Circulation AHA SCIENTIFIC STATEMENT Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV A Scientific Statement From the American Heart Association ABSTRACT: As early and effective antiretroviral therapy has become more Matthew J. Feinstein, widespread, HIV has transitioned from a progressive, fatal disease to a MD, MSc, FAHA, Chair chronic, manageable disease marked by elevated risk of chronic comorbid Priscilla Y. Hsue, MD, Vice diseases, including cardiovascular diseases (CVDs). Rates of myocardial Chair infarction, heart failure, stroke, and other CVD manifestations, including Laura A. Benjamin, PhD pulmonary hypertension and sudden cardiac death, are significantly Gerald S. Bloomfield, MD, higher for people living with HIV than for uninfected control subjects, MPH, FAHA even in the setting of HIV viral suppression with effective antiretroviral Judith S. Currier, MD therapy. These elevated risks generally persist after demographic and Matthew S. Freiberg, MD, MSc clinical risk factors are accounted for and may be partly attributed to Steven K. Grinspoon, MD chronic inflammation and immune dysregulation. Data on long-term Jules Levin, MS Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 CVD outcomes in HIV are limited by the relatively recent epidemiological Chris T. Longenecker, MD, transition of HIV to a chronic disease. Therefore, our understanding FAHA of CVD pathogenesis, prevention, and treatment in HIV relies on large Wendy S. Post, MD, MS observational studies, randomized controlled trials of HIV therapies that On behalf of the American are underpowered to detect CVD end points, and small interventional Heart Association studies examining surrogate CVD end points. The purpose of this Prevention Science document is to provide a thorough review of the existing evidence Committee of the Council on HIV-associated CVD, in particular atherosclerotic CVD (including on Epidemiology and myocardial infarction and stroke) and heart failure, as well as pragmatic Prevention and Council recommendations on how to approach CVD prevention and treatment on Cardiovascular and Stroke Nursing; Council in HIV in the absence of large-scale randomized controlled trial data. This on Clinical Cardiology; statement is intended for clinicians caring for people with HIV, individuals and Stroke Council living with HIV, and clinical and translational researchers interested in HIV- associated CVD. Key Words: AHA Scientific Statements ◼ cardiovascular diseases ◼ HIV ◼ preventive medicine © 2019 American Heart Association, Inc. https://www.ahajournals.org/journal/circ Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 TBD TBD, 2019 e1 Feinstein et al Cardiovascular Disease in People With HIV ith contemporary antiretroviral therapy (ART), risks.5,25–27 Several studies have found that lower CD4 people living with HIV (PLWH) are living lon- count is associated with higher MI risks5,25–27; similarly, ger1 and experiencing a rising burden of car- a lower CD4/CD8 ratio is associated with more coro- W 2,3 28 diovascular diseases (CVDs). Relative risks of various nary atherosclerosis. Moreover, PLWH who achieve CVD manifestations are generally 1.5- to 2-fold greater sustained HIV viral suppression5 or have few, if any, for PLWH compared with uninfected individuals.4 Al- cardiovascular risk factors23 have higher MI risks than though the relative risk has decreased with effective people without HIV infection. This excess MI risk may AND GUIDELINES ART, there is a large and rising absolute burden of CVD be greater among women living with HIV/AIDS.24,29 CLINICAL STATEMENTS STATEMENTS CLINICAL among PLWH (conceptual model in Figure 1).2–4 In a PLWH also have significantly elevated risks for stroke. In meta-analysis of 793 635 individuals with a total of 3.5 HIV-endemic populations in Sub-Saharan Africa, HIV is million person-years of follow-up, the global burden of the leading risk factor for stroke in young cohorts, with HIV-associated CVD tripled over the past 2 decades and a population-attributable fraction of almost 50%.30 accounted for 2.6 million disability-adjusted life-years Women with HIV may be at particularly elevated risk per year, with the greatest impact in Sub-Saharan Af- compared with uninfected women.31 Both immunosup- rica and the Asia-Pacific regions (Figure 2).4 PLWH have pression and HIV viremia appear to be risk factors: Both an excess risk of myocardial infarction (MI),5,6 ischemic lower CD4 count and higher levels of HIV viremia are stroke,7,8 heart failure (HF),9,10 pulmonary hyperten- associated with greater stroke risk.7,30,32–34 Coinfection sion,11,12 and venous thrombosis.13,14 Underlying mech- with HIV and hepatitis C (versus HIV infection alone) anisms likely include an interplay among traditional risk may increase stroke risk further.35 factors, HIV-specific factors (eg, chronic immune acti- vation/inflammation),15,16 ART-related dyslipidemia and other metabolic comorbidities,17,18 behavioral factors HIV-ASSOCIATED HF 5,19 (eg, smoking), and disparities in access to or receipt Given the excess risk of coronary heart disease, it is not of care.20–22 surprising that PLWH also have elevated HF risks, with current estimates ranging from a 1.5- to 2-fold greater HIV-ASSOCIATED ATHEROSCLEROTIC risk for HF among PLWH compared with uninfected individuals after adjustment for relevant confound- 9,10,36,37 Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 CVD: MI AND STROKE ers. However, this excess risk is not entirely attrib- Over the past decade, a variety of studies from around utable to MI; after adjustment for prior MI, PLWH still the world have reported an excess risk of MI among have a >1.5-fold higher hazard for HF than uninfected PLWH compared with uninfected people. The risk rang- individuals.10 This risk extends to both HF with preserved es from a 50% relative risk increase to a doubling of ejection fraction (HFpEF) and HF with reduced ejection risk.5,23–25 Regardless of study, HIV-related viremia and fraction (EF). Similar to MI risks, unsuppressed HIV viral immune dysfunction are associated with higher MI load and lower CD4 count are associated with higher Figure 1. Conceptual model of the changing epidemiology of myocardial infarction (MI) and heart failure (HF) risk in HIV. ART indicates antiretroviral therapy; and CVD, cardiovascular disease. e2 TBD TBD, 2019 Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 Feinstein et al Cardiovascular Disease in People With HIV CLINICAL STATEMENTS STATEMENTS CLINICAL AND GUIDELINES Downloaded from http://ahajournals.org by [email protected] on June 3, 2019 Figure 2. Global burden of atherosclerotic cardiovascular disease in people living with HIV. A, Population-attributable fraction by country and (B) disability-adjusted life-years per 100 000 people by country. Reprinted from Shah et al.4 Copyright © 2018, American Heart Association, Inc. HF risks for PLWH.10,38 The epidemiology and charac- have reported that PLWH have an excess risk of periph- teristics of HF in HIV are discussed in greater detail in eral artery disease compared with uninfected individu- the HF Pathogenesis and Presentation in HIV section als.42,43 HIV-related pulmonary arterial hypertension has of this document. been well described since the 1990s and is considered to be in group 1 of the World Health Organization clas- sification of pulmonary hypertension.44–49 The preva- OTHER MANIFESTATIONS OF CVD lence of HIV-associated pulmonary arterial hypertension In contrast to the evidence linking HIV infection to MI, is considerably higher than pulmonary arterial hyper- HF, and stroke, there are fewer studies of atrial fibril- tension in the general population,50 and ART has not lation, sudden cardiac death, and peripheral artery changed this epidemiology.51 Elevated pulmonary ar- disease. However, 1 study reported that PLWH have a tery systolic pressure has also been reported in HIV.11,52 4-fold greater rate of sudden cardiac death compared As a result of limited data, treatment goals are similar with expected rates in the general population.39 Low to those of other pulmonary arterial hypertension sub- CD4 counts (<200 cells/mm3) are associated with el- groups.53 Finally, given the confluence of sleep disor- evated incidence40 and prevalence41 of atrial fibrillation ders, particularly obstructive sleep apnea, with CVD,54 among PLWH, but it is unclear whether PLWH without it is also worth noting that HIV is associated with sleep detectable HIV viremia or immune compromise have el- impairment in general55–57 and that obstructive sleep evated atrial fibrillation risks. Similarly, several studies apnea may be underdiagnosed among PLWH.58,59 Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000695 TBD TBD, 2019 e3 Feinstein et al Cardiovascular Disease in People With HIV PATHOPHYSIOLOGY AND Although treatment with ART reduces levels of circu- PRESENTATION OF ATHEROSCLEROTIC lating inflammation markers, many markers of inflam- mation remain elevated with viral suppression in PLWH CVD AND HF IN HIV relative to uninfected individuals.79 Furthermore, several After 2 decades of progress in studying the elevated studies have included PLWH who are able to maintain risks for CVD among PLWH, the underlying mechanisms an undetectable HIV RNA level despite not being on and biology of this process still remain incompletely de- ART (elite controllers) and demonstrated heightened AND GUIDELINES fined. Furthermore, delineating