HIV, Subclinical Cardiovascular Disease, and Clinical Progression

People living with HIV have higher risks of cardiovascular disease (CVD) including myocardial infarction,^1,2 heart failure,^3,4 stroke,⁵ pulmonary hypertension,⁶ and sudden cardiac death than those without HIV.⁷ These excess CVD risks persist in the modern HIV treatment era and are not readily explained by demographic, environmental, or clinical confounding factors. Nor are these HIV-associated CVD risks explained by antiretroviral therapy (ART)⁸; the net cardiovascular and overall benefits of effective HIV treatment clearly outweigh the risks.^8,9 Thus, refining HIV-specific contributors to CVD pathogenesis is critically important for identifying novel diagnostic and therapeutic targets and potentially informing CVD risk stratification for people with HIV.

Given well-established associations of subclinical imaging markers of vascular and myocardial disease with clinical CVD in the general population and limited power to evaluate overt clinical CVD events in many HIV cohorts, studies of people living with HIV have commonly relied on imaging-based surrogate markers of CVD. Imaging studies have yielded important general insights into the immunopathogenesis of HIV-related CVD. These studies have corroborated observational and mechanistic data implicating immune dysregulation, metabolic disturbances, and chronic inflammatory activation as central contributors to HIV-associated CVDs.⁹ Yet there is considerable interstudy heterogeneity and different studies have yielded divergent conclusions on questions as fundamental as whether people living with HIV actually have more subclinical coronary atherosclerosis than people without HIV.

In this issue of JAMA, Hudson et al¹⁰ undertook the important task of reviewing and synthesizing studies of imaging-based subclinical CVD measurements in people living with HIV. The authors separately grouped studies that measured myocardial fibrosis, proxy-measured by late gadolinium enhancement on cardiac magnetic resonance (MR) imaging; coronary atherosclerosis, assessed by computed tomographic coronary angiography; and vascular inflammation, measured by positron emission tomography (PET).

The authors identified 45 studies: 16 involved cardiac MR; 16, computed tomographic coronary angiography; 10, vascular PET; and 3, computed tomographic coronary angiography and vascular PET. The review included 5218 individuals living with HIV (mean age, 48.5 years; 24% women) and 2414 individuals without HIV. The studies were highly heterogeneous in size (range, 11 to 953) and in patient characteristics; eg, the mean ages of people living with HIV ranged from 22 to 60 years, and they had widely varying prevalence of clinical risk factors such as smoking and hypertension. HIV-uninfected control groups were likewise highly heterogeneous, as were the matching criteria: control groups ranged from 4 years younger to 14 years older than the people living with HIV to whom they were matched in individual studies. These differences are potential sources of confounding for comparisons by HIV status given the strong influence of age on subclinical CVD progression.

In light of substantial heterogeneity in study populations and, per the authors’ review, moderate to high risk of bias in 78% (35 of 45) of the studies analyzed, it is not surprising that associations of HIV with CVD imaging markers varied considerably by individual study. Nevertheless, some unifying findings were apparent and clearly elucidated by the authors’ summaries and discussion. These included (1) the prevalence of myocardial fibrosis among people living with HIV ranged from 5% to 84% and was higher than it was among HIV-uninfected control populations; (2) the prevalence of any coronary plaque among people living with HIV ranged from 17% to 84%, but conclusions varied on whether people living with HIV had more prevalent coronary plaque than HIV-uninfected controls; and (3) higher vascular inflammatory measurements on PET imaging were reported among people living with HIV than among controls.

A somewhat surprising finding, due to known higher risk of myocardial infarction among people living with HIV,^1,2 was that there was not a consistently higher prevalence of coronary atherosclerosis for people living with HIV vs controls in all studies. Yet on closer examination, it is not clear whether this reflects true biology or whether it is an artifact of heterogeneous study populations and comparison groups. Several studies observed 1.8- to 5-fold higher prevalence of coronary plaque in people living with HIV than in the HIV-uninfected control groups, but the 2 largest studies, which had control populations that were an average of 4 and 14 years older than their comparison with HIV groups,^11,12 observed no significant HIV-associated difference in coronary plaque prevalence. Another factor limiting unifying, generalizable conclusions related to HIV serostatus-based differences in subclinical CVD is that none of the 45 studies analyzed were conducted in low-income countries, many of which have high HIV endemicity.

Overall, the authors’ thorough review clearly highlights the limitations of current data and demonstrates how little can be definitively concluded regarding effects of general HIV serostatus on subclinical CVD. Yet this question–how HIV serostatus as a whole is associated with different subclinical measures of CVD–may be of limited importance given the already established, data-driven^1-5,7 consensus^9,13 that people living with HIV in general are at increased risk of overt clinical CVD.

A more relevant next set of questions, therefore, may not relate to how the general entity of HIV is associated with CVD but rather which specific factors among people living with HIV predispose some to CVD and protect others from CVD. Immune pathogenesis and progression of HIV are highly heterogeneous, with important and varied implications for CVD: people living with HIV taking ART who have lower CD4 cell counts (eg, <200 or <350 cells/μL), detectable viremia, or both are at substantially higher CVD risk than people living with HIV taking ART with no detectable viremia and minimal CD4 cell count decline, whose CVD risks may not differ meaningfully from those of HIV-uninfected persons.

From a clinical CVD risk stratification standpoint, considering HIV as a singular CVD risk-enhancing factor is therefore less likely to be informative than a nuanced approach incorporating HIV-specific factors linked with CVD such as sustained viremia, low CD4 cell count, a history of lipodystrophy, and coinfection with hepatitis C virus.^1,3-5,7,9 For instance, a person with a history of sustained HIV viremia, opportunistic infections, lipodystrophy, and current CD4 cell count of 250 cells/μL may have nearly twice the risk of myocardial infarction and heart failure compared with an HIV-uninfected person with an otherwise similar clinical profile.^1-4,9 From a CVD prevention standpoint, this could prompt a related upward adjustment in perceived CVD risk and perhaps a lower threshold to consider CVD-preventive therapy.⁹ Meanwhile, a person who started ART soon after HIV exposure and diagnosis, without ever experiencing significant CD4 cell count decline, may have marginal HIV-associated increase in CVD risk.¹⁴ Accordingly, this person might require minimal, if any, HIV-driven adjustment to perceived CVD risk and related thresholds for CVD-preventive therapy.

Scientifically, disaggregating immune phenotypes among people living with HIV also offers considerable promise. The general immunologic natural history of treated HIV consists of an initial CD4 cell count decline followed by incomplete recovery, with related myeloid (eg, monocyte or macrophage) activation and biasing of the T-cell repertoire toward net-inflammatory responses. Yet these immunopathogenic courses vary considerably from person to person based on host and virologic factors. Accordingly, to cultivate specific, perhaps targetable, insights related to CVD mechanisms in people living with HIV will require precise study design to ensure selection of patients with specific immune phenotypes of interest. Absent more precise phenotyping, broad aggregation of people living with HIV with divergent immune phenotypes (eg, patients with CD4 cell counts <350 cells/μL in the same analytic groups as those with CD4 cell counts >700 cells/μL) may preclude clinically meaningful insights into why some progress to CVD and others do not.

Ultimately, while the heterogeneity in study populations observed by Hudson et al¹⁰ highlights limitations of current data of subclinical CVD among people living with HIV, it also serves as a helpful reminder of the need to consider HIV immunopathogenic variation. Questions comparing people living with HIV as a whole vs HIV-uninfected persons reflect an underlying assumption of pathogenic similarity among people living with HIV and distract from the perhaps more important question of which factors among people living with HIV make some more likely to develop CVD than others. Future studies recognizing the fundamental immunologic heterogeneity among people living with HIV and probing this factor have the opportunity to advance important clinical and scientific knowledge on precise immunopathogenic factors underlying CVD in specific HIV populations.