1
NeurologicalNeurological
Manifestations ofManifestations of
HIV/AIDSHIV/AIDS
David M. Simpson, MDDavid M. Simpson, MD
Pr...
2
History of Neuro-AIDS
Snider W, Simpson D, et al. Ann Neurol 1983;14:403-418
HIV and the Nervous System:HIV and the Nerv...
3
NeuroNeuro--AIDS: Types of ComplicationsAIDS: Types of Complications
•• Secondary neurologic complicationsSecondary neur...
4
Incidence of Neurologic ComplicationsIncidence of Neurologic Complications
of HIV Infection: MACSof HIV Infection: MACS
...
5
Terminology of CognitiveTerminology of Cognitive
ImpairmentImpairment
•• HIVHIV--AssociatedAssociated NeurocognitiveNeur...
6
CrossCross--sectionalsectional NeurocognitiveNeurocognitive
PerformancePerformance
N = 1308N = 1308
0%
10%
20%
30%
40%
5...
7
ALLRT Study DesignALLRT Study Design
•• Prospective, observational cohortProspective, observational cohort
•• N = 1160 s...
8
Sustained NeurocognitiveSustained Neurocognitive
Impairment in ALLRTImpairment in ALLRT
Robertson K, et al. AIDS 2007;21...
9
Factors Associated with SustainedFactors Associated with Sustained
Mild Cognitive Impairment (n=991)Mild Cognitive Impai...
10
Clinical Features of HIVClinical Features of HIV--AssociatedAssociated
Neurocognitive Impairment (NI)Neurocognitive Imp...
11
MCMD
(n=49)
NPI
(n=109)
NL
(n=256)
1.0
0.8
0.6
0.
4
0.2
0.0
0
(n=414)
2
(n=274)
4
(n=66)
6
(n=17)
Years From Baseline E...
12
Neuroradiologic Features of HIVNeuroradiologic Features of HIV--DD
•• Cerebral atrophyCerebral atrophy
•• White matterW...
13
Possible Causes of NeurocognitivePossible Causes of Neurocognitive
Impairment Related to HIVImpairment Related to HIV
•...
14
CNS
Lymph nodes
Testes
Peripheral
blood
Lymph nodes
Importance of AttackingImportance of Attacking
All HIV ReservoirsAl...
15
Crossing the Blood Brain Barrier
ECS: Extracellular space
CSF: Cerebrospinal fluid
Adapted from Groothius DR, et al. J ...
16
AntiAnti--HIV Drugs: CNS PenetrationHIV Drugs: CNS Penetration
Fusion inhibitorsFusion inhibitors
< 0.05< 0.05Tenofovir...
17
Derivation of CPE ScoringDerivation of CPE Scoring
SystemSystem
•• Penetration of ARV drugs was characterized using aPe...
18
Study ResultsStudy Results -- Cont.Cont.
•• Higher CPE scoresHigher CPE scores
correlated with lowercorrelated with low...
19
Neurocognitive ImprovementNeurocognitive Improvement
& CSF Viral Load Suppression& CSF Viral Load Suppression
Χ2 = 6.3;...
20
Antiretroviral Efficacy in HIVAntiretroviral Efficacy in HIV
DementiaDementia
•• AZT only agent with demonstrated effic...
21
Neuropathy TypesNeuropathy Types
Distal
Polyneuropathy
Mononeuropathy
Mononeuropathy
Multiplex
Brachial
Plexopathy
Infl...
22
Distal Polyneuropathy:Distal Polyneuropathy:
Clinical SignsClinical Signs
•• Depressed ankle reflexes relative to knees...
23
Quality of Life and HIVQuality of Life and HIV--
Associated Neuropathic PainAssociated Neuropathic Pain
Ellis R, et al....
24
Drugs Associated With PNDrugs Associated With PN
•• AntibacterialsAntibacterials
-- dapsonedapsone
-- ethionamideethion...
25
Nucleoside AnalogueNucleoside Analogue--Related DSPRelated DSP
•• ClinClin indistinguishable fromindistinguishable from...
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Microsoft PowerPoint - Simpsons Slides-FNL-NYN

  1. 1. 1 NeurologicalNeurological Manifestations ofManifestations of HIV/AIDSHIV/AIDS David M. Simpson, MDDavid M. Simpson, MD Professor of NeurologyProfessor of Neurology Director,Director, NeuroNeuro--AIDS Research ProgramAIDS Research Program Director, Clinical Neurophysiology LabsDirector, Clinical Neurophysiology Labs The Mount Sinai Medical CenterThe Mount Sinai Medical Center New York, New YorkNew York, New York Declining Mortality with ARV in USADeclining Mortality with ARV in USA 19941994--19971997
  2. 2. 2 History of Neuro-AIDS Snider W, Simpson D, et al. Ann Neurol 1983;14:403-418 HIV and the Nervous System:HIV and the Nervous System: Major IssuesMajor Issues •• 40% to 70% of patients with HIV have central or40% to 70% of patients with HIV have central or peripheral nervous system involvementperipheral nervous system involvement •• Neurologic disorders frequently misdiagnosedNeurologic disorders frequently misdiagnosed •• Viral differences in CNS and plasmaViral differences in CNS and plasma •• Role of hepatitis C coinfectionRole of hepatitis C coinfection •• AntiretroviralsAntiretrovirals -- Penetration of blood brain barrierPenetration of blood brain barrier -- Efficacy in dementiaEfficacy in dementia -- Toxicity: CNS (EFV), PNS (Toxicity: CNS (EFV), PNS (““dd--drugsdrugs””))
  3. 3. 3 NeuroNeuro--AIDS: Types of ComplicationsAIDS: Types of Complications •• Secondary neurologic complicationsSecondary neurologic complications -- 2200 immune suppression (opportunisticimmune suppression (opportunistic infection, lymphoma)infection, lymphoma) -- ↓↓ incidence postincidence post--HAARTHAART •• Primary neurologic disordersPrimary neurologic disorders enigmaticenigmatic -- HIV dementia in adultsHIV dementia in adults -- Encephalopathy in childrenEncephalopathy in children -- HIVHIV--associated (vacuolar) myelopathyassociated (vacuolar) myelopathy -- Distal peripheral neuropathyDistal peripheral neuropathy Prevalence of NeurologicPrevalence of Neurologic Complications in HIV/AIDSComplications in HIV/AIDS < 5< 5MyopathyMyopathy < 5< 5 NeuroNeuro-- syphilissyphilis 55--10?10?MyelopathyMyelopathy 2020 MinorMinor cognitivecognitive motormotor disorderdisorder 1010--1515 ((↓↓)) DementiaDementia 2525--3535NeuropathyNeuropathy %% ?? ImmuneImmune ReconstReconst.. SyndromeSyndrome < 5< 5CMV neuroCMV neuro < 5< 5StrokeStroke < 5< 5 CryptococcalCryptococcal meningitismeningitis < 5< 5CNS lymphomaCNS lymphoma 55ToxoplasmosisToxoplasmosis < 5< 5PMLPML %%
  4. 4. 4 Incidence of Neurologic ComplicationsIncidence of Neurologic Complications of HIV Infection: MACSof HIV Infection: MACS Calendar year Incidence rate (per 1000 person-years) Sacktor N. J NeuroVirology. 2002;8(supp 2):115-121. Introduction of HAART 0 1 2 3 4 5 6 7 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 Crypto Toxo PML PCNSL 0 5 10 15 20 25 30 35 '90 '92 '94 '96 '98 '00 HIVD Introduction of HAART Rising Prevalence of HIVRising Prevalence of HIV DementiaDementia 0 5 10 15 1994 1996 1998 2000 2001 ProportionwithHIVDementia Courtesy of S Letendre; Adapted from McArthur, et al, JNV, 2003
  5. 5. 5 Terminology of CognitiveTerminology of Cognitive ImpairmentImpairment •• HIVHIV--AssociatedAssociated NeurocognitiveNeurocognitive Disorders (HAND)Disorders (HAND) -- HIVHIV--Associated Dementia (HAD)Associated Dementia (HAD) •• AIDS Dementia Complex (ADC)AIDS Dementia Complex (ADC) -- Mild Neurocognitive DisorderMild Neurocognitive Disorder •• Minor Cognitive Motor Disorder (MCMD)Minor Cognitive Motor Disorder (MCMD) -- Asymptomatic Neurocognitive ImpairmentAsymptomatic Neurocognitive Impairment HIV ASSOCIATEDHIV ASSOCIATED NEUROCOGNITIVE DISORDERSNEUROCOGNITIVE DISORDERS (HAND) CRITERIA(HAND) CRITERIA > Mod> MildNone FUNCTIONAL IMPAIRMENT > Mod> Mild> Mild NEUROCOGN. IMPAIRMENT HIV- ASSOCIATED DEMENTIA MILD NEUROCOGN DISORDER ASYMPTOMATIC NEUROPSYCH IMPAIRMENT
  6. 6. 6 CrossCross--sectionalsectional NeurocognitiveNeurocognitive PerformancePerformance N = 1308N = 1308 0% 10% 20% 30% 40% 50% 60% Normal Mild Mild- Moderate Moderate Moderate- Severe Severe NC Normal NC Impaired CHARTER 2008 NC Impairment in the PreNC Impairment in the Pre--ARV,ARV, PrePre--HAART and HAART ErasHAART and HAART Eras 0% 25% 50% 75% 100% HIV- CDC-A CDC-B CDC-C PercentImpaired Grant (1987) HNRC-500 (1995) CHARTER (2008)
  7. 7. 7 ALLRT Study DesignALLRT Study Design •• Prospective, observational cohortProspective, observational cohort •• N = 1160 subjects participating in ACTGN = 1160 subjects participating in ACTG clinical trialsclinical trials •• Median age = 41 yearsMedian age = 41 years •• ≥≥ 3 ARV agents for3 ARV agents for ≥≥ 20 weeks20 weeks -- 50% Rx50% Rx--naive and 50% experiencednaive and 50% experienced •• NeuroNeuro substudysubstudy:: NeurocognNeurocogn. and PN. and PN batteriesbatteries Robertson K, et al. AIDS. 2007;21:1915-1921. ALLRT ALLRT: ACTG Longitudinal Linked Randomized Trials ACTG: AIDS Clinical Trials Group Prevalent MildPrevalent Mild NeurocognitiveNeurocognitive Impairment in ALLRTImpairment in ALLRT Robertson K, et al. AIDS 2007;21:1915-1921. ALLRT Baseline Test • Mild impairment 61% unimpaired 39% impaired n=1160 Baseline: 20 weeks on ART in parent ACTG study
  8. 8. 8 Sustained NeurocognitiveSustained Neurocognitive Impairment in ALLRTImpairment in ALLRT Robertson K, et al. AIDS 2007;21:1915-1921. ALLRT • Baseline impaired • Follow-up at 48 wk • Sustained impairment 78% unimpaired 22% impaired n=991 Incident NeurocognitiveIncident Neurocognitive Impairment in ALLRTImpairment in ALLRT Robertson K, et al. AIDS. 2007;21:1915-1921. ALLRT 79% unimpaired 21% impaired • Baseline unimpaired • Follow-up at 48 wk • Developed impairment n=615
  9. 9. 9 Factors Associated with SustainedFactors Associated with Sustained Mild Cognitive Impairment (n=991)Mild Cognitive Impairment (n=991) Robertson K, et al. AIDS. 2007;21:1915-1921. <0.01<0.011.18, 2.551.18, 2.551.731.73Nadir CD4 cell count, cells/mmNadir CD4 cell count, cells/mm33 <200 vs >350<200 vs >350 0.010.011.12 , 2.701.12 , 2.701.741.74CD4 cell count, cells/mmCD4 cell count, cells/mm33 <200 vs >350<200 vs >350 pp--valuevalue95% CI95% CIOdds RatioOdds RatioVariableVariable 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 ALLRT Multivariate Analysis Other Causes of NeurocognitiveOther Causes of Neurocognitive ImpairmentImpairment NotNot Related to HIVRelated to HIV •• Medical conditionsMedical conditions -- Nutritional/metabolicNutritional/metabolic causescauses11 -- Vascular diseaseVascular disease22 -- Hepatitis CHepatitis C33 -- Depression/otherDepression/other psychiatricpsychiatric conditionsconditions11 -- Sleep disordersSleep disorders44 •• ConcomitantConcomitant medicationsmedications11 •• Substance useSubstance use22 •• Increased survival ofIncreased survival of HIVHIV--infected individualsinfected individuals55 -- Effects of agingEffects of aging -- Overlap withOverlap with AlzheimersAlzheimers 1http://clinicaloptions.com 2Ghafouri M, 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.
  10. 10. 10 Clinical Features of HIVClinical Features of HIV--AssociatedAssociated Neurocognitive Impairment (NI)Neurocognitive Impairment (NI) Cognition Memory loss Concentration Mental slowing Comprehension Behavior Apathy Depression Agitation, mania Motor Unsteady gait Poor coordination Tremor Clinical FeaturesClinical Features Functional ImpairmentFunctional Impairment •• Activities of daily livingActivities of daily living -- Medication adherenceMedication adherence -- Driving (2Driving (2--3 times as likely to fail tests)3 times as likely to fail tests) -- HHousehold financesousehold finances -- MMeal preparationeal preparation •• Vocational functioningVocational functioning -- 5 times more likely to complain of problems5 times more likely to complain of problems performing their jobsperforming their jobs -- Twice as likely to be unemployedTwice as likely to be unemployed Courtesy of S Letendre
  11. 11. 11 MCMD (n=49) NPI (n=109) NL (n=256) 1.0 0.8 0.6 0. 4 0.2 0.0 0 (n=414) 2 (n=274) 4 (n=66) 6 (n=17) Years From Baseline Evaluation 8 ProportionRemainingAlive Clinical FeaturesClinical Features Earlier MortalityEarlier Mortality Ellis R. Arch Neurol 1997;54:46-424 Clinical Features of HIVD in AdultsClinical Features of HIVD in Adults •• Clinical symptoms manifest in:Clinical symptoms manifest in: -- CognitionCognition -- BehaviorBehavior -- Motor skillsMotor skills •• Diagnosis of exclusion:Diagnosis of exclusion: -- Mass lesions, meningitis,Mass lesions, meningitis, drugs, psychological changesdrugs, psychological changes -- W/U: Bloods, radiology, CSFW/U: Bloods, radiology, CSF
  12. 12. 12 Neuroradiologic Features of HIVNeuroradiologic Features of HIV--DD •• Cerebral atrophyCerebral atrophy •• White matterWhite matter abnlabnl -- SymmetricalSymmetrical -- ConfluentConfluent •• Distinguish fromDistinguish from multifocal lesionsmultifocal lesions T2-weighted coronal (left) and axial (right) MRI Pathogenesis of HIV DementiaPathogenesis of HIV Dementia •• MultifactorialMultifactorial •• Direct vs. indirect mechanisms of HIVDirect vs. indirect mechanisms of HIV effect on braineffect on brain -- Direct: microglial HIV infection, CSF HIV viralDirect: microglial HIV infection, CSF HIV viral loadload -- Indirect: cytokines (TNFIndirect: cytokines (TNF--αα), cellular channels), cellular channels (Ca, NMDA)(Ca, NMDA)
  13. 13. 13 Possible Causes of NeurocognitivePossible Causes of Neurocognitive Impairment Related to HIVImpairment Related to HIV •• Ongoing HIV replication in theOngoing HIV replication in the brainbrain11 •• Discordant viral load in the plasmaDiscordant viral load in the plasma and CSFand CSF22 •• Different viral strains in brain andDifferent viral strains in brain and plasmaplasma33 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 inCSF Viral Load and Cognitive Function in Advanced HIV Infection: PreAdvanced HIV Infection: Pre--HAARTHAART Figure courtesy of Sacktor N HIVCSFlogcopies/mL McArthur 1997 Brew 1996 Ellis 1997 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 HIV+ Nondemented MC/MD Mild Mod Severe HIV Dementia MC/MD, minor cognitive/motor disorder
  14. 14. 14 CNS Lymph nodes Testes Peripheral blood Lymph nodes Importance of AttackingImportance of Attacking All HIV ReservoirsAll HIV Reservoirs Kidneys BloodBlood--Brain BarrierBrain Barrier
  15. 15. 15 Crossing the Blood Brain Barrier ECS: Extracellular space CSF: Cerebrospinal fluid Adapted from Groothius DR, et al. J Neurovirol 1997;3:387-400 Brain Brain Brain Brain C S F Transport into the brain Transport into the CSF CSF into plasma Diffusion E C S E C S Drug Penetration into CNSDrug Penetration into CNS •• Characteristics that affect drug penetrationCharacteristics that affect drug penetration into the CNSinto the CNS -- Molecular Weight / SizeMolecular Weight / Size -- LipophilicityLipophilicity -- Protein BindingProtein Binding -- pH / IonizationpH / Ionization -- Molecular pumps (e.g., PMolecular pumps (e.g., P--glycoprotein)glycoprotein) -- Integrity of the bloodIntegrity of the blood--brain barrierbrain barrier -- Intracellular transfer via traffickingIntracellular transfer via trafficking
  16. 16. 16 AntiAnti--HIV Drugs: CNS PenetrationHIV Drugs: CNS Penetration Fusion inhibitorsFusion inhibitors < 0.05< 0.05TenofovirTenofovir NANAEnfuvirtideEnfuvirtide Nucleotide RT InhibitorsNucleotide RT Inhibitors 0.30.3 -- 1.351.35 0.160.16 -- 0.970.97 0.30.3 -- 0.420.42 0.160.16 -- 0.190.19 0.110.11 0.090.09 -- 0.370.37 0.040.04 Zidovudine (AZT)Zidovudine (AZT) Stavudine (d4T)Stavudine (d4T) Abacavir (ABC)Abacavir (ABC) Didanosine (Didanosine (ddlddl)) Lamivudine (3TC)Lamivudine (3TC) Zalcitabine (ddC)Zalcitabine (ddC) EmtricitabineEmtricitabine CSF/PlasmaCSF/Plasma RatioRatio Nucleoside RTNucleoside RT InhibitorsInhibitors CSF/PlasmaCSF/Plasma RatioRatio NonnucleosideNonnucleoside RT InhibitorsRT Inhibitors 0.020.02 -- 0.760.76 < 0.05< 0.05 < 0.05< 0.05 < 0.05< 0.05 < 0.05< 0.05 < 0.05< 0.05 0.00210.0021--0.02260.0226 < 0.05< 0.05 IndinavirIndinavir SaquinavirSaquinavir NelfinavirNelfinavir RitonavirRitonavir AmprenavirAmprenavir LopinavirLopinavir AtazanavirAtazanavir FosamprenavirFosamprenavir Protease InhibitorsProtease Inhibitors 0.280.28 -- 0.450.45 0.020.02 0.010.01 Nevirapine (NVP)Nevirapine (NVP) DelavirdineDelavirdine EfavirenzEfavirenz 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 CNSValidation of the CNS PenetrationPenetration--EffectivenessEffectiveness Rank for QuantifyingRank for Quantifying Antiretroviral Penetration IntoAntiretroviral Penetration Into the Central Nervous Systemthe Central Nervous System Letendre S, MarquieLetendre S, Marquie--Beck J,Beck J, CapparelliCapparelli E, Best B,E, Best B, Clifford D, Collier C,Clifford D, Collier C, GelmanGelman B, McArthur J,B, McArthur J, McCutchanMcCutchan J, Morgello S, Simpson D, Grant I, Ellis RJ, Morgello S, Simpson D, Grant I, Ellis R ArchArch NeurolNeurol 2008;65:652008;65:65--70.70.
  17. 17. 17 Derivation of CPE ScoringDerivation of CPE Scoring SystemSystem •• Penetration of ARV drugs was characterized using aPenetration of ARV drugs was characterized using a hierarchical approach based on the best availablehierarchical approach based on the best available evidenceevidence -- Data on chemical characteristics, CSF pharmacology, andData on chemical characteristics, CSF pharmacology, and effectiveness in the CNS were reviewedeffectiveness in the CNS were reviewed -- References included ARV package inserts, publishedReferences included ARV package inserts, published manuscripts, and conference abstractsmanuscripts, and conference abstracts •• To estimateTo estimate neuroeffectivenessneuroeffectiveness,, ARVsARVs were assignedwere assigned an individual CPE score:an individual CPE score: 1 = High1 = High 0.5 = Intermediate0.5 = Intermediate 0 = Low0 = Low CHARTER Letendre S, et al. Arch Neurol 2008;65:65-70. CNS PenetrationCNS Penetration--Effectiveness ScoreEffectiveness Score 11 0.50.5 00 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 InhibitorsInhibitors CHARTER Letendre S, et al. 13th CROI 2006:Abstract 74 Relationship between CNS penetration and clinical improvement has not been established
  18. 18. 18 Study ResultsStudy Results -- Cont.Cont. •• Higher CPE scoresHigher CPE scores correlated with lowercorrelated with lower HIV RNA levels in CSFHIV RNA levels in CSF (r =(r = --0.10.122, p = 0.008), p = 0.008)11 •• After accounting forAfter accounting for plasma viral loads,plasma viral loads, eacheach unit decrease inunit decrease in CPE rank wasCPE rank was associated with a 2.43associated with a 2.43-- fold increase in thefold increase in the odds of havingodds of having detectable CSF VLdetectable CSF VL11 •• CPE scores continue toCPE scores continue to be updated as morebe updated as more data are generateddata are generated Letendre S, et al. Arch Neurol 2008;65:65-70. CHARTER Oct 2003 – Jan 2006 •• Larger number of CSFLarger number of CSF--penetrating drugspenetrating drugs was associated with greater declines ofwas associated with greater declines of HIV RNA in CSFHIV RNA in CSF •• This effect was not attributable toThis effect was not attributable to -- Greater number of ARVs per regimenGreater number of ARVs per regimen -- Potency of antiretroviral drugsPotency of antiretroviral drugs Ann Neurol 2004;56:416-423
  19. 19. 19 Neurocognitive ImprovementNeurocognitive Improvement & CSF Viral Load Suppression& CSF Viral Load Suppression Χ2 = 6.3; p = .01 ImprovementinGDS atFollow-up 1.0 - .5 - 0.0 - -.5 - Not Suppressed N=14 Suppressed N=17 Letendre et al. Ann Neurol 2004;56:416-423 Rational Therapeutics for HIV DementiaRational Therapeutics for HIV Dementia MAOMAO--B inhibition; antiB inhibition; anti--apoptoticapoptoticSelegilineSelegiline AntiAnti--inflammatory;inflammatory; neuroprotectiveneuroprotectiveMinocyclineMinocycline Platelet activating factor (PAF)Platelet activating factor (PAF) antagonistantagonist LexipafantLexipafant NMDA channel blockadeNMDA channel blockadeMemantineMemantine Calcium channel blockadeCalcium channel blockadeNimodipineNimodipine TNF inhibitionTNF inhibitionThalidomideThalidomide AntiretroviralAntiretroviralHAARTHAART Mechanism of ActionMechanism of ActionTherapyTherapy
  20. 20. 20 Antiretroviral Efficacy in HIVAntiretroviral Efficacy in HIV DementiaDementia •• AZT only agent with demonstrated efficacy inAZT only agent with demonstrated efficacy in HIVHIV--associated dementia in RCTassociated dementia in RCT •• ACTG 005ACTG 005 -- AZT 2000 mg/d, 1000 mg/d, placeboAZT 2000 mg/d, 1000 mg/d, placebo -- Greatest neuropsychological improvement in high dose armGreatest neuropsychological improvement in high dose arm -- No data on lower dose AZTNo data on lower dose AZT -- Most otherMost other ARVsARVs not studiednot studied -- Methodologic challenges in HAART eraMethodologic challenges in HAART era •• AbacavirAbacavir vsvs placebo/optimized background ARVplacebo/optimized background ARV -- Negative forNegative for neuropsychneuropsych. improvement. improvement -- ↓↓CSF HIV VLCSF 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. Source: DHHS Guidelines. Adverse Effects WithAdverse Effects With Antiretroviral ClassesAntiretroviral Classes NRTIsNRTIs •• Peripheral neuropathyPeripheral neuropathy (ddC, d4T, ddI)(ddC, d4T, ddI) •• GI intolerance (AZT, ddI)GI intolerance (AZT, ddI) •• Anemia/bone marrowAnemia/bone marrow suppression (AZT)suppression (AZT) •• Pancreatitis (ddI, ddC)Pancreatitis (ddI, ddC) •• Oral ulcers (ddC)Oral ulcers (ddC) •• Myopathy (AZT, d4T)Myopathy (AZT, d4T) •• Lactic acidosis with hepaticLactic acidosis with hepatic steatosis (rare)steatosis (rare) NNRTIsNNRTIs •• Rash (EFV, DLV, NVP)Rash (EFV, DLV, NVP) •• Elevated transaminaseElevated transaminase levelslevels •• CNS effects (EFV)CNS effects (EFV) PIsPIs •• Metabolic abnormalitiesMetabolic abnormalities •• GI intoleranceGI intolerance •• Elevated transaminaseElevated transaminase levelslevels •• Nephrolithiasis (IDV)Nephrolithiasis (IDV)
  21. 21. 21 Neuropathy TypesNeuropathy Types Distal Polyneuropathy Mononeuropathy Mononeuropathy Multiplex Brachial Plexopathy Inflammatory Demyelinating Polyneuropathy Distal Polyneuropathy:Distal Polyneuropathy: SymptomsSymptoms •• Numbness/tingling/burning pain in the feetNumbness/tingling/burning pain in the feet •• Sensory complaints typically symmetricalSensory complaints typically symmetrical •• Weakness unusual until DSP advancedWeakness unusual until DSP advanced •• Frequently misdiagnosed (ie, ACTG 175)Frequently misdiagnosed (ie, ACTG 175) •• Affects quality of life and ARV adherenceAffects quality of life and ARV adherence
  22. 22. 22 Distal Polyneuropathy:Distal Polyneuropathy: Clinical SignsClinical Signs •• Depressed ankle reflexes relative to kneesDepressed ankle reflexes relative to knees (caution: combined CNS and PNS)(caution: combined CNS and PNS) •• Abnormal vibration in feetAbnormal vibration in feet •• Abnormal pinprick and cold (stockingAbnormal pinprick and cold (stocking-- glove distribution)glove distribution) •• Muscle strength (objective) usually normalMuscle strength (objective) usually normal Simpson. AIDS and the Nervous System. 2nd ed. Raven Press;1996:189. CHARTER: Peripheral NeuropathyCHARTER: Peripheral Neuropathy 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 n = 658 n = 452 n = 429
  23. 23. 23 Quality of Life and HIVQuality of Life and HIV-- Associated Neuropathic PainAssociated Neuropathic Pain Ellis R, et al. CHARTER, 2009 (unpubl) CHARTER: PN Risk FactorsCHARTER: PN Risk Factors Ellis R, et al. CROI 2009
  24. 24. 24 Drugs Associated With PNDrugs Associated With PN •• AntibacterialsAntibacterials -- dapsonedapsone -- ethionamideethionamide -- isoniazidisoniazid (especially if(especially if administered without pyridoxine)administered without pyridoxine) -- metronidazolemetronidazole -- streptomycinstreptomycin •• AntineoplasticsAntineoplastics -- vinblastinevinblastine sulfatesulfate -- vincristinevincristine sulfatesulfate -- cisplatincisplatin •• ARVsARVs -- d4Td4T -- ddCddC -- ddIddI -- PIs ?PIs ? •• Other agentsOther agents -- phenytoinphenytoin -- thalidomidethalidomide Adapted from Moyle. Drug Safety. 1998;Dec 19(6):481.
  25. 25. 25 Nucleoside AnalogueNucleoside Analogue--Related DSPRelated DSP •• ClinClin indistinguishable fromindistinguishable from DSP 2DSP 200 HIV (often overlap,HIV (often overlap, espesp withwith ↓↓ CD4)CD4) •• Pain usually resolvesPain usually resolves within 8 wks after drugwithin 8 wks after drug withdrawalwithdrawal •• PN signs may persist forPN signs may persist for >> 4 months after drug4 months after drug withdrawalwithdrawal •• ↓↓ use in US/Europe;use in US/Europe; common in developingcommon in developing worldworld •• Associated with:Associated with: -- Didanosine (Didanosine (ddIddI)) -- Stavudine (d4T)Stavudine (d4T) -- Zalcitabine (Zalcitabine (ddCddC)) Mount SinaiMount Sinai NeuroNeuro--AIDS Research ProgramAIDS Research Program NeurologyNeurology David M. Simpson, MDDavid M. Simpson, MD Jessica RobinsonJessica Robinson--Papp, MDPapp, MD Kathryn Elliott, MDKathryn Elliott, MD NeuropsychologyNeuropsychology David Dorfman, PhDDavid Dorfman, PhD Elizabeth Ryan, PhDElizabeth Ryan, PhD Neuropathology/Brain BankNeuropathology/Brain Bank Susan Morgello, MDSusan Morgello, MD Letty Mintz, NPLetty Mintz, NP NeuroradiologyNeuroradiology CheukCheuk Tang, PhDTang, PhD NeuroNeuro--AIDS Research TeamAIDS Research Team Mary Catherine George, CoordinatorMary Catherine George, Coordinator AIDS Center ClinicAIDS Center Clinic Fran Wallach, MDFran Wallach, MD NeuroNeuro--AIDS Research ConsortiumAIDS Research Consortium David Clifford, MD (PI)David Clifford, MD (PI) Mary GouldMary Gould

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