Association of Human Immunodeficiency Virus Infection and Incident Abdominal Aortic Aneurysm Among 143,001 Veterans

Introduction

Antiretroviral therapy (ART) has greatly increased the lifespan of people with human immunodeficiency virus (PWH).^1–4 Nevertheless, even with ART, PWH are faced with an increased risk of cardiovascular disease (CVD), including coronary artery disease (CAD),^5,6 stroke,^7,8 and peripheral artery disease (PAD).³ This excess risk is a function of the virus itself, some forms of antiretroviral therapy, and a high prevalence of traditional risk factors, especially smoking.⁹ The combination of HIV infection and traditional risk factors may result in increased levels of systemic inflammation,¹⁰ activation of innate and adaptive immune cells,¹¹ and endothelial dysfunction,¹⁰ each of which may independently increase the risk of CVD.

Despite multiple studies linking HIV infection to a range of CVDs, reports examining the association between HIV infection and abdominal aortic aneurysm (AAA) are sparse.^12,13 The most indicative report to date is a cross-sectional study reporting that PWH have a higher prevalence of AAA than matched uninfected controls.¹² Prior data demonstrating T cell infiltration into the AAA vessel wall and perivascular tissue suggest a potential immunologic link between HIV and AAA.^14–18 Some have further hypothesized that PWH, particularly those who have poorly controlled infection with lower CD4+ T cell counts and higher viral load, may also experience immunodeficiency-related bacterial invasion of the aortic wall triggering mycotic aneurysm formation, molecular mimicry between HIV proteins and the aortic wall leading to autoimmune-mediated aortic damage, and direct invasion of the aortic wall by the virus leading to extracellular matrix degradation.^19,20 Whether HIV infection in the absence of high viral load and low CD4+ T cell count is associated with incident AAA is unknown.

The goal of this study was to determine whether HIV infection in the absence of high viral load and low CD4+ T cell count is associated with incident AAA. Further, we investigated whether lower CD4+ T cell counts, elevated HIV viral load, and established cardiovascular risk factors contributed to AAA risk among PWH.

Methods

The United States Veterans Healthcare Administration (VHA) does not allow identifiable data sets to be used by non-Veterans Affairs (VA) investigators. However, after meeting all requirements per VA regulations, a deidentified data set can be provided to qualified investigators.

Results

The total population of 143,001 veterans included 43,766 PWH and 99,235 people without HIV. The mean age was 49.6 years among PWH and 50.6 years among people without HIV (Table 1). The majority of both groups were male, and nearly half were Black. At baseline, PWH had a higher prevalence of current smoking, but a lower prevalence of diabetes, CVD, hypertension, and statin use compared to people without HIV. Among PWH, the median CD4+ T cell count at baseline was 386 cells/mm³ with a median HIV-1 viral load of 1,004 copies/mL (37% achieved viral suppression).

Over a median follow-up period of 8.7 years, there were a total of 2,431 incident AAA events (26.4%, 641 among PWH), including 357 cases of surgical AAA repair (25.5%, 91 among PWH). Kaplan-Meier AAA-free survival curves showed a greater occurrence of AAA with increasing age, but these curves did not show evidence of higher unadjusted risk for PWH (log-rank p-value <0.001) (Figure 1).

Unadjusted AAA incidence rates were similar among PWH compared to those without HIV (Table 2). This finding persisted regardless of baseline CD4+ T cell count, baseline HIV viral load (Table 2), or stratification by age group (Table S2). Similarly, there was no difference in rates of AAA repair by HIV and age status (Table S2).

In age- and sex-adjusted models, there was no evidence that HIV infection was associated with an increased risk of AAA (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.94–1.13). This finding persisted in the fully adjusted models (HR_adj, 1.02; 95% CI, 0.92–1.13) (Table 2). Models stratified by baseline CD4+ T cell count and HIV viral load similarly did not show that HIV infection was associated with incident AAA. However, when CD4+ T cell count and HIV viral load were treated as time-varying covariates, the presence of CD4+ T cell counts <200 cells/mm³ (HR_adj, 1.29; 95% CI, 1.02–1.65) or HIV viral loads >500 copies/mL (HR_adj, 1.29; 95% CI, 1.09–1.52) was associated with higher risks of incident AAA compared to those without HIV infection.

Among PWH, age, current and former smoking, prevalent CVD, and hypertension were all significantly associated with an increased risk of incident AAA (Table 3). In contrast, Black and Hispanic (as compared to White) patients as well as those with prevalent diabetes or elevated HDL-C were significantly associated with a lower risk of incident AAA. These associations remained unchanged even after adjusting for time varying CD4+ T cell counts or HIV viral load.

Exploratory analyses among never smokers did not show evidence that HIV infection was associated with an increased risk of incident AAA (HR_adj, 1.04; 95% CI, 0.81–1.35) (Table 4). This lack of evidence persisted in models stratified by baseline CD4+ T cell count or HIV viral load. Among never smokers, models examining time-varying CD4+ T cell count and HIV viral load also showed no evidence of association for either low CD4+ T cell count (<200 cells/mm³) or high HIV viral load (>500 copies/mL) with incident AAA. Kaplan-Meier AAA-free survival curves among never smokers did not differ by HIV status (log-rank p-value <0.001) (Figure S2).

Discussion

In this large, racially diverse national cohort of more than 143,000 veterans without a clinical history of AAA, there was no evidence that HIV infection was associated with an increased risk of incident AAA after adjusting for traditional CVD risk factors, substance use, and other important comorbidities. In contrast, patients with low CD4+ T cell counts or high HIV viral loads over time did have an increased risk of incident AAA compared to those without HIV infection. Among PWH, age, current and former smoking, prevalent CVD, hypertension, and elevated LDL-C were all significantly associated with an increased risk of incident AAA whereas Black and Hispanic (as compared to White) patients as well as those with prevalent diabetes and elevated HDL-C were significantly associated with a lower risk of incident AAA. In exploratory analyses, there was also no evidence that HIV was associated with incident AAA among never smokers.

To our knowledge, this is the largest and only study examining the association between HIV infection and incident AAA that also accounts for time-updated measures of viral suppression. Our findings suggest that, compared to people without HIV, there is an excess risk of AAA among PWH but only among those who have sustained low CD4+ T cell counts or elevated HIV viral load. Further, we also reported that among PWH, traditional risk factors, like smoking and hypertension, were associated with an increased risk of AAA. Until recently there were only rare case reports linking various aortic pathologies to HIV infection.^33,34 In 2021, a study reported a higher prevalence of AAA among PWH compared to matched controls.¹² In contrast to our study, the Copenhagen Comorbidity in HIV Infection (COCOMO) study assessed the prevalence of both AAA and thoracic aortic aneurysms using screening computed tomography (CT) imaging of the aorta. AAA was defined as an abdominal aorta measuring at least 3.0 cm. Using this definition, the prevalence of AAA was 5.4% and 1.9% for people with and without HIV, respectively. The strongest risk factors for AAA were age and male sex; associations with traditional AAA risk factors such as smoking, hypertension, and hyperlipidemia did not reach statistical significance.

The inconsistencies between these two studies may be explained in part due to differences in study design, sample size, and definitions used for AAA. For example, the COCOMO study was a cross-sectional screening study involving 1,782 participants with largely controlled HIV designed to image the abdominal aorta to identify AAA of any size. The VACS was a prospective observational study involving 143,001 participants with varying degrees of HIV viral control and immunodeficiency designed to look at incident AAA and large AAA requiring surgery using administrative data across a national health care system. COCOMO had the advantage of detecting AAA of any size, whereas the VACS has the statistical power to examine HIV and other important risk factors with incident events and to further stratify these analyses by time updated HIV viral load and CD4+ T cell count. Taken together, these studies suggest that the HIV virus, particularly when not controlled, as well as traditional risk factors like smoking cigarettes and hypertension may be contributing to the development of AAA among PWH. Whether people with HIV are at risk for future smaller aneurysms and whether these smaller aneurysms are at risk of rupture at smaller sizes even with HIV viral control remains unclear.

The exact mechanism underlying the association of AAA among PWH who have low CD4+ T cell counts or poor HIV viral control compared to those without HIV remains unclear. This pattern is consistent with prior reports examining HIV and other CVD including acute myocardial infarction,⁶ stroke,^7,8 and PAD.³ Prior work demonstrates that low CD4+ T cell counts and unsuppressed HIV viremia are associated with increases in systemic inflammation, immune activation, monocyte activation, altered coagulation, and endothelial dysfunction.^11,25 Each of these may play an important role in the development of AAA.^10,35–37 Whether a lack of HIV suppression and immunodeficiency also leads to HIV viral invasion of the aortic wall, extracellular matrix degradation, and subsequent AAA development is unclear.^19,20 Characterization of ex vivo human AAA tissue suggest that inflammation and T cell infiltration are key features of AAA formation, and it is possible that immune cell dysregulation in poorly controlled HIV may similarly play a role in AAA development in this patient population.^14–18 In this study, traditional AAA risk factors identified in the general population were also associated with incident AAA among those with HIV.

These findings have important implications for PWH. First and foremost, viral suppression and prevention of immunodeficiency remain critical in this population. While this is not a randomized controlled trial, we observed no excess risk of AAA among those who had suppressed HIV viral loads or elevated total CD4+ T cell counts over time. Second, the management of modifiable AAA risk factors, such as hypertension, and management of existing CVDs, are likely very important for the prevention of AAA. Successful treatment of cigarette smoking, however, may be essential. As with PAD, cigarette smoke is a major risk factor for AAA.³⁸ Smoking is common among PWH and rarely treated; even when treated, it frequently results in relapse.^9,39 However, recent studies demonstrate that pharmacotherapy can result in smoking cessation even among high-risk PWH who have multimorbidity and polysubstance use.^40–42 In contrast, people of color and those with diabetes had a lower risk of incident AAA in the VACS. While etiologies underlying these associations are not clear, lower rates and risk of AAA in the Black community³⁸ as well as in those with diabetes⁴³ is a well described phenomenon in the general population.

There are several limitations of the current analysis. First, the study population is predominantly male, and our findings may not generalize to women. Second, subjects underwent AAA detection as part of clinical care rather than universal screening for the purposes of our study. It is possible that universal AAA screening could have impacted our findings through the identification of additional small AAAs, although the clinical significance of these remains unclear. Third, our outcomes were identified through administrative claims data and not manually adjudicated. Finally, our observational study design is potentially subject to residual confounding.

Conclusions

In a large, prospective epidemiologic assessment of incident AAA in a racially diverse population of over 143,000 people, we found evidence that HIV infection was associated with an increased risk of AAA among PWH who had low CD4+ T cell counts or lacked HIV viral suppression over time. Among PWH, the presence of established AAA risk factors was associated with an increased risk of AAA. Our results suggest that successful treatment of HIV and the identification and treatment of traditional, modifiable AAA risk factors may be important for the prevention of incident AAA among PWH. Future studies should examine the association between HIV and incident AAA and, if confirmed in other cohorts, should examine the underlying mechanisms for AAA among PWH.

Supplementary Material