The association between HIV and stroke remained significant and was only minimally attenuated after adjustment for age, gender, and race in a multivariable model (Table 2, Model 1). After controlling for traditional stroke risk factors, HIV remained an independent predictor of stroke (HR: 1.21, 95% CI: 1.01 to 1.46, P = 0.043) (Table 2, Model 2).
In gender-specific Cox proportional hazard models, the HR for HIV infection was statistically significant for women (HR: 2.16; 95% CI: 1.53 to 3.04, P < 0.001) but not men (HR: 1.18; 95% CI: 0.95 to 1.47, P = 0.14). The association between ischemic stroke and HIV infection remained statistically significant in women after adjusting for demographics alone or demographics and established stroke risk factors (Table 2).
Predictors of Stroke
In addition to HIV status, other significant predictors of ischemic stroke in the overall group included age, hypertension, smoking, structural heart disease, and atrial fibrillation (Table 3). Dyslipidemia was associated with a decreased risk of stroke. The fully adjusted overall model showed female gender to be associated with a decreased risk of stroke, despite the higher relative contribution of HIV to stroke risk among women in gender-stratified models (Table 3).
Within the HIV cohort, atrial fibrillation (HR: 3.15, 95% CI: 1.26 to 7.87, P = 0.014), age (HR: 1.06 per year, 95% CI: 1.03 to 1.09, P < 0.001), a higher log-transformed viral load (HR: 1.10, 95% CI: 1.04 to 1.17, P = 0.001), and a history of CNS infections or malignancy (HR: 2.75, 95% CI: 1.26 to 6.03, P = 0.011) were associated with an increased risk of stroke. NNRTI use (vs. no NNRTI use) was associated with a decreased risk of stroke when represented as ever use (HR: 0.38, 95% CI: 0.19 to 0.76, P = 0.006) but not when represented as duration of use (HR: 0.89, 95% CI: 0.71 to 1.10, P = 0.28). Longer duration of any ART use, however, was associated with a significantly decreased risk of stroke (HR: 0.79, 95% CI: 0.71 to 0.88, P < 0.001). When evaluated as a dichotomous variable, an undetectable viral load defined as HIV RNA ≤400 copies/mL was associated with a decreased risk of stroke (HR: 0.45, 95% CI: 0.25 to 0.81, P = 0.008). CD4 cell count was not significantly associated with stroke when included as either the nadir value (Table 4) or the most recent value (HR: 0.98 per 50 unit increment, 95% CI: 0.93 to 1.03, P = 0.46). Significant risk factors for stroke among the non-HIV cohort are also shown in Table 4, and are generally similar to those reported previously.14
Sensitivity analyses were performed investigating the effects of dyslipidemia on stroke risk. In the overall model, dyslipidemia alone (HR: 1.28, 95% CI: 1.12 to 1.46, P < 0.001) was associated with increased stroke risk. In a model with HIV added, both HIV status (HR: 1.37, 95% CI: 1.14 to 1.65, P = 0.001) and dyslipidemia (HR: 1.26, 95% CI: 1.10 to 1.44, P = 0.001) were independently associated with increased stroke risk. Among females, dyslipidemia alone was associated with increased stroke risk (HR: 1.65, 95% CI: 1.26 to 2.17, P < 0.001) but was not significantly associated with stroke when age was added (HR: 1.01, 95% CI: 0.76 to 1.34, P = 0.93). Among males, dyslipidemia alone was not significantly associated with stroke (HR: 1.09, 95% CI: 0.94 to 1.27, P = 0.27) but was associated with decreased stroke risk when age was added (HR: 0.84, 95% CI: 0.72 to 0.98, P = 0.029).
In a separate sensitivity analysis, statin use was associated with decreased stroke risk when included in the overall model (HR: 0.77, 95% CI: 0.65 to 0.93, P = 0.005) and in the HIV-only model (HR: 0.43, 95% CI: 0.18 to 1.03, P = 0.059). There was no interaction between statin use and dyslipidemia with respect to stroke risk in the analysis.
We observed higher stroke rates among HIV-infected patients compared with non–HIV-infected patients in a large clinical care observational cohort in an era of combination ART use, following more than 4000 HIV-infected patients for over 25,000 person-years. Our data suggest that HIV is an independent predictor of ischemic stroke, after adjusting for known stroke risk factors. The increase in stroke risk was most pronounced in HIV-infected women and in younger age groups. Furthermore, within HIV-infected patients, stroke risk was increased in association with increasing viral load, suggesting that poorer virologic control and its inflammatory and immunologic sequelae may increase cerebrovascular risk.
There are only limited studies of stroke in HIV-infected patients. Much of our understanding of the natural history of cerebrovascular disease in patients with HIV infection stems from case reports and retrospective studies of patients with advanced disease and severe immunosuppression,6,15,16 many before the widespread use of ART.5,7 Cerebrovascular events in these early studies were frequently attributable to concomitant opportunistic infections, lymphoproliferative disorders and other malignancies, endocarditis, or cardiomyopathy. Previous estimates of the prevalence of stroke in HIV-infected patients, ranging from 4% to 30%, originate from autopsy studies of patients dying from AIDS.17-21 More recent estimates range from an annual incidence of 216 transient ischemic events and strokes per 100,000 population22 to 166 ischemic strokes per 100,000 patient-years.10 Most recently a Danish study compared rates of a broad cerebrovascular endpoint in HIV-infected patients versus a population-based control group and found rates to be increased in the HIV group, with rate ratios similar to those found in the present study.9 Risk was increased in patients both with and without vascular risk factors; however, multivariate modeling including vascular risk factors such as smoking and HIV-related factors was not performed. Our data advance this understanding by investigating stroke rates in an HIV cohort over a period of widespread ART use, using a validated specific endpoint definition, adjusting for individual stroke risk factors including smoking and investigating the association of stroke with clinical stage of HIV infection and with specific ART classes.
Our data demonstrate overall stroke rates of 5.27 per 1000 person-years in HIV-infected versus 3.75 in non-HIV-infected patients, for a HR of 1.40. Overall stroke rates were comparable to established rates for the general population.23,24 The HR was attenuated in part accounting for traditional stroke risk factors consistent with the conclusion that these risk factors play a role in the pathogenesis of stroke in the HIV population. In particular, smoking and hypertension were risk factors that were more highly prevalent among the HIV population and significantly associated with stroke in the fully adjusted model. Our data suggest that these risk factors might therefore be particularly targeted for intervention in the HIV population.
Although traditional stroke risk factors are likely to play a role in HIV-related stroke risk, HIV remained an independent predictor of stroke after adjustment for these factors. Taken together with the increased stroke rate seen in association with increasing viral load among the HIV group, these data suggest that stroke risk in the HIV population is attributable, in part, to factors other than known traditional vascular risk factors. Hypotheses to explain this excess risk include inflammation, endothelial dysfunction, and macrophage activation. Inflammation underlies the pathogenesis, progression, and complications of atherosclerosis.25 HIV itself, independent of ART use, has been shown to induce endothelial dysfunction, an early marker of atherosclerosis,26,27 and multiple studies have demonstrated increased levels of inflammatory markers in HIV-infected patients.28 Moreover, an immune-mediated prothrombotic state with elevated d-dimer,29 tissue plasminogen activator antigen, and plasminogen-activator inhibitor-1, markers of impaired fibrinolysis associated with risk of CHD, may also confer stroke risk.30,31 Macrophage activation, seen even among those with well-controlled infection and recently associated with noncalcified plaque, may also play a role in the premature development of atherosclerosis.32
Gender-specific analyses revealed a striking increase in ischemic stroke risk in HIV-infected women compared with non-HIV-infected controls. Importantly, the study included sufficient data on women, who represented 36% of the total person-years. Prior studies have demonstrated a greater relative risk of myocardial infarction in women comparing HIV-infected to HIV-uninfected patients.3,4 This study shows a similar gender effect for stroke, which may be due in part to a lower baseline risk for stroke in women, amplifying the relative impact of an HIV-specific effect in this gender. The increased relative risk of ischemic stroke in HIV-infected women may also be explained by increased use of oral contraception or hormone replacement therapy among HIV-infected women; relatively greater differences in rates of traditional stroke risk factors including abdominal adiposity and inflammation33,34; differing efficacy of stroke prevention measures by gender35; or lower rates of stroke risk factor modification in women due to perception of lower risk by physician36 or patient.37,38 Relatively increased stroke rates in HIV-infected women may also be explained by higher levels of immune activation compared with HIV-infected men after accounting for HIV RNA level.39
The increased risk of ischemic stroke in the HIV cohort was limited to younger age groups (18–49 years). A similar pattern was seen in a retrospective analysis of CHD in HIV-infected patients using California Medicaid claims data.1 The effect of HIV on stroke may be more pronounced in younger patients before traditional age-related vascular risk factors begin to play a major role in the development of clinically apparent ischemic stroke, as CVD risk is generally very low in apparently healthy young people. The observed increase in stroke risk in younger age groups identifies an obvious need to determine the etiology of increased strokes among young HIV-infected patients and underscores the need for early identification of those at risk accompanied by appropriate risk factor modification.
Within the HIV-infected cohort, higher viral load was associated with an increased risk of ischemic stroke. Previous studies have linked viral load to subclinical atherosclerosis40 and endothelial dysfunction,41,42 and patients treated with interrupted ART in the SMART trial had higher rates of cardiovascular events.29 Likewise, lower CD4 count has been associated with increased subclinical carotid atherosclerosis and progression of disease43,44 and to increased rates of cardiovascular events.45,46 Higher viral load and lower CD4 count may serve as surrogate markers for chronic inflammation and immune dysfunction which have been hypothesized to confer increased vascular risk. Conversely, being virologically suppressed for an extended period might decrease vascular risk. In this study, longer duration of ART within the HIV cohort was associated with a decreased risk of stroke. Consistent with our data, shorter duration of any ART use has been shown to be an independent predictor of ischemic cerebrovascular events,10 and improvement in intracranial vessel stenoses has been shown to occur 6 months after ART initiation.15
The use of NNRTIs at any point in time was found to be associated with a decreased risk of ischemic stroke. In contrast to PIs and NRTIs, which have been shown to confer increased risk of CVD in previous studies,47,48 no consistent association between NNRTI use and risk of CVD has been identified. NNRTIs have been specifically linked to an improved lipid risk profile and elevation of HDL, an association which may help to explain the protective effect of this class of drugs. When represented as duration of medication use, however, NNRTIs were not associated with decreased stroke risk. Medication data in clinical care cohorts is subject to confounding by indication, although one would expect preferential use of NNRTIs in patients at high vascular risk (by clinicians who avoid the PI class) to lead to increased rather than decreased stroke risk.
Our study was limited by our necessary reliance on ICD codes to establish diagnoses of outcome and covariates. To strengthen the reliability of these data, we conducted a rigorous validation study to maximize sensitivity and specificity of codes for ischemic stroke. Importantly, the overall rates of ischemic stroke in our non-HIV-infected reference group are comparable to those published from large population-based cohorts.23,24 In our study, data on certain stroke risk factors, such as intravenous drug use, were not available for the majority of the patients in the cohort. However, intravenous drug use was not thought to be appropriate for inclusion in the primary analyses due to its potential for collinearity with valvular heart disease and endocarditis. Importantly, we were able to include data on smoking—a known major stroke risk factor—through use of a novel natural language processing tool to extract smoking data from free text notes.
As the HIV population ages, chronic diseases, particularly those of a vascular nature, have become increasingly clinically relevant. We demonstrate the novel finding that stroke risk is increased for HIV patients relative to control patients and that this risk persists in part after accounting for traditional stroke risk factors. Furthermore, we show that increased stroke risk is driven, in large part, by events in women and young patients. The demonstrated association between HIV and stroke should prompt medical providers to view HIV as a risk factor for stroke and to have a low threshold to aggressively modify vascular risk, particularly in women and the young—groups not typically identified as high risk. Long-term prospective studies with non-HIV-infected controls are necessary to further elucidate the interaction of chronic HIV infection, ART, and traditional vascular risk factors and their effect on the risk of cerebrovascular disease.
The authors are grateful to Shawn Murphy, MD, PhD (Massachusetts General Hospital Laboratory of Computer Science) and the Partners HealthCare Research Patient Data Registry group for facilitating use of their database and natural language processing tool.
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Keywords:Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.
HIV; stroke; cerebrovascular; cardiovascular; vascular risk factors