4th Annual Workshop on

Global HIV Clinical Pharmacology Capacity Building and

Implementation Research

Stefano Bonora, MD, University of Torino, Italy

Integrating HIV pharmacogenomics and pharmacology in

implementation research

Ospedale Amedeo di Savoia

521T>C

SLCO1B1

521T>C

Lopinavir

Hartkoorn et al 2010Kohlrausch et al. 2010

LopinavirCYP3A4

SLCO1B1

SLCO1B1 521 CC genotype

Hyperbilirubinaemia is a frequent complication of atazanavir-containing antiretroviral therapy and its severity is related to UDP-glucuronosyl transferase (UGT) 1A1*28 polymorphism

• 51 HIV-1-infected patients on boosted atazanavir were prospectively enrolled in the study. 25 patients with a UGT1A1*28 allele switched to 400 mg of unboosted atazanavir.

• 78% TDF-containing backbone

At 48 weeks, 24/25 switching patients presented undetectable HIV RNA with no significant change in CD4 T cell count (1 patient resumed ATV/R)

ABCB1

ABCCs

SLCO1B1

CYP3A4

Atazanavir disposition

PXR

CYP3A

DrugATP ADP + Pi

ABCB1

DrugATP ADP + Pi

OATP1B1

Pregnane X receptor

Atazanavir pharmacogenetics

Poli-locus approach considering 3 SNPs:- ABCB1 3435C>T- SLCO1B1 521T>C- PXR 63396C>T

Working hypothesis

PG-guided dosing of unboosted ATV (200 BID in case of unfavourable genetic score, standard 400 QD in case of favourable genetic score) could lead to optimization of ATV exposure co-administered with TDF

2-3

80 patients enrolled under successful ATV/r 300/100 + TDF/FTC

1:1 Randomization

Control Group (n = 40) switching to ATV 400 mg QD

PG-guided Group (n = 40) switching to ATV 400 mg QD

or 200 mg bid

PG Score assignment

2 - 3 0 - 1

ATV 400 mg QD

ATV 200 mg bid

ATV 400 mg QD

% Pts. [ATV] > 150 ng/mL % Pts. [ATV] > 150 ng/mL

Primary endpoint: 12 weeks ---------------------------------------------------------------------------------------

2ndary endpoints: 48 weeks ---------------------------------------------------------------------------------------

% Pts. HIV-RNA< 50 copies/mL % Pts. HIV-RNA< 50 copies/mL

Bilirubin & lipid parameters vs BLBilirubin & lipid parameters vs BL

Example of PG interpretation

Score 1 = 200 mg BID dosing

CROI 2013

D’Avolio A et al. J Pharm and Biom analysis 2010

Influence of CYP2B6 and ABCB1 SNPs on Nevirapine Plasma Concentrations in Burundese HIV-positive Patients Using Dried Sample Spot Devices

A Calcagno, A D’Avolio, M Simiele,J Cusato, R Rostagno, V Libanore, L Baietto, M Siccardi, S Bonora and G Di Perri.

• A cross-sectional analysis in 204 HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, Africa.

• After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature.

• Single nucleotide polymorphisms in CYP2B6 and ABCB1 (using a real time PCR technique) were analysed and associated to nevirapine plasma trough levels.

BJCP 2011

Calcagno A, et al. BJCP 2011

Nevirapine Concentrations and CYP2B6 516G>T

PK and PG with DSSD

NevirapineCYP3A4CYP2B6

Schipani et al 2011

200 mg bid

400 mg qid

Darunavir CSF penetration QD vs. BID

41 patients on DRV/r containing regimens26 on DRV/r (800/100 Once-Daily) and 15 on DRV/r (600/100 Twice-Daily)

Calcagno A, Yilmaz A et al. AIDS 2012

Pharmacogenetics and PK - DRV

Calcagno A, Yilmaz A et al. AIDS 2012

Conclusion

Which contibution from pharmacogenetics coupled with modern pharmacological tools for modern HAART?

-Toxicity (e.g. ATV)

-Dose personalisation/reduction

-Penetration in reservoirs

Acknowledgments

TORINO:Stefano Bonora

Antonio D’Avolio

Andrea Calcagno

Valeria Ghisetti

Mauro Sciandra

Marco Siccardi

Daniel Gonzalez de Requena

Lorena Baietto

Cristina Tettoni

Sabrina Audagnotto

Letizia Marinaro

Margherita Bracchi

Laura Trentini

Marco Simiele

Giancarlo Orofino

LONDON:Marta Boffito

Anton Pozniak

ROMA:Andrea Antinori

Emanuele Nicastri

Giuseppe Ippolito

LIVERPOOL:David Back

Saye Khoo

Andy Owen

Anna Lucchini

Filippo Lipani

Francesco G. De Rosa

Roberto Bertucci

Agostino Maiello

Pino Cariti

Bernardino Salassa

Magister Sinicco

MILANO:

Massimo GalliStefano Rusconi