Imaging to Endpoints: Cardiovascular Disease Risk Assessment in HIV

The remarkable evolution of the HIV epidemic from a near uniformly fatal condition to a chronic viral infection now managed for many patients with one pill once-a-day marks one of the great accomplishments of medicine in recent decades. Life expectancy estimates for persons living with HIV with access to antiretroviral therapy (ART) are beginning to approach life expectancy estimates of the general population ¹. However, not long after the wide spread use of combination ART for the treatment of HIV, clinicians began to recognize undesirable effects of HIV therapy such as dyslipidemia and alterations in body fat distribution. These observations stimulated considerable attention from HIV providers and researchers to identify and understand cardiovascular disease risk associated with HIV and its therapy.

Early large cohort studies designed to evaluate cardiovascular disease (CVD) outcomes in the context of HIV demonstrated an increased risk of myocardial infarction (MI) in association with increasing years of ART exposure, and observational patient registries showed that rates of MI in persons living with HIV are increased compared to uninfected contemporaries.^{2, 3}. Subsequent cohort studies have consistently validated these observations, identifying approximately 1.5-fold higher risk of acute MI in in persons living with HIV compared to uninfected controls. In these studies, the enhanced risk of CVD associated with a diagnosis of HIV was found to be independent of traditional CVD risk factors, which are often enriched in HIV-infected populations^{4, 5}. Considerable efforts are underway to optimize CVD risk assessment and to characterize the unique contribution that HIV and immune activation play in the pathophysiology of CVD in in persons living with HIV. Recent estimates for the aging characteristics of the HIV-infected population suggest that by 2030 as many as 73% of persons living with HIV will be over the age of 50 years⁶, therefore the prevalence of CVD, an anticipated consequence of aging, can be expected to rise. Strategies for accurate identification of at-risk patients and development of effective approaches to CVD risk reduction will become increasingly important for the care of persons living with HIV in the future.

In the current issue of Circulation: Cardiovascular Imaging, Janjua and colleagues⁷ present the results of a study that leverages a large multi-institutional patient data registry to expand our current knowledge of CVD risk in HIV and provides an important link between an observed biomarker of atherosclerosis, namely carotid plaque, and subsequent CVD events. This retrospective study used available data from diagnostic contrast-enhanced CT scans from persons living with HIV without history of atherosclerosis (n=209) and similar non-HIV infected controls (n=168), to compare the presence and characteristics of carotid plaque and to determine the relationship between carotid plaque and subsequent CVD events.

The study shows that persons living with HIV had significantly higher rates of any carotid plaque, non-calcified carotid plaque and high-risk plaque compared to controls. However, there were important differences between the HIV group and controls. The majority (60%) of HIV subjects had one or more traditional CVD risk factors, while 64% of controls had no CVD risk factors identified (p<0.001). In addition, 25% of the HIV subjects had a history of cocaine exposure compared to only 4% of controls, and hepatitis C infection was present in 18% of the HIV subjects. Non-traditional risk factors for atherosclerotic disease such as cocaine and chronic hepatitis C infection are associated with carotid plaque in HIV ⁸. Further, chronic cocaine use was associated with a 2-fold increased risk of coronary artery plaque in HIV, independent of traditional risk factors and ART exposure ⁹. Differences in routine practices for inquiring about and documenting traditional CVD risk factors and substance use by providers caring for persons living with HIV and non-HIV-infected patients may create reporting bias and underestimate the prevalence of these risk factors in the control group. Nonetheless, the mismatch in traditional CVD risk factors, as well as cocaine exposure, may account for the much of the observed difference between groups in the presence of carotid plaque.

The present report may not have had optimally matched controls or been sufficiently large to tease out the contribution of non-HIV risk factors towards the prevalence of carotid plaque, however, the novel and informative observation that carotid plaque predicted later ASCVD events advances the field of CVD investigation in HIV. In multivariable analysis adjusted for traditional CVD risk factors, the presence of any carotid plaque among HIV subjects was associated with an increased risk of an CVD events (HR 2.84, CI 1.05–7.63, p=0.03). Similar associations were observed between non-calcified carotid plaque and high risk plaque, and the risk of subsequent CVD events in HIV subjects. These data are consistent with research in the general population. For example, Cao and colleagues showed that the presence of intermediate and high-risk carotid plaque on carotid ultrasound conferred approximately a 2-fold increased risk of CVD event after adjustment for traditional CVD risk factors in the Cardiovascular Health Study, a study of adults (≥ 65 years) without known CVD¹⁰. In the younger Multi-Ethnic Study of Atherosclerosis (MESA) cohort study, carotid plaque score was also a significant predictor of CVD events after adjustment for traditional risk factors (HR 1.27, 95% CI 1.16–1.40, p< 0.001) ¹¹. The observed link between asymptomatic carotid plaque and subsequent CVD events in a cohort of persons living with HIV supports the potential utility of carotid plaque measurements as a biomarker of CVD risk stratification and CVD risk reduction.

The overwhelming majority of HIV research evaluating carotid atherosclerosis and carotid intima media thickness (cIMT) has utilized ultrasound technology and not CT imaging, as used in the current report. While both are non-invasive imaging approaches, the additional burden of radiation exposure and contrast administration limits the broader appeal for the use of CT as a general screening tool in large populations. Radiation risk is further accentuated by the presence of the thyroid gland in the field of view and may explain the conspicuously low number of carotid CT studies related to atherosclerosis in asymptomatic populations, particularly those that may require follow up. Therefore, it would be difficult to justify using this technology as a means of identifying or monitor asymptomatic HIV subjects at high-risk for cardiovascular events.

Admittedly, Janjua and colleagues⁷ did not prospectively apply carotid CT as general screening tool. The investigators evaluated carotid CT retrospectively among a population with clinically indicated neck CT data, but additional limitations to this approach exist. The use of <3mm spotty calcifications and 1mm diameter foci of low attenuation (<40HU) as signs of high risk plaque would require higher resolution acquisitions (more radiation) and perfectly timed contrast administration. The latter component is even more critical as some high risk plaques may enhance or washout rapidly depending on the inflammatory status in addition to the wide range of variability in densities noted in atherosclerotic plaque^12–14. Many of the challenges associated with CT are overcome by high field MRI which has improved signal to noise and as well as spatial and temporal resolution^15–17. The technical versatility of MRI also allows for plaque characterization^{12, 14}. The relative technical simplicity, mobility and lower cost of ultrasound places this modality at an advantage for claustrophobic patients and locations that might not have the MRI capabilities^{12, 14}. Given these factors and available alternatives, translation of the findings of this study into clinical practice may be challenging.

The era of big data has arrived and its application in healthcare to infectious diseases and HIV are underway¹⁸. While carotid CT may not be the optimal approach to prospective CVD risk screening, as access to large patient data registries with high quality, reliable medical information and imaging data becomes more readily available, additional studies of this nature will be feasible. Triant and colleagues³ completed one of the earlier studies to use this approach to effectively demonstrate an increased risk of myocardial infarction in HIV relative to a general contemporary population. The application of this strategy to evaluate the role of incidental carotid plaque identified by CT to predict CVD events in HIV provides valuable new data that may be used to inform future research and management of CVD risk stratification and risk reduction in HIV.

As the HIV population ages, CVD associated morbidity and mortality is expected to rise. Multiple large observational cohorts have established a 1.5 to 2-fold increased risk of CVD in persons living with HIV compared to uninfected controls. Excess CVD observed in HIV is likely attributable to multiple factors including traditional CVD risk factors, HIV-related inflammation and immune activation, as well as possible off target effects of HIV therapy. Carotid plaque in the general population is predictive of CVD events, and Janjua and colleagues demonstrate that this relationship also holds true in HIV subjects. Research efforts continue to focus on identification of biomarker and imaging correlates of CVD in HIV, and large prospective trials such as REPRIEVE, a study of pitavastatin to reduce incident CVD, are underway to establish optimal strategies to address the excess CVD risk associated with HIV infection.