Overview. HIV Brain Injury. HIV characteristics. HIV Dementia 11/6/2010

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Overview HIV Brain Injury Victor Valcour MD Associate Professor Division of Geriatric Medicine and Department of Neurology/UCSF The neuropathology of HIV HIV Dementia a current snapshot Scenarios of

1 Overview HIV Brain Injury Victor Valcour MD Associate Professor Division of Geriatric Medicine and Department of Neurology/UCSF The neuropathology of HIV HIV Dementia a current snapshot Scenarios of rapid progression Immune Reconstitution Inflammatory Syndrome (IRIS) CNS escape Acute infection HIV characteristics HIV Dementia Recommended Reading Ellis, Langford, and Masliah. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nature Reviews 2007 Primate lentiviruses recognize CD4 as a receptor protein Immunosepression due to depletion of t-helper cells Regulatory genes - neurotoxicity vif, vpr, vpu, tat, rev, nef, env Env polymorphisms resulting in clade specificity Implications for international setting Unclear neuropathogenesis by clade 1

Critical role of inflammation Capillary lumen (1) HIV-infected monocytes, some activated Histopathological hallmarks Perivascular monocytes Identified with CD14 and CD45

HIV into the brain - infection establishment in perivascular macrophages (4) Neuronal dysfunction and death (5) Altered integrity of the BBB facilitating further

ation of infected M/MФ Brew et al 1998 Cellular co-receptors required for infection (e.g.

2 Critical role of inflammation Capillary lumen (1) HIV-infected monocytes, some activated Histopathological hallmarks Perivascular monocytes Identified with CD14 and CD45 markers Consistently the most highly infected cells Multinucleated Giant Cell Blood Brain Barrier (3) Impacts brain cells leading to cognitive dysfunction (2) Transfer of HIV into the brain - infection establishment in perivascular macrophages (4) Neuronal dysfunction and death (5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ Brew et al 1998 Cellular co-receptors required for infection (e.g. CD4) thus, neurons not thought to have substantial infection CD4 cells HIV in human hosts (aseptic) meningitis, radiculitis, myelitis dementia, myelopathy, neuropathy viral setpoint opportunistic infections Plasma HIV RNA Clinical Features Cognition Memory loss Concentration Mental slowing Comprehension weeks months years Time Behavior Apathy Depression Agitation, mania Motor Unsteady gait Poor coordination Tremor 2

Clinical Characteristics Presenting symptoms Neuropsychological

10 0 Memory Gait Mental Slow ing Depression Tremors Behavioral

Exam Mean (95% CI) 10 5 0 Older All Younger Normal MC/MD HAD

HAD MRI findings A 79 year old male with HIV Dementia Absence of

3 Clinical Characteristics Presenting symptoms Neuropsychological deficit Prominent motor part of advanced disease Memory Gait Mental Slow ing Depression Tremors Behavioral changes Apathy Other Unified Parkinson Disease Rating Scale M otor Exam Mean (95% CI) Older All Younger Normal MC/MD HAD Valcour 2008 J Neurovirology Advanced disease Clinical Features of HAD MRI findings A 79 year old male with HIV Dementia Absence of opportunistic infection Periventricular white matter hyperintensities Atrophy 3

Dementia among HIV patients 1996 - Post-HAART realities Cognitive Impairment despite

Cognitive Impairment in HIV 22% Mildly Impaired 17% Moderately Impaired 39% Impaired

4 Dementia among HIV patients Post-HAART realities Cognitive Impairment despite HAART survival Proportion Impaired HIV- CDC-A CDC-B CDC-C (1987)Grant Pre- ARV (1995)HNRC-500 Pre-HAART (2007)CHARTER HAART Grant et al Conference on Retroviruses and Opportunistic Infections Brain Impairment and HIV Cognitive Impairment in HIV 22% Mildly Impaired 17% Moderately Impaired 39% Impaired HIV-associated Dementia (HAD) Mild Neurocognitive Disorder (NMD) HIV Asymptomatic Neurocognitive Impairment HIV infection 21% Developed impairment after 48 weeks of HAART Robertson K, et al. AIDS Neurology

Functional consequences of cognitive impairment in HIV Diagnostic Transitions from Baseline to Year 1 100% 2.94% 17.07% 17.86% Year 1 Diagnosis as a % of Baseline 21.95% 41.18% 67.86% Diagnosis 53.

5 Functional consequences of cognitive impairment in HIV Diagnostic Transitions from Baseline to Year 1 100% 2.94% 17.07% 17.86% Year 1 Diagnosis as a % of Baseline 21.95% 41.18% 67.86% Diagnosis 53.57% 38.24% 60.98% 17.86% 28.57% 0% 17.65% 10.71% 3.57% Normal NP Abnormal MC/MD HAD (N=37) (N=53) (N=39) (N=30) Baseline Diagnosis Normal NP Abnormal MC/MD HAD Heaton et al JINS 2004 There is considerable movement in the MCMD and HAD arms Approximately one-third of HAD patients improve and 18% of MCMD patients decline at one year CD68 expression in hippocampus Elevated despite viral control with HAART Anthony, Bell, et al. J Neuropath Exp Neurol 2005 VAMC ID Rounds Feb 2009 Gonzalez-Scrano et al

HIV DNA in CD14+ cells Correlation to HAD HAART naïve Thais Aging with HIV infection The Honolulu Advertiser, 2003 Valcour J Leukocyte Biol 2010 The New York Times, 2007 Tau expression in

6 HIV DNA in CD14+ cells Correlation to HAD HAART naïve Thais Aging with HIV infection The Honolulu Advertiser, 2003 Valcour J Leukocyte Biol 2010 The New York Times, 2007 Tau expression in hippocampus Elevated despite viral control with HAART Prevalence of Dementia % of population Age Anthony, Bell, et al. J Neuropath Exp Neurol

7 IRIS Clinical Presentation Immune Reconstitution Inflammatory Syndrome (IRIS) Recommended reading: Johnson and Nath Neurological complications of immune reconstitution in HIV-infected populations. Annals of the New York Academy of Sciences 2010 Profound immune response -often to previously unrecognized or subclinical pathogens Two main categories: Simultaneous ( Unmasking ): inflammatory immune response against an opportunistic pathogen previously uncontrolled or untreated Delayed ( Paradoxical ): inflammatory immune response against an antigen previously controlled or treated IRIS Clinical Presentation Some speculation that autoimmune phenomenon can underlie some IRIS Emergence of clear autoimmune phenomenon have been described (Guillain-Barre, Graves Disease)* Independent t-cell mediated encephalitis without identified pathogen Descriptions of paradoxical worsening with treatment of other infections prior to HAART can occur with TB, MAI leprosy treatment -confirms that the response is due to immune reconstitution not HAART CNS-IRIS Defining Features 1. Worsening of neurological status after HAART 2. Deterioration of or new radiological findings suggestive of inflammation 3. Occurring in the context of HIV control decrease in plasma HIV viral load of > 1 log appears to be a better marker than CD4 count recovery 4. Symptoms not explained by: (1) newly acquired disease; (2) ARV side effects; (3) usual course of other illnesses 5. If biopsy -histopathology confirms T cell lymphocytic infiltration *Chen et al, Medicine

8 HIV in human hosts Timing of IRIS 4-20 weeks, increasing freq. HAART CD4 CD4 cells Plasma HIV RNA CD4 cells Plasma HIV RNA viral setpoint viral setpoint CD8 Viral load weeks months years weeks months Time Time Most cases occur within the first 3 months of therapy Risk Factors Severe immune suppression -low CD4 count at HAART initiation (nadir) Implications for populations with delayed diagnosis (aged, women, international settings) Known presence opportunistic infections High initial viral load and rapid decline in viral load (likely a better predictor than rate of CD4 rise) Possibly genetic risks polymorphisms in cytokine and MHC genes Unclear association: timing of HAART c/t OI treatment Epidemiology of IRIS Systemic IRIS 15-35% of individuals initiating HAART CNS-IRIS 0.9% of adults (1.5% if CD4 T cell count <200) Most common CNS-IRIS is caused by the JC virus (PML-IRIS) Other pathogens Viruses: Herpes Viruses [VZV, CMV (retinitis), EBV, HSV 1 and 2], parvovirus, BK virus, HTLV 2, Fungal pathogens: Cryptococcus neoformans, Candida Bacterial pathogens: Mycobacterium (M. tuberculosis, M. leprae, M. avium) Parasitic pathogens: Toxoplasma gondii 8

Clinical Course of CNS IRIS Radiology of PML-IRIS Varies greatly based on severity and underlying pathogen Severity Asymptomatic only radiological changes are noted Symptomatic, with recovery

9 Clinical Course of CNS IRIS Radiology of PML-IRIS Varies greatly based on severity and underlying pathogen Severity Asymptomatic only radiological changes are noted Symptomatic, with recovery clinical deterioration and imaging confirmation Catastrophic severe neurological deficits can lead to coma, herniation, death PML IRIS associated with high rate of mortality (>40%) and long-term morbidity Confluent, bilateral, asymmetric, white matter changes Similar to chronic PML Key differentiation = presence of inflammation: additional peripheral enhancement and/or mass effect Johnson and Nath, Ann NY Acad Sci 2010 Histopathology and biomarkers Biomarkers needed Cytokines? (IL-6); Genetic? Histopathology Inflammatory cells: Predominantly CD8 t cells, typically in the perivascular spaces macrophages, CD4+ t cells also present Brain biopsy sensitivity and specificity: 64-96% and 100% in PML-IRIS IRIS Treatment No published randomized trials to direct recommendations Exclude non-iris possible explanations Drug toxicities, interactions, poor HAART adherence, other diseases with progression Continue HAART No guarantee that the condition will not recur once HAART is resumed Likely and increased risk of HIV and OI progression if HAART is stopped 9

10 IRIS Treatment use of steroids Catastrophic cases Despite lack of published data, likely needed, high doses Symptomatic cases -Use of steroids is controversial Inflammatory response likely beneficial to controlling pathogen In non-hiv diseases, use of adjuvant steroids accepted CSF Escape Case Capillary lumen (1) HIV-infected monocytes, some activated HAART 45 year old male from Dublin with chronic well-controlled HIV infection Presents with acute exacerbation of depression requiring hospitalization Blood Brain Barrier (3) Impacts brain cells leading to cognitive dysfunction (2) Transfer of HIV into the brain - infection establishment in perivascular macrophages (5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ? Psychomotor slowing, depressed affects, markedly decreased response times (4) Neuronal dysfunction and death 10

Compartments Antiretrovirals: CNS Penetration-Effectiveness CPE and CSF viral load poor better NRTI didanosine emtricitabine abacavir tenofovir lamivudine zidovudine zalcitabine stauvudine NNRTI

11 Compartments Antiretrovirals: CNS Penetration-Effectiveness CPE and CSF viral load poor better NRTI didanosine emtricitabine abacavir tenofovir lamivudine zidovudine zalcitabine stauvudine NNRTI efavirenz delavirdine nevirapine PI nelfinavir amprenavir amprenavir-r ritonavir atazanavir indinavir-r saquinavir atazanavir-r lopinavir-r tipranavir-r indinavir enfuviride Courtesy: S. Letendre, UCSD Proportion with detectable virus in CSF HAART with higher BBB penetration Letendre et al 2008 Arch Neurol Compartments CSF viral load and cognition Improved control of CSF HIV RNA relates to greater improvements in cognitive performance Ellis et al Ann Neurol 2004 Acute meningoencephalitis Case Series Case series 3 cases Suppressed plasma HIV RNA presenting with acute meningoencephalitis All had detectable virus in CSF ( 7059, 180,692, and 11,227 copies/ml) All had MRI changes All responded to change in ARVs Representative T2 image Wendel and McArthur CID

12 Subacute 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 < Memoryd/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 Canestri et al CID 2010 Plasma HIV RNA Subacute Neurological Syndromes Case Series All but one had CSF pleocytosis and/or elevated protein levels resistance-associated mutations seen in 7 of 8 CSF strains that were genotyped Optimization of HAART in response to resistance mutations identified or to increase CSN penetration effectiveness resulted in suppression of HIV RNA in CSF and clinical improvement for all Canestri et al CID 2010 Practical implications An approach to impairment in HIV All cases presented with sub-acute symptom progression -? Approach for the 50% of subjects with chronic impairment Current published studies are mixed Provides no basis for using neuro-haart in asymptomatic patients Lancet Neurology

13 HIV in human hosts (aseptic) meningitis, radiculitis, myelitis Acute HIV CD4 cells Plasma HIV RNA viral setpoint weeks months years Time Laboratory Staging of Acute HIV-1 Infection Acute HIV Infection Impact on the brain Fiebig 1 (5 days) Fiebig 2 (10 days Fiebig 3 (14 days) Fiebig et al., AIDS

14 Main Clinical Phlebotomy Questionnaires Leukopheresis Days 0, 2, 3, 5, 7, 10 Wks 2, 4, 8, 12, 16, 20, 24 then every 24 wks till 96 wks Gut Colon biopsy Procedures Compartment (optional) Neuro MRI/MRS LP NP test Genital Semen, anal, cervical Wks 0, 24, 96 Wks 0, 6, 12, 24, 48, 96 D 0, 3, 7, LP wks 0, 24, 96 wks 2, 4, 12, 24, 48, 72, 96 Acute Retroviral Syndrome (ARS) Of 11 subjects, 9 subjects (82%) had ARS Symptoms N(%) Fever 8(72.7) Oral ulcer 5(45.4) Sore throat 5(45.4) Headache 4(36.4) Myalgia 4(36.4) Anorexia 4(36.4) Diarrhea 4(36.4) Skin rash 4(36.4) Adenopathy 2(18.2) Arthalgia 2(18.2) Genital ulcer 1(9.1) Oral candidiasis 1(9.1) Vaginal candidiasis 1(9.1) ID Age/ge nder Characteristics and neurological profile of acute HIV infected subjects at enrollment Risk Fiebig HIV RNA CD4/CD8 Subtype ARS symptoms 1 28yr/F Hetero III 794, /264 CRF01_AE Yes Headache (yes or no) No CSF cell count RBC=0,WBC=0 2 28yr/M MSM III 1,069, /238 NT Yes Yes RBC=0,WBC= yr/M MSM III 302, /917 NT Yes No RBC=10,WBC= yr/F Hetero IV 571, /1227 CRF01_AE Yes No RBC=10,WBC= yr/M Hetero III 258, /245 CRF01_AE Yes Yes RBC=8,WBC=0 6 25yr/M MSM II 150, /203 NT No No Not done 7 23yr/M MSM II 285, /191 CRF01_AE Yes No RBC=1,WBC=0 8 24yr/M MSM III 81, /500 B No Yes RBC=2,WBC=1 HIV CNS penetration during acute Infection 9 25yr/M MSM III 48, /998 NDY Yes No RBC=0,WBC= yr/M MSM III >750, /426 NDY Yes No RBC=1,WBC= yr/M MSM II 276, /271 NDY Yes Yes RBC=10,WBC=0 All had normal CSF protein and sugar 14

15 Early inflammation in Acute HIV Major unanswered Questions Cho/Cr Feibig 1&2 : BG MRS Basal Ganglia Feibig 3&4 : BG MRS Feibig Control : BG CSF Cytokines before and after megahaart Our there founder viruses in CSF that may uncover aspects of neurotropism Do CNS outcomes depend on early immune responses Is there a CNS impact of treatment within the first weeks of infection Conclusions HIV-related brain injury remains frequent despite HAART There is evidence that on-going brain inflammation may be occurring Infiltration of macrophages at autopsy Circulating HIV DNA Conclusions HIV can present as a rapidly progressive dementia syndrome Immune Reconstitution Inflammatory Syndrome In association with opportunistic infection Autoimmune phenomenon CNS escape syndromes Acute HIV 15

A B C D Top Thank you Special Thanks: Krista Nicolas Edgar Busovaca Stephanie Chaio Lauren Wendelken Howard Rosen, Bruce Millerand the Memory and Aging Center Staff Cecilia Shikuma, Bruce

16 A B C D Top Thank you Special Thanks: Krista Nicolas Edgar Busovaca Stephanie Chaio Lauren Wendelken Howard Rosen, Bruce Millerand the Memory and Aging Center Staff Cecilia Shikuma, Bruce Shiramizuand the Hawaii Center for AIDS Jintanat Ananworanichand the Southeast Asia Research Collaboration with Hawaii (SEARCH, Jerome Kim and the US Army HIV Research team Our research subjectsin California, Hawaii and Thailand Research support R01 NS061696(Monocyte HIV DNA and HIV Dementia) K23AG032872(Brain Impact of Aging with HIV) R21-MH086341(Neurological Complications of Acute HIV Infection) UCSF AIDS Research Institute(NeuroImaging Correlates to Dementia in HIV over 60) UCSF-GladstoneCenter for AIDS Research (NeuroImaging Correlates to Dementia in HIV over 60) Hillblom Foundation(Cognitive Impact of Insulin Resistance in Aging HIV Patients) P50 AG (UCSF Alzheimer s Disease Research Center) Disclosures: Dr. Valcour has provided consultative services to GlaxoSmithKline, Merck, and Abbott 16

HIV Neurology Persistence of Cognitive Impairment Despite cart

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