Curr Treat Options Cardio Med (2014) 16:346 DOI 10.1007/s11936-014-0346-x
Prevention (L Sperling and D Gaita, Section Editors)
Cardiovascular Disease Associated with the Human Immunodeficiency Virus: An Update Thomas S. Metkus Jr., MD Todd T. Brown, MD, PhD Wendy S. Post, MD, MS* Address *Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA Email: [email protected]
Published online: 7 September 2014 * Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Prevention Keywords Prevention
I
Human immunodeficiency virus
I
Cardiovascular disease
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Antiretroviral therapy
Opinion statement With the advent of increasingly available antiretroviral therapy (ART), the life expectancy of HIV-infected persons is increasing. As they age, HIV-infected persons have increased propensity to typical diseases of aging including cardiovascular disease and accelerated atherosclerosis. The pathogenesis of HIV-associated atherosclerosis is complex and involves a state of chronic inflammation, exposure to traditional risk factors, and metabolic side effects of ART. Treatment of HIV-associated atherosclerosis should include special attention to drug-drug interactions and is best accomplished by a multidisciplinary team experienced in the care of HIV-infected persons.
Introduction In the United States, nearly 50,000 patients were newly infected with HIV in the past year, an incidence rate that has been stable over prior years [1]. It is estimated that over 1 million Americans are living with HIV, and globally, over 33 million patients are living with HIV [2]. With the advent and increasing distribution of antiretroviral therapy, patients with HIV are less likely to die from HIV-related causes [3, 4] and are predisposed to
other typical diseases of aging including metabolic bone disease [5], frailty [6], cancer, and accelerated atherosclerosis and cardiovascular disease [7]. With HIV patients’ lifespans approaching that of non-HIV-infected individuals [8, 9], the focus will increasingly shift from management of HIVrelated complications to prevention and management of non-HIV-related complications including cardiovascular disease. It is estimated that as
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many as 15 % of HIV-infected patients will die of cardiovascular causes [10], which would translate
to approximately 5 million cardiovascular deaths worldwide.
Epidemiology of atherosclerosis and cardiovascular events in HIV-infected persons HIV-infected individuals have an increased propensity to acute cardiovascular events and premature atherosclerosis. Triant et al in 2007 reported a 1.7 relative risk for myocardial infarction in HIV compared with non-HIV-infected subjects [11]. In a large cohort based in the Veterans Affairs hospital system, a 50 % increase in myocardial infarction was observed above that expected from traditional risk factors in HIV-infected individuals [12••]. An increased rate of stroke has also been observed [13] with a hazard ratio of similar magnitude. Consistent with these results, observational studies have shown a higher prevalence of subclinical atherosclerosis among HIV-infected persons. Our group reported that HIV-infected men with no prior history of coronary revascularization had a higher presence and extent of noncalcified coronary plaque assessed by computed tomography (CT) angiogram even after adjustment for cardiac risk factors compared with HIV-uninfected men in the Multicenter AIDS Cohort Study [14••]. Similar results were seen in a study from Massachusetts General Hospital, which reported increased coronary plaque as assessed by CT angiography, specifically noncalcified coronary plaque, in HIVinfected women [15] and men [16] compared with HIV negative controls. Carotid intima-media thickness has also been demonstrated to be increased and progression of carotid intima-media thickness was more rapid in HIVinfected patients as compared to age and gender matched HIV negative controls [17]. A survey of administrative health database in Ontario demonstrated that HIV-infected patients had a higher prevalence of both peripheral arterial disease and stroke [18]; in a second study, nearly 20 % of patients with HIV had an abnormal ankle-brachial index either at rest or after exercise [19]. The pathophysiology of the accelerated atherosclerosis and acute cardiovascular events in HIV-infected individuals is multifactorial and includes an increased prevalence of traditional cardiovascular risk factors, a systemic inflammatory response associated with chronic HIV infection, and metabolic side effects associated with antiretroviral therapy. We will review the recent literature on each of these predisposing factors in turn.
Traditional cardiovascular risk factors The use of tobacco products is higher in HIV-infected population compared with the general population. O’Cleirigh and colleagues reported that persons with HIV smoked at nearly three times the rate of the general population, with overall smoking rate of nearly 60 % [20]. The same investigators also report higher rates of substance abuse including specifically cocaine, which predisposes to premature atherosclerosis, acute myocardial infarction mediated by vasospasm and thrombosis, and alcohol that could predispose to alcoholic cardio-
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myopathy. Tobacco use may be synergistically worse in HIV-infected patients compared with HIV negative patients because of increased immune activation in smokers [21]. Given the disproportionate representation of lower income groups among those with HIV infection, it is likely that access to heart-healthy foods and other healthy lifestyle components such as regular exercise are less among the total HIV population in the United States and worldwide [22]. Management of traditional cardiovascular risk factors in the HIV-infected population is of paramount importance and there is great unmet need. In a multinational survey, less than one in five HIV-infected individuals reported discussing cardiovascular disease prevention with their physician including alarmingly 44 % of smokers who were never offered a means for smoking cessation [23]. These data suggest that, in addition to increasing effort and study toward managing the HIV specific propensity to atherosclerosis, an equivalent focus should remain on traditional cardiovascular risk factor modification in this population.
Systemic inflammation and hypercoagulability in HIV infected persons HIV infection is associated with a state of systemic chronic inflammation; chronic inflammation in a variety of noncardiac conditions has been demonstrated to be atherogenic [24]. Markers of macrophage activation have been demonstrated to be elevated in HIV-infected individuals and associated with higher burden of coronary plaque [25]. In addition to increased circulating levels of inflammatory markers, HIV infection is associated with inflammation of the blood vessels themselves: HIV-infected subjects and controls matched for age and cardiac risk factors underwent 18F-FDG-PET to assess arterial wall inflammation. HIVinfected individuals had significantly higher arterial wall inflammation compared to uninfected controls, a difference that correlated with higher serum markers of inflammation [26••]. In addition to systemic inflammation, other circulating factors including adipokines may be involved in the pathogenesis of HIV associated atherosclerosis [27], and this is an area requiring further study. The milieu of chronic inflammation and disordered adipokine metabolism in HIV-infected patients has the potential to interact synergistically with a general propensity toward hypercoagulability. In a group of patients with poorly controlled HIV and low CD4 counts, D-dimer levels and other serologic markers of thrombosis were elevated compared to age matched controls, and these markers of hypercoagulability improved with better control of HIV [28]. This finding may underlie the increased rates of clinical venous thromboembolism; venous thromboembolism rates were increased in HIV-infected patients compared with population controls in the Danish HIV Cohort study [29]. Patients with venous thromboembolism have higher levels of P-selectin as a marker for endothelial dysfunction that may play a part in this hypercoagulability [30].
The role of antiretroviral therapy and HIV clinical factors Antiretroviral therapy (ART) itself is an important contributor to the risk of premature coronary disease in HIV-infected patients. Since its advent in the
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Curr Treat Options Cardio Med (2014) 16:346 mid-1990s, the complexity of ART has grown dramatically with introduction of multiple new drug classes. Typical ART drug regimens include three total drugs incorporating two different drug classes [31]. The different drug classes available include nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors, and fusion and entry inhibitors. Protease inhibitors were the first class of drugs implicated in premature coronary artery disease with associations noted between MI and protease inhibitor use in retrospective [32] and time series analyses [33]. A widely cited analysis published in 2003 from the Data collection on Adverse events of Anti-HIV Drugs (D:A:D)study included over 23,000 patients in a prospective observational cohort study; the authors demonstrated that combination ART including either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor increased the risk for myocardial infarction [34].The overall risk was quite low, with only 126 total patients having myocardial infarction. Abacavir, a nucleoside reverse transcriptase inhibitor, and didanosine have also been implicated in causing cardiovascular events in an analysis of the D:A:D study [35]. The respective relative risks, however, were small, and a subsequent analysis including a retrospective study of over 36,000 patients treated for HIV at Veterans Affairs hospitals demonstrated no association between specific ART agents and myocardial infarction or stroke [36]. Over the time period encompassing this study, the overall rate of death from any cause declined and the risk of dying from cardiovascular disease also declined, and the authors conclude that the marked benefits of ART are not attenuated by an increase in cardiovascular disease [36]. There are no randomized controlled trials of specific ART agents designed with adequate follow-up and sufficient power to address the optimal ART regimen to mitigate cardiovascular risk, however, available studies suggest that the overall contribution of ART to cardiovascular risk is small at a population level [34]. It is anticipated that the current generation of ART induces fewer metabolic side effects. ART is recommended for all HIV-infected patients irrespective of CD4 count, and an assessment of cardiovascular risk is not germane to the decision to start ART if it is otherwise indicated [31]. The nadir CD4 count, however, may be a marker of future cardiovascular risk. In a cross-sectional study of almost 10,000 HIV-infected participants enrolled in three randomized controlled trials, lower CD4 counts were correlated with higher D-dimer levels and higher levels of systemic inflammation as assessed by C-reactive protein and interleukin-6 levels in HIV-infected patients [37]. D-dimer levels were in turn correlated with mortality [37]. Lower nadir CD-4 count was associated with progression of carotid intima-media thickness over 6 years of follow-up [38] and with coronary artery stenosis [14••]. A lower CD4 count may also be associated with endothelial dysfunction- nadir CD4 count less than 350 cells/ mm3 was associated with lower brachial artery flow-mediated dilatation [39]. Episodic use of ART to keep the CD4 count greater than 350 cells/mm3 was compared with continuous use of ART in a randomized controlled trial; the episodic use of ART was associated with a 1.8 greater hazard for cardiovascular disease [40]. Overall, these results do support early initiation of ART to be used continually to decrease cardiovascular risk. Further data will be forthcoming—the START study is an ongoing randomized controlled trial of deferred initiation of ART until CD4 count is less than 350 cells/mm3 vs ini-
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tiation at CD4 count of greater than 500 cells/mm3 [41]. The data also implies that the universal HIV screening program currently recommended [42], with the aim to identify and, therefore, treat asymptomatic HIV before progression to clinical AIDS, would also decrease cardiovascular risk.
HIV associated metabolic abnormalities The signs of subcutaneous lipoatrophy and truncal lipohypertrophy, as well as the metabolic syndrome of elevated triglyceride levels, low HDL cholesterol levels, and impaired glucose regulation are all associated with HIV [43]. Subcutaneous lipoatrophy refers to loss of subcutaneous fat and is most associated with the use of older nucleoside reverse transcriptase inhibitors stavudine and zidovudine, which are rarely used in the developed world. In contrast, the gain of abdominal and visceral adiposity associated with HIV infection has not been linked to one specific ART drug [43]. The dyslipidemia phenotype associated with HIV includes elevated triglycerides, low total and HDL cholesterol levels, and increased levels of small, dense LDL particles [44, 45]. Because of the many possible combinations of different ART agents, the effect of any single agent on the plasma lipid profile is difficult to ascertain. In general, total and HDL cholesterol increase after ART initiation as part of a “return to health” phenomenon in those patients who initiate therapy at a lower CD4 count [43]. In the randomized controlled trials of most modern and recently studied ART regimens, total, HDL, and LDL cholesterol levels increase mildly to moderately with therapy as do triglycerides, although the ratio of total to HDL cholesterol decreases [43]. Among protease inhibitors, lopinavir has been demonstrated to have more severe effects on the lipid profile compared with atazanavir [46]. Substituting a newer ART agent from the integrase inhibitor class in lieu of protease inhibitor has also been shown to have superior effects on the lipid profile [47]. In addition to dyslipidemia, impaired glucose metabolism is a final and synergistic component of the HIV associated metabolic syndrome, with impaired glucose metabolism present in up to 25 % of HIV-infected patients [48].
Screening for cardiovascular disease Given the metabolic comorbidities and propensity toward cardiovascular disease in HIV-infected patients reviewed above, the question of whether and how to screen for cardiovascular disease is of paramount importance. HIVinfected patients’ cardiovascular risk should be regularly assessed as part of routine primary care. The history should include symptoms suggestive of vascular disease such as angina, dyspnea, claudication, or transient neurologic phenomena. Family history of premature vascular disease should be assessed. HIV specific risk factors for vascular disease should be sought, as reviewed above, and include nadir CD4 count and ART treatment history. A screening lipid profile and fasting serum glucose or hemoglobin A1C should be obtained in all patients. The recent 2013 American College of Cardiology/ American Heart Association guidelines for management of elevated blood cholesterol [49] have embraced new paradigms for assessing cardiovascular
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Curr Treat Options Cardio Med (2014) 16:346 risk, therapies of elevated blood cholesterol, and treatment targets in the general population. These guidelines recommend assessing risk using the Pooled Cohort Equation and prescribing statin therapy for patients with manifest vascular disease, for those with diabetes, for those with LDL cholesterol greater than 190 mg/dL, and to consider the risks and benefits of statin therapy for those with a greater than 7.5 % 10-year risk [49]. Noteworthy, however, are the facts that patients with clinical diagnoses of HIV were not specifically included in the derivation cohort for the Pooled Cohort Equation, and that patients with HIV often have low levels of both total and HDL cholesterol as discussed. Although there are no data as yet on the performance of the Pooled Cohort Equation in the HIV population, other evidence suggests that routine risk calculators such as Framingham may underestimate risk in the HIV-infected population [50]. There are no data to suggest that routine screening of HIV-infected patients with cardiovascular stress testing, ankle-brachial index, or cerebrovascular or coronary imaging improves outcomes.
Approach to primary and secondary cardiovascular disease prevention The foundation of primary and secondary prevention of cardiovascular disease includes exercise, dietary modification, and lipid lowering drug therapy in HIVinfected patients as in the general population in addition to control of hypertension, diabetes, and smoking cessation. With regard to exercise, there are few quality data on benefits in HIV-infected patients. General recommendations are for three or four sessions per week of 40 minutes of moderate to intense physical activity [51]. It is reasonable to extend these recommendations to HIV-infected patients as well, given that available data specific to HIV-infected populations are scarce. A small randomized controlled trial of pioglitazone and exercise training did not show a benefit on reducing insulin resistance in HIV-infected patients, however, a small sample size left it likely underpowered to detect a difference [52]. Supervised exercise training did improve HDL levels and VO2 max in a group of 10 HIV-infected patients [53]. Similarly, it is reasonable to extend recommendations for a heart healthy diet from those for the general population to the HIV-infected population. Adherence to a Mediterranean diet was associated with improved dyslipidemia and indices of the metabolic syndrome in 227 HIV-infected patients [54]. The Mediterranean diet and DASH diet [55] both are reasonable dietary strategies [51]. With regard to management of dyslipidemia in the HIV-infected population, there are no randomized controlled trials with cardiovascular events as the primary outcome—available data focus on the outcomes of change in lipid levels. Statin therapy remains a cornerstone of management of dyslipidemia. Rosuvastatin has been demonstrated to reduce systemic inflammatory markers in an observational study of HIV-infected patients with statins prescribed for dyslipidemia [56]. A 10 mg dose of rosuvastatin also decreased Lp(a) levels in HIV-infected participants compared with placebo [57]. The pleotropic effect of statins in this patient population should not be overlooked. In a retrospective analysis from the AIDS Clinical Trials Group,
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statin use was associated with a lower relative risk of non-AIDS defining cancer [58]. This association requires further study with regard to extent and mechanism. The challenge of drug-drug interactions between statin therapy and ART will be discussed below. With regard to nonstatin lipid lowering therapy, our group [59] and others [60] have shown that omega-3 fatty acid supplementation improves triglyceride levels in HIV-infected patients with dyslipidemia. It is noteworthy, however, that in the general population, randomized controlled trials have not demonstrated a benefit to omega-3 fatty acid supplementation on cardiovascular outcomes [61]. A randomized controlled trial investigated the effect of fenofibrate, niacin, and combination therapy on lipid levels in HIVinfected patients with hypertriglyceridemia. Fenofibrate reduced triglyceride levels and non-HDL c levels, niacin raised HDL levels, and the combination therapy provided maximal benefit with reduced triglycerides and non-HDL C and increased HDL [62]. In HIV patients as in the general population, addition of nonstatin medications for dyslipidemia has not been shown to change cardiovascular outcomes [63] and consistent with recent guidelines, statin therapy should remain the cornerstone of dyslipidemia treatment given proven benefits. There are challenges to management of cardiovascular risk in the HIVinfected population, some unique and some similar to those faced in risk factor modification in general. Adherence to therapy, both lifestyle and pharmacologic, may be difficult particularly given that HIV-infected patients are taking multiple other important medications. Drug-drug interactions remain a concern, and involvement of a pharmacist experienced in the management of HIV-infected patients is invaluable. The most common and concerning drug-drug interaction involves statins and inhibitors of cytochrome P4503A4 (CYP3A4), including protease inhibitors and the newer pharmacologic booster, cobicistat. Serum levels of statins metabolized by CYP3A4, such as simvastatin and lovastatin, are markedly elevated with protease inhibitor co-administration, and these statins should not be used [64] if protease inhibitors or cobicistat are part of the ART regimen. In the same study, atorvastatin levels were increased modestly, however, atorvastatin can likely be used at a lower dose with gradual up-titration [43]. Similarly, rosuvastatin levels are modestly increased in the presence of protease inhibitor co-administration but rosuvastatin can be used clinically at low doses with gradual up-titration [65]. Pravastatin should be dose adjusted
Fig. 1. Components of an HIV multidisciplinary clinic.
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Curr Treat Options Cardio Med (2014) 16:346 downward when the ART regimen includes darunavir. Fluvastatin and pitavastatin as well as niacin and fibrates can be used in HIV-infected patients similarly to HIV uninfected patients [43]. Given the changing face of the HIV epidemic and growing medical complexity of caring for these patients, optimal care is delivered by a multidisciplinary subspecialty clinic. Such a clinic is diagrammed in Fig. 1 and includes primary care providers with special training and expertise in caring for HIV-infected patients, Infectious Diseases specialists, involvement with social workers, nutritionists, exercise physiologists, and subspecialists with interest and experience caring for HIV-infected patients. The scope of relevant subspecialties is broad and germane to the scope of this review includes cardiologists and endocrinologists.
Conclusions In conclusion, HIV-infected patients are living longer and non-HIV-related comorbidities including cardiovascular disease are an increasingly important cause of morbidity and mortality. HIV infection predisposes patients to premature atherosclerosis via multiple mechanisms including systemic inflammation, comorbid risk factors, and metabolic side effects of ART. In the absence of further data, screening for cardiovascular disease and primary and secondary prevention of cardiovascular disease in HIV-infected patients should utilize established guidelines for the general population, and therapy has special considerations including attention to drug-drug interactions. Future studies incorporating cardiovascular endpoints in HIV-infected patients are needed.
Compliance with Ethics Guidelines Conflict of Interest Dr Thomas Metkus and Dr Todd T. Brown each declare no potential conflicts of interest. Dr Wendy Post reports grants from NIH. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.
2.
CDC. HIV Surveillance Report, 2011; vol. 23. http:// www.cdc.gov/hiv/topics/surveillance/resources/reports/. 2013 [cited 2013 6 June 2014]. http://aids.gov/hiv-aids-basics/hiv-aids-101/globalstatistics/index.html. [cited 2014 6 June 2014].
3.
Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio Monforte A, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 2003;362(9377):22–9.
Curr Treat Options Cardio Med (2014) 16:346 4.
Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145(6):397–406. 5. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies. J Infect Dis. 2012;205 Suppl 3:S391–8. 6. Brothers TD, Rockwood K. Biologic aging, frailty, and age-related disease in chronic HIV infection. Curr Opin HIV AIDS. 2014;9(4):412–8. 7. Boccara F, Lang S, Meuleman C, Ederhy S, MaryKrause M, Costagliola D, et al. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol. 2013;61(5):511–23. 8. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372(9635):293–9. 9. 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 immunodeficiency syndrome-negative individuals followed simultaneously in longterm cohort studies, 1984–2008. Am J Epidemiol. 2013;177(2):116–25. 10. Palella Jr FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. 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(1):27–34. 11. 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(7):2506–12. 12.•• Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614–22. This large cohort study assessed HIV as a risk factor for acute myocardial infarction in over 80,000 subjects followed in the Veterans Affairs system. HIV-infected and uninfected persons were matched and followed prospectively. HIVinfected persons had increased risk of acute myocardial infarction even after adjustment for traditional cardiovascular risk factors. 13. Chow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system. J Acquir Immune Defic Syndr. 2012;60(4):351–8. 14.•• Post WS, Budoff M, Kingsley L, Palella Jr FJ, Witt MD, Li X, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med. 2014;160(7):458–67. This study from our group assessed the association between coronary atherosclerosis and HIV using coronary CT angi-
Page 9 of 11, 346 ography in HIV-infected and uninfected gay and bisexual men. HIV infection was associated with an increased prevalence and extent of noncalcified plaques. Nadir CD4+ T cell count and years on HAART were associated with coronary artery stenosis greater than 50%. 15. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208(11):1737–46. 16. Lo J, Abbara S, Shturman L, Soni A, Wei J, RochaFilho JA, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS. 2010;24(2):243–53. 17. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109(13):1603–8. 18. Kendall CE, Wong J, Taljaard M, Glazier RH, Hogg W, Younger J, et al. A cross-sectional, populationbased study measuring comorbidity among people living with HIV in Ontario. BMC Public Health. 2014;14:161. 19. Periard D, Cavassini M, Taffe P, Chevalley M, Senn L, Chapuis-Taillard C, et al. High prevalence of peripheral arterial disease in HIV-infected persons. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008;46(5):761–7. 20. O'Cleirigh C, Valentine SE, Pinkston M, Herman D, Bedoya CA, Gordon JR, et al. The unique challenges facing HIV-positive patients who smoke cigarettes: HIV viremia, art adherence, engagement in HIV care, and concurrent substance use. AIDS Behav. 2014. 21. Valiathan R, Miguez MJ, Patel B, Arheart KL, Asthana D. Tobacco smoking increases immune activation and impairs T-cell function in HIV infected patients on antiretrovirals: a cross-sectional pilot study. PLoS One. 2014;9(5):e97698. 22. Kalichman SC, Hernandez D, Cherry C, Kalichman MO, Washington C, Grebler T. Food insecurity and other poverty indicators among people living with HIV/AIDS: effects on treatment and health outcomes. J Community Health. 2014. 23. Sherer R, Solomon S, Schechter M, Nachega JB, Rockstroh J, Zuniga JM. HIV provider-patient communication regarding cardiovascular risk: results from the 2010 AIDS treatment for life international survey. J Int Assoc Providers AIDS Care. 2014;13(4):342–5. 24. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95. 25. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with
346, Page 10 of 11 noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011;204(8):1227–36. 26.•• Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in patients with HIV. JAMA. 2012;308(4):379–86. The authors performed cardiac FDG-PET imaging in patients with and without HIV. HIV-infected patients had more FDG uptake in the aortic wall as compared to controls suggesting increased arterial inflammation. Circulating markers of systemic inflammation were also higher in HIV-infected persons. 27. Ketlogetswe KS, Post WS, Li X, Palella Jr FJ, Jacobson LP, Margolick JB, et al. Lower adiponectin is associated with subclinical cardiovascular disease among HIV-infected men. AIDS. 2014;28(6):901–9. 28. Jong E, Louw S, van Gorp EC, Meijers JC, ten Cate H, Jacobson BF. The effect of initiating combined antiretroviral therapy on endothelial cell activation and coagulation markers in South African HIV-infected individuals. Thromb Haemost. 2010;104(6):1228– 34. 29. Rasmussen LD, Dybdal M, Gerstoft J, Kronborg G, Larsen CS, Pedersen C, et al. HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study. HIV Med. 2011;12(4):202– 10. 30. Musselwhite LW, Sheikh V, Norton TD, Rupert A, Porter BO, Penzak SR, et al. Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV. AIDS. 2011;25(6):787–95. 31. Burgess MJ, Kasten MJ. Human immunodeficiency virus: what primary care clinicians need to know. Mayo Clin Proc. 2013;88(12):1468–74. 32. Henry K, Melroe H, Huebsch J, Hermundson J, Levine C, Swensen L, et al. Severe premature coronary artery disease with protease inhibitors. Lancet. 1998;351(9112):1328. 33. Holmberg SD, Moorman AC, Williamson JM, Tong TC, Ward DJ, Wood KC, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet. 2002;360(9347):1747–8. 34. Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349(21):1993–2003. 35. 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 antiHIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318–30. 36. 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(8):702–10.
Curr Treat Options Cardio Med (2014) 16:346 37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Borges AH, O'Connor JL, Phillips AN, Baker JV, Vjecha MJ, Losso MH, et al. Factors associated with D-dimer levels in HIVinfected individuals. PLoS One. 2014;9(3):e90978. Volpe GE, Tang AM, Polak JF, Mangili A, Skinner SC, Wanke CA. Progression of carotid intima-media thickness and coronary artery calcium over 6 years in an HIV-infected cohort. J Acquir Immune Defic Syndr. 2013;64(1):51–7. Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dube MP, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152 s. J Am Coll Cardiol. 2008;52(7):569– 76. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. Babiker AG, Emery S, Fatkenheuer G, Gordin FM, Grund B, Lundgren JD, et al. Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. Clin Trials. 2013;10(1 Suppl):S5–36. Moyer VA. Screening for HIV: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013;159(1):51–60. Brown TT, Glesby MJ. Management of the metabolic effects of HIV and HIV drugs. Nat Rev Endocrinol. 2012;8(1):11–21. Feingold KR, Krauss RM, Pang M, Doerrler W, Jensen P, Grunfeld C. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab. 1993;76(6):1423–7. Tien PC, Schneider MF, Cox C, Cohen M, Karim R, Lazar J, et al. HIV, HAART, and lipoprotein particle concentrations in the Women's Interagency HIV Study. AIDS. 2010;24(18):2809–17. Cohen C, Nieto-Cisneros L, Zala C, Fessel WJ, Gonzalez-Garcia J, Gladysz A, et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin. 2005;21(10):1683–92. Martínez E, Larrousse M, Llibre JM, Gutiérrez F, Saumoy M, Antela A, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697–707. Samaras K. The burden of diabetes and hyperlipidemia in treated HIV infection and approaches for cardiometabolic care. Curr HIV/AIDS Rep. 2012;9(3):206–17.
Curr Treat Options Cardio Med (2014) 16:346 49.
50.
51.
52.
53.
54.
55.
56.
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;63(25 Pt B):2889–934. 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 predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med. 2006;7(4):218– 30. Eckel RH, Jakicic JM, Ard JD, Miller NH, Hubbard VS, Nonas CA, et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;63(25 Pt B):2960–84. Cade WT, Reeds DN, Overton ET, Herrero P, Waggoner AD, Laciny E, et al. Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials. 2013;14(6):303–12. Garcia A, Fraga GA, Vieira Jr RC, Silva CM, Trombeta JC, Navalta JW, et al. Effects of combined exercise training on immunological, physical and biochemical parameters in individuals with HIV/AIDS. J Sports Sci. 2014;32(8):785–92. Tsiodras S, Poulia KA, Yannakoulia M, Chimienti SN, Wadhwa S, Karchmer AW, et al. Adherence to Mediterranean diet is favorably associated with metabolic parameters in HIV-positive patients with the highly active antiretroviral therapy-induced metabolic syndrome and lipodystrophy. Metab Clin Exp. 2009;58(6):854–9. Karanja N, Erlinger TP, Pao-Hwa L, Miller 3rd ER, Bray GA. The DASH diet for high blood pressure: from clinical trial to dinner table. Cleve Clin J Med. 2004;71(9):745–53. Calza L, Vanino E, Salvadori C, Manfredi R, Colangeli V, Cascavilla A, et al. Tenofovir/ emtricitabine/efavirenz plus rosuvastatin decrease serum levels of inflammatory markers more than antiretroviral drugs alone in antiretroviral therapy-
Page 11 of 11, 346
57.
58.
59.
60.
61.
62.
63.
64.
65.
naive HIV-infected patients. HIV Clin Trials. 2014;15(1):1–13. Eckard AR, Jiang Y, Debanne SM, Funderburg NT, McComsey GA. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis. 2014;209(8):1156–64. Overton ET, Kitch D, Benson CA, Hunt PW, Stein JH, Smurzynski M, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;56(10):1471–9. Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14(9):530–9. Oliveira JM, Rondo PH. Omega-3 fatty acids and hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: systematic review and metaanalysis. HIV Clin Trials. 2011;12(5):268–74. Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800–8. Balasubramanyam A, Coraza I, Smith EO, Scott LW, Patel P, Iyer D, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011;96(7):2236–47. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002;41(14):1195–211. Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008;47(5):570–8.
Prevention (L Sperling and D Gaita, Section Editors)
Cardiovascular Disease Associated with the Human Immunodeficiency Virus: An Update Thomas S. Metkus Jr., MD Todd T. Brown, MD, PhD Wendy S. Post, MD, MS* Address *Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA Email: [email protected]
Published online: 7 September 2014 * Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Prevention Keywords Prevention
I
Human immunodeficiency virus
I
Cardiovascular disease
I
Antiretroviral therapy
Opinion statement With the advent of increasingly available antiretroviral therapy (ART), the life expectancy of HIV-infected persons is increasing. As they age, HIV-infected persons have increased propensity to typical diseases of aging including cardiovascular disease and accelerated atherosclerosis. The pathogenesis of HIV-associated atherosclerosis is complex and involves a state of chronic inflammation, exposure to traditional risk factors, and metabolic side effects of ART. Treatment of HIV-associated atherosclerosis should include special attention to drug-drug interactions and is best accomplished by a multidisciplinary team experienced in the care of HIV-infected persons.
Introduction In the United States, nearly 50,000 patients were newly infected with HIV in the past year, an incidence rate that has been stable over prior years [1]. It is estimated that over 1 million Americans are living with HIV, and globally, over 33 million patients are living with HIV [2]. With the advent and increasing distribution of antiretroviral therapy, patients with HIV are less likely to die from HIV-related causes [3, 4] and are predisposed to
other typical diseases of aging including metabolic bone disease [5], frailty [6], cancer, and accelerated atherosclerosis and cardiovascular disease [7]. With HIV patients’ lifespans approaching that of non-HIV-infected individuals [8, 9], the focus will increasingly shift from management of HIVrelated complications to prevention and management of non-HIV-related complications including cardiovascular disease. It is estimated that as
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many as 15 % of HIV-infected patients will die of cardiovascular causes [10], which would translate
to approximately 5 million cardiovascular deaths worldwide.
Epidemiology of atherosclerosis and cardiovascular events in HIV-infected persons HIV-infected individuals have an increased propensity to acute cardiovascular events and premature atherosclerosis. Triant et al in 2007 reported a 1.7 relative risk for myocardial infarction in HIV compared with non-HIV-infected subjects [11]. In a large cohort based in the Veterans Affairs hospital system, a 50 % increase in myocardial infarction was observed above that expected from traditional risk factors in HIV-infected individuals [12••]. An increased rate of stroke has also been observed [13] with a hazard ratio of similar magnitude. Consistent with these results, observational studies have shown a higher prevalence of subclinical atherosclerosis among HIV-infected persons. Our group reported that HIV-infected men with no prior history of coronary revascularization had a higher presence and extent of noncalcified coronary plaque assessed by computed tomography (CT) angiogram even after adjustment for cardiac risk factors compared with HIV-uninfected men in the Multicenter AIDS Cohort Study [14••]. Similar results were seen in a study from Massachusetts General Hospital, which reported increased coronary plaque as assessed by CT angiography, specifically noncalcified coronary plaque, in HIVinfected women [15] and men [16] compared with HIV negative controls. Carotid intima-media thickness has also been demonstrated to be increased and progression of carotid intima-media thickness was more rapid in HIVinfected patients as compared to age and gender matched HIV negative controls [17]. A survey of administrative health database in Ontario demonstrated that HIV-infected patients had a higher prevalence of both peripheral arterial disease and stroke [18]; in a second study, nearly 20 % of patients with HIV had an abnormal ankle-brachial index either at rest or after exercise [19]. The pathophysiology of the accelerated atherosclerosis and acute cardiovascular events in HIV-infected individuals is multifactorial and includes an increased prevalence of traditional cardiovascular risk factors, a systemic inflammatory response associated with chronic HIV infection, and metabolic side effects associated with antiretroviral therapy. We will review the recent literature on each of these predisposing factors in turn.
Traditional cardiovascular risk factors The use of tobacco products is higher in HIV-infected population compared with the general population. O’Cleirigh and colleagues reported that persons with HIV smoked at nearly three times the rate of the general population, with overall smoking rate of nearly 60 % [20]. The same investigators also report higher rates of substance abuse including specifically cocaine, which predisposes to premature atherosclerosis, acute myocardial infarction mediated by vasospasm and thrombosis, and alcohol that could predispose to alcoholic cardio-
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myopathy. Tobacco use may be synergistically worse in HIV-infected patients compared with HIV negative patients because of increased immune activation in smokers [21]. Given the disproportionate representation of lower income groups among those with HIV infection, it is likely that access to heart-healthy foods and other healthy lifestyle components such as regular exercise are less among the total HIV population in the United States and worldwide [22]. Management of traditional cardiovascular risk factors in the HIV-infected population is of paramount importance and there is great unmet need. In a multinational survey, less than one in five HIV-infected individuals reported discussing cardiovascular disease prevention with their physician including alarmingly 44 % of smokers who were never offered a means for smoking cessation [23]. These data suggest that, in addition to increasing effort and study toward managing the HIV specific propensity to atherosclerosis, an equivalent focus should remain on traditional cardiovascular risk factor modification in this population.
Systemic inflammation and hypercoagulability in HIV infected persons HIV infection is associated with a state of systemic chronic inflammation; chronic inflammation in a variety of noncardiac conditions has been demonstrated to be atherogenic [24]. Markers of macrophage activation have been demonstrated to be elevated in HIV-infected individuals and associated with higher burden of coronary plaque [25]. In addition to increased circulating levels of inflammatory markers, HIV infection is associated with inflammation of the blood vessels themselves: HIV-infected subjects and controls matched for age and cardiac risk factors underwent 18F-FDG-PET to assess arterial wall inflammation. HIVinfected individuals had significantly higher arterial wall inflammation compared to uninfected controls, a difference that correlated with higher serum markers of inflammation [26••]. In addition to systemic inflammation, other circulating factors including adipokines may be involved in the pathogenesis of HIV associated atherosclerosis [27], and this is an area requiring further study. The milieu of chronic inflammation and disordered adipokine metabolism in HIV-infected patients has the potential to interact synergistically with a general propensity toward hypercoagulability. In a group of patients with poorly controlled HIV and low CD4 counts, D-dimer levels and other serologic markers of thrombosis were elevated compared to age matched controls, and these markers of hypercoagulability improved with better control of HIV [28]. This finding may underlie the increased rates of clinical venous thromboembolism; venous thromboembolism rates were increased in HIV-infected patients compared with population controls in the Danish HIV Cohort study [29]. Patients with venous thromboembolism have higher levels of P-selectin as a marker for endothelial dysfunction that may play a part in this hypercoagulability [30].
The role of antiretroviral therapy and HIV clinical factors Antiretroviral therapy (ART) itself is an important contributor to the risk of premature coronary disease in HIV-infected patients. Since its advent in the
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Curr Treat Options Cardio Med (2014) 16:346 mid-1990s, the complexity of ART has grown dramatically with introduction of multiple new drug classes. Typical ART drug regimens include three total drugs incorporating two different drug classes [31]. The different drug classes available include nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors, and fusion and entry inhibitors. Protease inhibitors were the first class of drugs implicated in premature coronary artery disease with associations noted between MI and protease inhibitor use in retrospective [32] and time series analyses [33]. A widely cited analysis published in 2003 from the Data collection on Adverse events of Anti-HIV Drugs (D:A:D)study included over 23,000 patients in a prospective observational cohort study; the authors demonstrated that combination ART including either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor increased the risk for myocardial infarction [34].The overall risk was quite low, with only 126 total patients having myocardial infarction. Abacavir, a nucleoside reverse transcriptase inhibitor, and didanosine have also been implicated in causing cardiovascular events in an analysis of the D:A:D study [35]. The respective relative risks, however, were small, and a subsequent analysis including a retrospective study of over 36,000 patients treated for HIV at Veterans Affairs hospitals demonstrated no association between specific ART agents and myocardial infarction or stroke [36]. Over the time period encompassing this study, the overall rate of death from any cause declined and the risk of dying from cardiovascular disease also declined, and the authors conclude that the marked benefits of ART are not attenuated by an increase in cardiovascular disease [36]. There are no randomized controlled trials of specific ART agents designed with adequate follow-up and sufficient power to address the optimal ART regimen to mitigate cardiovascular risk, however, available studies suggest that the overall contribution of ART to cardiovascular risk is small at a population level [34]. It is anticipated that the current generation of ART induces fewer metabolic side effects. ART is recommended for all HIV-infected patients irrespective of CD4 count, and an assessment of cardiovascular risk is not germane to the decision to start ART if it is otherwise indicated [31]. The nadir CD4 count, however, may be a marker of future cardiovascular risk. In a cross-sectional study of almost 10,000 HIV-infected participants enrolled in three randomized controlled trials, lower CD4 counts were correlated with higher D-dimer levels and higher levels of systemic inflammation as assessed by C-reactive protein and interleukin-6 levels in HIV-infected patients [37]. D-dimer levels were in turn correlated with mortality [37]. Lower nadir CD-4 count was associated with progression of carotid intima-media thickness over 6 years of follow-up [38] and with coronary artery stenosis [14••]. A lower CD4 count may also be associated with endothelial dysfunction- nadir CD4 count less than 350 cells/ mm3 was associated with lower brachial artery flow-mediated dilatation [39]. Episodic use of ART to keep the CD4 count greater than 350 cells/mm3 was compared with continuous use of ART in a randomized controlled trial; the episodic use of ART was associated with a 1.8 greater hazard for cardiovascular disease [40]. Overall, these results do support early initiation of ART to be used continually to decrease cardiovascular risk. Further data will be forthcoming—the START study is an ongoing randomized controlled trial of deferred initiation of ART until CD4 count is less than 350 cells/mm3 vs ini-
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tiation at CD4 count of greater than 500 cells/mm3 [41]. The data also implies that the universal HIV screening program currently recommended [42], with the aim to identify and, therefore, treat asymptomatic HIV before progression to clinical AIDS, would also decrease cardiovascular risk.
HIV associated metabolic abnormalities The signs of subcutaneous lipoatrophy and truncal lipohypertrophy, as well as the metabolic syndrome of elevated triglyceride levels, low HDL cholesterol levels, and impaired glucose regulation are all associated with HIV [43]. Subcutaneous lipoatrophy refers to loss of subcutaneous fat and is most associated with the use of older nucleoside reverse transcriptase inhibitors stavudine and zidovudine, which are rarely used in the developed world. In contrast, the gain of abdominal and visceral adiposity associated with HIV infection has not been linked to one specific ART drug [43]. The dyslipidemia phenotype associated with HIV includes elevated triglycerides, low total and HDL cholesterol levels, and increased levels of small, dense LDL particles [44, 45]. Because of the many possible combinations of different ART agents, the effect of any single agent on the plasma lipid profile is difficult to ascertain. In general, total and HDL cholesterol increase after ART initiation as part of a “return to health” phenomenon in those patients who initiate therapy at a lower CD4 count [43]. In the randomized controlled trials of most modern and recently studied ART regimens, total, HDL, and LDL cholesterol levels increase mildly to moderately with therapy as do triglycerides, although the ratio of total to HDL cholesterol decreases [43]. Among protease inhibitors, lopinavir has been demonstrated to have more severe effects on the lipid profile compared with atazanavir [46]. Substituting a newer ART agent from the integrase inhibitor class in lieu of protease inhibitor has also been shown to have superior effects on the lipid profile [47]. In addition to dyslipidemia, impaired glucose metabolism is a final and synergistic component of the HIV associated metabolic syndrome, with impaired glucose metabolism present in up to 25 % of HIV-infected patients [48].
Screening for cardiovascular disease Given the metabolic comorbidities and propensity toward cardiovascular disease in HIV-infected patients reviewed above, the question of whether and how to screen for cardiovascular disease is of paramount importance. HIVinfected patients’ cardiovascular risk should be regularly assessed as part of routine primary care. The history should include symptoms suggestive of vascular disease such as angina, dyspnea, claudication, or transient neurologic phenomena. Family history of premature vascular disease should be assessed. HIV specific risk factors for vascular disease should be sought, as reviewed above, and include nadir CD4 count and ART treatment history. A screening lipid profile and fasting serum glucose or hemoglobin A1C should be obtained in all patients. The recent 2013 American College of Cardiology/ American Heart Association guidelines for management of elevated blood cholesterol [49] have embraced new paradigms for assessing cardiovascular
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Curr Treat Options Cardio Med (2014) 16:346 risk, therapies of elevated blood cholesterol, and treatment targets in the general population. These guidelines recommend assessing risk using the Pooled Cohort Equation and prescribing statin therapy for patients with manifest vascular disease, for those with diabetes, for those with LDL cholesterol greater than 190 mg/dL, and to consider the risks and benefits of statin therapy for those with a greater than 7.5 % 10-year risk [49]. Noteworthy, however, are the facts that patients with clinical diagnoses of HIV were not specifically included in the derivation cohort for the Pooled Cohort Equation, and that patients with HIV often have low levels of both total and HDL cholesterol as discussed. Although there are no data as yet on the performance of the Pooled Cohort Equation in the HIV population, other evidence suggests that routine risk calculators such as Framingham may underestimate risk in the HIV-infected population [50]. There are no data to suggest that routine screening of HIV-infected patients with cardiovascular stress testing, ankle-brachial index, or cerebrovascular or coronary imaging improves outcomes.
Approach to primary and secondary cardiovascular disease prevention The foundation of primary and secondary prevention of cardiovascular disease includes exercise, dietary modification, and lipid lowering drug therapy in HIVinfected patients as in the general population in addition to control of hypertension, diabetes, and smoking cessation. With regard to exercise, there are few quality data on benefits in HIV-infected patients. General recommendations are for three or four sessions per week of 40 minutes of moderate to intense physical activity [51]. It is reasonable to extend these recommendations to HIV-infected patients as well, given that available data specific to HIV-infected populations are scarce. A small randomized controlled trial of pioglitazone and exercise training did not show a benefit on reducing insulin resistance in HIV-infected patients, however, a small sample size left it likely underpowered to detect a difference [52]. Supervised exercise training did improve HDL levels and VO2 max in a group of 10 HIV-infected patients [53]. Similarly, it is reasonable to extend recommendations for a heart healthy diet from those for the general population to the HIV-infected population. Adherence to a Mediterranean diet was associated with improved dyslipidemia and indices of the metabolic syndrome in 227 HIV-infected patients [54]. The Mediterranean diet and DASH diet [55] both are reasonable dietary strategies [51]. With regard to management of dyslipidemia in the HIV-infected population, there are no randomized controlled trials with cardiovascular events as the primary outcome—available data focus on the outcomes of change in lipid levels. Statin therapy remains a cornerstone of management of dyslipidemia. Rosuvastatin has been demonstrated to reduce systemic inflammatory markers in an observational study of HIV-infected patients with statins prescribed for dyslipidemia [56]. A 10 mg dose of rosuvastatin also decreased Lp(a) levels in HIV-infected participants compared with placebo [57]. The pleotropic effect of statins in this patient population should not be overlooked. In a retrospective analysis from the AIDS Clinical Trials Group,
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statin use was associated with a lower relative risk of non-AIDS defining cancer [58]. This association requires further study with regard to extent and mechanism. The challenge of drug-drug interactions between statin therapy and ART will be discussed below. With regard to nonstatin lipid lowering therapy, our group [59] and others [60] have shown that omega-3 fatty acid supplementation improves triglyceride levels in HIV-infected patients with dyslipidemia. It is noteworthy, however, that in the general population, randomized controlled trials have not demonstrated a benefit to omega-3 fatty acid supplementation on cardiovascular outcomes [61]. A randomized controlled trial investigated the effect of fenofibrate, niacin, and combination therapy on lipid levels in HIVinfected patients with hypertriglyceridemia. Fenofibrate reduced triglyceride levels and non-HDL c levels, niacin raised HDL levels, and the combination therapy provided maximal benefit with reduced triglycerides and non-HDL C and increased HDL [62]. In HIV patients as in the general population, addition of nonstatin medications for dyslipidemia has not been shown to change cardiovascular outcomes [63] and consistent with recent guidelines, statin therapy should remain the cornerstone of dyslipidemia treatment given proven benefits. There are challenges to management of cardiovascular risk in the HIVinfected population, some unique and some similar to those faced in risk factor modification in general. Adherence to therapy, both lifestyle and pharmacologic, may be difficult particularly given that HIV-infected patients are taking multiple other important medications. Drug-drug interactions remain a concern, and involvement of a pharmacist experienced in the management of HIV-infected patients is invaluable. The most common and concerning drug-drug interaction involves statins and inhibitors of cytochrome P4503A4 (CYP3A4), including protease inhibitors and the newer pharmacologic booster, cobicistat. Serum levels of statins metabolized by CYP3A4, such as simvastatin and lovastatin, are markedly elevated with protease inhibitor co-administration, and these statins should not be used [64] if protease inhibitors or cobicistat are part of the ART regimen. In the same study, atorvastatin levels were increased modestly, however, atorvastatin can likely be used at a lower dose with gradual up-titration [43]. Similarly, rosuvastatin levels are modestly increased in the presence of protease inhibitor co-administration but rosuvastatin can be used clinically at low doses with gradual up-titration [65]. Pravastatin should be dose adjusted
Fig. 1. Components of an HIV multidisciplinary clinic.
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Curr Treat Options Cardio Med (2014) 16:346 downward when the ART regimen includes darunavir. Fluvastatin and pitavastatin as well as niacin and fibrates can be used in HIV-infected patients similarly to HIV uninfected patients [43]. Given the changing face of the HIV epidemic and growing medical complexity of caring for these patients, optimal care is delivered by a multidisciplinary subspecialty clinic. Such a clinic is diagrammed in Fig. 1 and includes primary care providers with special training and expertise in caring for HIV-infected patients, Infectious Diseases specialists, involvement with social workers, nutritionists, exercise physiologists, and subspecialists with interest and experience caring for HIV-infected patients. The scope of relevant subspecialties is broad and germane to the scope of this review includes cardiologists and endocrinologists.
Conclusions In conclusion, HIV-infected patients are living longer and non-HIV-related comorbidities including cardiovascular disease are an increasingly important cause of morbidity and mortality. HIV infection predisposes patients to premature atherosclerosis via multiple mechanisms including systemic inflammation, comorbid risk factors, and metabolic side effects of ART. In the absence of further data, screening for cardiovascular disease and primary and secondary prevention of cardiovascular disease in HIV-infected patients should utilize established guidelines for the general population, and therapy has special considerations including attention to drug-drug interactions. Future studies incorporating cardiovascular endpoints in HIV-infected patients are needed.
Compliance with Ethics Guidelines Conflict of Interest Dr Thomas Metkus and Dr Todd T. Brown each declare no potential conflicts of interest. Dr Wendy Post reports grants from NIH. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.
2.
CDC. HIV Surveillance Report, 2011; vol. 23. http:// www.cdc.gov/hiv/topics/surveillance/resources/reports/. 2013 [cited 2013 6 June 2014]. http://aids.gov/hiv-aids-basics/hiv-aids-101/globalstatistics/index.html. [cited 2014 6 June 2014].
3.
Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio Monforte A, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 2003;362(9377):22–9.
Curr Treat Options Cardio Med (2014) 16:346 4.
Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145(6):397–406. 5. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies. J Infect Dis. 2012;205 Suppl 3:S391–8. 6. Brothers TD, Rockwood K. Biologic aging, frailty, and age-related disease in chronic HIV infection. Curr Opin HIV AIDS. 2014;9(4):412–8. 7. Boccara F, Lang S, Meuleman C, Ederhy S, MaryKrause M, Costagliola D, et al. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol. 2013;61(5):511–23. 8. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372(9635):293–9. 9. 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 immunodeficiency syndrome-negative individuals followed simultaneously in longterm cohort studies, 1984–2008. Am J Epidemiol. 2013;177(2):116–25. 10. Palella Jr FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. 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(1):27–34. 11. 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(7):2506–12. 12.•• Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614–22. This large cohort study assessed HIV as a risk factor for acute myocardial infarction in over 80,000 subjects followed in the Veterans Affairs system. HIV-infected and uninfected persons were matched and followed prospectively. HIVinfected persons had increased risk of acute myocardial infarction even after adjustment for traditional cardiovascular risk factors. 13. Chow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system. J Acquir Immune Defic Syndr. 2012;60(4):351–8. 14.•• Post WS, Budoff M, Kingsley L, Palella Jr FJ, Witt MD, Li X, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med. 2014;160(7):458–67. This study from our group assessed the association between coronary atherosclerosis and HIV using coronary CT angi-
Page 9 of 11, 346 ography in HIV-infected and uninfected gay and bisexual men. HIV infection was associated with an increased prevalence and extent of noncalcified plaques. Nadir CD4+ T cell count and years on HAART were associated with coronary artery stenosis greater than 50%. 15. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208(11):1737–46. 16. Lo J, Abbara S, Shturman L, Soni A, Wei J, RochaFilho JA, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS. 2010;24(2):243–53. 17. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109(13):1603–8. 18. Kendall CE, Wong J, Taljaard M, Glazier RH, Hogg W, Younger J, et al. A cross-sectional, populationbased study measuring comorbidity among people living with HIV in Ontario. BMC Public Health. 2014;14:161. 19. Periard D, Cavassini M, Taffe P, Chevalley M, Senn L, Chapuis-Taillard C, et al. High prevalence of peripheral arterial disease in HIV-infected persons. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008;46(5):761–7. 20. O'Cleirigh C, Valentine SE, Pinkston M, Herman D, Bedoya CA, Gordon JR, et al. The unique challenges facing HIV-positive patients who smoke cigarettes: HIV viremia, art adherence, engagement in HIV care, and concurrent substance use. AIDS Behav. 2014. 21. Valiathan R, Miguez MJ, Patel B, Arheart KL, Asthana D. Tobacco smoking increases immune activation and impairs T-cell function in HIV infected patients on antiretrovirals: a cross-sectional pilot study. PLoS One. 2014;9(5):e97698. 22. Kalichman SC, Hernandez D, Cherry C, Kalichman MO, Washington C, Grebler T. Food insecurity and other poverty indicators among people living with HIV/AIDS: effects on treatment and health outcomes. J Community Health. 2014. 23. Sherer R, Solomon S, Schechter M, Nachega JB, Rockstroh J, Zuniga JM. HIV provider-patient communication regarding cardiovascular risk: results from the 2010 AIDS treatment for life international survey. J Int Assoc Providers AIDS Care. 2014;13(4):342–5. 24. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95. 25. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with
346, Page 10 of 11 noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011;204(8):1227–36. 26.•• Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in patients with HIV. JAMA. 2012;308(4):379–86. The authors performed cardiac FDG-PET imaging in patients with and without HIV. HIV-infected patients had more FDG uptake in the aortic wall as compared to controls suggesting increased arterial inflammation. Circulating markers of systemic inflammation were also higher in HIV-infected persons. 27. Ketlogetswe KS, Post WS, Li X, Palella Jr FJ, Jacobson LP, Margolick JB, et al. Lower adiponectin is associated with subclinical cardiovascular disease among HIV-infected men. AIDS. 2014;28(6):901–9. 28. Jong E, Louw S, van Gorp EC, Meijers JC, ten Cate H, Jacobson BF. The effect of initiating combined antiretroviral therapy on endothelial cell activation and coagulation markers in South African HIV-infected individuals. Thromb Haemost. 2010;104(6):1228– 34. 29. Rasmussen LD, Dybdal M, Gerstoft J, Kronborg G, Larsen CS, Pedersen C, et al. HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study. HIV Med. 2011;12(4):202– 10. 30. Musselwhite LW, Sheikh V, Norton TD, Rupert A, Porter BO, Penzak SR, et al. Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV. AIDS. 2011;25(6):787–95. 31. Burgess MJ, Kasten MJ. Human immunodeficiency virus: what primary care clinicians need to know. Mayo Clin Proc. 2013;88(12):1468–74. 32. Henry K, Melroe H, Huebsch J, Hermundson J, Levine C, Swensen L, et al. Severe premature coronary artery disease with protease inhibitors. Lancet. 1998;351(9112):1328. 33. Holmberg SD, Moorman AC, Williamson JM, Tong TC, Ward DJ, Wood KC, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet. 2002;360(9347):1747–8. 34. Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349(21):1993–2003. 35. 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 antiHIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318–30. 36. 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(8):702–10.
Curr Treat Options Cardio Med (2014) 16:346 37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Borges AH, O'Connor JL, Phillips AN, Baker JV, Vjecha MJ, Losso MH, et al. Factors associated with D-dimer levels in HIVinfected individuals. PLoS One. 2014;9(3):e90978. Volpe GE, Tang AM, Polak JF, Mangili A, Skinner SC, Wanke CA. Progression of carotid intima-media thickness and coronary artery calcium over 6 years in an HIV-infected cohort. J Acquir Immune Defic Syndr. 2013;64(1):51–7. Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dube MP, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152 s. J Am Coll Cardiol. 2008;52(7):569– 76. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. Babiker AG, Emery S, Fatkenheuer G, Gordin FM, Grund B, Lundgren JD, et al. Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. Clin Trials. 2013;10(1 Suppl):S5–36. Moyer VA. Screening for HIV: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013;159(1):51–60. Brown TT, Glesby MJ. Management of the metabolic effects of HIV and HIV drugs. Nat Rev Endocrinol. 2012;8(1):11–21. Feingold KR, Krauss RM, Pang M, Doerrler W, Jensen P, Grunfeld C. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab. 1993;76(6):1423–7. Tien PC, Schneider MF, Cox C, Cohen M, Karim R, Lazar J, et al. HIV, HAART, and lipoprotein particle concentrations in the Women's Interagency HIV Study. AIDS. 2010;24(18):2809–17. Cohen C, Nieto-Cisneros L, Zala C, Fessel WJ, Gonzalez-Garcia J, Gladysz A, et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin. 2005;21(10):1683–92. Martínez E, Larrousse M, Llibre JM, Gutiérrez F, Saumoy M, Antela A, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697–707. Samaras K. The burden of diabetes and hyperlipidemia in treated HIV infection and approaches for cardiometabolic care. Curr HIV/AIDS Rep. 2012;9(3):206–17.
Curr Treat Options Cardio Med (2014) 16:346 49.
50.
51.
52.
53.
54.
55.
56.
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;63(25 Pt B):2889–934. 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 predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med. 2006;7(4):218– 30. Eckel RH, Jakicic JM, Ard JD, Miller NH, Hubbard VS, Nonas CA, et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;63(25 Pt B):2960–84. Cade WT, Reeds DN, Overton ET, Herrero P, Waggoner AD, Laciny E, et al. Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials. 2013;14(6):303–12. Garcia A, Fraga GA, Vieira Jr RC, Silva CM, Trombeta JC, Navalta JW, et al. Effects of combined exercise training on immunological, physical and biochemical parameters in individuals with HIV/AIDS. J Sports Sci. 2014;32(8):785–92. Tsiodras S, Poulia KA, Yannakoulia M, Chimienti SN, Wadhwa S, Karchmer AW, et al. Adherence to Mediterranean diet is favorably associated with metabolic parameters in HIV-positive patients with the highly active antiretroviral therapy-induced metabolic syndrome and lipodystrophy. Metab Clin Exp. 2009;58(6):854–9. Karanja N, Erlinger TP, Pao-Hwa L, Miller 3rd ER, Bray GA. The DASH diet for high blood pressure: from clinical trial to dinner table. Cleve Clin J Med. 2004;71(9):745–53. Calza L, Vanino E, Salvadori C, Manfredi R, Colangeli V, Cascavilla A, et al. Tenofovir/ emtricitabine/efavirenz plus rosuvastatin decrease serum levels of inflammatory markers more than antiretroviral drugs alone in antiretroviral therapy-
Page 11 of 11, 346
57.
58.
59.
60.
61.
62.
63.
64.
65.
naive HIV-infected patients. HIV Clin Trials. 2014;15(1):1–13. Eckard AR, Jiang Y, Debanne SM, Funderburg NT, McComsey GA. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis. 2014;209(8):1156–64. Overton ET, Kitch D, Benson CA, Hunt PW, Stein JH, Smurzynski M, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;56(10):1471–9. Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14(9):530–9. Oliveira JM, Rondo PH. Omega-3 fatty acids and hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: systematic review and metaanalysis. HIV Clin Trials. 2011;12(5):268–74. Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800–8. Balasubramanyam A, Coraza I, Smith EO, Scott LW, Patel P, Iyer D, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011;96(7):2236–47. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002;41(14):1195–211. Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008;47(5):570–8.
