HIV-related factors increase risk of stroke

HIV-related risk factors seem to increase the risk of stroke – the sudden death of brain cells due to a rupture or obstruction of blood vessels in the brain – according to ongoing research in a growing number of large epidemiological cohort studies. Recent data from five of these were presented during the first-ever poster discussion session on stroke at the Conference on Retroviruses and Opportunistic Infections (CROI 2016), which took place last month in Boston.

Among the key findings:

• In addition to traditional cardiovascular risk factors for stroke, HIV-related factors such as viral load and CD4 cell count were significantly associated with the risk of stroke in one study.
• As in the general population, ischaemic stroke (a stroke due to an obstruction in a blood vessel in the brain) is much more common among people living with HIV than haemorrhagic stroke (when a weakened blood vessel in the brain bulges or ruptures).
• Age, elevated blood pressure and a CD4 cell count of less than 200 cells/mm³ were the strongest and most common risk predictors in people with HIV for both types of stroke in another study.
• The association between elevated blood pressure and haemorrhagic stroke appeared slightly stronger, but injecting drug use and a previous AIDS diagnosis, in addition to traditional cardiovascular risk factors, were more strongly associated with ischaemic stroke among people with HIV according to one analysis.
• Although male sex is a traditional risk factor for stroke, women living with HIV have about twice the risk of stroke as HIV-negative women; however, the risk decreases the longer they are on antiretroviral therapy (ART).
• A Spanish study showed that stroke incidence and mortality have been decreasing among people living with HIV in the ART era – as long as they do not have hepatitis C virus (HCV). Among those with HCV co-infection, stroke incidence and mortality have been steadily increasing, although it is not clear whether this is due to HCV itself or related risk factors such as drug use.
• Another study found that when compared to HIV-negative people carefully matched to have similar traditional stroke risk factors, HIV-positive individuals without prior cardiovascular disease had an increased prevalence of carotid plaque, as well as an increased incidence of stroke and transient ischaemic attacks (TIAs) that produce stroke-like symptoms for less than 24 hours.

Stroke in people with HIV

Stroke is a relatively neglected aspect of HIV-related disease, according to Richard Price of the University of California at San Francisco, who moderated the poster discussion session. He believes this may be partly because strokes are relatively uncommon, and because it tends to get addressed as part of the broader aspect of cardiovascular disease in people with HIV. Another reason may be that stroke is underemphasised, underreported or misreported because of challenges in characterising it and confirming a diagnosis.

But given the consequences of stroke – which can include permanent paralysis, loss of speech and death – it is important to determine whether there are aspects of HIV-associated stroke that are distinct from non-HIV-related stroke and from other HIV-related cardiovascular disease.

Risk factors for stroke with a more certain diagnosis

Much of the earlier research on stroke in people with HIV came from small single-site studies that used diagnostic criteria which may not have caught all the strokes accurately and which did not provide much information about the types of stroke.

So the first study presented in the session attempted to ascertain what the risk factors are for different types of stroke in a very large HIV cohort study, the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The analysis included 17,000 people with HIV who experienced 212 strokes over the course of the study.

The researchers used more sensitive diagnostic criteria to detect and classify the types and subtypes of stroke, with each diagnosis confirmed by two neurologists (or two out of three when there were discrepancies). They also determined whether a stroke occurred in the setting of an acute infection (such as toxoplasmosis) or drug use.

Most of the strokes (81%) were ischaemic, 10% were haemorrhagic and the remainder could not be classified. Among the ischaemic strokes, 30% were small vessel, 28% were cardioembolic, 19% were atheroembolic and 23% were other types or unknown.

Risk factors strongly associated with stroke included smoking (adjusted hazard ratio [aHR] 2.23) and diabetes (aHR 2.74). In addition to traditional cardiovascular risk factors such as age and sex, HIV factors were also significantly associated with these outcomes, such as time-updated viral load (aHR 1.08 for each log higher) and time-updated CD4 cell count (aHR 0.88 for each 100 cells/mm³ lower).

Approximately a fifth of the strokes occurred among people who had an acute infection of some sort, and approximately a fifth occurred in the setting of substance use.

“Strokes were predominantly ischaemic and associated not only with traditional risk factors but with lower CD4 count and higher viral load suggesting we have one more reason to be initiating ART a little earlier rather than later,” said Heidi Crane of the University of Washington in Seattle, who presented the study.

Predictors of ischaemic and haemorrhagic stroke

Another study investigated whether there were differences in risk factors for haemorrhagic and ischaemic strokes in the more than 43,000 HIV-positive participants in the D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) cohort between 1999 and 2014. The study used separate univariable and multivariable regression models to identify associations between demographic, cardiovascular and HIV-related risk factors for both types of stroke.

There were 83 haemorrhagic and 296 ischaemic stroke events during the study period. Risk factors included older age, male sex, smoking, elevated blood pressure, previous cardiovascular disease, diabetes, dyslipidaemia (abnormal blood fat levels), a body mass index below 18, injecting drug use and a previous AIDS diagnosis.

The greater risk for haemorrhagic stroke associated with elevated blood pressure and low CD4 cell count was not seen when formally tested in another model. However, this may have been due to a limited number of haemorrhagic strokes. Analyses on competing risks are still ongoing, according to presenter Camilla Hatleberg of the University of Copenhagen in Denmark.

“Our findings are mostly similar to those reported in the general population, and emphasise the need for preventive measures in screening,” she said. “Further research is needed into the use of stratified stroke risk factors to provide more precise risk estimation.”

HIV-related factors increase stroke risk in women

Felicia Chow of the University of California at San Francisco previously presented data from the Partners Healthcare System cohort, which includes over 4000 people with HIV and over 30,000 HIV-negative control subjects, showing that HIV is an independent risk factor for ischaemic stroke (hazard ratio 1.21). The researchers then looked more closely at the data.

“We stratified by sex, and after doing that we found that a lot of the increased stroke risk in this cohort was actually driven by women,” Chow said.

She and her colleagues performed another study of 1200 women with HIV and over 12,000 control women to see whether the increased ischaemic stroke risk in women with HIV persisted after adjustment for demographics, ischaemic stroke risk factors, and sex-specific stroke risk factors including menopause status, oestrogen use, pregnancy, history of eclampsia, hysterectomy, migraines and depression.

Before adjustment for other factors, the hazard ratio for HIV being associated with ischaemic stroke was 2.43. After adjustment for age, race, vascular and sex-specific risk factors, HIV infection was still associated with nearly twice the risk of ischaemic stroke (hazard ratio 1.88).

Treating HIV earlier might help mitigate the risk, however. In an HIV-only model adjusted for age and race, each additional year of ART use was associated with a 13% lower risk of ischaemic stroke.

ART and HCV-related risk factors

The protective effect of ART was confirmed by a study in Spain that ran from 1997 to 2011. Researchers used the Spanish Minimum Basic Data Set – a clinical and administrative database with information obtained at hospital discharge, with an estimated coverage of around 98% of admissions at nearly 300 public hospitals.

Data on more than 3400 individuals with HIV, including close to 1000 people with HIV and HCV co-infection living in Spain during the study period, were obtained from the National Centre of Epidemiology.

The incidence of stroke among these hospitalised HIV-positive patients was quite high, but among people with HIV alone it fell progressively over the course of the study, from 16.0 events per 10,000 person-years in the years between 1997 and 1999 down to 9.2 events during 2000 to 2003 and 5.5 events during 2004 to 2011. Strokes have increased, however, among people who are both HIV- and HCV-positive.

During the discussion, other presenters noted that they had not observed a growing risk among people with HIV and HCV co-infection, but said that it was difficult to tease this out from the increased risk associated with drug use.

Juan Berenguer of Hospital General Universitario Gregorio Marañón in Madrid, who presented the data, agreed.

“Many studies – not only this – have identified HCV co-infection as a risk factor,” he said. “The problem is, what is due to biology, to the HCV, and what is due to lifestyle? I think it is very difficult to tease apart the contribution, but probably lifestyle [matters] a lot – including drug use and the complications of drug use.”

Carotid plaque and cerebrovascular events

Carotid plaque, a build-up of cholesterol and other debris in the carotid arteries on each side of the neck, occurs often in people living with HIV and is associated with worse clinical outcomes. The final study presented during the stroke session, by Sumbal Janjua of Massachusetts General Hospital in Boston, found that carotid plaque is common in individuals with HIV even prior to cardiovascular disease and was associated with an increased risk of subsequent cerebrovascular events.

This was a retrospective multi-site study of people with neck CAT scans with contrast (which can reveal carotid plaque) from six partner institutions between 2005 and 2014. The analysis excluded anyone with prior cardiovascular or cerebrovascular disease, as well as anyone who had incomplete scans.

The study included 182 people with HIV and 159 HIV-negative controls matched for age, sex, diabetes, hypertension, hyperlipidaemia and baseline medications. The prevalence of any carotid plaque was significantly higher in the HIV cohort as compared to the matched controls. Also, the prevalence of non-calcified plaque and other plaque features deemed to pose a high risk of cerebrovascular events – including spotty calcification scores and low attenuation – was higher in the HIV cohort as compared to the matched controls.

Discussion

Plaques, particularly in the carotid arteries, may significantly increase the risk of ischaemic stroke if they become dislodged and migrate to the brain, forming an obstruction that cuts off the flow of blood and oxygen.

More research is needed to ascertain exactly how HIV increases the risk of plaques, but in the discussion session Chow noted a previously published study that reported that monocyte activation is higher in people with HIV – and highest of all in women with HIV – and that this correlated with coronary artery calcification as well.

How to most effectively prevent stroke in people living with HIV – other than to reduce traditional risk factors and to provide earlier ART – is the topic of ongoing research.