hiv neurology - networkhiv cogni
TRANSCRIPT
CAB59:HIVandneurocogni5veimpairment
Friday8thJuly2016
HIVNeurology
ConsultantNeurologist,Chelsea&WestminsterHospital&ImperialCollegeNHSTrust(CharingCrossHospital),London
Dr Nick Davies
Aimsoftalk
• Pre-ARTNeurology
• Post-ART• IRIS• Cogni<veImpairment:HAND;drugtoxicity
• Majoromissions• PeripheralNeuropathy• Stroke(MylesConnor)
Introduc<on
• WhatistheHumanImmunodeficiencyVirus?• Retrovirus(ssRNA);possessesreversetranscriptase• Infects:
• CD4Thelpercells• Macrophages• Dendri<ccells• Microglia
• Lymphotropic&Neurotropic• M-tropic(CCR5);T-tropic(CXCR4)• HIV-1&HIV-2• HIV-1clades(AtoE)–BcommonestUS&Europe
NeurologicalComplica<onsofImmunosuppression
Davies, N. & Thwaites, G. Infections of the nervous system. Pract Neurol 11, 121-131 (2011).
An<-retroviralTherapy
Source: Yin et al. HIV in the UK 2014 Report: data to end of 2013. Nov 2014; PHE, London
Sites of Action of Current Antiretroviral Drug Classes
Source of image: http://en.wikipedia.org/wiki/File:HIV-drug-classes.svg
ImmuneRecons<tu<onInflammatorySyndrome(IRIS)
Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).
• Definition: “a paradoxical deterioration in clinical status attributable
to the recovery of the immune system during HAART.”
1 Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).
IRIS:Classifica<on1
Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).
IRIS:Classifica<on1
Simultaneous = Unmasked Delayed = Paradoxical
14/8/15 04/9/15
14/8/15 04/9/15 06/10/15
IRIS:Classifica<on1
1Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010). 2 Miller, R.F., Isaacson, P.G., Hall-Craggs, M., et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 108, 17-23 (2004).
CD8 Encephalitis2
Autoimmune Conditions: • GBS • SLE • Grave’s disease
Without HIVE
With HIVE
HIVCogni<veImpairmentpre-cART
Navia et al (Price) The AIDS Dementia Complex Annals of Neurology 19: 517-524 McArthur, J.C., Brew, B.J. & Nath, A. Neurological complications of HIV infection. Lancet Neurol. 4, 543-555 (2005).
Manji (2013) HIV, Dementia, & ARVs: 30 years of an epidemic JNNP 84: 1126-37
• HIVdemen<a;HIVencephalopathy;AIDSdemen<acomplex• Life<meprevalence15%• 30%terminalAIDS• Subcor<caldemen<a–triad:
• CogniHon;• MotorfuncHon;• Behaviour
HIVCogni<veImpairment:ArrivalofART• HIVDemen<anowonlyseenbecause:
– Burnt-out–damagesustainedpriortoART– LatepresentaHon– Non-adherencetoARVs– Rarelyinpa<entswhereCNS&systemicinfec<onfollownon-parallelcourses
• Long-termnon-progressors• OnART;differentresistancepa`erns “Compartmentphenomenon”
“SymptomaHcCSFescape”» Canbefulminantwithseizures
Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25, 561-575 (2011).
HIVCogni<veImpairment:cART-era
• Pa<entswithsystemiccontrolofHIVandhighCD4cellcountscomplainingof:– Mildmemoryproblems– Slowness– DifficulHesinconcentraHon– DifficulHesinplanning– DifficulHesinmulHtasking
• Pa<entswithneurodegenera<vedisease– ARVs
Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25, 561-575 (2011).
Anewterminology:HAND
1Antinori, A., et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69, 1789-1799 (2007). 2Gisslen, M., Price, R.W. & Nilsson, S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 11, 356 (2011).
Frascati Criteria1
Nb If criterion has Normal distribution 2.3% fall >2SD; 15.9% >1 SD2
HIVCogni<veImpairment:ART-era• CHARTERstudy(CNSHIVARVTherapyEffectsResearch)
• 52%Cogni<veimpairment(n=1555)– 33%Asymptoma<cNeurocogImpairment– 12%MildNeurocogDisorder– 2%HAD
• HigherincidenceCIinthosewithmorecomorbi<es
– 40%;59%;83%
Heaton, R.K., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75, 2087-2096 (2010).
HIVCogni<veImpairment:cART-era• Whataboutconfounds?1
– Currentdruguse– Hepa<<sCco-infec<on– Depression– “Burntout”CNSdisease
• HANDincidence– Virologicallysuppressed:18%– Non-virologicallysuppressed:24%
• UKstudyinsuppressedasymptoma<c:19%2
1Cysique, L.A. & Brew, B.J. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol 17, 176-183 (2011). 2Garvey, L., Surendrakumar, V. & Winston, A. Low Rates of Neurocognitive Impairment Are Observed in Neuro-Asymptomatic HIV-Infected Subjects on Effective Antiretroviral Therapy. HIV Clin Trials 12, 333-338 (2011).
STUDIES TYPICALLY CROSSECTIONAL NOT LONGITUDINAL
SummaryofRevised(2010)CNSPenetra<on-Effec<veness(CPE)RankingofARVs
4 3 2 1 NRTIs AZT ABC ddI TDF
FTC 3TC dDI
d4T NNRTIs NVP DLV ETV
EVF PIs
IDV/r DRV/r ATV/r NFV
FPV/r ATV RTV IDV FPV SQV/r
LPV/r SQV
Fusion/Entry Inhibitors
MVC
Integrase inhibitors
RAL ENF
Letendre, S et al. 17th CROI 2010. Abstract 430.
HIVCogni<veImpairment:cART-era• CPEEvidence:
– Smurzynskietal• Cross-sec<onalstudy;VL<50• HigherCPEscoreinthoseon>3ARVsbe`erthanlowerCPEscore
– Marraetal• DichotomisedCPE(old)>2or<2• HigherCPEassociatedwithgreaterCSFsuppression
• ThosewithimpairedneuropsychatentrydidworsewithhigherCPE
1Smurzynski et al Effects of CNS ARV penetration of cognitive in ALLRT AIDS 2011; 25: 357-365 2Marra, C.M., et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23, 1359-1366 (2009)
HIVCogni<veImpairment:cART-era
• ProblemswithCPE:• Categorical not ordinal • Methodology not transparent:
• Hard to independently validate • Weighting for each criterion?
• ARV-ARV interactions not considered • No accounting for the effect of an impaired BBB • Anatomy: CSF not “a liquid brain biopsy” • Efficacy in brain cells not assessed specifically • Toxicity (CNS/CVS) not considered
Slide from Dr Anton Pozniak; Consultant Physician, C&W.
HIVCogni<veImpairment:cART-era
• RandomisedcontroltrialhighCPEvslowCPE– No neuropsychological benefit at 16 weeks
– Higher detectable plasma HIV viral load in high CPE group (i.e. treatment failure)
Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, Clifford DB, Best BM, May S, Umlauf A, Cherner M, Sanders C, Ballard C, Simpson DM, Jay C, McCutchan JA. Randomized Trial of Central Nervous System-Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder. Clin Infect Dis. 2014 Jan 14.
HIVCogni<veImpairment:Toxicity
• ACTG5170Mul<centrestudyofdiscon<nua<onofARVsinthosewithCD4>350
• MixtureofARVs
Robertson, K.R., et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74, 1260-1266 (2010).
Winston, A., et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med (2011). EFAVIRENZ
An Approach to Assessment & Treatment of Cognitive Impairment in ART-treated HIV patients.
From: Davies & Brew (2014) Clinical Aspects of HIV-Related Neurocognitive Disorders In: HIV & Psychiatry, Editors: Joska, Stein & Grant. DOI: 10.1002/9781118339503.ch3
HIVCogni<veImpairment:cART-era
• Whatwillbetheeffectoflong-termARVexposuretotheCNS?– Mitochondria;proteosomes
• Whatwillbetheeffectofvasculardysfunc<on?• Whatwillbetheeffectofdyslipidaemia?