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4th Annual Workshop on

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. SLCO1B1. 521T>C .

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4th Annual Workshop on

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  1. 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

  2. Lopinavir SLCO1B1 521T>C 521T>C

  3. Lopinavir CYP3A4 SLCO1B1 Kohlrausch et al. 2010 Hartkoornet al 2010

  4. SLCO1B1 521 CC genotype

  5. Hyperbilirubinaemiais a frequentcomplication of atazanavir-containingantiretroviraltherapy and itsseverityisrelated to UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism • 51 HIV-1-infected patients on boostedatazanavirwereprospectivelyenrolled in the study. 25 patients with a UGT1A1*28 allele switched to 400 mg of unboostedatazanavir. • 78% TDF-containingbackbone

  6. At 48 weeks, 24/25 switchingpatientspresentedundetectableHIV RNA with no significantchange in CD4 T cellcount (1 patientresumed ATV/R)

  7. Atazanavir disposition ABCB1 SLCO1B1 ABCCs CYP3A4

  8. ATP ATP ADP + Pi ADP + Pi Pregnane X receptor CYP3A PXR ABCB1 Drug Drug OATP1B1

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

  10. Workinghypothesis PG-guideddosingofunboosted ATV (200 BID in case ofunfavourablegenetic score, standard 400 QD in case offavourablegenetic score) couldleadtooptimizationof ATV exposureco-administeredwith TDF

  11. 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 2-3 ATV 400 mg QD 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

  12. Exampleof PG interpretation Score 1 = 200 mg BID dosing

  13. CROI 2013

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

  15. Influence of CYP2B6 and ABCB1SNPs on Nevirapine Plasma Concentrations in Burundese HIV-positive Patients Using Dried Sample Spot DevicesA Calcagno, A D’Avolio, M Simiele,JCusato, RRostagno, V Libanore, L Baietto, M Siccardi, SBonoraand G Di Perri. • A cross-sectionalanalysis in 204 HIV-positive nevirapine-treatedpatients in Kiremba, north of Burundi, Africa. • Afterbloodwithdrawalwholebloodwasstored on driedbloodspots and plasma (aftercentrifugation) wasplaced on dried plasma spot devices and storedat room temperature. • Single nucleotide polymorphisms in CYP2B6 and ABCB1 (using a real time PCR technique) wereanalysed and associated to nevirapine plasma troughlevels. BJCP 2011

  16. Nevirapine Concentrations and CYP2B6 516G>T PK and PG with DSSD Calcagno A, et al. BJCP 2011

  17. Nevirapine CYP3A4 CYP2B6 200 mg bid 400 mg qid Schipani et al 2011

  18. Darunavir CSF penetration QD vs. BID 41 patients on DRV/rcontainingregimens 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

  19. Pharmacogenetics and PK - DRV Calcagno A, Yilmaz A et al. AIDS 2012

  20. Conclusion Whichcontibution from pharmacogeneticscoupled with modernpharmacologicaltools for modern HAART? -Toxicity (e.g. ATV) -Dose personalisation/reduction -Penetration in reservoirs

  21. 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 Anna Lucchini Filippo Lipani Francesco G. De Rosa Roberto Bertucci Agostino Maiello Pino Cariti Bernardino Salassa Magister Sinicco LIVERPOOL: David Back Saye Khoo Andy Owen LONDON: Marta Boffito Anton Pozniak ROMA: Andrea Antinori Emanuele Nicastri Giuseppe Ippolito MILANO: Massimo Galli Stefano Rusconi

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