Stefano Bonora Università di Torino 12 Aprile 2013

1. L’importanza delle interazioni farmacologiche nella gestione dell’HIV/AIDS, delle comorbosità e della co-infezione HCV Stefano Bonora Università di Torino 12 Aprile 2013

2. Premessa • Un farmaco introdotto nell’organismo (per via orale, parenterale, ecc.) può subire varie trasformazioni, in funzione delle sue caratteristiche fisico-chimiche, ed essere eliminato per vie diverse, in varie forme molecolari. • Può accadere che un farmaco non venga quasi per nulla modificato e sia eliminato come tale, oppure che subisca numerose trasformazioni verso forme che possono essere ancora farmacologicamente attive (o anche più attive rispetto alla molecola originale) oppure del tutto inerti (non attive) per quanto concerne l’effetto desiderato.

3. Premessa • Le interazioni possono avere differenti meccanismi (non solo inibizione o induzione del metabolismo). • Le interazioni possono alterare la quantità di farmaco disponibile nell’organismo con potenziale impatto su efficacia e tossicità. • L’effetto di un farmaco interagente nel tempo è diverso in funzione del meccanismo di interazione.

4. Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs OUTLINE

5. Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs OUTLINE

6. Considerations in Management of the Older HIV Patient Earlier appearance of co-morbidities supports an earlier ‘older’ age designation in HIV patients, ie 55 vs 65 years!

7. B B < 50 years < 50 years A A 60 60 < 50 years < 50 years ? 50 years 50 50 *** *** *** 50 years ? >50 years 50 50 40 40 40 40 *** *** *** 30 30 patients (%) patients (%) 30 30 Patients (%) patients (%) 20 20 *** *** *** 20 20 *** *** *** *** *** *** *** *** *** ** ** ** ** ** ** *** *** *** 10 10 10 10 *** *** *** *** *** *** * * * 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 >8 >8 diuretics hormones analgesics methadone CNS agents antilipidemics ACE inhibitors Beta blockers anti-infectives Number of co-medications diuretics number of co-medications insulin/antidiabetics hormones analgesics methadone cardiovascular drugs gastrointestinal drugs angiotensin II inhibitors CNS agents antilipidemics ACE inhibitors Betablockers anti-infectives calcium channel inhibitors antiplatelets/anticoagulants insulin/antidiabetics angiotensin II inhibitors cardiovascular drugs gastrointestinaldrugs calciumchannelinhibitors antiplatelets/anticoagulants Drug Interactions will be greater as patients age > 50 years Marzolini C et al J AntimicrobChemother 2011;66:2107

8. HIV drugs amongst the most therapeutically risky - 20-40% patients on ARVs at risk of clinically significant interactions PIs > NNRTIs >> MVC/RAL > NRTIs - PIs associated with 5-fold prevalence risk of significant DDIs compared to raltegravir, and 10-fold risk compared to NRTIs Physicians recognise only around a third correctly - Pharmacist pre-screening of 200 HIV clinic patients told physicians something they did not know about medication history (20%), adherence (31%) or drug interactions (38%), and changed patient management in 13.6% Failure to Recognise Drug Interactions Patel et al. Ann Pharmacother 2011, Miller et al Pharmacother 2007;27:1379, Evans-Jones et al. CID 2010;50:1419, de Maat et al. Ann Pharmacother 2002;36:410-15 Mok et al. Am J Health Sys Pharm 2008;65:55, Seden et al. Int J STD AIDS 2012 (in press) Seden et al (unpublished)

9. Quindi • Il rischio di interazione è funzione del numero di farmaci assunti dal paziente. • Tale rischio è probabilmente sottostimato nella pratica clinica. • Alcune classi di farmaci hanno un rischio di interazione significativamente ridotto rispetto ad altre (per es. INI, inibitori dell’integrasi vs. NNRTI o IP).

10. Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs OUTLINE

11. Drug Interaction Data for RPV (Rilpivirina) Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4

12. Rilpivirine Drug Interaction:Rationale for Contraindication & Spacing • H2 antagonists must be taken 12 hours before or 4 hours after RPV since when taken 2 hours before RPV resulted in 85% reduction in RPV exposures • PPIs are contraindicated with RPV due to significant 40% reduction in RPV exposure • Antacids should be given ≥ 2h before or ≥ 4h after RPV RPV/TVD US Prescribing Information, Gilead Sciences, Inc. July 22, 2011 Do not copy or distributeAtripla does NOT have an indication for the treatment of naïve patients and there is NO Atripla promotion concerning treatment NAÏVE patients. For internal Gilead use only Eviplera does NOT have an indication for the treatment of experienced patients and there is NO Eviplera promotion concerning treatment experienced patients and until Italian AIC is granted

13. Tuberculosis Protease inhibitors NNRTIs Entry / Integrase inhibitors Fonte: http://www.hiv-druginteractions.org/

14. EfficacyOutcomes, W24 ANRS 12 180 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24,mITT (M=F, D/C=F) Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F)

15. Immunosuppressant agents CNI: cyclosporine, tacrolimus (CYP3A, Pgp) Antimetabolites: mycophenolate (UGT) Mamalian target-of-rapamycin (mTOR) inhibitors: sirolimus, everolimus (CYP3A, Pgp) Van Maarseveen EM, et al. AIDS Pat Care & STD 2012

16. Antineoplastic agents Edmunds-Ogbuokiri et al. HIV Clinician 2009

17. Recreationaldrugs Antoniou et al. Ann Pharmacother 2002

19. Summary of Telaprevir – ARV interactions *TVR dose 1125mg q8h

20. Summary of Boceprevir – ARV interactions ? ? ? ? * vs. historical controls

21. Epatite C e HIV: cenni • Per una persona sieropositiva, che deve assumere una terapia per tutta la vita, prendersi cura del proprio fegato è una priorità. • Il fegato è il principale organo deputato al metabolismo e alla detossificazione dai farmaci e, quindi, soggetto a danno da parte delle sostanze chimiche e farmacologiche da cui ci depura. • Oggi esistono terapie che aumentano in modo sostanziale la possibilità di un successo terapeutico per la cura dell’epatite. • Affiancare queste nuove terapie a combinazioni farmacologiche anti-HIV con scarse interazioni aumenta la probabilità dell’esito positivo di questo percorso, come ci dicono gli studi clinici sui farmaci anti-HIV di nuove classi (es.: INI).

22. Epidemiology New antiretrovirals/drugs combination Sources of information Manegement of DDIs OUTLINE

24. Statins and HAART: management of drug-drug interactions Nachega JB et al AIDS 2012

25. Cardiovascular drugs and HAART: scarce data • Digoxinserumconcentrationswereincreased by 86% with RTV coadministration due to inhibition of P- glycoprotein(NO DATA IN HIV+) • Manyantiarrhythmicmedications are CYP450 3A4 substrates. The use of amiodarone, bepridil, flecainide, propafenone and quinidineare contraindicated with PI/rdue to the potentialrisk of exacerbatingcardiacarrhythmias (NO CLINICAL DATA).

26. Corticosteroids • Case report of Cushing’s syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops1 • Cushing’s syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs2–4 • Several cases of Cushing’s syndrome with inhaled fluticasone and ritonavir7 CHECK EVERY KIND OF MEDICATION Check every route of administration 1.Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6:10. 3. Danaher PJ, et al. Orthopedics 2009;32:450. 4.Ramanathan R, et al. Clin Infect Dis. 2008;47:e97–9. 5. Gray D, et al. S Afr Med J. 2010;100:296–7. 6. Frankel JK, & Packer CD. Ann Pharmacother. 2011;45:823–4. 7. Foisy MM, et al. HIV Medicine 2008;9:389–96.

27. Le interazioni farmacologiche esistono e bisogna conviverci. • Il numero di possibili interazioni è altissimo, pertanto non è prevedibile avere dati certi di farmacocinetica per tutte le possibili interazioni. • http://www.hiv-druginteractions.org è importante per il clinico ma non è RISOLUTIVO.

28. Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs HIV+ vs Healthy volunteers Interindividual variability Clinical significance New mechanisms? OUTLINE

29. PK differences (versus healthy volunteers) *Compared to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairment ҰHealthy individuals with and without moderate hepatic impairment

30. Physiological changes (versus healthy volunteers) * Decreased albumin associated more with cirrhosis and significant liver damage † Significantly lower than HIV or HCV mono-infected patients 1Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–12003Nagao Y & Sata M. Virology Journal 2010;7:375; 4Monga HK, et al. Clin Infect Dis 2001;33:240–7; 5Boffito M, et al. Drug Metab Dispos 2002;30:859–60; 6Ozeki T, et al. Br J Exp Path 1988;69:589–95 7Welage LS, et al. Clin Infect Dis 1995;21:1431–38; 8Nam YJ, et al. Korean J Hepatol 2004;10:216–22

31. DHHS Guidelines (2002 -2008): Rifabutin 150 mg (half dose) every other day or three times a week is recommended

32. 10 patients with HIV infection and active tuberculosis • Lopinavir-ritonavir at, twice daily + rifabutin at 150 mg thrice weekly: 9 of 10 had low rifabutin Cmax values • values for the area under the plasma concentration–time curve of rifabutinwere as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance • One of the 10 patients experienced relapse with acquired rifamycin resistance.

33. % Inhibiition Concentration IC50 IC50 IC50 IC50 Time                                                                Oneconcentrationdoesnotfitallpatients!!

34. Pravastatin and DRV/RTV Sekar VJ, et al. Pharmacology Workshop. 2007. Abstract 55.

35. Statistical vs. Clinical Significance • A statistically significant effect may not be clinically relevant • A clinically relevant PK interaction would require a dose modification/warning/contra-indication A consistent 10% decrease in AUC in 10 subjects is statistically significant (p<0.01), but not clinically relevant. Adapted from D Back

36.                         Therapeutic window Narrow therapeutic window Wide therapeutic window Adverse events Adverse events Drug concentration Drug concentration   Therapeutic failure Therapeutic failure Adapted from D Back

37. Ci sono scenari clinici dove il valore aggiunto di QD e STR rispetto a schemi più complessi (BID o QD multipill) può essere controbilanciato da altri fattori? • Farmaci concomitanti (QD o BID)? • Tollerabilità a lungo termine?

38. Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time 100 86 81 76 75 71% 80 82 79 60 69 67 61% HIV RNA Levels <50 Copies/mL Percent of Patients with 40 20 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. 281 278 279 280 281 281 277 280 281 281 277 279 Efavirenz 600 mg qHS. 282 282 282 281 282 282 281 281 282 282 282 279 Non-Completer = Failure Approach

39. Yearly Efficacy Analyses

40. Sensitivity Analyses of Virologic Efficacy at Week 240

41. Subgroup Analyses

42. Specific Drug-Related Clinical Adverse Experiences Occurring in ≥ 5% of Either Group

43. Patients who tolerated EFV, with less than 50 copies/ml HIV-RNA, were randomized into two groups: the RAL-first group started with RAL (400 mg twice daily) and EFV placebo, and the EFV- first group with EFV (600 mg once daily) and RAL placebo. After 2 weeks, both groups switched to the alternate regimen. Half of patients previously on a stable EFV preferred to switch to RAL, after double-blind exposure to RAL for 2 weeks. Substitution of EFV by RAL significantly impacted on lipid levels, stress, and anxiety scores.

44. Altri esempi Studio STaR (Glasgow, Cohen O425) Spring 2 e Single (Glasgow, Eron P204) Sailing (Atlanta, Croi 2013, Pozniak 179 LB)

45. Grazie al contributo di MSD Italia