AHA Statement on HIV and Cardiovascular Disease: Clinical Strategies and Future Challenges

Widespread use of antiretroviral therapy (ART) coupled with strategies to expand testing and promote engagement in care has transformed human immunodeficiency virus (HIV) to a chronic disease with a near-normal lifespan. While overall morbidity and mortality in this population have dramatically improved over the past decades, rates of chronic noncommunicable diseases – including cardiovascular disease (CVD) – are increased relative to those of the general population. Moreover, the HIV population is aging as a group and will thus confront elevated rates of aging-related diseases. These factors result in a significant and increasing burden of cardiovascular disease in people living with HIV (PLWH).^1,2 This increased burden is in part driven by novel CVD risk factors which are not included in established CVD prevention and treatment paradigms. Targeted, HIV-specific prevention and treatment strategies for cardiovascular disease are therefore indicated but have been lacking to date. The 2019 Scientific Statement, “Characteristics, Prevention, and Management of Cardiovascular Disease in Persons Living with Human Immunodeficiency Virus (HIV)” (Scientific Statement on CVD in HIV) plays a critical role in filling this gap, providing evidence-based clinical strategies to prevent and manage CVD in this at-risk population.

Multiple studies indicate that the CVD risk factor profile differs for HIV and that novel risk factors including HIV-related inflammation and immune activation impart risk beyond that of traditional CVD risk factors. While traditional CVD risk factors occur at increased rates in PLWH and may have been modulated by older ART drugs, these factors do not fully explain the increased CVD risk observed in the HIV population. Extensive research into the pathophysiology of HIV-associated CVD suggests that inflammation and immune activation contribute significantly to increased risk.

The landmark SMART³ and START⁴ studies have increased knowledge on the impact of inflammation in HIV-associated CVD. The SMART study demonstrated an association of inflammatory markers IL-6 and d-dimer with both HIV treatment interruption and mortality; the START study revealed an association of earlier treatment initiation – leading to abbreviated duration of viremia and blunted immune activation – with a significant reduction of non-AIDS events (although not CVD per se). HIV disease markers also correspond to CVD risk in HIV, with significant associations of lower CD4 count and increased HIV RNA with hard CVD outcomes including myocardial infarction (MI) and stroke.

Despite robust translational and epidemiologic data supporting the contribution of novel risk factors to CVD risk in HIV, current clinical strategies do not reflect this mechanism. The development of targeted management strategies for HIV-associated CVD has been relatively limited, and guidance on management of CVD in HIV-infected women is even more so. Over a decade ago, the American Heart Association (AHA) and American Academy of HIV Medicine convened a multidisciplinary State-of-the-Science Conference, the Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living with HIV/AIDS, to address this topic,⁵ making an important contribution to the field through six working groups with dedicated publications spanning the scope of HIV and CVD.

Yet further guidance on the topic is either outdated or limited in scope or transportability to the HIV population. From the HIV perspective, guidelines for evaluation and management of dyslipidemia in HIV were released through the Infectious Diseases Society of America in 2003⁶ and guidelines on the prevention and management of metabolic diseases in HIV were released through the European AIDS Clinical Society in 2008,⁷ but these to not reflect the contemporary era of HIV treatment. The 2013 Primary Care Guidelines for the Management of Persons Infected with HIV,⁸ while an extremely valuable resource for clinicians, are relatively limited in their discussion of management of CVD and metabolic complications as this was not the focus of the guidelines.

From the cardiovascular perspective, guidelines developed for the general population are of limited applicability to HIV populations in light of the exclusion of PLWH from many randomized controlled trials (RCT) and lack of large scale RCTs investigating CVD risk in HIV. In fact, the 2013 American College of Cardiology (ACC)/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Risk in Adults⁹ directly highlights individuals with HIV as a group for which “RCT evidence is insufficient for guiding clinical recommendations.” Moreover, the clinical algorithms and risk prediction functions utilized in mainstream cardiovascular guidelines^9,10 are reliant on traditional CVD risk factors and may thus have limited applicability and underestimate risk in groups with nontraditional risk factors such as the HIV population.

The 2018 ACC/AHA Multisociety Guideline on the Management of Blood Cholesterol¹¹ represents a recent advance in recognizing the need for tailored clinical strategies for CVD management in HIV. The guideline includes HIV as a risk enhancing factor which, if present, would favor the initiation of statin therapy in patients at intermediate predicted risk. HIV is also included in a dedicated section on “Adults with Chronic Inflammatory Disorders and HIV” that provides specific recommendations regarding statin initiation and monitoring of fasting lipid profile. While the inclusion of HIV in this guideline is important, there remains an urgent need for detailed clinical guidance on all aspects of CVD prevention and treatment in HIV, particularly with regards to HIV-specific risk factors. Together, these considerations underscore the importance of the 2019 Scientific Statement on CVD in HIV.

The objectives of the Scientific Statement on CVD in HIV are to review the existing evidence on HIV-associated CVD and to provide pragmatic recommendations on how to approach CVD prevention and treatment in HIV. A comprehensive review of the field includes the epidemiology, pathophysiology, and presentation of atherosclerotic CVD, stroke, and heart failure in HIV. The pathophysiology of HIV-associated CVD is complex and multifactorial, and the interplay between traditional risk factors, ART (including abacavir and contemporary protease inhibitors), and inflammation and immune activation is reviewed. Discussion of cardioprotective therapies in HIV encompasses statins, aspirin, and ART (although not necessarily early ART). Smoking is appropriately highlighted as a risk factor of critical public health importance in the HIV population. A section on pathophysiologic insights from imaging reviews several modalities widely used to assess surrogate markers of atherosclerosis in HIV given the relative absence of data on long-term CVD outcomes.

CVD risk assessment and prevention and treatment of HIV-associated CVD are reviewed in detail in the following sections of the statement. General population cardiovascular risk prediction functions, including the Framingham functions and the Pooled Cohort Equations (PCE),^10,11 have been shown to underestimate risk in several studies, yet the optimal risk estimator for HIV has not been identified. In terms of prevention, lifestyle optimization should focus on smoking cessation, and HIV-specific resources for exercise and physical activity are provided. A detailed discussion of statins includes a summary of drug-drug interactions and a description of REPRIEVE,¹² a large randomized placebo-controlled global trial addressing the hypothesis that statins will prevent cardiovascular disease in HIV-infected patients, particularly among patients who do not meet guidelines for clinical use of statins. REPRIEVE will specifically investigate differential effects of statins in women, who have been shown to have higher levels of immune activation compared with men and, in some studies, increased relative risk of CVD.

The statement highlights investigational approaches beyond statins to reduce inflammation as a CVD risk reduction strategy. This section includes a discussion of PCSK9 inhibition studies in the general population and in PLWH (the EPIC-HIV study underway), a summary of general population trials using the IL-1β inhibitor canakinumab (CANTOS)¹³ and low-dose methotrexate (CIRT),¹⁴ and discussion of current investigative efforts to identify targeted immunomodulatory therapies to reduce inflammation in HIV. While the focus of the statement is on ischemic CVD, there are also dedicated sections on the epidemiology, pathophysiology, and diagnosis/treatment of stroke and heart failure.

The cornerstone of the statement is Figure 4, which presents a practical algorithm for atherosclerotic CVD risk assessment and prevention in treated HIV infection based on evidence and expert consensus. The approach employs specified HIV-Related CVD Risk Enhancing Factors, including prolonged HIV viremia, delay in ART initiation, low current/nadir CD4, HIV treatment failure, several metabolic indices, or hepatitis C virus co-infection, to prompt an upward-adjustment of predicted risk using established risk estimation models. Based on this adjusted estimated risk or the presence of selected general population ASCVD Risk Enhancers from the 2018 ACC/AHA cholesterol guidelines¹¹ (including family history, elevated LDL-C, chronic kidney disease, presence of subclinical, atherosclerosis, or inflammatory biomarkers but excluding hypertriglyceridemia), a high- versus a low/moderate-risk approach is recommended. The high-risk approach includes lifestyle optimization (recommended for all patients) as well as lipid-lowering therapy with specific guidance on selection of statin, dosing, and alternative lipid-lowering agents.

A novel and important aspect of the statement is a section devoted to disparities in care and opportunities to address them. Multiple HIV-associated factors exacerbate vulnerability of this population and can result in inequitable health care delivery. Disparities exist in the management of acute coronary syndrome (ACS), including receipt of percutaneous coronary intervention (PCI), and in the uptake of secondary prevention interventions. The statement discusses opportunities for positive impact, including leveraging existing HIV infrastructure to integrate primary care services and expanding the HIV treatment cascade to include the prevention of chronic disease comorbidities.

The epilogue provides valuable insight from the Founder and Executive Director of the National AIDS Treatment and Advocacy Program (NATAP), a leader in HIV education and advocacy and in HIV and aging-related issues. This section provides perspective on the urgency of the needs of the aging HIV population, the relative lack of support services and programs for individuals aging with HIV and the clinicians caring for them, and the utility of a dedicated HIV-related aging entity to centralize advocacy efforts and serves as a call to action to the community.

Public health goals for HIV and CVD have historically been discrete. Most recently, the AHA and UNAIDS rolled out parallel initiatives, each with a target date of 2020. The AHA 2020 Impact Goal¹⁵ seeks to improve the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular diseases and stroke by 20% by 2020, while the UNAIDS 90-90-90 treatment target¹⁶ seeks to diagnose 90% of people living with HIV, treat 90% of people diagnosed with HIV, and virally suppress 90% of people receiving ART by 2020. Yet to achieve the goal of reducing the burden of CVD in HIV, these initiatives should intersect. Indeed, moving towards 90-90-90 may help to reach the 2020 Impact Goal, as viral suppression leads to decreased inflammation – a novel driver of CVD risk – and engagement in HIV care is likely to facilitate receipt of CVD care.

The Scientific Statement on CVD in HIV helps to conceptually and practically link these initiatives, filling a salient gap in clinical guidance on CVD in HIV. The statement is applicable to a wide audience including clinicians, individuals living with HIV, and researchers. Moreover, the statement brings together a multidisciplinary team comprised of specialists in cardiology, neurology, infectious diseases, endocrinology, and patient advocacy. One of its most important contributions is to systematically identify areas in need of more research, including large clinical trials of CVD prevention, implementation research, investigation of non-atherosclerotic CVD outcomes including heart failure and thrombosis, and research on HIV-associated CVD in resource-limited settings.

The 2019 Scientific Statement on CVD in HIV provides timely, evidence-based, clinically-relevant guidance on the prevention and management of CVD in HIV. This guidance will serve as a valuable tool for clinicians, researchers, advocates, and policy makers that will ultimately help to decrease the burden of CVD and positively impact the care and well-being of the aging HIV population.