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