HIV Neurology Persistence of Cognitive Impairment Despite cart

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1 HIV Neurology Persistence of Cognitive Impairment Despite cart Victor Valcour MD PhD Professor of Medicine Memory and Aging Center, Dept. of Neurology University of California San Francisco, USA 8 th International workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource Poor Settings; May 2014

2 Lecture Overview Update on the frequency and characteristics of cognitive disorders in the era of treatment Mechanisms of ongoing central nervous system (CNS) damage despite cart Ongoing injury from HIV itself and resorvoirs cart Too much? Too little? Cerebrovascular disease and other comorbidities

3 Very Early CNS Penetration and Brain Inflammation 0.35 Basal Ganglia 0.30 tcho/cr Acutes Chronics Controls Valcour et al JID 2012

4 HIV Neuropathology Perivascular monocytes and multinucleated giant cells (above) High frequency in white matter & deep grey matter Neuropathology of AIDS 1998

5 HIV-associated Cognitive Impairment Cognition Memory loss Concentration Mental slowing Comprehension Behavior Apathy Depression Agitation, Mania Motor Unsteady gait Poor coordination Tremor

6 Cognitive Diagnoses Pre-cART vs. Post-cART Pre-cART Post-cART HIV-associated dementia (HAD); Minor Neurocognitive disorder (MND); Asymptomatic Neurocognitive Impairment; (ANI) Neurocognitively normal (NN) n=1555 from US; subjects attending academic centers and have access to cart Modified from Ellis et al, 2007 Nat Rev Neurosci & Grant et al., 2009 CROI

7 Chaio et al AIDS Res Hum Retro 2013 Is ANI Really Asymptomatic? Performance on Tasks of Everyday Function Patients with Asymptomatic Neurocognitive Impairment (ANI) perform just as poorly on tasks of everyday functioning as do symptomatic subjects (MND)

8 Cognitive Deficits Despite cart Entebbe, Uganda 72% female, 83% were < 45 years old, 57% with < 8 years of education, ~2/3 on cart 64% scored <10/12 on the International HIV Dementia Scale Poor performance predicted by: Negative life events, stress and psychosocial impairment Nakku et al BMC Psychiatry 2013

9 HIV and Brain Atrophy 28 HIV+ from South Africa c/t 23 controls Subjects not on cart, CD4 ~ 190 cells, mean age 33 years Statistically significant levels of atrophy noted at thalamus, total white matter, & total grey matter Heaps et al JNV 2012

10 Tozzi et al JAIDS 2007 Persistent Cognitive Deficits n = 94 Neuropsychological impairment = (a) -1 SD on two tests or (b) -2 SD on one test out of 8 >50% probability of persistent neuropsychological deficits despite 5 years of cart

11 n=82 from South Africa; Severity of baseline deficits predicts 12 month deficits Joska et al BMC Infectious Ds Persistent deficits 12 months after initiation of cart

12 (a) ARV toxicity (b) poor CPE 5 1 CPE = CNS Penetration- Effectiveness

13 IQ measured by two separate techniques correlated to total infectious disease burden Hypothesized influence of competing metabolic demands during neurodevelopment

14 (a) ARV toxicity (b) poor CPE Persistent HIV associated effects despite suppression of plasma HIV RNA (viral load) CPE = CNS Penetration- Effectiveness

15 Evidence of Ongoing Neuronal Injury Despite cart Neurofilament (NFL) is a major structural element of myelinated fibers NFL is elevated in cart vs. controls; 85 subjects on cart for > 1 year with plasma HIV RNA < 50 copies Krut et al PlosOne 2014

16 Abnormalities in Diffusion Tensor Imaging in HIV n=56, all but 6 with suppressed plasma HIV RNA, age > 60 Broad abnormalities in DTI in HIV vs. controls; +: Exacerbated by APOE4 Fractional Anisotropy Nir et al. Human Brain Mapping 2013

17 Burdo et al AIDS 2013 Elevated scd163 Associated with Cognitive Impairment 34 CHARTER (US) participants with suppressed plasma HIV RNA, on cart > 1 year; CD4 > 500 CD163 = scavenger receptor involved in inflammation and secreted from monocytes as scd163 SCD163 elevated in cognitively impaired treated subjects

18 HIV DNA and Cognitive Impairment CD14+ HIV DNA Valcour et al Plos One 2013

19 Effect of cart on HIV Reservoir Size Before cart 6 months 12 months Differing response in those with dementia vs. those without Valcour et al J Leukocyte Biol 2010

20 Increased Macrophage Staining Despite cart n=10 cart vs. 9 NL Increased CD28 staining, a macrophage stain, seen in multiple brain areas, including frontal white matter and medial temporal lobes Anthony et all J Neuropath Exp Neuro 2005

21 7 asymptomatic subjects (9 years (3-22) of infection, on cart > 3 years, UD plasma HIV RNA 11 c -PK1116 PET ligand signal in corpus callosum, anterior cingulate, posterior cingulate, temporal and frontal lobes Correlated to poorer executive function Garvey et al AIDS 2014

22 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration- Effectiveness

23 Neuronal Injury linked to Antiretroviral Therapy Schinburg et al JNV 2005

24 Exposure of neuronal cultures to ARVs at concentrations that are anticipated in CSF resulted in neuronal damage Decreased axonal integrity, axonal beading

25 Cognitive Performance During Treatment Interruption 167 subjects, mean CD4 > 400 before interruption; had been on cart > 4 years Overall cognitive performance did not deteriorate, in fact, a small but statistically significant improvement was seen Robertson et al, Neurology 2010

26 CNS Penetration- Effectiveness Ranks 2010

27 CPE and CSF viral load Proportion with detectable virus in CSF cart with higher BBB penetrationeffectiveness score Letendre et al, 2008 Arch Neurol

28 CSF viral load and cognition Improved control of CSF HIV RNA relates to greater improvements in cognitive performance. Ellis et al, Ann Neurol 2004

29 Counter-intuitive: Changing ARVs to those with higher CPE resulted in inferior outcomes

30 CNS Escape: Sub-Acute or Acute Neurological Syndromes (Case Series) Age CD4 Months VL<50 Neurological symptoms ARVs CSF HIV RNA Persistent headache TDF/FTC/ATZr 12, Memory disorder, cerebellar ataxia AZT/3TC/IDVr/T < Cerebellar dysarthria, cerebellar ataxia 3TC/ABC/ATV/IDVr 1190 < Tactile allodynia TDF/FTC/fAPRr Glasgow Coma Score of 3 3TC/ABC/TDF/DRVr 5035 < Persistent Headache DRVr 580 < Memory d/o, cerebellar ataxia, pyramidal syndrome FTC/ABC/ATVr 558 < Lower limb dysesthesia and hypoesthesia 3TC/AZT/ABC/EFV 1023 < Memory d/o, left lower limb dysesthesia 3TC/DDI/TDF/NVP 586 < Temporospatial disorientation, cerebellar ataxia 3TC/AZT/ATV 880 < Memory d/o, cerebellar dysarthria LPVr Plasma HIV RNA Adapted from Canestri et al, CID 2010

31 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration- Effectiveness

32 Increasing Frequency of Ischemic Stroke in HIV Ovbagle and Nath 2011 Neurology & Chow et al 2011 JAIDS

33 White Matter Injury Subjects over the age of 60 in the US who are living with HIV as a chronic illness

34 Autopsy series in the US between 1999 to % had moderate to severe increased hyalinization of small vessels 25% had mild changes Associated with PI use;? Legacy effect Soontornniyomkij et al AIDS 2014

35 Conclusions Cognitive impairment remains frequent despite cart There is broad evidence that cart does not control HIV-related contributions

36 Conclusions Antiretroviral therapy may contribute to cognitive impairment There is broad acceptance that suppression of plasma HIV RNA is essential in the treatment of cognitive impairment Attention to CNS penetration effectiveness of ARVs is important in select circumstances

37 Conclusions The etiology of cognitive impairment is likely heterogeneous Contributions from cerebrovascular disease As patients age, neurodegeneration may be an issue Background comorbidity may play a role in the frequency of poor neuropsychological performance in some

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