HIV AND CEREBROVASCULAR DISEASE: AN INTERSECTION OF EPIDEMICS

Transcription

1 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

2 Global HIV prevalence An Intersection of Epidemics Global stroke incidence HIV and stroke are predicted to be 2 of the top 3 causes of mortality by 2030 Piot et al. NEJM 2013, Feigin et al. Lancet 2014

3 Changing patterns of mortality and morbidity in HIV Risk of mortality associated with AIDS and non-aids events Neuhas et al. AIDS 2010

4 An aging HIV population 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%

5 Risk of age-related comorbidities rises with older age in PLWH Hasse et al. CID 2011

6 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?

7 Elevated cerebrovascular risk in HIV Rates of stroke are increased in PLWH compared with agematched uninfected controls Relative risk of cerebrovascular disease 1.60 ( ) Rasmussen et al. AIDS 2011

8 Ischemic stroke incidence is increased in HIV HR 1.21* ( ) HR 1.76* ( ) HR 1.05* ( ) *Adjusted for demographics and ischemic stroke risk factors Chow et al. JAIDS 2012, Chow et al. CROI 2016

9 HIV is a risk factor for intracerebral hemorrhage Incidence rate ratio: 1.85 (95% CI , p=0.0001) Chow et al. Neurology 2014

10 Mechanisms of increased vascular risk in HIV Traditional stroke risk factors Impaired fibrinolysis/hypercoagulable state HIV infection Antiretroviral therapy Immunodeficiency Chronic inflammation, immune activation, endothelial dysfunction Cerebrovascular disease 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 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

11 D arminio Monforte AIDS 2004, Sabin Lancet 2008 Cardiovascular risk associated with ART exposure in D:A:D 207 combined first-ever cardio- and cerebrovascular 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

12 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 Baseline Hypercapnia Hypocapnia Measured cerebral vasoreactivity, marker of cerebrovascular endothelial function associated with large artery & small vessel disease, using transcranial Doppler breath-holding challenge Chow et al. ANA 2016, Vernieri et al. 1999,

13 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

14 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

15 Rasmussen AIDS 2011, Chow JAIDS 2012, Chow Neurology 2014, Vinikoor AIDS Res Hum Retroviruses 2013, Chow CROI 2016 Immunosuppression and uncontrolled viremia associated with greater cerebrovascular risk Association between CD4 count or viral load and stroke risk Study Predictor Outcome HR (95% CI) P value Danish HIV cohort (n=5031) Partners HIV cohort (n=2255) Partners HIV cohort (n=2278) North Carolina cohort (n=2515) CD4 200 Cerebrovascular events 2.26 ( ) NA Detectable VL Ischemic stroke 2.22 ( ) CD4 200 CD4 200 Detectable VL Intracerebral hemorrhage Cerebrovascular events 4.61 ( ) < ( ) 2.83 ( ) <0.01 <0.01

16 Stroke risk associated with unsuppressed viral load comparable to effect of aging by 15 years in ALLRT Chow et al. CROI 2016

17 Subramanian et al. JAMA 2012 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)

18 Contribution of HIV to vascular risk may vary across life course

19 Rates of stroke/tia by age in ALLRT cohort years No. of strokes Person-years 32,023 12,780 11,396 5,954 1,893 Rate (per 1000 PY) 1.69 ( ) 0.23 ( ) 1.49 ( ) 3.36 ( ) 7.39 ( )

20 Contribution of HIV infection to stroke risk 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

21 Greater proportion of risk attributed to HIV infection among younger patients Benjamin et al. Neurology 2016

22 Effect of HIV on ICH risk decreases with increasing age Effect of HIV decreased by 0.96 for every 1-year increase in age

23 Total cholesterol modifies the effect of HIV on cerebrovascular endothelial function

24 Effect of HIV on stroke risk may be more pronounced in women

25 Elevated ischemic stroke risk in PLWH primarily driven by women HR 1.21* ( ) HR 1.76* ( ) HR 1.05* ( ) *Adjusted for demographics and ischemic stroke risk factors Chow et al. JAIDS 2012, Chow et al. CROI 2016

26 Relative versus absolute rate differences in stroke risk 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 IRR 5.31 ( ) IRR 3.68 ( ) IRR 2.37 ( ) IRR 1.56 ( ) IRR 1.42 ( ) Overall IRR 2.39 ( )

27 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

28 Absolute rates of stroke/tia higher in women in ALLRT No. of strokes Person-years 32,023 25,871 6,242 Rate (per 1000 PY) 1.69 ( ) 1.40 ( ) 2.88 ( )

29 Rates of stroke/tia by sex and age

30 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

31 Is HIV-associated cognitive impairment a vascular phenomenon?

32 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)

33 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

34 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

35 White matter injury greater in PLWH over 60 Valcour et al. ISNV 2013, under review

36 Greater burden of white matter injury associated with worse executive function Valcour et al. ISNV 2013, under review

37 103 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

38 HIV modifies effect of age on microstructural white matter injury Seider et al. J Neurovirol 2015

39 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

40 Acknowledgements UCSF 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 TR NIH/Fogarty/UC Global Health Institute R25 TW009343