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