Stroke As a Complicating Comorbidity With HIV: A Report from CROI 2016

Improvements in antiretroviral therapy (ART) now allow most patients who can access and remain in care to durably suppress HIV replication. Recovery of immune function confers freedom from AIDS-related illnesses and greatly extends life expectancy. However, because of aging, a high prevalence of conventional risk factors, and chronic inflammation that persists during otherwise effective ART, co-morbidities including cardiovascular disease, cancer, cirrhosis, osteoporosis, and kidney disease are now common in HIV. 

Most health care providers working with HIV-infected patients now spend the majority of their time managing these illnesses. At the Conference on Retroviruses and Opportunistic Infections (CROI) 2016, a special session focused on stroke as a co-morbidity in HIV.

Although stroke is a major cause of morbidity and mortality in HIV, it is less well studied than coronary artery disease. This may be because the diagnosis of cerebral infarction is harder to validate than myocardial infarction and stroke pathogenesis is more diverse, involving ischemia, hemorrhage, thrombosis and embolization. Conditions other than atherosclerosis, including acute infections and substance abuse, more common in HIV, may trigger stroke.

Chow, et al examined the incidence and risk factors for stroke or transient ischemic attack (TIA) in 6933 participants in the ALLRT cohort, which provides long-term follow-up to ACTG ART trials.¹ The average age of the study cohort was 37 and 20% were women. Active injection drug use was rare (<1%). Stroke/TIA incidence was higher in women (2.88 vs. 1.40/1000 person-years in men) and in non-Hispanic blacks (2.51 vs. 1.56 in whites vs. 0.77/1000 person–years in Hispanics). In multivariable Poisson regression analysis, HIV RNA >200, hypertension, LDL >160, age (per 10 year increase) and renal dysfunction were associated with elevated relative risk (RR) (3.1, 2.8, 2.5, 2.1, 1.9, respectively). The risk associated with unsuppressed viral load was equivalent to 15 years of aging. After adjustment, female gender had a RR of 1.6 but was no longer significant. Hispanic ethnicity and, paradoxically, obesity were associated with lower risk in this analysis. The reason for latter association was unclear.

A second analysis focused on stroke in women. Women with HIV (n=1212) and HIV-uninfected demographically matched controls (n=12,040) followed by a Boston health care system were compared for ischemic stroke incidence and risk factors.² Stroke incidence was increased in HIV-infected women age 18-55 but did not differ greatly in older women. ART was found to be protective with a 13% reduction in stroke hazard for every year of treatment. Cox proportional hazards modeling showed the HIV-infection was associated with a stroke hazard ratio (HR) ranging for 1.9-2.4 depending on components of the model. In these analyses, adjustment was made for age, demographics, traditional and gender specific risk factors such as pregnancy history, menopausal status and hormone use.  

Crane et al analyzed the CNICs cohort (n=16,924) to characterize the features of and risk factors for stroke in HIV.₃ Unlike many other studies that rely on billing codes to identify cases, in this study all diagnoses were adjudicated by 2 neurologists using record review and standardized case definitions. Data from 212 adjudicated stroke cases were presented; 81% were ischemic, 10% hemorrhagic and 9% were indeterminate. Twenty percent occurred in the context of acute infection and 19% with drug abuse. Because adjudications were ongoing, incidence data was not presented. In a multivariable analysis, age (per year) and HIV RNA (per log) increased stroke risk by 7% and 8% respectively. Smoking, diabetes and black race all were associated with a 2-fold or greater increased risk. Higher CD4 reduced risk by 12% per 100 cells, but the effect of ART exposure was not specifically examined.

Investigators for the D:A:D study used their very large (n=43,564) and long-term (339,979 person-years) database to determine if risk factors for ischemic and hemorrhagic stoke differed [4]. Using Cox proportional hazards models to adjust for covariates, age, hypertension and CD4<200 were independently associated with both types of stroke. The effect of hypertension was stronger for hemorrhagic stroke. The traditional risk factors smoking, diabetes, dyslipidemia, previous cardiovascular disease, and male gender were significantly associated only with ischemic stroke. Risks associated with exposure to individual antivirals was not examined but there was no difference in exposure ART drug classes. History of injection drug use and AIDS diagnosis were also associated with risk of ischemic stroke. 

Berenguer et al reported trends in stroke incidence for HIV-infected individuals in Spain from 1997 to 2011.⁵ The database captured 98% of admissions to public hospitals. Hepatitis C-co-infection was present in 29%. Marked differences in stroke incidence trends were seen when HIV-mono-infected and co-infected individuals were compared. Stroke was initially much higher in mono-infection and declined throughout the study period, while the opposite trend was seen in co-infection. This pattern held for both ischemic and hemorrhagic stroke. By the end of the study period, incidence of both types of stroke had become higher in co-infected individuals. The reason for this divergent trend, and why stroke was much lower in co-infected patients during the early years of the analysis, is unclear. Reported drug use preceding stroke diagnosis was not different between the groups. Information on traditional risk factors, ART use, HIV RNA and CD4 counts were not described.

Taken together, these abstracts highlight stroke as another very important medical comorbidity in HIV that deserves more research and clinical focus. Traditional risk factors correlate with increased risk, but uncontrolled viral load and low CD4 are also important factors. ART appears to be protective. The excess of strokes in younger HIV-infected women seen in some but not all of these reports is alarming and not adequately explained. The observation should be validated by additional studies and its causes better understood. The decline of stroke rates in Spanish HIV-mono-infection individuals is consistent with reports of declining rates of coronary artery disease in HIV and in the general population, and may be attributable to better virologic and immunologic control along with improved management of traditional risk factors. The reported rising incidence of stroke in the HIV-co-infected individuals in Spain is very concerning. Further studies in Spain and elsewhere are need to confirm that the problem is real and understand its underlying cause. A substantial number of strokes were found to be associated with infection and drug use. Therefore, stroke prevention for HIV-infected patients must address these factors, control traditional risk factor, and employ early introduction of ART. 

References

1.     Chow F, Wilson MR, Wu K, et al. Stroke incidence highest in women and black HIV-infected participants in ALLRT cohort. Abstract 43.

2.     Chow F, Regan S, Looby SE, et al. Persistently increased ischemic stroke risk in HIV-infected women. Abstract 638.

3.     Crane HM, Chow F, Becker KJ, et al. Design, implementation, and findings of next-generation stroke adjudication in HIV. Abstract 636.

4.     Hatleberg CI, Kamara D, Ryom L, et al. Differences in predictors for ischaemic and haemorrhagic strokes in HIV+ individuals. Abstract 637.

5.     Berenguer J, Alvaro-Meca A, Diaz A, et al. Stroke in HIV-infected patients in the combination antiretroviral therapy era. Abstract 639.

All presented at: The Conference on Retroviruses and Opportunistic Infections 2016. Feb. 22-25, 2016. Boston.