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Tavola Rotonda Le tossicità d'organo in HIV Cervello: overview P. Bonfanti Struttura Complessa di Malattie Infettive, Ospedale Alessandro Manzoni, Lecco.

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Presentazione sul tema: "Tavola Rotonda Le tossicità d'organo in HIV Cervello: overview P. Bonfanti Struttura Complessa di Malattie Infettive, Ospedale Alessandro Manzoni, Lecco."— Transcript della presentazione:

1 Tavola Rotonda Le tossicità d'organo in HIV Cervello: overview P. Bonfanti Struttura Complessa di Malattie Infettive, Ospedale Alessandro Manzoni, Lecco Discussione Conduce: R. Visintini Servizio di Psicologia clinica e Psicoterapia, IRCCS Centro S. Raffaele del Monte Tabor, Università Vita-Salute, Milano

2 The Copernican Revolution Long-term Adverse Reactions Non Infectious Co-Morbidities

3 Non Infectious Co-Morbidities: Pathogenesis Traditional Risk Factors HIV Inflammation Drug Toxicities

4 Disturbi Neurocognitivi HIV-Associati (HIV-Associated Neurocognitive Disturbances, HAND) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69: Demenza HIV-Associata (HIV-Associated Dementia, HAD) (compromissione moderata-grave) Disturbo Neurocognitivo Lieve (Mild Neurocognitive Disorder, MND) (compromissione lieve) Deficit Neurocognitivo Asintomatico (Asymptomatic Neurocognitive Impairment, ANI)

5 Neurocognitive Impairment in the Pre- HAART and Post-HAART Eras Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant et al., CROI 2009 Incidence but not prevalence of HIV-associated neurocognitive disorders (HAND) has declined with HAART HAD MND ANI NN

6 Non Infectious Co-Morbidities: Pathogenesis Traditional Risk Factors HIV Inflammation Drug Toxicities

7 HIV brain infection and neurocognitive dysfunction 4. Macrophage activation 5. Neuronal dysfunction 1. Systemic HIV Replication Soluble factors 3. HIV replication in CNS macrophages BBB 2. HIV replication in trafficking mononuclear cells

8 CSF markers of HIV replication and immune activation Hagberg L. et al., 2010

9 Non Infectious Co-Morbidities: Pathogenesis Traditional Risk Factors HIV Inflammation Drug Toxicities

10 Risk factors and comomorbidities associated with HAND Risk Factors CD4 nadir Aging Microbial traslocation Anaemia Host genetic factors Viral genetic factors Comorbidities HCV Substance or alcohol abuse CVD disease and metabolic disorder Depression and other psyschiatric conditions Schouten J et al, AIDS 2011

11 Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons Wright EJ, et al. Neurology 2010

12 Non Infectious Co-Morbidities: Pathogenesis Traditional Risk Factors HIV Inflammation Drug Toxicities

13 Haas AIDS 2004, Haas JID 2005, Rotger Pharmacogenetics and Genomics 2005, Rotger CROI 2006, Rotger Clin Pharm Ther 2007 In < ½ of these patients: EFV therapy interruption or dose reduction because of toxicity Serum Efavirenz levels are associated with CYP2B6 516 G>T (the 2B6*6/*6 allele)

14 αββββ γ N°=363 Progetto SCOLTA Sicurezza e tollerabilità di raltegravir nella pratica clinica: focus sui sintomi a carico del sistema nervoso centrale Madeddu G et al, SIMIT 2010 α p=0,08 β p=n.s. γ p=0,05

15 CSF Plasma Mellgren A et al., Antiviral Ther 2005 HIV, cART and the CSF

16 Short-term kinetics of virological response in CSF and plasma of ART-treated patients Log10 HIV-1 RNA copies/ml Parallel CSF/plasma response Slower CSF response CSF Plasma Cinque et al., ARHR 2001

17 CNS Penetration-Effectiveness Ranks: Standard of evidence 4321 NRTIs Zidovudine AbacavirLamivudineDidanosine EmtricitabineStavudineTenofovir Zalcitabine NNRTIsNevirapineDelavirdineEtravirine Efavirenz PIsIndinavir-rDarunavir-rAtazanavirNelfinavir Fosamprenavir -r Atazanavir-rRitonavir Indinavir Fosamprena vir Saquinavir Lopinavir-rSaquinavir-r Tipranavir-r Entry Inhs Vicriviroc Maraviroc Enfuvirtide Integrase Inhs Raltegravir Red = Drug Characteristics Only, Yellow = PK Data, Green = PD Data Letendre et al, CROI 2010

18 CNS Penetration-Effectiveness Ranks CPE 2008 RanksCPE 2010 Ranks p = n = 467 Letendre S, et al. Arch Neurol 2008; 65:65-70 Letendre S, CROI 2010

19 Linee Guida Italiane

20 Spunti di discussione Come migliorare la diagnosi dei Disturbi Neurocognitivi HIV-associati? –Quali batterie di test neuropsicologici? –Rachicentesi: quali i pazienti candidati? Quali biomarkers? Diagnosi differenziale con disturbi neuropsichiatrici Valutazione delle co-morbidità –HCV –Danno vascolare Ottimizzazione della HAART


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