HIV AND CEREBROVASCULAR DISEASE: AN

INTERSECTION OF EPIDEMICS

Felicia C. Chow, MD, MAS

University of California, San Francisco

Departments of Neurology and Medicine (Infectious Diseases)

September 26, 2016

Global HIV prevalence

Global stroke incidence

An Intersection

of Epidemics

Piot et al. NEJM 2013, Feigin et al. Lancet 2014

HIV and stroke

are predicted to

be 2 of the top 3

causes of

mortality by 2030

Changing patterns of mortality and morbidity in HIV

Neuhas et al. AIDS 2010

Risk of mortality associated with AIDS and non-AIDS events

An aging HIV population

http://www.unaids.org/sites/default/files/media_asset/20131101_JC2563_hiv-and-aging_en_0.pdf

• An estimated 50% of PLWH in the US are

50 years of age and older

• Between 2010 and 2014, the proportion of

living HIV cases aged 50 and older in San

Francisco increased from 44% to 58%

Risk of age-related comorbidities

rises with older age in PLWH

Hasse et al. CID 2011

Outline

• What is the epidemiology of stroke in HIV infection?

• What are proposed mechanisms underlying elevated

stroke risk in people living with HIV (PLWH)?

• How do age and sex impact stroke risk in PLWH?

• Is HIV-associated neurocognitive impairment a vascular

disorder?

Rasmussen et al. AIDS 2011Relative risk of cerebrovascular disease 1.60 (1.30-1.95)

• Rates of stroke are

increased in PLWH

compared with age-

matched uninfected

controls

Elevated

cerebrovascular

risk in HIV

Ischemic stroke incidence is increased in HIV

HR 1.21*

(1.01-1.46)

HR 1.76*

(1.24-2.52)

HR 1.05*

(0.84-1.32)

Chow et al. JAIDS 2012, Chow et al. CROI 2016

*Adjusted for

demographics and

ischemic stroke risk

factors

Incidence rate ratio: 1.85

(95% CI 1.37-2.47, p=0.0001)

HIV is a risk factor for intracerebral hemorrhage

Chow et al. Neurology 2014

•Higher rates of

traditional vascular risk

factors including

smoking and substance

abuse

•Antiretroviral therapy

(ART)

•Chronic inflammation

and activation of the

immune system and

endothelium

HIV infection

Traditional stroke risk factors Antiretroviral therapy

Chronic inflammation, immune activation,

endothelial dysfunction

Cerebrovascular disease

Mechanisms of increased vascular risk in HIV

El Sadr NEJM 2006, Hsue AIDS

2009, Lichtenstein CID 2010, Triant

JAIDS 2010, Kaplan JID 2011, Friis-

Moller NEJM 2007, Worm JID 2010,

Grinspoon NEJM 2005

Impaired

fibrinolysis/hypercoagulable

stateImmunodeficiency

Cardiovascular risk associated with ART exposure in D:A:D

207

combined

first-ever

cardio- and

cerebro-

vascular

events: 5.7

per 1000 PY

(strokes=38)

-In adjusted model, incidence of vascular events increased by 26% for each year of exposure to ART

-When stroke examined separately (n=196), no significant association between ART and stroke

D’arminio Monforte AIDS 2004, Sabin Lancet 2008

Effect of ART on cerebral

endothelial function• 75 PLWH in Beijing (mean age,

41 yr; median time since diagnosis, 5 yr)

• 100% on ART and virally suppressed

• Majority of participants on 3TC + TDF or AZT + EFZ, NVP or LPV/r

• Measured cerebral vasoreactivity, marker of cerebrovascular endothelial function associated with large artery & small vessel disease, using transcranial Doppler breath-holding challenge

Baseline Hypercapnia Hypocapnia

Chow et al. ANA 2016, Vernieri et al. 1999, www.swedish.org/services/neurosciences-institute

Cerebrovascular endothelial function

worse among PLWH using lopinavir/ritonavir

• Use of LPV/r

associated with

lower cerebral

vasoreactivity,

independent of

vascular risk

factors, duration

of ART use and

time since HIV

diagnosis

Chow et al. ANA 2016

• Of 137 cases, 25% with mild cerebral SVD and 47% with moderate-severe SVD

• In multivariable analysis, PI-based regimen associated with significantly higher likelihood of mild (OR 2.7) and moderate (OR 2.4) SVD

• SVD at autopsy was associated with an antemortem diagnosis of cognitive impairment

Soontornniyomkij et al. AIDS 2014

Rasmussen AIDS 2011, Chow JAIDS 2012, Chow Neurology 2014, Vinikoor AIDS Res Hum Retroviruses 2013, Chow CROI 2016

Study Predictor Outcome HR (95% CI) P

value

Danish HIV

cohort (n=5031)

CD4 ≤200 Cerebrovascular

events

2.26 (1.05-4.86) NA

Partners HIV

cohort (n=2255)

Detectable VL Ischemic stroke 2.22 (1.23-4.00) 0.008

Partners HIV

cohort (n=2278)

CD4 ≤200 Intracerebral

hemorrhage

4.61 (2.09-10.17) <0.001

North Carolina

cohort (n=2515)

CD4 ≤200

Detectable VL

Cerebrovascular

events

3.36 (1.92-5.88)

2.83 (1.64-4.87)

<0.01

<0.01

Association between CD4 count or viral load and stroke risk

Immunosuppression and uncontrolled viremia

associated with greater cerebrovascular risk

Stroke risk associated with unsuppressed viral load

comparable to effect of aging by 15 years in ALLRT

Chow et al. CROI 2016

2.10

3.10

Role of inflammation in cardiovascular risk in HIV

• Inflammation and immune activation associated with subclinical cardiovascular disease in HIV

• Even in treated, virally suppressed PLWH, aortic and carotid arterial inflammation is greater compared with matched controls and correlates with greater inflammation (IL6, CRP) and monocyte activation (sCD163)

Subramanian et al. JAMA 2012

Contribution of HIV to vascular risk

may vary across life course

Rates of stroke/TIA by age in ALLRT cohort

No. of strokes 54 3 17 20 14

Person-years 32,023 12,780 11,396 5,954 1,893

Rate (per 1000 PY) 1.69 (1.27-2.20) 0.23 (0.05-0.69) 1.49 (0.87-2.39) 3.36 (2.05-5.19) 7.39 (4.04-12.41)

years

• Prospective case-control study of 222 cases of acute stroke (78% ischemic, 22% hemorrhagic) and 503 population controls in Blantyre, Malawi

• Median age 60 years for cases, 57 years for controls

• HIV prevalence 31% in cases, 19% in controls

Benjamin et al. Neurology 2016

Contribution of HIV infection to stroke risk

Greater proportion of risk attributed to HIV

infection among younger patients

Benjamin et al. Neurology 2016

Effect of HIV on ICH risk decreases with increasing age

• Effect of HIV decreased by 0.96 for every 1-year increase in age

Total cholesterol modifies the effect of HIV on

cerebrovascular endothelial function

Effect of HIV on stroke risk may be

more pronounced in women

Elevated ischemic stroke risk in PLWH

primarily driven by women

HR 1.21*

(1.01-1.46)

HR 1.76*

(1.24-2.52)

HR 1.05*

(0.84-1.32)

Chow et al. JAIDS 2012, Chow et al. CROI 2016

*Adjusted for

demographics and

ischemic stroke risk

factors

Relative versus absolute rate differences in stroke risk

IRR 5.31

(1.67-14.72)

IRR 3.68

(1.50-8.20)

IRR 2.37

(1.10-4.69)

IRR 1.56

(0.48-4.04)

IRR 1.42

(0.50-3.34)

Overall IRR

2.39 (1.62-

3.43)

Abs Rate

Diff 2.48

Abs Rate

Diff 2.15

Abs Rate

Diff 2.59

Abs Rate

Diff 2.16

Abs Rate

Diff 4.24

Overall

2.46

Higher monocyte activation in women with HIV

• HIV+ women have elevated immune activation compared with uninfected women

and HIV+ men, independent of viral load, particularly with increasing age

• Elevated immune activation correlates with greater burden of non-calcified

coronary plaque in HIV+ women compared to uninfected controls and HIV+ men

Fitch et al. JID 2013

No. of strokes 54 36 18

Person-years 32,023 25,871 6,242

Rate (per 1000 PY) 1.69 (1.27-2.20) 1.40 (0.98-1.93) 2.88 (1.71-4.56)

Absolute rates of stroke/TIA

higher in women in ALLRT

Rates of stroke/TIA by sex and age

Contribution of reduced ovarian reserve to CV risk

greater than traditional vascular risk in women with HIV

HIV-infected women (n=49)

HIV-uninfected women (n=25)

Looby et al. AIDS 2015

Is HIV-associated cognitive impairment a

vascular phenomenon?

Vascular risk and cognitive impairment in PLWH

• In Hawaii Aging with HIV cohort (n=~200), diabetes

increased adjusted odds of HIV-associated dementia

5.73-fold and increasing insulin resistance was associated

with worse cognitive performance, even in individuals

without diabetes (Valcour JAIDS 2005, Valcour JAIDS 2006)

• In neurology substudy of SMART (n=292, median CD4

538), pre-existing cardiovascular disease was associated

with 6.2-fold higher adjusted odds of cognitive impairment(Wright Neurology 2010)

Vascular risk may play greater role than HIV infection

• Cross-sectional study of effect of cardiovascular risk on cognition in 428 HIV+ (mean CD4 536), 207 HIV- men from MACS

• Carotid intima-media thickness or coronary artery calcium associated with worse psychomotor speed or memory but HIV status was not

Becker et al. Neurology 2009

White matter

hyperintensities

• Radiological marker

of cerebral small

vessel ischemic

disease, along with

lacunar strokes and

cerebral microbleeds

• Associated with

increased risk of

stroke and cognitive

impairment

White matter injury greater in PLWH over 60

Valcour et al. ISNV 2013, under review

Greater burden of white matter injury

associated with worse executive function

Valcour et al. ISNV 2013, under review

• 103 HIV-infected men on cART, 70 uninfected individuals; median age 54

• HIV status and older age associated with WMH burden

• Associated between HIV and poorer cognitive function attenuated by addition of WMH to model

Su et al. AIDS 2016

HIV modifies effect of age on microstructural

white matter injury

Seider et al. J Neurovirol 2015

Summary and discussion

• Risk of ischemic and hemorrhagic stroke is elevated in PLWH

• Traditional vascular risk factors only partially mediate the elevated stroke risk in PLWH

• Specific antiretroviral medications may increase cerebrovascular risk through impaired cerebrovascular endothelial function

• Impact of HIV infection on stroke risk varies across the life course

• Cerebral small vessel disease plays a role in the pathophysiology of cognitive impairment in HIV infection

AcknowledgementsUCSF

• Richard Price

• Phyllis Tien

• Priscilla Hsue

• Peter Bacchetti

• Yifei Ma

ACTG DACS 319 Team

• Michael Wilson (UCSF)

• Kunling Wu (Harvard)

• Ron Bosch (Harvard)

• Ron Ellis (UCSD)

• Benjamin Linas (Boston University)

Peking Union Medical College Hospital

• Taisheng Li

• Huanling Wang

• Yanling Li

• Yinghuan Hu

Harvard / Massachusetts General Hospital

• Virginia Triant

• Susan Regan

• Steve Feske

Northwestern

• Farzaneh Sorond

Wake Forest

• Cheryl Bushnell

Funding

• KL2 TR000143-10

• NIH/Fogarty/UC Global Health Institute R25 TW009343