Increased incidence of ischemic stroke amongst HIV positive cohort
Muirgen Stack, HIV i-Base
A retrospective analysis performed by Felicia Chow and colleagues published in the 1st August issue of the Journal of AIDS showed a significant increase in the incidence of ischemic strokes within an HIV positive cohort compared to HIV negative controls matched for age, gender and race. The relative increase in stroke rates was highest amongst women and younger patients. 
Whilst HIV infection has become established as a risk factor for developing such non-AIDS defining illnesses as cardiovascular disease (CVD) and osteoporosis (and increased fragility-fracture risk), analysis of stroke in this context has so far languished. [2,3] However, although a recent study has shown a higher ratio of strokes being attributed to HIV-infected persons, this was not a direct comparison of stroke incidence between persons with and without HIV. 
A total of 4308 HIV positive patients were analysed from the Research Patient Data Registry (RPDR) clinical care database from Massachusetts General Hospital and Brigham and Women’s Hospital (US) between 1996 and 2007. International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes were used to ascertain HIV status and ischemic stroke (from the category of ischemic cerebrovascular disease). If multiple strokes were reported as per ICD-9-CM codes, only the first was included. A control group of 32,423 was generated by matching HIV negative patients from the RPDR to patients in HIV cohort in a 10:1 ratio on the basis of age, gender and race.
Primary demographics between the two study groups were well matched: mean age of 41.6 vs 40.8, percentage of women 31% vs 35%, race; white 53% vs 52%, black 21% vs 22% and hispanic 17% vs 17% for HIV positive and HIV negative respectively.
Within the HIV positive cohort: mean (SD) CD4 count and CD4 nadir were 473 (+/-317) cells/mm3 and 271 (+/-252) cells/mm3, respectively. The percentage of patients with a viral load below 400 HIV RNA copies/mL was 73% and percentage of patients with CNS infection/malignancy was 4%. Previous ARV use included 95% NRTI, 56% NNRTI and 67% PI use (from the N= 2105 patients with antiretroviral therapy (ART) data).
The proportion of HIV-infected patients with traditional stroke risk factors including hypertension, diabetes mellitus, dyslipidemia, smoking, cardiomyopathy, left sided valvulvar heart disease, coronary heart disease (CHD) and heart failure was significantly higher than in the HIV negative cohort (P < 0.001 for all comparisons).
The incidence rate (IR/1000 patient years) of ischemic stroke was 5.27 vs 3.75 in the positive vs negative groups respectively, resulting in an unadjusted hazard ratio (HR) of 1.40 (95% CI: 1.17 to 1.69, P < 0.001). In these unadjusted incidence rates, HIV infection was associated with higher rates of stroke amongst those younger than 50. Between 18-29 years the IR was 3.87 vs 0.88 giving an incidence rate ratio (IRR) of 4.42 (95% CI: 1.56 to 11.09, p=0.004), between 30-39 years the IR was 3 vs 1.02 giving an IRR of 2.96 (95% CI: 1.69 to 4.96, p < 0.001) and between 40-49 years the IR was 4.02 vs 2.62 giving an IRR of (95% CI: 1.06 to 2.17, p=0.02) in the positive vs negative groups respectively. For men specifically however, only HIV positive patients between 30-39 years had elevated stroke rates that remained significant: IR of 2.84 vs 1.28 giving an IRR of 2.23 (95% CI: 1.07 to 4.26, p=0.022) in the positive vs negative groups respectively. Once age, gender, race and the traditional stroke risk factors were accounted for, HIV infection remained an independent predictor of stroke with a hazard ratio (HR) of 1.21 95% CI: 1.01 to 1.46, P = 0.043.
Within the HIV cohort, age (HR: 1.06 per year, 95% CI: 1.03 to 1.09, p <0.001), female gender (HR: 1.76; 95%CI 1.24 to 2.52, p=0.002), 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 stoke. Conversely, longer duration of any ART use was associated with a significantly decreased risk of stroke (HR: 0.79, 95% CI: 0.71 to 0.88, p <0.001). Most recent CD4 cell count and nadir value were not associated with stroke risk.
Careful interpretation is needed to distinguish the causality from traditional risk factors (which were more common in the HIV-infected cohort) and what may be an indication of HIV specific aetiology i.e. high viral load increasing stroke risk.
The increased stroke risk in HIV-infected women is also notable, and may in part be attributable to “lower baseline risk for stroke in women, amplifying the relative impact of an HIV-specific effect” as speculated by the authors.
Finally, the role of HIV increasing stroke risk in younger people (18-49 years) is intriguing, as the effect from traditional risk factors on stroke risk tends to increase with age. However, before inferring a more pronounced effect of HIV infection on stroke risk in younger persons, it is important not to make a more general underestimation of stroke incidence in persons below 45 years. 
- Chow F et al. Comparison of Ischemic Stroke Incidence in HIV-infected and Non-HIV-Infected Patients in a US Health Care System. JAIDS (1 August 2012) 60:351-358.
- Currier J et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation (June 2008) 118:e29-35.
- McComsey G et al. Bone Disease in HIV infection: A Practical Review and Recommendations for HIV Care Providers. Clin Infect Dis (15 October 2010) 51 (8):937-946.
- Ovbiagele B et al. Increasing incidence of ischemic stroke in patients with HIV infection. Neurology (1 February 2011) 76:444-450.
- Marini C et al. Incidence of Stroke in Young Adults: A Review. Stroke Research and Treatment (2011) 2011:535-672.