators. 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;43:27e34. CAD in HIV 87 Author's personal copy Coronary Artery Disease in Patients with HIV Infection Abstract Introduction Pathophysiology of Coronary Artery Disease in Patients with HIV Infection Diagnosis Prevention Conclusion Conflict of interest References