Le tossicità d'organo in HIV Cervello: overview P. Bonfanti 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

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

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

Disturbi Neurocognitivi HIV-Associati (HIV-Associated Neurocognitive Disturbances, HAND) Deficit Neurocognitivo Asintomatico (Asymptomatic Neurocognitive Impairment, ANI) Demenza HIV-Associata (HIV-Associated Dementia, HAD) (compromissione moderata-grave) Disturbo Neurocognitivo Lieve (Mild Neurocognitive Disorder, MND) (compromissione lieve) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69: 1789-99

Neurocognitive Impairment in the Pre-HAART and Post-HAART Eras HAD MND ANI NN 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

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

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

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

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

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

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

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

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

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

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

Short-term kinetics of virological response in CSF and plasma of ART-treated patients Parallel CSF/plasma response Slower CSF response 6 5 4 Log10 HIV-1 RNA copies/ml 3 6 5 4 3 CSF Plasma Cinque et al., ARHR 2001

CNS Penetration-Effectiveness Ranks: Standard of evidence Red = Drug Characteristics Only, Yellow = PK Data, Green = PD Data   4 3 2 1 NRTIs Zidovudine Abacavir Lamivudine Didanosine Emtricitabine Stavudine Tenofovir Zalcitabine NNRTIs Nevirapine Delavirdine Etravirine Efavirenz PIs Indinavir-r Darunavir-r Atazanavir Nelfinavir Fosamprenavir-r Atazanavir-r Ritonavir Indinavir Fosamprenavir Saquinavir Lopinavir-r Saquinavir-r Tipranavir-r Entry Inhs  Vicriviroc Maraviroc Enfuvirtide Integrase Inhs Raltegravir Letendre et al, CROI 2010

CNS Penetration-Effectiveness Ranks CPE 2008 Ranks CPE 2010 Ranks Letendre S, et al. Arch Neurol 2008; 65:65-70 Letendre S, CROI 2010

Linee Guida Italiane

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