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CLINICAL SCIENCE

HIV infection and incidence of ischemic stroke

Marcus, Julia L.a; Leyden, Wendy A.a; Chao, Chun R.b; Chow, Felicia C.c; Horberg, Michael A.d; Hurley, Leo B.a; Klein, Daniel B.e; Quesenberry, Charles P. Jra; Towner, William J.f; Silverberg, Michael J.a

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doi: 10.1097/QAD.0000000000000352
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Abstract

Introduction

Combination antiretroviral therapy (ART) has dramatically improved survival among HIV-positive individuals. By 2015, over half of the HIV-positive population in the United States will be 50 years of age or older [1]. As this population ages, aging-associated conditions such as cardiovascular disease increasingly contribute to morbidity and mortality [2], with a doubling of ischemic stroke hospitalizations among HIV-positive individuals during 1997–2006 [3]. However, age-adjusted rates of ischemic stroke in this population may have stabilized or decreased in recent years with improvements in risk factor management or the wider and earlier use of ART regimens associated with improved lipid profiles [4,5]. Furthermore, it is unclear whether HIV-positive individuals with well controlled infection are at an increased risk of ischemic stroke, independent of age, compared with HIV-negative individuals.

Although numerous studies have explored the risk of myocardial infarction associated with HIV infection [6–11], few large-scale epidemiologic studies have directly compared ischemic stroke incidence and risk factors by HIV status. Although ischemic stroke rates are reportedly higher in HIV-positive individuals compared with the general population [12,13], few studies have directly compared these patients with an internal control group of HIV-negative individuals. In one of the only studies examining ischemic stroke using an internal HIV-negative comparison group and with adjustment for stroke risk factors, Chow et al.[14] found an elevated risk of ischemic stroke among approximately 4000 HIV-positive individuals. Although that study identified high HIV RNA but not low CD4+ cell count as a risk factor, others have found that low CD4+ cell count is associated with increased risk [12,13,15]. Findings on the relationship of ART use and ischemic stroke have also been mixed, with some studies suggesting that longer duration of any ART use is associated with a decreased risk [14,16] and others finding no association [12,13].

In this study, we determined the association of HIV infection and immunodeficiency with ischemic stroke in a large cohort of nearly 25 000 HIV-positive individuals, with a demographically similar comparison group of HIV-negative individuals from the same healthcare system. Among HIV-positive individuals, we assessed the role of traditional and HIV-specific risk factors for ischemic stroke, including CD4+ cell counts, HIV RNA levels, and class-specific duration of ART use.

Methods

Study design, setting, and population

We conducted a cohort study of HIV-positive and HIV-negative members of Kaiser Permanente Northern and Southern California (KPNC and KPSC, respectively), large integrated healthcare systems providing comprehensive medical services to over 30% of insured Californians [17]. The study population was selected from a previously described cohort [18]. HIV-positive individuals were identified using HIV registries that include all known HIV/AIDS cases since the early 1980s for KPNC and 2000 for KPSC, with HIV-positive status confirmed by review of medical charts or medical center case lists. Individuals not included in the registries were considered HIV-negative. Eligible individuals included adult (≥18 years of age) Kaiser Permanente members during 1996–2011 for KPNC and 2000–2011 for KPSC. HIV-negative members were frequency-matched 10 : 1 to HIV-positive individuals by age (5-year age groups), sex, medical center, and initial calendar year of follow-up. The start of follow-up for each individual (baseline) was the earliest date on or after January 1, 1996 (January 1, 2000, for KPSC), when eligibility criteria were met. Individuals were followed until the earliest of an ischemic stroke, death, termination of membership, or 31 December 2011. The institutional review boards at KPNC and KPSC approved this study with a waiver of written informed consent.

Study measurements

HIV registries were used to obtain HIV status, race/ethnicity, and HIV-transmission risk factor. For KPNC only, additional data were extracted by chart review on dates of first ART use and beginning of known HIV infection.

Data extracted from Kaiser Permanente's electronic medical record (EMR) included laboratory test results (CD4+ cell counts and HIV RNA levels); pharmacy prescription fills (ART, lipid-lowering therapy, and antihypertension medications); age; health plan enrollment periods; dates of death from hospital records, California death certificates, and Social Security Administration datasets; and inpatient or outpatient clinical diagnoses, including overweight/obesity [International Classification of Disease codes, version 9 (ICD-9): 278, 259.9, V85, internal weight/height codes], smoking/tobacco use (ICD-9: 305.1, V15, V65, 649, internal social history codes), drug/alcohol abuse (ICD-9: 291, 292, 303–305.0, 305.2–305.5), diabetes (ICD-9: 250.xx, 357.2, 362.0, 366.41, 648.0, laboratory measurements, or medication use for KPSC and an internal Diabetes Registry for KPNC [19]), and hypertension (ICD-9: 401–405 or antihypertension medication use).

The outcome of interest was incident ischemic stroke, defined as a primary diagnosis in the EMR of an acute ischemic cerebrovascular event (ICD-9: 433.x1; 434, excluding 434.x0; or 436). This selection of codes has been found to have high specificity and positive predictive value for ischemic stroke [20]. Cases were limited to ischemic stroke because of the known atherosclerotic risks of ART use that can lead to ischemic events [21–23], and because, in contrast to hemorrhagic stroke, its incidence among HIV-infected individuals has reportedly increased over time [3]. Individuals were excluded if they had an ischemic stroke diagnosis within 2 years prior to baseline.

Statistical analysis

Variables for analyses included age (<40, 40–49, 50–64, ≥65 years), sex, race/ethnicity (white, black/African American, Hispanic/Latino, Asian/Pacific Islander, other; with imputed data where missing [24,25]), calendar era (1996–1999, 2000–2003, 2004–2007, 2008–2009, 2010–2011), and socioeconomic status (SES, calculated as neighborhood SES index based on census measures of income, occupation, and education [26]). Other covariates were smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy use, all defined as ever/never from 2 years prior to baseline through the end of follow-up. Among HIV-positive individuals, we evaluated any prior ART use, recent (i.e., prior 6 months) and duration of protease inhibitor use, recent and duration of nonnucleoside reverse transcriptase inhibitor (NNRTI) use, duration of known HIV infection (≥10, 5–9.9, <5 years), HIV-transmission risk factor (MSM, heterosexual sex, injection drug use, unknown), recent (i.e. prior 6 months) and nadir (i.e., lowest recorded in Kaiser Permanente) CD4+ cell counts (<200, 200–499, ≥500 cells/μl), and recent HIV RNA levels (≥10 000, 500–9999, <500 copies/ml). Time-dependent variables were age, calendar era, diabetes, hypertension, lipid-lowering therapy use, ART use (prior and duration), duration of known HIV infection, and recent CD4+ cell counts and HIV RNA levels; these were updated continuously except for CD4+ and HIV RNA variables, which were updated at 6-month intervals.

We compared individual characteristics by HIV status at baseline using the Pearson χ2 test for categorical variables and the Kruskal–Wallis test for continuous variables. We computed ischemic stroke incidence rates per 100 000 person-years by HIV status. We used Poisson regression models to estimate the percentage change in rates over calendar time by HIV status and stratified by age group. Using HIV-negative individuals as the reference group, rate ratios for stroke were obtained from Poisson models for HIV infection overall and stratified by sex and immunodeficiency characteristics. We used likelihood-ratio tests to assess effect modification across sex strata, and χ2 tests for trend across CD4+ and HIV RNA strata. Adjusted models included terms for HIV infection, age, sex, calendar era, race/ethnicity, SES, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy.

To identify ischemic stroke risk factors among HIV-positive individuals, we obtained adjusted rate ratios for recent and nadir CD4+ cell count, recent HIV RNA level, prior ART use, HIV-transmission risk factor, and duration of known HIV infection, in addition to age, sex, calendar era, race/ethnicity, SES, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. In the subset with a complete history of protease inhibitor and NNRTI use, we examined the association of cumulative protease inhibitor and NNRTI use in models adjusting for baseline CD4+, baseline HIV RNA, and the covariates described above, with additional models that also included terms for recent protease inhibitor and NNRTI use.

Opportunistic infections with neurologic involvement can mimic the symptoms of ischemic stroke [27]; because these infections mainly occur at low CD4+ cell counts, it has been suggested that their misclassification may induce a noncausal association between immunodeficiency and ischemic stroke [15]. To assess potential misclassification, an HIV physician (coauthor D.B.K.) conducted a chart review of HIV-positive cases diagnosed within KPNC to identify events caused by opportunistic infections or other central nervous system processes that may mimic strokes. A random sample of 15 cases was selected for review from each of three recent CD4+ cell count strata (<200, 200–499, and ≥500 cells/μl) to determine if any observed misclassification was more frequent at lower CD4+ cell counts. Overall, 44/45 (98%) were identified as true ischemic strokes, with the one noncase from a patient with CD4+ cell count less than 200 cells/μl. Based on this review, we concluded there was minimal outcome misclassification, and that differential misclassification by CD4+ cell count was also minimal. To further exclude the possibility of misclassification, we conducted a sensitivity analysis in which we fit adjusted models comparing stroke incidence by HIV status, with HIV-positive individuals stratified by recent CD4+ cell count and excluding cases occurring within three months of an opportunistic infection with neurologic involvement (i.e. toxoplasmosis, cytomegalovirus, cryptococcosis, central nervous system lymphoma, or progressive multifocal leukoencephalopathy).

Analyses were conducted in SAS 9.1 (Cary, North Carolina, USA). Statistical tests were two-sided, and statistical significance was defined as P < 0.05.

Results

Study population

The study population included 24 768 HIV-positive and 257 600 HIV-negative individuals, contributing a mean of 4.9 and 5.9 person-years/individual, respectively (Table 1). Individuals were similar by HIV status with respect to the matching factors of age and sex, although small differences in age and other characteristics were statistically significant owing to large sample size. The groups differed by race/ethnicity, with HIV-positive individuals more frequently white or black/African-American and HIV-negative individuals more frequently Hispanic/Latino or Asian/Pacific Islander. HIV-positive individuals more frequently had a history of smoking, alcohol abuse, and drug abuse, whereas overweight/obesity, diabetes, hypertension, and lipid-lowering therapy use were similar by HIV status. Among HIV-positive individuals, MSM was the most common transmission risk factor. Nearly half had used ART prior to baseline, with 85.8% having used ART by the end of follow-up.

Table 1
Table 1:
Baseline characteristics of individuals by HIV status, Kaiser Permanente California, 1996–2011 (N = 282 368).

Ischemic stroke incidence by HIV status

The ischemic stroke incidence rate per 100 000 person-years was 125 for HIV-positive individuals (151 events) and 74 for HIV-negative individuals (1128 events), with an unadjusted rate ratio of 1.7 [95% confidence interval (CI) 1.4–2.0; Table 2). Compared with HIV-negative individuals, HIV-positive individuals were at increased risk of ischemic stroke independent of traditional stroke risk factors, with an adjusted rate ratio of 1.4 (95% CI 1.2–1.7).

Table 2
Table 2:
Rate ratiosa (95% confidence interval) for ischemic stroke by HIV status and stratified by CD4+ cell count and HIV RNA levels, Kaiser Permanente California, 1996–2011 (N = 282 368).

Ischemic stroke incidence by HIV status: stratified by age, calendar era, and sex

Among individuals 18–49 years of age, rates decreased over calendar time for HIV-positive individuals (−7.8% per year, P = 0.04) while increasing for HIV-negative individuals (+5.6% per year, P = 0.001), with a significant difference in slopes by HIV status (P = 0.001; Fig. 1a). Among individuals 50–64 years of age, rates decreased for HIV-positive individuals (−7.7% per year, P = 0.004) but remained stable for HIV-negative individuals (−0.4% per year, P = 0.67), with a significant difference in slopes (P = 0.01; Fig. 1b). Stroke rates nearly converged by HIV status in both age groups by 2010–2011. Among individuals 65 years of age or older, declines were not statistically significant among HIV-positive (−1.3% per year, P = 0.81) or HIV-negative individuals (−1.9% per year, P = 0.18), and rates remained higher for HIV-positive individuals across all calendar eras, with no difference in slopes by HIV status (P = 0.90). In unadjusted sex-stratified analysis, the association of HIV infection with stroke was present in both men (rate ratio 1.7, 95% CI 1.4–2.0) and women (rate ratio 2.1, 95% CI 1.2–3.7); after adjustment, this association remained significant in men (rate ratio 1.4, 95% CI 1.2–1.7) but not women (rate ratio 1.5, 95% CI 0.9–2.8), although there was no difference in adjusted rate ratios between men and women (P = 0.34).

Fig. 1
Fig. 1:
Crude rates of ischemic stroke by HIV status and stratified by age and calendar era, Kaiser Permanente California, 1996–2011 (N = 282 368).Rates for HIV-positive individuals are shown by solid lines whereas rates for HIV-negative individuals are shown by dotted lines. Rates are shown separately for ages 18–49 (Panel a), 50–64 (Panel b) and ≥65 years (Panel c). Rates are shown on the graphs for the first and last calendar eras. Percentages indicate the percentage change in stroke incidence rates per year; corresponding P values were obtained from Poisson models. Slopes differ significantly by HIV status for ages 18–49 (P = 0.001) and 50–64 years (P = 0.01), but not for age ≥65 years (P = 0.90). Data were insufficient for HIV-positive individuals ≥65 years of age diagnosed with stroke during 1996–1999.

Ischemic stroke incidence by HIV status: stratified by CD4+ cell count and HIV RNA

Compared with HIV-negative individuals, HIV-positive individuals with recent CD4+ cell count of 500 cells/μl or higher or HIV RNA less than 500 copies/ml had no excess risk of stroke in adjusted models; however, incidence was elevated among HIV-positive individuals with recent CD4+ cell count 200–499 cells/μl (rate ratio 1.3, 95% CI 1.02–1.7) and less than 200 cells/μl (rate ratio 3.2, 95% CI 2.3–4.4; P trend <0.001), and among those with recent HIV RNA 500–9999/ml (rate ratio 1.9, 95% CI 1.3–2.9) and 10 000/ml or higher (rate ratio 2.5, 95% CI 1.8–3.5; P trend <0.001). Although stroke risk increased as nadir CD4+ decreased (P trend <0.001), there was a significant association only in the lowest CD4+ category, with an adjusted rate ratio of 1.6 for CD4+ cell count less than 200 cells/μl (95% CI 1.3–2.1) compared with HIV-negative individuals.

Risk factors for ischemic stroke among HIV-positive individuals

Among HIV-positive individuals, recent CD4+ cell count less than 200/μl compared with 500/μl or higher was independently associated with an increased risk of ischemic stroke (rate ratio 2.5, 95% CI 1.3–4.6; Table 3); however, being HIV-positive for 5–9 years (rate ratio 0.6, 95% CI 0.4–0.9) or 10 years or longer (rate ratio 0.6, 95% CI 0.4–1.0) compared with less than 5 years was associated with a lower risk (Table 3). Several traditional risk factors were associated with stroke among HIV-positive individuals, including age 50–64 (rate ratio 5.2, 95% CI 2.6–10.2) and 65 years or older (rate ratio 11.5, 95% CI 5.4–24.4) compared with 18–39 years, alcohol/drug abuse (rate ratio 2.0, 95% CI 1.5–2.9), and hypertension (rate ratio 3.3, 95% CI 2.2–4.7); overweight/obesity was associated with a reduced risk (rate ratio 0.5, 95% CI 0.3–0.7). Longer duration of protease inhibitor use was associated with an increased stroke risk in unadjusted analysis, with a rate ratio of 1.13 (95% CI 1.01–1.27) per year of use, but the association did not remain after adjusting for either baseline or all covariates (Table 4). There was no association between duration of NNRTI use, or recent NNRTI or protease inhibitor use, and ischemic stroke.

Table 3
Table 3:
Risk factors for ischemic stroke among HIV-positive individuals, Kaiser Permanente California, 1996–2011 (N = 24 768).
Table 4
Table 4:
Antiretroviral therapy class duration and risk of ischemic stroke, Kaiser Permanente California, 1996–2011 (N = 14 438).

Assessment of potential stroke misclassification

We identified 10 HIV-positive stroke cases with a recently diagnosed opportunistic infection, including multifocal leukoencephalopathy (n = 4), cryptococcosis (n = 3), and cytomegalovirus (n = 3). After excluding these cases, the rate ratios for recent CD4+ cell count less than 200 cells/μl and recent CD4+ cell count 200–499 cells/μl were 2.8 (95% CI 2.0–4.0) and 1.2 (95% CI 0.9–1.6), respectively, compared with HIV-negative individuals. These estimates were similar in magnitude to the rate ratios of 3.2 for recent CD4+ cell count less than 200 cells/μl and 1.3 for recent CD4+ cell count 200–499 cells/μl from the full cohort analysis including all HIV-positive stroke cases.

Discussion

In this large cohort of HIV-positive and HIV-negative adults from the same healthcare system, we found a 40% increased risk of ischemic stroke for HIV-positive individuals after adjustment for age, sex, year, race/ethnicity, SES, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. Immunodeficiency and HIV viremia, but not duration of protease inhibitor or NNRTI use, contributed to this elevated risk. Recent CD4+ cell count was a stronger risk factor than nadir CD4+, suggesting an effect of current immunodeficiency on ischemic stroke risk. Notably, HIV-positive individuals with recent CD4+ cell count 500/μl or higher or recent HIV RNA less than 500/ml had no excess risk of ischemic stroke compared with HIV-negative individuals.

Our finding that HIV infection is associated with a higher risk of ischemic stroke is consistent with previous studies. In the Partners Healthcare System in Boston, Chow et al.[14] identified higher ischemic stroke rates compared with our estimates, possibly resulting from a higher prevalence of risk factors or use of a less specific case definition. However, the Partners study reported a similar relative risk for HIV infection, with a hazard ratio of 1.2 compared with our rate ratio of 1.4 [14]. The authors adjusted for several risk factors, including smoking and hypertension, but not alcohol/drug abuse, which we found to be an independent risk factor among HIV-positive individuals. Other studies evaluating the relationship between HIV infection and ischemic stroke reported rate ratios of 1.5 [12] and 1.6 [13] compared with the general population, but use of external comparison groups did not allow for risk factor adjustment.

We found that, although ischemic stroke rates remained stable among HIV-positive individuals 65 years of age or older, rates among younger HIV-positive individuals decreased over time. Rates converged by HIV status among individuals under age 65 in 2010–2011, similar to trends in myocardial infarction in this cohort [28]. In unadjusted age-stratified analysis, the Partners study found that HIV infection was associated with higher relative rates of ischemic stroke for those under age 50 [14], but this association was not examined over time. Although a study of hospital admissions noted a substantial increase in ischemic stroke hospitalizations among HIV-positive individuals [3], this study did not account for an aging HIV population and concluded in 2006. As awareness of ART-associated cardiovascular complications has increased, improved risk factor management among HIV-positive individuals may have contributed to a decreasing risk over time. It may also be that stroke risk has been mitigated by the earlier and wider use of lipid-friendlier ART regimens [4,5].

Although we confirmed the association of several traditional risk factors with ischemic stroke among HIV-positive individuals, HIV infection was associated with stroke even after adjustment for these factors. These results suggest that stroke risk in HIV-positive individuals is not fully attributable to a higher prevalence of stroke risk factors. Additionally, compared with HIV-negative individuals, we observed an association of recent CD4+ cell count, nadir CD4+ cell count, and recent HIV RNA with increased risk. Inflammation, which has been implicated in atherosclerosis development in the general population [29], and immune activation may play a role in ischemic stroke risk in HIV infection. Inflammation-induced endothelial dysfunction may contribute to the pathogenesis of both large and small vessel-related stroke through accelerated atherosclerosis and lipohyalinosis [30]. Furthermore, impaired fibrinolysis and hypercoagulability have been observed in HIV-infected individuals and may result in a prothrombotic state leading to increased stroke risk [31]. Markers of inflammation, immune activation, and coagulation in HIV-infected individuals have been associated with cardiovascular biomarkers and other surrogate tests that predict a composite outcome of cardiovascular events, including stroke [32–37].

In contrast to previous findings on myocardial infarction in the same cohort [11], we found that recent CD4+ cell count was a stronger risk factor than nadir CD4+ cell count. The Partners study found that recent HIV RNA, but not recent or nadir CD4+, was a risk factor [14], but several others identified recent immunodeficiency as a risk factor for the composite outcome of cerebrovascular events [12,13]. The multicohort D:A:D study found that recent but not nadir CD4+ cell count was associated with stroke (ischemic or hemorrhagic), but suggested the association may have resulted from outcome misclassification at low CD4+ cell count counts [15]. In our study, a chart review identified minimal misclassification, and the association of recent CD4+ cell count remained after excluding potentially misclassified strokes that may have been mimicked by an opportunistic infection. While further research is needed to confirm whether this association is causal, our results suggest that maintenance of immune function may protect against ischemic stroke. Furthermore, given recent calls to abandon CD4+ monitoring among HIV-positive individuals with viral suppression [38,39], our data suggest that CD4+ cell count may be useful beyond its role in HIV disease monitoring.

There are several limitations to our study. First, we relied on ICD-9 codes to identify strokes and misclassification may have occurred, particularly at low CD4+ cell counts. However, we used a combination of codes that has been shown to be highly specific for ischemic stroke [20], and chart review of a subset of cases across CD4+ strata indicated minimal misclassification. Second, because risk factors were collected from the EMR, there may have been some misclassification and we could not analyze these variables with a high level of detail; for example, we were unable to differentiate specific types of drugs associated with stroke, such as cocaine or amphetamine [40]. Third, data were not available on some risk factors, such as cardiomyopathy, valvular abnormalities, atrial fibrillation, or aspirin/warfarin use; however, in the Partners study, adjustment for these factors had a minimal impact on the rate ratio associated with HIV infection [14]. Finally, our individuals were mostly men, reflecting the HIV epidemiology of California.

Our study also has several strengths. First, to our knowledge, this is the largest study to directly compare ischemic stroke by HIV status. Second, we used a cohort of HIV-positive and matched HIV-negative individuals from the same healthcare system, thus minimizing the selection biases that can be introduced by using an external comparison group. Third, we expand on the existing literature by comparing rates by HIV status both overall and stratified by CD4+ cell counts and HIV RNA levels, allowing us to determine that HIV-positive individuals with well controlled infection approach the same ischemic stroke risk as the general population. Fourth, we used a highly specific outcome definition and found minimal evidence of misclassification. Fifth, because we extracted data from the comprehensive EMR, we were able to control for multiple risk factors and it is unlikely we missed any stroke events. Finally, the Kaiser Permanente membership mirrors the age, sex, and race/ethnicity distributions of the California population [17,41], and the demographics of HIV-positive Kaiser Permanente members are comparable to those of reported AIDS cases in California [42]. Thus, our results are likely to be generalizable to other individuals in California and other states.

In summary, our study demonstrated a higher risk of ischemic stroke among HIV-positive compared with HIV-negative individuals independent of stroke risk factors; we also observed that this increased risk has diminished over time among individuals under 65 years of age. Recent CD4+ cell count was the strongest HIV-specific risk factor, suggesting an effect of current immunodeficiency on ischemic stroke risk. If this association is causal, early and consistent treatment with ART to maintain immune function, combined with mitigation of stroke risk factors, may result in a similar risk of ischemic stroke among HIV-positive individuals compared with the general population.

Acknowledgements

J.L.M. and M.J.S. had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. M.J.S. was responsible for the overall conception and design of the study and obtaining funding. J.L.M. was responsible for drafting the article. C.C. and M.J.S. were responsible for administrative, technical, and logistic support. C.P.Q. provided statistical expertise. W.A.L. and L.B.H. collected and assembled data. W.A.L. performed data analysis. D.B.K. performed chart reviews. All coauthors were responsible for interpretation of the data, critical revision of the article, and final approval of the article.

This research was supported by a research grant from Pfizer Pharmaceuticals. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

This research was supported by a research grant from Pfizer Pharmaceuticals. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Conflicts of interest

J.L.M., D.B.K., and F.C.C. report no potential conflicts. W.A.L. and C.R.C. report research grant support from Pfizer. M.A.H., M.J.S., and C.P.Q. report research grant support from Pfizer and Merck. L.B.H. reports research grant support from Merck. W.J.T. reports research grant support from Pfizer, Merck, Gilead, Bristol-Myers Squibb, ViiV Healthcare, and Vertex.

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Keywords:

AIDS; CD4+; HIV; neurological; risk factors; stroke

© 2014 Lippincott Williams & Wilkins, Inc.