• Like
  • Save

Loading…

Flash Player 9 (or above) is needed to view presentations.
We have detected that you do not have it on your computer. To install it, go here.

Like this document? Why not share!

Microsoft PowerPoint - Simpsons Slides-FNL-NYN

on

  • 1,605 views

 

Statistics

Views

Total Views
1,605
Views on SlideShare
1,605
Embed Views
0

Actions

Likes
0
Downloads
30
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Microsoft PowerPoint - Simpsons Slides-FNL-NYN Microsoft PowerPoint - Simpsons Slides-FNL-NYN Document Transcript

    • Neurological Manifestations of HIV/AIDS David M. Simpson, MD Professor of Neurology Director, Neuro-AIDS Research Program Neuro- Director, Clinical Neurophysiology Labs The Mount Sinai Medical Center New York, New York Declining Mortality with ARV in USA 1994-1997 1
    • History of Neuro-AIDS Snider W, Simpson D, et al. Ann Neurol 1983;14:403-418 HIV and the Nervous System: Major Issues • 40% to 70% of patients with HIV have central or peripheral nervous system involvement • Neurologic disorders frequently misdiagnosed • Viral differences in CNS and plasma • Role of hepatitis C coinfection • Antiretrovirals - Penetration of blood brain barrier - Efficacy in dementia - Toxicity: CNS (EFV), PNS (“d-drugs”) (“ drugs” 2
    • Neuro-AIDS: Types of Complications • Secondary neurologic complications - 20 immune suppression (opportunistic infection, lymphoma) - ↓ incidence post-HAART post- • Primary neurologic disorders enigmatic - HIV dementia in adults - Encephalopathy in children - HIV-associated (vacuolar) myelopathy HIV- - Distal peripheral neuropathy Prevalence of Neurologic Complications in HIV/AIDS % % Neuropathy 25-35 25- PML <5 10-15 10- Dementia Toxoplasmosis 5 (↓) Minor CNS lymphoma <5 cognitive Cryptococcal 20 <5 motor meningitis disorder Myelopathy 5-10? CMV neuro <5 Myopathy <5 Stroke <5 Neuro- Neuro- Immune Reconst. Reconst. <5 Syndrome ? syphilis 3
    • Incidence of Neurologic Complications of HIV Infection: MACS Incidence rate (per 1000 person-years) Introduction Introduction of HAART Crypto of HAART 7 Toxo PML 35 6 PCNSL 30 HIVD 5 25 4 20 3 15 2 10 1 5 0 0 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '90 '92 '94 '96 '98 '00 Calendar year Sacktor N. J NeuroVirology. 2002;8(supp 2):115-121. Rising Prevalence of HIV 15 Dementia Proportion with HIV Dementia 10 5 0 1994 1996 1998 2000 2001 Courtesy of S Letendre; Adapted from McArthur, et al, JNV, 2003 4
    • Terminology of Cognitive Impairment • HIV-Associated Neurocognitive Disorders (HAND) - HIV-Associated Dementia (HAD) • AIDS Dementia Complex (ADC) - Mild Neurocognitive Disorder • Minor Cognitive Motor Disorder (MCMD) - Asymptomatic Neurocognitive Impairment HIV ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) CRITERIA ASYMPTOMATIC MILD HIV- NEUROPSYCH NEUROCOGN ASSOCIATED IMPAIRMENT DISORDER DEMENTIA NEUROCOGN. IMPAIRMENT > Mild > Mild > Mod FUNCTIONAL IMPAIRMENT None > Mild > Mod 5
    • Cross-sectional Neurocognitive Performance 60% N = 1308 50% NC Normal 40% NC Impaired 30% 20% 10% 0% Normal Mild Mild- Moderate Moderate- Severe Moderate Severe CHARTER 2008 NC Impairment in the Pre-ARV, Pre-HAART and HAART Eras Grant (1987) HNRC-500 (1995) CHARTER (2008) 100% 75% Percent Impaired 50% 25% 0% HIV- CDC-A CDC-B CDC-C 6
    • ALLRT ALLRT Study Design • Prospective, observational cohort • N = 1160 subjects participating in ACTG clinical trials • Median age = 41 years • ≥ 3 ARV agents for ≥ 20 weeks - 50% Rx-naive and 50% experienced Rx- • Neuro substudy: Neurocogn. and PN batteries ALLRT: ACTG Longitudinal Linked Randomized Trials ACTG: AIDS Clinical Trials Group Robertson K, et al. AIDS. 2007;21:1915-1921. ALLRT Prevalent Mild Neurocognitive Impairment in ALLRT Baseline Test • Mild impairment 39% 61% impaired unimpaired Baseline: 20 weeks on ART in parent ACTG study n=1160 Robertson K, et al. AIDS 2007;21:1915-1921. 7
    • ALLRT Sustained Neurocognitive Impairment in ALLRT • Baseline impaired • Follow-up at 48 wk 22% impaired • Sustained impairment 78% unimpaired n=991 Robertson K, et al. AIDS 2007;21:1915-1921. ALLRT Incident Neurocognitive Impairment in ALLRT • Baseline unimpaired • Follow-up at 48 wk 21% • Developed impairment impaired 79% unimpaired n=615 Robertson K, et al. AIDS. 2007;21:1915-1921. 8
    • ALLRT Factors Associated with Sustained Mild Cognitive Impairment (n=991) Multivariate Analysis Variable Odds Ratio 95% CI p-value CD4 cell count, cells/mm3 1.74 1.12 , 2.70 0.01 <200 vs >350 Nadir CD4 cell count, cells/mm3 1.73 1.18, 2.55 <0.01 <200 vs >350 Adjusted for race, education, age, sex, and antiretroviral history Virologic response at 16 weeks and baseline HIV-1 RNA was not significantly associated with prevalent impairment Robertson K, et al. AIDS. 2007;21:1915-1921. Other Causes of Neurocognitive Impairment Not Related to HIV • Medical conditions • Concomitant - Nutritional/metabolic medications1 causes1 • Substance use2 - Vascular disease2 • Increased survival of - Hepatitis C3 HIV-infected individuals5 HIV- - Depression/other - Effects of aging psychiatric - Overlap with conditions1 Alzheimers - Sleep disorders4 1http://clinicaloptions.com 2GhafouriM, et al. Retrovirology 2006;3:1-11. 3Letendre S, et al. 4th IAS 2007: Oral WeAb201. 4Nokes K, et al. J Assoc Nurs AIDS Care 2001:12:17-22. 5Robertson K, et al. AIDS 2007;21:1915-1921. 9
    • Clinical Features of HIV-Associated Neurocognitive Impairment (NI) Cognition Memory loss Concentration Mental slowing Comprehension Behavior Motor Apathy Unsteady gait Depression Poor coordination Agitation, mania Tremor Clinical Features Functional Impairment • Activities of daily living - Medication adherence - Driving (2-3 times as likely to fail tests) (2- - Household finances - Meal preparation • Vocational functioning - 5 times more likely to complain of problems performing their jobs - Twice as likely to be unemployed Courtesy of S Letendre 10
    • Clinical Features 1.0 Earlier Mortality Proportion Remaining Alive 0.8 NL (n=256) 0.6 NPI (n=109) 0. MCMD 4 (n=49) 0.2 0.0 0 2 4 6 8 (n=414) (n=274) (n=66) (n=17) Years From Baseline Evaluation Ellis R. Arch Neurol 1997;54:46-424 Clinical Features of HIVD in Adults • Clinical symptoms manifest in: - Cognition - Behavior - Motor skills • Diagnosis of exclusion: - Mass lesions, meningitis, drugs, psychological changes - W/U: Bloods, radiology, CSF 11
    • Neuroradiologic Features of HIV-D • Cerebral atrophy • White matter abnl - Symmetrical - Confluent • Distinguish from multifocal lesions T2-weighted coronal (left) and axial (right) MRI Pathogenesis of HIV Dementia • Multifactorial • Direct vs. indirect mechanisms of HIV effect on brain - Direct: microglial HIV infection, CSF HIV viral load - Indirect: cytokines (TNF-α), cellular channels (TNF- (Ca, NMDA) 12
    • Possible Causes of Neurocognitive Impairment Related to HIV • Ongoing HIV replication in the brain1 • Discordant viral load in the plasma and CSF2 • Different viral strains in brain and plasma3 1McArthur J, et al. J Neurovirol 2003;9:205-221. 2Lanier E, et al. AIDS 2001;15:747-751. 3Letendre S, et al. 4th IAS 2007: Oral WeAb201. CSF Viral Load and Cognitive Function in Advanced HIV Infection: Pre-HAART 5.5 McArthur 1997 HIV CSF log copies/mL 5.0 Brew 1996 4.5 Ellis 1997 4.0 3.5 3.0 2.5 2.0 1.5 HIV+ MC/MD Mild Mod Severe Nondemented HIV Dementia MC/MD, minor cognitive/motor disorder Figure courtesy of Sacktor N 13
    • Importance of Attacking All HIV Reservoirs CNS Lymph nodes Lymph nodes Kidneys Peripheral blood Testes Blood-Brain Barrier 14
    • Crossing the Blood Brain Barrier Brain Brain E Transport C E C into the CSF S C S F CSF into S Brain Brain plasma Transport into Diffusion the brain ECS: Extracellular space CSF: Cerebrospinal fluid Adapted from Groothius DR, et al. J Neurovirol 1997;3:387-400 Drug Penetration into CNS • Characteristics that affect drug penetration into the CNS - Molecular Weight / Size - Lipophilicity - Protein Binding - pH / Ionization - Molecular pumps (e.g., P-glycoprotein) P- - Integrity of the blood-brain barrier blood- - Intracellular transfer via trafficking 15
    • Anti-HIV Drugs: CNS Penetration Nucleoside RT CSF/Plasma Nonnucleoside CSF/Plasma Inhibitors Ratio RT Inhibitors Ratio Zidovudine (AZT) 0.3 - 1.35 Nevirapine (NVP) 0.28 - 0.45 Stavudine (d4T) 0.16 - 0.97 Delavirdine 0.02 Abacavir (ABC) 0.3 - 0.42 Efavirenz 0.01 Didanosine (ddl) (ddl) 0.16 - 0.19 Protease Inhibitors Lamivudine (3TC) 0.11 Indinavir 0.02 - 0.76 Zalcitabine (ddC) 0.09 - 0.37 Saquinavir < 0.05 Emtricitabine 0.04 Nelfinavir < 0.05 Nucleotide RT Inhibitors Ritonavir < 0.05 Tenofovir < 0.05 Amprenavir < 0.05 Lopinavir < 0.05 Fusion inhibitors Atazanavir 0.0021-0.0226 0.0021- Enfuvirtide NA Fosamprenavir < 0.05 Antinori A, et al. CROI 2002. #438-W. McArthur JC et al. J Neurovirol. 2003;9:205-221. Atazanavir Prescribing Information. Data on file; Gilead Sciences, Inc. Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier C, Gelman B, McArthur J, McCutchan J, Morgello S, Simpson D, Grant I, Ellis R Arch Neurol 2008;65:65-70. 16
    • CHARTER Derivation of CPE Scoring System • Penetration of ARV drugs was characterized using a hierarchical approach based on the best available evidence - Data on chemical characteristics, CSF pharmacology, and effectiveness in the CNS were reviewed - References included ARV package inserts, published manuscripts, and conference abstracts • To estimate neuroeffectiveness, ARVs were assigned neuroeffectiveness, an individual CPE score: 1 = High 0.5 = Intermediate 0 = Low Letendre S, et al. Arch Neurol 2008;65:65-70. CNS Penetration-Effectiveness Score CHARTER 1 0.5 0 NRTIs Abacavir Emtricitabine Didanosine Zidovudine Lamivudine Tenofovir Stavudine Zalcitabine NNRTIs Delavirdine Efavirenz Nevirapine PIs Amprenavir/r Amprenavir Nelfinavir Indinavir/r Atazanavir Ritonavir Lopinavir/r Atazanavir/r Saquinavir Indinavir Saquinavir/r Tipranavir/r Fusion Enfuvirtide Inhibitors Relationship between CNS penetration and clinical improvement has not been established Letendre S, et al. 13th CROI 2006:Abstract 74 17
    • CHARTER Study Results - Cont. • Higher CPE scores correlated with lower Oct 2003 – Jan 2006 HIV RNA levels in CSF (r = -0.12, p = 0.008)1 0.12 • After accounting for plasma viral loads, each unit decrease in CPE rank was associated with a 2.43- 2.43- fold increase in the odds of having detectable CSF VL1 • CPE scores continue to be updated as more data are generated Letendre S, et al. Arch Neurol 2008;65:65-70. • Larger number of CSF-penetrating drugs was associated with greater declines of HIV RNA in CSF • This effect was not attributable to - Greater number of ARVs per regimen - Potency of antiretroviral drugs Ann Neurol 2004;56:416-423 18
    • Neurocognitive Improvement & CSF Viral Load Suppression Improvement in GDS 1.0 - .5 - at Follow-up 0.0 - Χ2 = 6.3; p = .01 -.5 - Not Suppressed Suppressed N=14 N=17 Letendre et al. Ann Neurol 2004;56:416-423 Rational Therapeutics for HIV Dementia Therapy Mechanism of Action HAART Antiretroviral Thalidomide TNF inhibition Platelet activating factor (PAF) Lexipafant antagonist Nimodipine Calcium channel blockade Memantine NMDA channel blockade Selegiline MAO-B inhibition; anti-apoptotic MAO- anti- Minocycline Anti-inflammatory; neuroprotective Anti- 19
    • Antiretroviral Efficacy in HIV Dementia • AZT only agent with demonstrated efficacy in HIV-associated dementia in RCT HIV- • ACTG 005 - AZT 2000 mg/d, 1000 mg/d, placebo - Greatest neuropsychological improvement in high dose arm - No data on lower dose AZT - Most other ARVs not studied - Methodologic challenges in HAART era • Abacavir vs placebo/optimized background ARV - Negative for neuropsych. improvement neuropsych. - ↓CSF HIV VL Sidtis JJ et al. Ann Neurol. 1993;33:343-349. Brew B et al. Proc of the 12th World AIDS Conference. Geneva, SZ. 1998. Adverse Effects With Antiretroviral Classes NRTIs NNRTIs • Peripheral neuropathy • Rash (EFV, DLV, NVP) (ddC, d4T, ddI) • Elevated transaminase levels • GI intolerance (AZT, ddI) • CNS effects (EFV) • Anemia/bone marrow suppression (AZT) • Pancreatitis (ddI, ddC) PIs • Oral ulcers (ddC) • Metabolic abnormalities • Myopathy (AZT, d4T) • GI intolerance • Elevated transaminase • Lactic acidosis with hepatic levels steatosis (rare) • Nephrolithiasis (IDV) Source: DHHS Guidelines. 20
    • Neuropathy Types Inflammatory Distal Mononeuropathy Demyelinating Polyneuropathy Multiplex Polyneuropathy Mononeuropathy Brachial Plexopathy Distal Polyneuropathy: Symptoms • Numbness/tingling/burning pain in the feet • Sensory complaints typically symmetrical • Weakness unusual until DSP advanced • Frequently misdiagnosed (ie, ACTG 175) • Affects quality of life and ARV adherence 21
    • Distal Polyneuropathy: Clinical Signs • Depressed ankle reflexes relative to knees (caution: combined CNS and PNS) • Abnormal vibration in feet • Abnormal pinprick and cold (stocking- glove distribution) • Muscle strength (objective) usually normal Simpson. AIDS and the Nervous System. 2nd ed. Raven Press;1996:189. CHARTER: Peripheral Neuropathy n = 429 n = 452 n = 658 57% of HIV+ subjects had ≥ 1 sign of PN. Among those with PN signs, Sx including paresthesias and pain affected 61%. Ellis R, et al. CROI 2009 22
    • Quality of Life and HIV- Associated Neuropathic Pain Ellis R, et al. CHARTER, 2009 (unpubl) CHARTER: PN Risk Factors Ellis R, et al. CROI 2009 23
    • Drugs Associated With PN • Antibacterials • ARVs - dapsone - d4T - ethionamide - ddC - isoniazid (especially if - ddI administered without pyridoxine) - metronidazole - PIs ? - streptomycin • Antineoplastics • Other agents - vinblastine sulfate - phenytoin - vincristine sulfate - thalidomide - cisplatin Adapted from Moyle. Drug Safety. 1998;Dec 19(6):481. 24
    • Nucleoside Analogue-Related DSP • Clin indistinguishable from • Associated with: DSP 20 HIV (often overlap, 0 esp with ↓ CD4) - Didanosine (ddI) (ddI) • Pain usually resolves within 8 wks after drug withdrawal - Stavudine (d4T) • PN signs may persist for > 4 months after drug withdrawal - Zalcitabine (ddC) (ddC) • ↓ use in US/Europe; common in developing world Mount Sinai Neuro-AIDS Research Program Neurology Neuro-AIDS Research Team Neuro- David M. Simpson, MD Mary Catherine George, Coordinator Jessica Robinson-Papp, MD Robinson- Kathryn Elliott, MD AIDS Center Clinic Neuropsychology Fran Wallach, MD David Dorfman, PhD Elizabeth Ryan, PhD Neuro-AIDS Research Consortium Neuro- Neuropathology/Brain Bank David Clifford, MD (PI) Susan Morgello, MD Mary Gould Letty Mintz, NP Neuroradiology Cheuk Tang, PhD 25