Victor G. Valcour, MD Professor of Medicine University of California San Francisco San Francisco, California Neurologic Complications of HIV AU Edited:

Victor G. Valcour, MD Professor of Medicine University of California San Francisco San Francisco, California Neurologic Complications of HIV AU Edited: 12/09/15 New Orleans, Louisiana: December 15-17, 2015

of 49 Learning Objectives After attending this presentation, participants will be able to: Describe the frequency, severity, and burden of cognitive impairment in HIV in the era of combination antiretroviral therapy Recognize multiple likes of evidence supporting ongoing HIV- related brain injury despite suppression of plasma HIV RNA to undetectable levels Describe the role of comorbidity as contributors to cognitive symptoms in the current era

of 49 Clinical Features of Impairment Cognition Memory loss Concentration Mental slowing Behavior Apathy Depression Agitation, Mania Motor Unsteady gait Poor coordination Tremor

of 49 HIV-Associated Neurocognitive Disorders (HAND) HANDNo HAND HIV infection HIV Asymptomatic Neurocognitive Impairment Mild Neurocognitive Disorder (MND) HIV-associated Dementia (HAD) HAND terminology implies that the etiology is HIV; but, likely multifaceted Neurology 2007

of 49 ARS Question 1

of 49 Prevalence of Cognitive Diagnoses Modified from Nat Rev Neurosci 2007 Lower incidence, but, no change in prevalence Lesser severity Most HAND cases are asymptomatic Pre-cART Post-cART HAD MND ANI NL

of 49 SHOULD WE WORRY ABOUT “ASYMPTOMATIC” NEUROCOGNITIVE IMPAIRMENT? Stephanie Chiao & Lauren Wendelken

of 49 Cognitive Performance No difference in summary neuropsychological testing scores between those who were asymptomatic (ANI) and those who were symptomatic (MND/HAD) COHIV-NLANISNI Controls Cognition asymptomatic symptomatic HIV neg. HIV+ NL

of 49 Everyday Function 1.Memory 2.Judgment 3.Driving (Attention/Executive) 4.Bill Pay (Language and calculations) 5.Map (Spatial ability) Total NAB Score NAB = Neuropsychological Assessment Battery, a series of everyday function testing

of 49 Is the Cognitive Impairment Real? DTI measures in HIV vs. controls Human Brain Mapping 2012

of 49 Asymptomatic Case 79 year old male, brain MRI with broad atrophy including central atrophy and large areas of confluent white matter injury

of 49 Conversion to Symptomatic Impairment 347 subjects, 90 months of follow-up Conversion to symptomatic From CROI 2012 – Igor Grant - Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A CHARTER Longitudinal Study Neurology 2014

of 49 The Role of Confounding Factors

of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration- Effectiveness Slide 17 of 49

of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration- Effectiveness 1 2 3 45 5 Slide 18 of 49

of 49 (a) ARV toxicity (b) poor CPE CPE = CNS Penetration- Effectiveness 1 Slide 19 of 49

of 49 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

of 49 Abnormalities in Diffusion Tensor Imaging n=56, all but 6 with suppressed plasma HIV RNA, age > 60 Broad abnormalities in DTI in HIV vs. controls; +: Exacerbated by APOE4 Nir et al. Human Brain Mapping 2013 Fractional Anisotropy

of 49 Elevated sCD163 Associated with 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 Burdo et al AIDS 2013

of 49 Effect of cART on HIV Reservoir Size Valcour et al J Leukocyte Biol 2010 Before cART6 months12 months Differing response in those with dementia vs. those without

of 49 Increased Macrophage Staining Despite cART n=10 cART vs. 9 NL Anthony et al J Neuropath Exp Neuro 2005

of 49 7 asymptomatic subjects, mean 9 years of HIV – on cART > 3 years, undetectable plasma HIV RNA PET Scan with 11 c -PK1116 PET ligand Microglial activation noted – signal in corpus callosum, anterior cingulate, posterior cingulate, temporal and frontal lobes – Correlated to poorer executive function Garvey et al AIDS 2014

of 49 Maraviroc Intensification for HAND Reduction of inflammation Reduction of HIV DNA reservoir Cognitive improvement J Neurovirology 2014

of 49 Neuronal Injury linked to Antiretroviral Therapy Schinburg et al JNV 2005

of 49 Healthy neurons Neurons treated for 7 days with ARV Slide 30 of 49

of 49 Cognitive Performance During Treatment Interruption 167 subjects, mean CD4 > 400 before interruption; had been on cART > 4 years Robertson et al, Neurology 2010

of 49 Ovbiagele and Nath 2011 Neurology & Chow et al 2011 JAIDS Increasing Frequency of Ischemic Stroke in HIV

of 49 Metabolic Disorders and Cerebrovascular Disease Number of cerebrovascular risk factors and cognitive performance # CVD risk factors

of 49 White Matter Injury Subjects over the age of 60 in the US who are living with HIV as a chronic illness

of 49 Soontornniyomkij et al AIDS 2014 Autopsy series in the US between 1999 to 2011 Associated with PI use; ? Legacy effect Mild Moderate Severe 50 % of cases

of 49 CNS Escape: Sub-Acute or Acute Neurological Syndromes (Case Series) AgeCD4Months VL<50 Neurological symptomsARVsCSF HIV RNAPlasma HIV RNA 5059236Persistent headacheTDF/FTC/ATZr12,885147 4919011Memory disorder, cerebellar ataxiaAZT/3TC/IDVr/T20845<50 4340018Cerebellar dysarthria, cerebellar ataxia3TC/ABC/ATV/IDVr1190<50 5043268Tactile allodyniaTDF/FTC/fAPRr87078 3610775Glasgow Coma Score of 33TC/ABC/TDF/DRVr5035<50 4763164Persistent HeadacheDRVr580<50 4454414Memory d/o, cerebellar ataxia, pyramidal syndromeFTC/ABC/ATVr558<50 5336012Lower limb dysesthesia and hypoesthesia3TC/AZT/ABC/EFV1023<50 6814712Memory d/o, left lower limb dysesthesia3TC/DDI/TDF/NVP586<50 6853418Temporospatial disorientation, cerebellar ataxia3TC/AZT/ATV880<50 5659310Memory d/o, cerebellar dysarthriaLPVr6099483 Canestri et al, CID 2010

of 49 Adapted from JAMA 2013 Projected based on 2008 CDC data Projected Proportion of HIV Over 50+ Years Old

of 49 Mills et al NEJM 2012 Aging with HIV – An International Issue

of 49 Prevalence of Dementia * Comorbidities: HIV infection, Hepatitis C, Cerebrovascular disease, lifestyle factors Prevalence

of 49 Considerations Age and HIV impact cognition, but not synergistically (additive) – Nevertheless, older individuals are more likely to meet a threshold of important amounts of decline Older patients tend to be more symptomatic Age is not the most important determinant of cognition in HIV – The variation in age is as great as the variation across ages

of 49 Where do we go from here? Treatment options Antiretroviral treatment considerations Treatments for neurodegenerative disorders? Exercise Cognitive stimulation Treatment of morbidities Safety in the home/ advanced planning

of 49 Summary Cognitive impairment remains frequent despite cART cART does not control HIV-related contributions Antiretroviral therapy may contribute to cognitive impairment Suppression of plasma HIV RNA is essential in the treatment of cognitive impairment – Attention to CNS penetration effectiveness of ARVs is important in select (uncommon) circumstances

of 49 Summary The etiology of cognitive impairment is likely heterogeneous – Contributions from cerebrovascular disease – With age, possibly neurodegenerative disorders – Background comorbidity may play a role in the frequency of poor neuropsychological performance in some

Victor G. Valcour, MD Professor of Medicine University of California San Francisco San Francisco, California Neurologic Complications of HIV AU Edited:

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Victor G. Valcour, MD Professor of Medicine University of California San Francisco San Francisco, California Neurologic Complications of HIV AU Edited:

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