Assessing Risk for Cardiovascular Disease in Patients With Human Immunodeficiency Virus
2010; Lippincott Williams & Wilkins; Volume: 121; Issue: 5 Linguagem: Inglês
10.1161/cir.0b013e3181d2c863
ISSN1524-4539
Autores Tópico(s)HIV Research and Treatment
ResumoHomeCirculationVol. 121, No. 5Assessing Risk for Cardiovascular Disease in Patients With Human Immunodeficiency Virus Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAssessing Risk for Cardiovascular Disease in Patients With Human Immunodeficiency VirusWhy it Matters Paul E. Sax, MD Paul E. SaxPaul E. Sax From the Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Originally published25 Jan 2010https://doi.org/10.1161/CIR.0b013e3181d2c863Circulation. 2010;121:620–622Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 25, 2010: Previous Version 1 Physicians who regularly see patients with human immunodeficiency virus (HIV) are commonly asked the prognosis of someone with HIV infection today. Although the estimates vary depending on the CD4 cell count and age at diagnosis, studies suggest that survival for most people with HIV is currently measured in decades, not years.1,2 For example, in one study from Denmark the estimated median survival from age 25 in HIV-infected patients without hepatitis C was 39 years. Indeed, these per-person gains in survival accrued from antiretroviral therapy (ART) are of a magnitude unmatched in treatment of other diseases.3Article see p 651Effective ART has therefore led to a marked shift in the age distribution among people with HIV in the United States, and it is estimated that by 2015 more than half will be over 50 years of age.4 Given this improved survival, it is not surprising that people with HIV in whom therapy is successful are increasingly at risk for diseases of aging, in particular cardiovascular, renal, and "non-AIDS" neoplastic diseases. Furthermore, these complications seem to be occurring at higher rates than in age-matched control individuals, likely accounting for the fact that survival of HIV patients still does not match that in the uninfected population,1 even though viral replication can be controlled in the vast majority of patients in care.5 In addition, clinical observations from clinicians and patients, some of which have prominently appeared in the lay press,6,7 cite a process of accelerated aging and debility among those with HIV despite effective treatment.With cardiovascular disease (CVD) in particular, several studies have documented that HIV itself is a potent risk factor. In one cross-sectional study of 433 HIV-positive patients and 5749 uninfected control individuals, carotid-artery intima-media thickness was significantly greater in ART-treated HIV-positive patients than in the control individuals even after adjustment for demographic variables and traditional CVD risk factors.8 Indeed, the independent effect of HIV appeared to be of a similar magnitude to that of standard cardiac risk factors. An analysis of acute myocardial infarctions in a large healthcare system found that the rate of acute myocardial infarction among individuals with HIV was nearly 2-fold higher than in those without HIV, even after adjustment for age, gender, race, hypertension, diabetes mellitus, and dyslipidemia.9What might be the explanation for the increased incidence of CVD among people with HIV? Several factors are likely contributing: (1) Patients with HIV infection have a high rate of other behavioral and demographic cardiac risk factors, especially smoking and lower socioeconomic status10; (2) both HIV infection and several antiretroviral agents are associated with potentially atherogenic dyslipidemia,11 and some antiviral agents may worsen cardiovascular risk independently of their effect on lipids12; and (3) HIV infection is associated with abnormal levels of both inflammation and immune activation, even among those who are asymptomatic and have relatively normal CD4 cell counts.Strong support for the potentially deleterious effects of inflammation on outcomes in HIV comes from a comparative study of continuous versus intermittent ART.13 In the Strategies for Management of ART (SMART) study, patients with CD4 cell counts >350 cells/mm and no active symptoms of HIV disease were randomized to continuous ART or intermittent treatment, with therapy in the latter group to be resumed if the CD4 cell count fell to 250 cells or less. The study was stopped early because of an increased risk of both AIDS and non-AIDS events in those receiving intermittent treatment. Analysis of stored samples showed that the risk of all-cause mortality was strongly associated with levels of interleukin-6 and D-dimer, and that these levels were markedly higher in those receiving intermittent therapy.14 Unfortunately, although ART may reduce some markers of inflammation, levels of high-sensitivity C-reactive protein, interleukin-6, D-dimer, and cystatin-C were higher in treated HIV patients than in uninfected age-matched control individuals.15 Similarly, a prospective clinical trial comparing different treatment regimens showed that levels of high-sensitivity C-reactive protein were not reduced by durably suppressive ART over 96 weeks.16Inasmuch as heart disease is an increasing problem for HIV patients, an important clinical and research challenge is to identify potentially modifiable risk factors.17 In this issue of Circulation, Choi and colleagues evaluated data from the national registry of HIV-infected patients in the Veterans Health Administration, the largest provider of HIV care in the United States, to explore the association of kidney disease with incident atherosclerotic CVD and heart failure.18 Kidney function was assessed using the Modification of Diet in Renal Disease formula to estimate glomerular filtration rate (GFR), and albuminuria was defined by urine dipstick measurements.The study included over 17 000 patients, with 833 atherosclerotic and 370 heart failure endpoints. Kidney disease was strongly associated with both CVD and heart failure: those with eGFR 30-fold higher. In multivariable models, with adjustment for well-recognized cardiovascular risk factors as well as HIV RNA and CD4 cell count, both eGFR and albuminuria remained independently associated with the composite outcome of either atherosclerotic CVD or heart failure.Strengths of this study include its large size and inclusion of a population with universal access to care and treatment. In addition, the use of laboratory markers of kidney disease that are readily available to clinicians increases the likelihood that the findings will have practical applications. Indeed, measurement of serum creatinine (needed to calculate the eGFR by Modification of Diet in Renal Disease) and an annual urinalysis are already recommended as part of routine care.19Potential limitations of this study include the small proportion of women in the cohort, limiting generalizability, and the inability to exclude residual confounding. These issues notwithstanding, there is little reason to doubt the results. Kidney disease is well known in HIV-uninfected populations to be strongly associated with both CVD and heart failure, and the effect would plausibly be even stronger in patient populations already at greater risk for heart disease, such as those with HIV. In addition, the results offer a possible avenue for therapeutic intervention (for example, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) to improve both renal and cardiac outcomes.The importance of this study is amplified by the high rate of kidney disease in patients with HIV. Kidney function is abnormal in up to 30% of patients with HIV, owing to a variety of factors, including HIV itself, the nephrotoxic effect of certain antiviral drugs, and the disproportionate burden of HIV infection among individuals of African descent, who are known to have increased susceptibility to HIV nephropathy in particular and renal disease in general.20 The results also provide a potential epidemiological explanation for the observed association between use of the antiretroviral agent abacavir and cardiovascular risk,21 inasmuch as abacavir is preferentially prescribed in place of tenofovir (which has potential nephrotoxicity) for individuals with abnormal renal function.In summary, the study by Choi et al is a timely example of the burgeoning field in HIV medicine that is exploring long-term noninfectious complications. For those of us who cared for patients with HIV before 1996, when the average life expectancy for individuals with advanced AIDS was <18 months,22 the very existence of this field represents both a therapeutic miracle and a substantial clinical and research challenge.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Sources of FundingThis editorial was supported by grants NIH/U01 AI27659 and NIAID/R0 AI42006.DisclosuresDr Sax has served as a consultant or on scientific advisory boards for Abbott, BMS, Gilead, GSK, Merck, Tibotec, and Pfizer; he has received research grant support from GSK, Merck, and Tibotec.FootnotesCorrespondence to Paul E. Sax, MD, Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Harvard Medical School, Boston, MA 02115. E-mail [email protected] References 1 Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, Vaeth M, Obel N. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med. 2007; 146: 87–95.CrossrefMedlineGoogle Scholar2 Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, Pellegrin JL, Katlama C, Dabis F. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007; 46: 72–77.CrossrefMedlineGoogle Scholar3 Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, Weinstein MC, Freedberg KA. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006; 194: 11–19.CrossrefMedlineGoogle Scholar4 Effros RB, Fletcher CV, Gebo K, Halter JB, Hazzard WR, Horne FM, Huebner RE, Janoff EN, Justice AC, Kuritzkes D, Nayfield SG, Plaeger SF, Schmader KE, Ashworth JR, Campanelli C, Clayton CP, Rada B, Woolard NF, High KP. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis. 2008; 47: 542–553.CrossrefMedlineGoogle Scholar5 Gill VS, Lima VD, Zhang W, Wynhoven B, Yip B, Hogg RS, Montaner JS, Harrigan PR. Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection. Clin Infect Dis. 2010; 50: 98–105.CrossrefMedlineGoogle Scholar6 Gross J. AIDS patients face downside of living longer. New York Times, January 6 2008. Available at http://www.nytimes.com/2008/01/06/health/06HIV.html. Accessed January 20, 2010.Google Scholar7 France D. Another kind of AIDS crisis. New York Magazine, November 1, 2009. Available at http://nymag.com/health/features/61740/. Accessed January 20, 2010.Google Scholar8 Grunfeld C, Delaney JA, Wanke C, Currier JS, Scherzer R, Biggs ML, Tien PC, Shlipak MG, Sidney S, Polak JF, O'Leary D, Bacchetti P, Kronmal RA. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009; 23: 1841–1849.CrossrefMedlineGoogle Scholar9 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: 2506–2512.CrossrefMedlineGoogle Scholar10 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: 1074–1081.CrossrefMedlineGoogle Scholar11 Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella F, Visscher B, Evans R, Kingsley LA. Impact of HIV infection and HAART on serum lipids in men. JAMA. 2003; 289: 2978–2982.CrossrefMedlineGoogle Scholar12 Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, Thiebaut 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: 1723–1735.CrossrefMedlineGoogle Scholar13 El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fatkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006; 355: 2283–2296.CrossrefMedlineGoogle Scholar14 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 infection. PLoS Med. 2008; 5: e203.CrossrefMedlineGoogle Scholar15 Neuhaus J, Jacobs D, the INSIGHT SMART, MESA and CARDIA Study Groups. Markers of inflammation, coagulation, and renal function in HIV-infected adults in the Strategies for Management of ART Study and in 2 large population-based studies, coronary artery risk development in young adults and multi-ethnic study of atherosclerosis. [Abstract 740.] 16th Conference on Retroviruses and Opportunistic Infections. February 8–11, 2009; Montreal, Canada.Google Scholar16 Shikuma C, Zheng E, Ribaudo H. 96-week effects of suppressive efavirenz containing ART, abacavir, and sex on high-sensitivity C-reactive protein: ACTG A5095 [Abstract 736]. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. February 8–11, 2009; Montreal, Canada.Google Scholar17 Grinspoon SK, Grunfeld C, Kotler DP, Currier JS, Lundgren JD, Dubé MP, Lipshultz SE, Hsue PY, Squires K, Schambelan M, Wilson PW, Yarasheski KE, Hadigan CM, Stein JH, Eckel RH. State of the science conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation. 2008; 118: 198–210.LinkGoogle Scholar18 Choi AI, Yongmei L, Deeks SG, Grunfeld C, Volberding PA, Shlipak MG. The association between kidney function and albuminuria with cardioavascular events in HIV-infected persons. Circulation. 2010; 121: 651–658.LinkGoogle Scholar19 Aberg JA, Kaplan JE, Libman H, Emmanuel P, Anderson JR, Stone VE, Oleske JM, Currier JS, Gallant JE; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009; 49: 651–681.CrossrefMedlineGoogle Scholar20 Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, Fields TA, Svetkey LP, Flanagan KH, Klotman PE, Winston JA. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int. 2004; 66: 1145–1152.CrossrefMedlineGoogle Scholar21 D:A:D Study Group, Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, D'Arminio Monforte A, Friis-Møller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008; 37: 1417–1426.Google Scholar22 Apolonio EG, Hoover DR, He Y, Saah AJ, Lyter DW, Detels R, Kaslow RA, Phair JP. Prognostic factors in human immunodeficiency virus-positive patients with a CD4+ lymphocyte count <50/microL. J Infect Dis. 1995; 171: 829–836.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Brouillette J, Cyr S and Fiset C (2019) Mechanisms of Arrhythmia and Sudden Cardiac Death in Patients With HIV Infection, Canadian Journal of Cardiology, 10.1016/j.cjca.2018.12.015, 35:3, (310-319), Online publication date: 1-Mar-2019. Côté J, Cossette S, Ramirez-Garcia P, Rouleau G, Auger P, Boudreau F and Gagnon M (2017) Improving Health and Reducing Comorbidity Associated with HIV: The Development of TAVIE en santé , a Web-Based Tailored Intervention to Support the Adoption of Health Promoting Behaviors among People Living with HIV , BioMed Research International, 10.1155/2017/4092304, 2017, (1-10), . 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Kirton C (2011) HIV, Nursing, 10.1097/01.NURSE.0000391398.13322.18, 41:1, (36-43), Online publication date: 1-Jan-2011. kirton C (2011) Cambios en la epidemia de la infección por el VIH, Nursing (Ed. española), 10.1016/S0212-5382(11)70211-4, 29:4, (8-15), Online publication date: 1-Apr-2011. Philipp C (2010) The Aging Patient with Hemophilia: Complications, Comorbidities, and Management Issues, Hematology, 10.1182/asheducation-2010.1.191, 2010:1, (191-196), Online publication date: 4-Dec-2010. February 9, 2010Vol 121, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/CIR.0b013e3181d2c863PMID: 20100977 Originally publishedJanuary 25, 2010 Keywordsinflammationrisk factorscardiovascular diseasesAIDSalbuminuriaEditorialsPDF download Advertisement SubjectsEpidemiology
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