David B. Clifford, MD Washington University in St. Louis. Disclaimers

Transcription

1 HIV Associated Neurocognitive Disorders (HAND) David B. Clifford, MD Washington University in St. Louis Disclaimers Funding: NIH: NIAID, NINDS, NIMH, NIA, Fogarty Consulting: Biogen, Cytheris, Genzyme, Pfizer, Genentech, Jannsen, Millennium, Novartis, BMS, Roche Clinical study support: Biogen, Glaxo, Pfizer, BMS, Neurogesx, Genentech 1

2 HIV 1 Associated Neurologic Problems Primary HIV associated conditions HIV associated neurocognitive disorder and dementia Myelopathy Peripheral neuropathy Myopathy HIV Associated Dementia (HAD) Slide 4 Decreased concentration Motor slowing Behavioral changes 2

3 Slide 5 HIV-Associated Dementia (HAD) Formerly AIDS Dementia Complex Occurs with low CD4 Progressive untreated death in 6 months Correlates at least moderately to active viral replication (in CNS) CSF VL high Correlates to immune activation markers Pathology: Multinucleated giant cells Slide 6 Approved Antiretroviral Agents DDC 3TC 3TC/ZDV DLV ABC TDF 3TC/ABC FTC/TDF ETR ZDV DDI d4t NVP EFV ABC/3TC/ZDV TDF/FTC/EFV SQV NFV LPV/r T-20 TPV SQV.sgc APV ATV DRV Nucleoside RTI Non-Nucleoside RTI Protease Inhibitor Fusion Inhibitor CCR Inhibitor Integrase Inhibitor RTV IDV RFV MVC RTG 3

4 Slide 7 Slide 8 Successful HIV Therapy Helps ( A Lot) Probable dementia Toxoplasmosis Progressive multifocal leukoencephalopathy Probable or possible dementia Cryptococcal meningitis CNS lymphoma Incidence rates er 1,000 person-years) (pe Multicenter AIDS Cohort Calendar Year HAART Sacktor, personal comm 200 4

5 Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras 100% Grant 1987 HNRC CHARTER 2008 Slide 9 Per rcent Impaired 75% 50% 25% 0% HIV- CDC-A CDC-B CDC-C Frascati Classification of HIV Associated Neurocognitive Disorders (HAND) ANI = Asymptomatic neurocognitive impairment MND = Mild neurocognitive disorder HAD = HIV 1 associated dementia 5

6 HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria HIV-associated Dementia marked cognitive impairment with marked functional impairment Mild Neurocognitive Disorder cognitive impairment with mild functional impairment Asymptomatic Neuropsychological Impairment abnormality in two or more cognitive abilities Antinori, et al., Neurology 2007 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria HIV-associated Dementia marked cognitive impairment with marked functional impairment Mild Neurocognitive Disorder cognitive impairment with mild functional impairment Asymptomatic Neuropsychological Impairment abnormality in two or more cognitive abilities Antinori, et al., Neurology 2007 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 6

7 Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A CHARTER Longitudinal Study Robert Heaton, PhD 1, Donald Franklin, BS 1, Steven Woods, PsyD 1, Christina Marra, MD 2, David Clifford, MD 3, Benjamin Gelman, MD,PhD 4, Justin McArthur, MBBS 5, Susan Morgello, MD 6, Allen McCutchan, MD 1, and Igor Grant, MD 1 for the CHARTER Group 1 University of California, San Diego; 2 University of Washington, Seattle; 3 Washington University, St. Louis; 4 University of Texas Medical Branch, Galveston; 5 Johns Hopkins University, 6 Mount Sinai School of Medicine CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO Diagnosis CHARTER Neurocognitive Test Battery Verbal Fluency» Letter Fluency» Category Fluency Speed of Information Proc.» WAIS-III Symbol Search» WAIS-III Digit Symbol» Trail Making Test Part A Attention/Working Memory» Paced Auditory Serial Addition Test - 50» WAIS-III Letter-Number Sequencing Motor» Grooved Pegboard Abstraction/Executive» Wisconsin Card Sorting Test 64» Trail Making Test Part B Learning and Memory» Hopkins Verbal Learning Test-R» Brief Visuospatial Memory Test-R» Story Memory Test» Figure Memory Test Everyday Functioning: Patient s Assessment of Own Functioning Inventory Activities of Daily Living Scale CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 7

8 Participants 347 longitudinal CHARTER participants with up to 90 months of follow-up (median 45.2 months)» 226 NML cases: No neurocognitve impairment and no selfreported or observed declines in everyday functioning» 121 ANI cases: Neurocognitvely impaired, but no self-reported or observed declines in everyday functioning Participants completed neuromedical, laboratory, neurocognitive, and both self-report and performancebased measures of everyday functioning approximately every 6 months CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO Self-Report Functional Impairment Measures Patients Assessment of Own Functioning Inventory (PAOFI): Measures cognitive complaints over 5 domains (eg., memory, language, cognition)» Symptomatic = 3 or more complaints Activities of Daily Living (ADL): Measures increased dependence in completing basic activities of daily living (eg., housekeeping, cooking, managing g finances)» Symptomatic = declines in 2 or more areas at least partially attributed to cognitive problems Self-report symptomatic HAND requires both PAOFI and ADL to be symptomatic CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 8

9 Performance-based Functional Impairment Measures Medication Management Test-Revised (MMT-R): Assesses ability to perform tasks related to medication management» Tasks include ability to correctly place pills in a pill organizer according to prescription schedule and ability to infer answers from prescription labels» Symptomatic = Score 1SD below the mean of cognitively normal sample Valpar System 3000 Work Samples and Computerized Assessment: Assesses abilities considered important for performing work-related tasks» Symptomatic = Score 1SD below the mean of cognitively normal sample CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO Baseline Comparison of ANI and NML: Background Characteristics NML (n=226) ANI (n=121) P-value Age 43.0 (8.6) 44.8 (8.0) Education 12.9 (2.4) 13.5 (2.2).04 % Male 81.9% 81.8% % Caucasian 45.6% 46.3% % Lifetime Substance Dx 71.2% 69.4% % with Comorbidity 22.6% 44.6% <.0001 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 9

10 Baseline Comparison of ANI and NML: Disease Characteristics NML (n=226) ANI (n=121) P-value % AIDS 56.2% 62.8% Current CD4 459 [ ] 425 [ ] Nadir CD4 201 [61-370] 162 [38-273].03 % on ART 66.2% 72.7% Est. Duration HIV+ (months) (75.0) (81.6) % HCV+ 20.4% 27.3 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO ANI Increases Risk for Symptomatic HAND: Based on Self-Report of Functional Impairment NML: n=226 ANI: n=121 (Asymptomatic) Surviving ( p=.003 Relative Risk: 2.30 CI: 1.38, 3.86 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 10

11 ANI Increases Risk for Symptomatic HAND: Performance-based Functional Impairment NML: n=226 ANI: n=121 Surviving (Asymptomatic) p<.0001 Relative Risk: 4.70 CI: 2.93, 7.71 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO ANI Increases Risk for Symptomatic HAND: Self-report or Performance-based NML: n=226 ANI: n=121 Surviving (Asymptomatic) p<.0001 Relative Risk: 3.02 CI: 2.08, 4.42 CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 11

12 Asymptomatic Neurologic Impairment May Predict Functional Decline Mechanism remains uncertain Cannot write off this substantial portion of successfully treated HIV patients Tracking change in this population is challenging Measures of cognitive function that can be repeated and tracked might be of value CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO International HIV Dementia Scale International HIV Dementia Scale Naming four objects Fingertapping Luria psychomotor learning task Recall of names Sacktor et al. Neurology ;1:A CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 12

13 CogState Executive Function ures/12_minute%20brochure%20rev 6_LowRes.pdf CROI 2010, Winston, et al CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO Diagnosis NPZ -4 used in ACTG Trail making A and B Symbol digit test Hopkins Verbal Learning test Robertson, et al, ALLRT CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO 13

14 Cognitive Screening Montreal Cognitive Assessment (MoCA) Broad balanced test Online and free Bedside scoring Being assessed in comparison with tools currently used that require licenses, and norming CNS HIV NEUROBEHAVIORAL HIV ANTI-RETROVIRAL THERAPY RESEARCH EFFECTS PROGRAM RESEARCH UNIVERSITY OF OF CALIFORNIA, SAN SAN DIEGO Cognitive Dysfunction in HIV AIDS Dementia (now HAD) Pre HAART HAND (ANI/MND) Post HAART 14

15 Slide 29 To develop effective treatment we need to know causes HAND now Evidence for direct viral mechanism poor Cytokines that formerly were most closely associated no longer provide reliable signal by the way, I m from Missouri where famously you have to Show me. Noninfectious pathologies and minimal changes correlated with HIV associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms 88% of sample had HAND 17.5 % has parenchymal HIV brain pathology which was associated to nadir CD4 and plasma viral load 15

16 Slide 31 To develop effective treatment we need to know causes HAND now? Co-morbidities Virus Inflammation Drugs Perfusion/Vascular Is this all due to non-hivassociated co-morbidities? Slide 32 Contribution of other factors to cognitive performance?trauma?drugs?hepatitis?cmv?psychiatric dx/rx 16

17 Neurocognitive Impairment by Co-Morbidity Status Slide 33 impairment % Total Minimal Moderate Severe Slide 34 Co-morbidity Large effect of co-morbid associated impairment masks HIV associated findings Only in the clean group can one see impact of HIV viral load, CD4 nadir Co-morbidity may set up environment for ongoing pathologic interaction with HIV and/or its consequences like inflammation 17

18 Slide 35 To develop effective treatment we need to know causes HAND now? Co-morbidities Virus Inflammation Drugs Perfusion/Vascular Viral Escape Slide 36 CNS is functional compartment Viral isolates may be unique Cells infected in CNS are monocytes/macrophag es with unique viral requirements Rx may differ Untreated HIV CSF generally one log lower VL than periphery During HAD CSF VL rises with autonomous CNS isolates Most often when peripheral virus controlled so is CSF 18

19 Peluso, Spudich et al, Poster 489 Symptomatic Viral Escape Slide 37 Controlled plasma viral load Subacute onset of new neurologic symptoms CSF demonstrated independent replication Drug selection based on virus in CSF improved clinical condition Implications of Viral Escape HIV therapy is not perfect Viral replication sometimes occurs in CNS and generates important resistance mutations Attention to virus in CNS remains critical Justify CSF analysis when new neurologic problems occur in HIV patient, even with good control in plasma Rarity suggest it doesn t explain common HAND 19

20 Slide 39 Does viral subtype matter? Work in Uganda with dementia suggests difference in risk between Subtype A and D Work in Ethiopia suggests Subtype C might have less neurovirulence Projects in Cape Town and in Brazil are addressing potential differences, to date seems less likely to be important HIV infection in the brain may not be fully reflected in blood studies and therapies not as effective in brain. 20

21 Slide 41 CNS Penetration-Effectiveness Ranks NRTIs Zidovudine Abacavir Lamivudine Didanosine Emtricitabine Stavudine Tenofovir Zalcitabine NNRTIs Nevirapine Delavirdine Etravirine Efavirenz PIs Indinavir-r Darunavir-r Atazanavir Nelfinavir Fosamprenavirr Atazanavir-r Ritonavir Indinavir Fosamprenavir Saquinavir Lopinavir-r Saquinavir-r Tipranavir-r Entry Inhs Vicriviroc Maraviroc Enfuvirtide Integrase Inhs Raltegravir CNS Penetration-Effectiveness Ranks Slide 42 Letendre S, et al. Arch Neurol 2008; 65:65-70 CPE 2010 Ranks Cross-Sectional Analysis 21

22 Slide 43 CNS Penetration Effectiveness Unproven CIT2 a randomized trial of rx based on CPE has been stopped Lack of proof by underpowered study doesn t completely discredit this idea More potent delivery of drugs contemplated, eg nanoparticles Drug entry might be double edged sword Toxicity of drugs is an increasing concern Slide 44 Damaged brain may heal poorly CD4 Nadir Legacy of prior damage Nadir CD4 count CHARTER analysis suggest significant impact of nadir <350 Data too limited to test higher h nadirs Treating a scar? Tough target Implies earlier rx could be helpful CROI 2010, Poster 429, Ellis, et al 22

23 Reduced Risk of NCI in those with Absent History of Severe Immunosuppression and Good Virologic Control 0.7 Nadir CD4 > 200/ Detectable VL 0.6 Nadir CD4 < 200/ Detectable VL lity of Impairment Nadir CD4 < 200/ Undetectable VL Probabi Nadir CD4 > 200/ Undetectable VL Changes in Brain Cortex: Damage to the computer Vacuolar Changes Synaptophysin 23

24 Slide 47 To develop effective treatment we need to know causes HAND now Co-morbidities Virus Inflammation Drugs Perfusion/Vascular Inflammation Ongoing Chronic Inflammation Biology of HIV includes chronic immune activation Microbial translocation/lps associated with dementia Slide 48 Brenchley et al, Nature Med,

25 ~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx Slide 50 CSF Viral Escape Can Drive Ongoing CNS Immune Activation 25

26 Detection of microglial cell activation in patients on suppressive ART Garvey et al, CROI2012 Garvey L et al. CROI #78LB Accrual of inflammation in brain attenuated with ART in early infection CROI 2012 Young et al. Abstract #79 26

27 CMV Might Drive Inflammation and Neurocognitive Change CMV powerful antigenic stim that may reactivate and drive chronic inflammation Increases with aging and severity of nadir CD4 In 138 CHARTER patients serum CMV IgG correlated with neurocognitive impairment Fits model of co morbidity driving impairment Letendre, et al, Abstract 466, CROI 2012 Adjunctive Studies for HAND CPI 1189 (TNF alpha antagonist) Lexipafant (Platelet activating factor antagonist) Memantine (NMDA antagonist) Minocycline (Anti inflammatory and p38 MAP kinase inhibitor) Nimodipine (Calcium channel antagonist) Nitroglycerin (Vasodilator) OPC (antioxidant) Pentoxifylline (Platelet activating factor antagonist, TNAa antagonist) Peptide T (possible chemokine receptor blocker) Prednisone (Macrophagesuppression) Selegiline (deprenyl) (Monoamine oxidase B inhibitor) Thioctic acid (antioxidant) Valproic acid unknown Lithium GSK 3βinhibtion Cochrane Review,

28 Minocycline for HAND SIV model data Potential mechanisms Anti inflammatory/ neuroprotective via suppression of p38 MAP kinase Anti oxidant via inos inhibition Anti apoptotic Inhibits matrix metalloproteinases that may damage BBB?Anti viral effect in SIV A5235 is open placebo controlled dti trial of minocycline for HIV patients with cognitive impairment 28

29 A5235: Minocycline vs Placebo x 24 wks Pre-post NPZ8 Plot for A Week NPZ Minocycline Placebo Baseline NPZ8 Slide 58 To develop effective treatment we need to know causes HAND now? Co-morbidities Virus Inflammation Drugs Perfusion/Vascular 29

30 ARV Interruption Improves NP Performance Does CPE have a downside? A5170 found stopping ARV resulted in cognitive improvement ACTG 736 results suggested poorer performance in better penetrating regimens Elevated penetration could cause increased toxicity A=Control, B=ATV, C=EFV (dendrites), D=EFV(neuron loss) A C MAP 2 B D CROI 2010, Liner et al, Poster

31 Aging/HAART/HAND Does HIV or its therapy accelerate aging? Path evidence of premature p tau and amyloid Driving force could be chronic inflammatory or toxic Findings were subclinical but evident at post mortem Anthony et al, Acta Neuropathol, 2006 NNTC evaluation in HIV subjects yo Neuritic α synuclein in 12/73 HIV+ and not controls β amyloid deposits in 35/36 HIV brains Not found in association with HIV brain pathology Suggest accelerated degenerative disease not directly HIV virus driven 31

32 Chronic inflammatory state may lead to amyloid deposition TAT inhibition of neprilysn Ubiquitinproteosome dysfunction Potential Mechanisms Neurology, Dec

33 CSF Amyloid β 1 42 Is Low in Cognitively Impaired HIV+ Patients CSF Tau Not Elevated 33

34 Better Biomarkers: CSF Amyloid and PET PIB Biology of low CSFAB42 appears different in HIV and AD PIB binding correlates to low CSF AB42 in AD In HIV, low CSF AB42 is NOT associated itdwith extracellular amyloid deposits Ances and Clifford, Archives of Neurology, 2012 A. HIV +, Low Aβ1 42, cog N B. Community, Low Aβ 1 42, cog N Alzheimer s Disease in HIV AD is common and will likely occur in HIV patients as they age Rx for AD advancing, and specific dx will be important Anticholinesterase rx NMDA antagonist (memantine) HAND may be distinguished by: Lack of tau elevations in CSF Lack of PIB binding amyloid on PET scanning of brain More data needed on biology of amyloid in HIV (as well as AD!) 34

35 Slide 69 To develop effective treatment we need to know causes HAND now? Co-morbidities Virus Inflammation Drugs Perfusion/Vascular CROI 2010 Cardiovascular Risks Associated with Poor Cognitive Performance in SMART Study Traditional HIV associatedrisk factors were not associated with baseline NP performance CVD risk factors were associated with poorer baseline performance 35

36 Multicenter AIDS Cohort After accounting for education, depression and race Carotid intima media thickness (IMT) and GFR associated with psychomotor speed IMT associated with memory HIV serostatus not associated with poorer cognitive performance overall In HIV+, HIV detection in plasma associated with poorer memory HIV Indirectly Contributes to Cognitive Impairment? HIV Carotid Intima Thickening Age HBP DM Lipids Slide 72 Cognitive Normal Cognitive Impaired 36

37 Slide 73 Effects of HIV and Aging on rcbf Cere m/min) ebral blood flow (ml/100gm Age (years old) Ances et al., JID, Feb 2010 Slide 74 Blood Flow May be Biomarker for HIV Synaptodendritic Injury/Inflammation HIV Normal Synaptodendritic Density Normal Cerebral Blood Flow Masliah et al, Ann Neurol 1997 Masliah et al, Ann Neurol 1997 Disruption or Loss of Synaptodendritic communic ation Reduced d Cerebral Blood Flow HAART 37

38 Modifiable Risk Factors Slide 75 Smoking Diet Glucose Lipids Exercise Physical Mental Rest Modifiable Risk Factors Slide 76 Smoking Diet Glucose Lipids Exercise Physical Mental Rest 38

39 Overall NC Impairment status at baseline and last visit: No major cohort worsening Baseline Last Visit NP Normal Mild NCI NP Normal Mild NCI Moderate NCI Moderate NCI 8% 11% 38% 54% 29% 60% 77 Slide 78 Conclusions Cognitive functions remain impaired in many optimally treated HIV patients Optimal therapy should avoid low nadir CD4, optimize HIV control, minimize chronic immune activation, and optimize cerebral perfusion Healthy lifestyles as well as HIV control should contribute to better neurologic outcomes 39

40 Washington U Beau Ances Turner Overton ACTU and NARC staff NARC investigators Ned Sacktor Justin McArthur David Simpson Christina Marra Giovanni Schifitto Scott Evans CHARTER investigators Ron Ellis Scott Letendre Igor Grant NIH: NINDS (NARC and CHARTER) NIH: NIMH (CHARTER and CIT2) NIH: NIAID (ACTU) NIH: Fogarty (West Africa) Thanks 40