This editorial refers to ‘Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons’†, by P.E. Tarr et al., on page 2147. Over the past two decades, a lot of hypotheses have been generated on whether HIV infection or the antiretroviral agents used to treat HIV infection are contributing/causing accelerated atherosclerosis.1–4 Due to the remarkable success of modern combination antiretroviral therapy (cART), HIV infection has become a chronic disease with a normal life expectancy in high-income countries.5,6 However, a concurrent rise in the incidence of non-communicable diseases, including liver, renal, and particularly cardiovascular disease, has been reported in regions with wide access to cART.7 The increased prevalence of coronary heart disease (CHD) in the HIV-infected population may be related to the longer life expectancy resulting from sustained suppression of HIV viral replication and to the increase of traditional risk factors for cardiovascular disease (CVD), common in the HIV-infected population.8 Globally, the rates of HIV infection are highest in sub-Saharan Africa. Eastern Europe and Southeast Asia are now faced with an emerging epidemic fuelled in part by the lack of preventative initiatives.9,10 However, in developed countries with easy access to cART, HIV-infected patients live longer, and diseases of older age (e.g. cancer and CVD) are now the most prominent cause of death.7 Despite the evidence that HIV infection carries a higher risk of developing CHD, the mechanisms responsible for the heightened risk are not completely understood. The pathogenesis of atherosclerosis in HIV infection most probably results from complex interactions between traditional risk factors, direct effects of uncontrolled HIV replication, and the harmful side effects of some antiretroviral medications; dyslipidaemia, insulin resistance, endothelial dysfunction, and other metabolic disorders may be caused by a certain class of antiretroviral drugs, particularly protease inhibitors.11,12 Moreover, it is well recognized that there is an increased prevalence of traditional risk factors for CHD in the HIV-infected population.13 Furthermore, the immune system also plays a critical role in the development and progression of atherosclerosis in the HIV-infected population. Higher levels of inflammatory markers, such as C-reactive protein, interleukin-6, and tumour necrosis (TNF) have been measured in HIV-positive compared with HIV-negative subjects.14,15 The risk for myocardial infarction (MI) is increased >4-fold in HIV-infected patients with elevated C-reactive protein levels.15 Higher levels of interleukin-6, soluble TNF receptor I, soluble TNF receptor II, and D-dimer, and a higher kynurenine to tryptophan ratio at 1 year post-cART therapy have been associated with the occurrence of MI and stroke.16 Large observational studies in Europe and in the USA have investigated the epidemiology of CHD in the HIV-infected population.17,18 These and other studies suggest that HIV infection increases the overall risk for CHD by 1.5- to 2.0-fold.18 Interestingly, an analysis of cohorts over different time frames suggests that the prevalence rates of CHD are falling, presumably due to early recognition and prevention of traditional risk factors and the use of newer antiretroviral drug regimens.19 Thus, the focus of research has shifted to the detection of subclinical atherosclerosis as a surrogate for clinical events. Non-invasive imaging studies, such as carotid intima-media thickness (cIMT) and coronary computed tomography angiography (CCTA), indicate an increased prevalence of subclinical atherosclerosis in HIV-positive compared with HIV-negative individuals. A meta-analysis of 13 observational studies suggests a trend toward an increase of cIMT in HIV-positive compared with HIV-negative subjects.20 Increased cIMT has been observed in early childhood in HIV-infected children receiving cART, suggesting that the atherosclerotic process is activated very early on in HIV-infected patients who do not have the traditional cardiovascular risk factors.21 The typical coronary plaque in HIV-infected patients is a non-calcified atherosclerotic plaque.22 A recent meta-analysis of 1229 asymptomatic HIV-infected patients on cART demonstrated a three-fold higher prevalence of non-calcified coronary artery plaques (so-called vulnerable plaques) on CCTA, compared with HIV-negative control subjects. In addition, patients with low CD4+ cell counts had evidence of more vulnerable plaques, further supporting the notion that uncontrolled and/or advanced HIV infection could contribute to a rise in CVD risks.23 Two studies in the USA have compared CCTA findings in HIV-positive and HIV-negative individuals; one study conducted by Post et al. in the Multicenter AIDS Cohort Study (MACS) showed a higher prevalence of any coronary plaques and of non-calcified plaques in HIV-positive compared with HIV-negative US men;24 however, in the second study, conducted by Lai et al., CCTA findings were similar between HIV-positive and HIV-negative African Americans with high levels of cocaine use.25 In this issue of the journal, Tarr et al. longitudinally followed 428 HIV-positive Swiss HIV Cohort Study participants and 276 concurrently enrolled HIV-negative controls.26 The authors compared the prevalence of subclinical coronary atherosclerosis and assessed the association between traditional cardiovascular risk factors, HIV infection, and subclinical coronary artery disease (CAD) using the coronary artery calcium (CAC) score and CCTA. As expected, age, male sex, and traditional risk factors were significantly associated with subclinical CAD. However, HIV infection did not independently contribute to calcium score, any plaques, non-calcified/mixed plaques, or high-risk plaques on CCTA. On the contrary, while HIV infection was not associated with increased subclinical atherosclerosis, it was associated with fewer calcified plaques and lower coronary segment severity score (SSS) and segment involvement score (SIS) compared with HIV-negative subjects. The association of cardiovascular events and the duration of cART or advanced immunosuppression in the setting of HIV infection remains a subject of ongoing debate. The authors did not identify any association of cART duration with either calcified or non-calcified plaques. Lastly, they found that a low nadir of CD4+ cell count was associated with non-calcified plaques, consistent with the Multicenter AIDS Cohort Study (MACS), supporting the recently established recommendation for the early initiation of antiretroviral therapy. These results appear to contradict the CCTA study conducted in the USA by Post et al. that noted a higher prevalence of any plaques and of non-calcified plaques in HIV-positive compared with HIV-negative US men who have sex with men.24 However, CCTA findings in the present study are similar to the findings reported by Lai et al. in 1257 HIV-positive and HIV-negative African Americans with high levels of cocaine use.25 Explanations for these different results are purely speculative, but may include early HIV treatment, a more homogenous population, easy access to medical care, regular follow-up, very high rates of viral suppression, modern cART regimens, and decreasing smoking rates in recent years in the Swiss HIV Cohort Study—all suggesting that this population appears healthier than the one studied in the MACS study. Additional explanations for those discrepancies may include differences in demographics, cardiovascular risk profile, drug use patterns, geographic origin of participants, and exposure to different antiretroviral drug regimens. Over the past two decades, modern cART regimens have become more effective in suppressing HIV viral replication and are better adhered to, due to the reduced pill burden and the frequency of administration. The newest drug formulations are also less toxic. Consequently, these improvements have substantially contributed to changing the face of CVD among HIV-infected patients. Both HIV infection and CVD are global health issues. As the HIV-infected population ages, the potential increase in CHD will pose future challenges to clinicians and health authorities. Available data support the presence of an accelerated process of atherosclerosis in the HIV-infected population due to multiple risk factors that include a higher prevalence of traditional risk factors, emerging new risk factors (i.e. the role of HIV infection itself and of the inflammation and immune activation) in uncontrolled or poorly controlled HIV replication, and the potential contribution by some of the older antiretroviral agents. This new study by Tarr et al. shows a similar prevalence of non-calcified/mixed plaques and high-risk plaques, fewer calcified coronary plaques, and lower coronary atherosclerosis involvement and severity scores in HIV-positive compared with HIV-negative individuals with similar Framingham risk scores. These findings appear to be consistent with recent studies showing that rates of MI were similar in HIV-positive and HIV-negative non-smokers in Denmark,27 and that smoking, but not HIV status, had a strong impact on cardiovascular risk in the Swiss HIV Cohort Study.28 Figure 1 View largeDownload slide Key points regarding HIV infection and cardiovascular disease. Figure 1 View largeDownload slide Key points regarding HIV infection and cardiovascular disease. Taken together, these findings may help to attenuate the concerns about accelerated subclinical atherosclerosis in the HIV-positive population and support the notion that easy access to medical care, modern antiretroviral drug regimens, and the now well-established recommendation for early initiation of antiretroviral therapy in conjunction with aggressive primary and secondary prevention of CVD may have a significant impact on reducing coronary heart disease in the HIV-infected population. Future research efforts should focus on communities with limited resources and on developing countries with high HIV infection burden that are implementing the World Health Organization (WHO) recommendations to start modern antiretroviral therapy in all HIV-infected people as soon as possible after diagnosis regardless of CD4+ cell count or the stage of disease at diagnosis.29 Conflict of interest: none declared. References 1 Périard D , Telenti A , Sudre P , Cheseaux JJ , Halfon P , Reymond MJ , Marcovina SM , Glauser MP , Nicod P , Darioli R , Mooser V . Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study . Circulation 1999 ; 100 ; 700 – 705 . Google Scholar CrossRef Search ADS PubMed 2 Friis-Moller N , Weber R , Reiss P et al. Cardiovascular disease risk factors in HIV patients – association with antiretroviral therapy: results from the DAD study . AIDS 2003 ; 17 ; 1179 – 1193 . 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J Acquir Immune Defic Syndr 2009 ; 51 : 268 – 273 . Google Scholar CrossRef Search ADS PubMed 16 Tenorio AR , Zheng Y , Bosch RJ , Krishnan S , Rodriguez B , Hunt PW , Plants J , Seth A , Wilson CC , Deeks SG , Lederman MM , Landay AL. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS defining morbid events during suppressive antiretroviral treatment . J Infect Dis 2014 ; 210 : 1248 – 1259 . Google Scholar CrossRef Search ADS PubMed 17 Bozzette SA , Ake CF , Tam HK , Chang SW , Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection . N Engl J Med 2003 ; 348 : 702 – 710 . Google Scholar CrossRef Search ADS PubMed 18 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 myocardial infarction . N Engl J Med 2003 ; 349 : 1993 – 2003 . Google Scholar CrossRef Search ADS PubMed 19 Klein DB , Leyden WA , Xu L , Chao CR , Horberg MA , Towner WJ , Hurley LB , Marcus JL , Quesenberry CP Jr , Silverberg MJ. Declining relative risk for myocardial infarction among HIV-positive compared with HIV-negative individuals with access to care . Clin Infect Dis 2015 ; 60 : 1278 – 1280 . Google Scholar CrossRef Search ADS PubMed 20 Hulten E , Mitchell J , Scally J , Gibbs B , Villines TC. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies . Heart 2009 ; 95 : 1826 – 1835 . Google Scholar CrossRef Search ADS PubMed 21 McComsey GA , O’Riordan M , Hazen SL , El-Bejjani D , Bhatt S , Brennan ML , Storer N , Adell J , Nakamoto DA , Dogra V. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children . AIDS 2007 ; 21 : 921 – 927 . Google Scholar CrossRef Search ADS PubMed 22 Fishbein GA , Micheletti RG , Currier JS , Singer E , Fishbein MC. Atherosclerotic oxalosis in coronary arteries . Cardiovasc Pathol 2008 ; 17 : 117 – 123 . Google Scholar CrossRef Search ADS PubMed 23 D’Ascenzo F , Cerrato F , Calcagno A , Grossomarra W , Ballocca F , Omedè P , Montefusco A , Veglia S , Barbero U , Gili S , Cannillo M , Pianelli M , Mistretta E , Raviola A , Salera D , Garabello D , Mancone M , Estrada V , Escaned J , De Marie D , Abbate A , Bonora S , Zoccai GB , Moretti C , Gaita F. High prevalence at computed coronary tomography of non-calcified plaques in asymptomatic HIV patients treated with HAART: a meta-analysis . Atherosclerosis 2015 ; 240 : 197 – 204 . Google Scholar CrossRef Search ADS PubMed 24 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 . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: May 3, 2018
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