Workshop 2 ldquoIl paziente con problematicheneuropsichiatriche e neurocognitiverdquoModeratori E Sagnelli F SuterDiscussant Fv Schloesser

Caratteristiche farmacologicheS Bonora

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

Estimation of Penetration-Effectiveness in CNSBetter Penetration = Lower CSF Viral Loads

Letendre S et al 17th CROI 2010 Abstract 172

FAQs

bull Il CPE score ha limiti interpretativi

Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv

Raltegravir concentrations in blood (red) and CSF (blue)

IC50

Croteau et al AAC December 2010

IC50 32 ngml

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

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

Estimation of Penetration-Effectiveness in CNSBetter Penetration = Lower CSF Viral Loads

Letendre S et al 17th CROI 2010 Abstract 172

FAQs

bull Il CPE score ha limiti interpretativi

Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv

Raltegravir concentrations in blood (red) and CSF (blue)

IC50

Croteau et al AAC December 2010

IC50 32 ngml

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Estimation of Penetration-Effectiveness in CNSBetter Penetration = Lower CSF Viral Loads

Letendre S et al 17th CROI 2010 Abstract 172

FAQs

bull Il CPE score ha limiti interpretativi

Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv

Raltegravir concentrations in blood (red) and CSF (blue)

IC50

Croteau et al AAC December 2010

IC50 32 ngml

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

FAQs

bull Il CPE score ha limiti interpretativi

Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv

Raltegravir concentrations in blood (red) and CSF (blue)

IC50

Croteau et al AAC December 2010

IC50 32 ngml

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Raltegravir concentrations in CSF are in the therapeutic range for inhibition of wild-type hiv

Raltegravir concentrations in blood (red) and CSF (blue)

IC50

Croteau et al AAC December 2010

IC50 32 ngml

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Plasma and CSF raltegravir concentrations

CSF raltegravir concentrations- median 184 ngml- range 20 ndash 126- CSFplasma ratio 003

Yilmaz et al PloS One 2009 Sep 14(9)e6877

IC95 9 ndash 15 ngml1

1Iwamoto et al Clin Pharmacol Ther 2008 83293-299

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

CAVEATS of measuring CSF drug concentration

In the majority of cases the ISF concentration is lower than CSF concentration A downward CSF-to-ISF concentration gradient is particularly a concern when efflux transport at the BBB is likely (eg for candidate molecules that are substrates for P-glycoprotein mediated efflux)

The presence of drug in CSF only reflects extracellular drug availability and does not reveal access of drugs to the intracellular sites within the brain parenchyma

Macrophages as the main cells infected by HIV in the brain need to be considered in the evaluation of the potential efficacy of antivirals in CNS the efficacy of antivirals in such cells is not superimposable to that in lymphocytes

Shen Adv Drug Deliver rev 2004Perno CF et al Antiviral Research 2006

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazienti

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Population Pharmacokinetics in CSFProtease Inhibitors

Capparelli et al AIDS 2005 19949ndash952

Extent of CSF penetration was 023 of plasma concentrations

IC50 = 2 ngmL

Best et al AIDS 2009 23 83-87

Extent of CSF penetration was 1 of plasma concentrations

Lopinavir Atazanavir

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Etravirina NVP 400 QD Darunavirr 800100 QD Maraviroc 150 QD ATV unboosted Farmaci concomitanti EFV 600 RGV 800 bid con RIF

Dati PK mancanti o incompleti

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Virologic Failure in the CNS Presenting with Neurologic Symptoms

bull 11 patients with new neurological symptoms on ART

ndash Median CSF viral load 880 copiesmL ndash Median duration of ART 13 months

bull CSF-Plasma discordancendash CSF HIV RNA gt 200 copiesmL while

plasma levels were lt 50 copiesmL (n = 8) or

ndash CSF HIV RNA level that was 1 log gt plasma vira load (n = 3)

bull Resistance mutations detected in 7 of 8 CSF specimensndash ART modified based on resistance

and CPEbull All patients clinically improved

with reduction of HIV in CSFCanestri et al Clinical Infectious Diseases 2010 50773ndash778

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

FAQs

bull Il CPE score ha limiti interpretativibull Il CPE score egrave valido per tutti i pazientibull Cosa posso fare per ottimizzare lrsquoattivitagrave

della HAART nel SNC

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

How could effectiveness of ART in CNS be optimised

- Adequate use of the CPE score (which role gt 8)

- TDM on CSF

- Increase of ARV dosing

- Pharmacogeneticsmodulation of transporter Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET Kuntner C et al Eur J Nucl Med Mol Imaging 2010

Antiretroviral Pharmacology in the Nervous System

bull Measure drug concentrations in CSF for all antiretroviralsndash Adequate sample size to accurately model

pharmacokineticsndash Prospect of new pharmacokinetic enhancers

bull Determine the relationship between CSF and intracellular and extracellular brain concentrationsndash Human Brain biopsies Autopsy studies Specialized

imagingndash Animal Ante-mortem CSF vs post-mortem brain tissue

bull Determine the correlates of inter-individual variabilityndash BBB permeability DMD gene variability Chronic Co-

infections Aging Body weight Adherencendash Adequate sample size to accurately estimate inter-

individual variability

Clinica Universitaria di Malattie Infettive Universitagrave di Torino

Laboratorio di Farmacologica clinica

Laboratorio di Biologia molecolare

Ringraziamenti

Prof Giovanni Di PerriMariaCristina TettoniLaura TrentiniLetizia MarinaroMargherita BracchiMarino BonassoBernardino SalassaCaterina BramatoIlaria Motta

Divisione Ospedaliera di Mal Inf TO

Giancarlo OrofinoFrancesca Gaiottino

Antonio DrsquoAvolioMarco SiccardiMauro SciandraLorena BaiettoMarco Simiele

Valeria GhisettiTiziano AlliceMaria Grazia Milia

Neurologia Ospedale Maria Vittoria

Daniele ImperialeGiulia GuastamacchiaLucia Appendino

Neuropsicologia Ospedale Maria Vittoria TO

Daniela Vai

Neuroradiologia Ospedale SGiovanni Bosco TO

Paolo VaudanoPaolo BusolliAdolfo Prochet

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Clinica Universitaria di Malattie Infettive Universitagrave di Torino

Laboratorio di Farmacologica clinica

Laboratorio di Biologia molecolare

Ringraziamenti

Prof Giovanni Di PerriMariaCristina TettoniLaura TrentiniLetizia MarinaroMargherita BracchiMarino BonassoBernardino SalassaCaterina BramatoIlaria Motta

Divisione Ospedaliera di Mal Inf TO

Giancarlo OrofinoFrancesca Gaiottino

Antonio DrsquoAvolioMarco SiccardiMauro SciandraLorena BaiettoMarco Simiele

Valeria GhisettiTiziano AlliceMaria Grazia Milia

Neurologia Ospedale Maria Vittoria

Daniele ImperialeGiulia GuastamacchiaLucia Appendino

Neuropsicologia Ospedale Maria Vittoria TO

Daniela Vai

Neuroradiologia Ospedale SGiovanni Bosco TO

Paolo VaudanoPaolo BusolliAdolfo Prochet

• Slide 1
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