tavola rotonda le tossicità d'organo in hiv cervello: overview p. bonfanti struttura complessa...
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Tavola RotondaLe tossicità d'organo in HIV
Cervello: overviewP. BonfantiStruttura Complessa di Malattie Infettive, Ospedale “Alessandro Manzoni”, Lecco
DiscussioneConduce: R. VisintiniServizio 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
Traditional Risk Factors
HIV Inflammation
HIV Inflammation
Drug Toxicities
Drug Toxicities
Disturbi Neurocognitivi HIV-Associati (HIV-Associated Neurocognitive Disturbances, HAND)
Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69: 1789-99
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)
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
Non Infectious Co-Morbidities: Pathogenesis
Traditional Risk Factors
Traditional Risk Factors
HIV Inflammation
HIV Inflammation
Drug Toxicities
Drug Toxicities
HIV brain infection and neurocognitive dysfunction
4. Macrophageactivation
5. Neuronaldysfunction
1. SystemicHIV Replication
Soluble
factors
3. HIV replication in CNS macrophages
BBB2. HIV replication in trafficking
mononuclear cells
CSF markers of HIV replicationand immune activation
Hagberg L. et al., 2010
Non Infectious Co-Morbidities: Pathogenesis
Traditional Risk Factors
Traditional Risk Factors
HIV Inflammation
HIV Inflammation
Drug Toxicities
Drug Toxicities
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
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
Traditional Risk Factors
HIV Inflammation
HIV Inflammation
Drug Toxicities
Drug Toxicities
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)
0
12
3
45
6
7
89
10
cefalea capogiro insonnia sognialterati
incubinotturni
almeno unsintomo
SNC
Perc
entu
ale d
i paz
ienti
Coorte raltegravir Coorte darunavir
α β β β β
γ
N°=363
Progetto SCOLTASicurezza e tollerabilità di raltegravir nella pratica clinica: focus sui sintomi a carico del sistema nervoso centrale
Madeddu G et al, SIMIT 2010
α p=0,08β p=n.s.γp=0,05
CSF
Plasma
Mellgren A et al., Antiviral Ther 2005
HIV, cART and the CSF
Short-term kinetics of virological response in CSF and plasma of ART-treated patients
3
4
5
Log
10 H
IV-1
RN
A c
opie
s/m
l
3
4
5
6
6
Parallel CSF/plasma response
Slower CSF response
CSFPlasma
Cinque et al., ARHR 2001
CNS Penetration-Effectiveness Ranks: Standard of evidence
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
Red = Drug Characteristics Only, Yellow = PK Data, Green = PD Data
Letendre et al, CROI 2010
CNS Penetration-Effectiveness Ranks
CPE 2008 Ranks CPE 2010 Ranks
p = 0.008n = 467
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