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
Lopinavir
521T>C
521T>C
Lopinavir
CYP3A4
SLCO1B1
Kohlrausch et al. 2010
Hartkoorn et al 2010
SLCO1B1 521 CC genotype
 Hyperbilirubinaemia is a
frequent complication
of atazanavir-containing
antiretroviral therapy
and its severity is
related to UDPglucuronosyl 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)
Atazanavir disposition
CYP3A4
Pregnane X receptor
CYP3A
PXR
ATP
Drug
ADP + Pi
ABCB1
ATP
Drug
ADP + Pi
OATP1B1
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
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
ATV
400 mg QD
22-3
-3
0-1
ATV
400 mg QD
ATV
200 mg bid
Primary endpoint: 12 weeks --------------------------------------------------------------------------------------% Pts. [ATV] > 150 ng/mL
% Pts. [ATV] > 150 ng/mL
2ndary endpoints: 48 weeks --------------------------------------------------------------------------------------% Pts. HIV-RNA< 50 copies/mL
% Pts. HIV-RNA< 50 copies/mL
Bilirubin & lipid parameters vs BL
Bilirubin & 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
Nevirapine Concentrations and CYP2B6 516G>T
PK and PG with DSSD
Calcagno A, et al. BJCP 2011
Nevirapine
CYP3A4
CYP2B6
200 mg bid
400 mg qid
Schipani et al 2011
Darunavir CSF penetration QD vs. BID
41 patients on DRV/r containing regimens
26 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
Darunavir CSF concentration (ng/ml)
150
OD
TD
100
50
2.75 ng/ml
0
AA
AG
AA
AG
OATP1A2 38 A>G
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
Anna Lucchini
Antonio D’Avolio
Filippo Lipani
Andrea Calcagno
Francesco G. De Rosa
Valeria Ghisetti
Roberto Bertucci
Mauro Sciandra
Agostino Maiello
Marco Siccardi
Pino Cariti
Daniel Gonzalez de
Requena
Bernardino Salassa
LIVERPOOL:
LONDON:
David Back
Marta Boffito
Saye Khoo
Anton Pozniak
Andy Owen
Magister Sinicco
Lorena Baietto
Cristina Tettoni
ROMA:
Sabrina Audagnotto
Andrea Antinori
Letizia Marinaro
Margherita Bracchi
Laura Trentini
Marco Simiele
Giancarlo Orofino
MILANO:
Emanuele Nicastri
Giuseppe Ippolito
Massimo Galli
Stefano Rusconi