Managing HIV Patients with Cardiac Disease: How to Avoid Going Into Heart Failure (the clinician, not the patient)

Transcription

1 Managing HIV Patients with Cardiac Disease: How to Avoid Going Into Heart Failure (the clinician, not the patient) Alice Tseng, Pharm.D., FCSHP, AAHIVP April 25, 2015

2

3 Higher Prevalence of Age-Related Comorbidities in HIV+ vs. Controls Pp 3.9% 9.0% 20.0% 46.9% Pp 0.5% 1.9% 6.6% 18.7% all p-values <0.001; comorbidities incl. DM, HTN, RF, CVE, fractures Pp prevalence seen cases aged was similar to that observed among controls aged controls (p=0.282) [Guaraldi et al. CID 2011;53(11): ]

4 Increased Cardiac Risk in HIV Contributing factors: HIV virus, ongoing inflammation, immune activation, endothelial injury, impaired HDL metabolism, disordered coagulation adverse effects of antiretrovirals (dyslipidemia, insulin sensitivity, body fat redistribution); higher prevalence of CV risk factors (smoking) Individuals with HIV have ~1.5-fold risk of MI relative to uninfected individuals Traditional risk factors biggest contributor

5

6 Antiretroviral Therapy for Treatment- Naïve Individuals as of April 8/15 NRTI backbone Tenofovir-FTC Abacavir/3TC (with DTG) Abacavir/3TC (with EFV, ATVr if VL<100,000) Integrase Inhibitor Dolutegravir Raltegravir Elvitegravir/cobicistat/ tenofovir/ftc If Clcr>70 ml/min PI Darunavir/ritonavir Darunavir/cobicistat Atazanavir/ritonavir or atazanavir/cobicistat NNRTI Efavirenz Rilpivirine If VL<100,000, CD4>200 DHHS Rating Recommended Alternative

7 HIV Treatment: What to Do Ensure at least 3 drugs in regimen NB: could be less than 3 pills (FDC, STRs, etc). Ritonavir or cobicistat do not count as active drugs! May be some exceptions, check with patient & HIV MD Patient may have own supply (esp if investigational) Administration: Check food (calorie, fat) requirements If NPO, check if crushing/liquid info available

8 HIV Treatment: What Not to Do! Do not administer incomplete (<3) regimen If suspected ADR, drug interaction, formulation issue: all or nothing Do not empirically decrease antiretroviral dose Exception: dosing in renal/hepatic dysfunction Do not substitute one antiretroviral for another without verification antiretrovirals are not automatically interchangeable, even within the same class

9 Check for Drug Interactions! Recommended Alternative Integrase Inhibitors Dolutegravir Raltegravir Elvitegravir/ cobicistat Protease Inhibitors (PI) Darunavir/ritonavir Darunavir/cobicistat Atazanavir/ritonavir Atazanavir/cobicistat Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz Etravirine Substrate UGT1A1 CYP3A4 CYP3A4, P-gp CYP3A4, 2B6 Inhibitor - Cobicistat/ritonavir: CYP3A4>2D6 P-gp, OATP1B1/3, BCRP CYP2C9, 2C19 (?) Inducer - CYP2C9 CYP1A2, 2B6, UGT CYP3A4, 2B6 Rilpivirine CYP3A4 - -

10 Significant Interactions Between Antiretrovirals and Calcium Channel Blockers Pharmacokinetic studies: Amlodipine: Protease inhibitors 90% AUC with indinavir/ritonavir NNRTIs Diltiazem: 90% AUC up amlodipine to 2-fold AUC with atazanavir, requiring 50% 2-fold dose reduction; AUC diltiazem69% AUC with efavirenz Case reports with protease inhibitors: 69% AUC diltiazem with efavirenz Felodipine, lacidipine: edema, dizziness, fatigue, extreme bradycardia, complete AV heart block, severe hypotension. Onset within 2-3 days after starting PI for PEP. Nifedipine: hypotension, heart block, acute renal insufficiency, edema. Symptoms resolved when PI d/c, recurred with rechallenge. Reyataz monograph. Puech et al. BJCP 2011;71: Glesby et al. CPT 2005;78: Izzedine et al. CPT 2004;75: Baeza et al. AIDS 2007;21: Rossi et al. Pharmacother 2002;22:

11 Mr. T

12

13 Using Statins with Ritonavir or Cobicistat- Boosted Regimens Lovastatin Simvastatin Pharmacokinetic Interaction 3059% AUC simvastatin with ritonavir/saquinavir Management CONTRAINDICATED Atorvastatin % AUC with PIs Start with lowest recommended dose, maximum 20 mg/day Rosuvastatin % AUC with PIs Start with lowest recommended dose, maximum 10 mg/day Pitavastatin No interaction with darunavir/ritonavir or lopinavir/ritonavir. No dose limitations Pravastatin 30-81% AUC with boosted PIs Start with lowest recommended dose [FDA HIV/AIDS Drug Safety Communication, March 1, 2012; Norvir, Prezista, Stribild, Prezcobix, Evotaz monographs]

14 Metabolic Profile of P2Y 12 Inhibitors Wang et al. Therapeutics and Clinical Risk Management 2015;11:

15 CYP2C19 Inhibitors with Clopidogrel Clopidogrel monograph: Avoid use of strong/moderate CYP2C19 inhibitors E.g., omeprazole, lansoprazole, cimetidine, ticlopidine, fluvoxamine, fluoxetine, moclobemide, felbamate, chloramphenicol, ketoconazole NNRTIs inhibit 2C19 (etravirine > efavirenz) Etravirine monograph: Activation of clopidogrel to its active metabolite may be decreased, consider alternatives Efavirenz: 17-29% AUC clopidogrel active metabolite; efavirenz due to 2B6 inhibition by clopidogrel Plavix monograph, Intelence monograph, Xu et al. Drug Metab Pharmacokinet 2013;28: Jiang et al. BJCP 2013

16 Role of CYP3A4 Inhibition on Clopidogrel Responsiveness? Farid et al. CPT 2007;31: In healthy subjects, ketoconazole 400 mg/day for 6 days AUC of clopidogrel's active metabolite by 22-29% and reduced IPA 28-33%. Zahno et al. Br J Clin Pharmacol 2010:161: In vitro study which suggests that at higher clopidogrel concentrations, CYP3A4 rather than CYP2C19 is mainly responsible for clopidogrel biotransformation Studies with calcium channel blockers reducing antiplatelet effect of clopidogrel Seo et al. Yonsei Med 2014;55:683-8 Siller-Matula et al. JACC 2008;52:

17 64 yr old HIV+ male with COPD, latent TB, CAD, recent NSTEMI, type 2 DM, sleep apnea, BPH Admitted with increasing SOB, fatigue, radiating chest pain; Dx: COPD exacerbation/pneumonia, ACS secondary to NSTEMI Meds: darunavir/ritonavir QD, tenofovir/ftc, INH, B6, clopidogrel, ASA, carvedilol, rosuvastatin, valsartan, sertraline, tamsulosin, esomeprazole Clopidogrel non-responsiveness noted (PFA-100, AggRAM tests); pt was CYP2C19 extensive metabolizer, excellent adherence Author suggest drug-drug interactions were primary cause of impaired clopidgrel activation and active platelet aggregation Isoniazid: potent CYP2C19, 3A4 inhibitor; ritonavir: potent CYP3A4 inhibitor. Esomeprazole: CYP2C19 inhibitor (contribution?)

18 Prodrug? Antiretroviral-Antiplatelet Interactions Metabolism/ Elimination PIs, cobicistat Efavirenz (inhibits CYP2C9/2C19) Etravirine (inh. CYP2C19) Clopidogrel (Plavix) Activated via CYP2C19 (major), 2C9, 2B6, 3A4 2C19, 2C9 (active metabolite) 22-29% active metabolite AUC, 28-33% IPA with ketoconazole 400 mg QD; case report of response with INH, RTV 17-29% active metabolite; EFV exposure Potential active metabolite Prasugrel (Effient) Activated via CYP3A4 (major), 2B6, 2C19, 2C9 2/3 urine, 1/3 feces (metabolite) 38% AUC active metabolite with ritonavir 100 mg x 1 (NB: no change in AUC or IPA with ketoconazole 400 mg x 6 days) OK OK Ticagrelor (Brilinta) CYP3A4, P-gp 5-fold AUC with ketoconazole; strong CYP3A4 inhibitors contraindicated OK (rifampin ticagrelor AUC 10%) OK (as above) Egan et al. Ann Pharmacother 2014;48(6): Wang et al. Ther Clin Risk Management 2015;11:449-67;

19 Mr. K

20 Co-administration of Rivaroxaban With Strong Inhibitors of CYP3A4/2J2, P-gp, BCRP: pharmacokinetic effects in healthy subjects Single dose rivaroxaban 10 mg plus steady-state A) ritonavir 600 mg BID B) ketoconazole 400 mg QD: 153% rivaroxaban AUC 158% rivaroxaban AUC NB: Ketoconazole 200 mg QD: 83% rivaroxaban AUC Mueck et al. BJCP 2013;76:

21 Rivaroxaban Interactions with Antiretrovirals: Potential Impact on Toxicity and Efficacy CYP3A4/Pgp Inhibitor (PI) 52 year old Caucasian male, HIV+ since 1984; suppressed on cart including darunavir/ ritonavir BID x 2 years Sustained leg fracture, surgeon Rx rivaroxaban 10 mg QD rivaroxaban TDM: 253 ug/l (population PK Cmax is 125 ug/l) rivaroxaban to 5 mg daily While abroad, patient experienced bloody diarrhea possibly related to effects of rivaroxaban Other causes of GI bleeding/diarrhea ruled out, Sx resolved after rivaroxaban d/c CYP3A4 Inducer (NNRTI) 60 yo male, HIV+ for 8 years, on nevirapine, AZT/3TC Also hypertension, dyslipidemia, CVA, polyneuropathy, osteoarthritis; no prior history of VTE Patient underwent total knee replacement, received dalteparin x 2 days, then rivaroxaban 10 mg starting on day 3 On day 4 (after 2 doses), patient presented to ER with SOB, chest pain, leg swelling left sided DVT Eventually discharged on warfarin Drug Interaction Probability Scale: possible drug interaction with NVP Lakatos B et al. Swiss Med Weekly 2014;144:w Bates et al. CJHP 2013;66:125-9.

22 Dabigatran Interactions with P-gp Inhibitors Dabigatran etexilate is a P-gp substrate % AUC with verapamil given simultaneously or 1 hr before DE; <20% AUC when DE given 2 hours before verapamil Case report of successful coadministration of dabigatran with lopinavir/r DE given 1 hr after ritonavir at expected highest inhibitory influence (?); initially Rx DE 75 mg BID x 5/7, 11 day washout, followed by DE 110 mg BID no accumulation of dabigatran 110 mg BID with ritonavir (dabigatran Ctrough similar with RE-LY data; low Ctrough with 75 mg BID) Ritonavir 100 mg plus DE (pharmacokinetic study): Slight (13% ) AUC of DE when administered 2 hours apart from ritonavir, no change in AUC with simultaneous administration Hartter et al. BJCP 2012;75: Barco et al. Thromb Haemost 2014;112. Gordon et al. 15 th Int Workshop HIV/HCV Clin Pharmacol 2014 [#P_14].

23 Antiretroviral-NOAC Interactions Dabigatran Etexilate (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Prodrug? Yes; P-gp substrate Metabolism/ Elimination Almost entirely renally cleared (GFR>30 ml/min) CYP3A4, 2J2, P-gp, BCRP CYP3A4>1A2, P-gp PIs, cobicistat OK (PK study, case report) 2.5-fold AUC with ritonavir (PK study, case report); strong CYP3A4 and P-gp inhibitors contraindicated 2-fold AUC with ketoconazole; strong CYP3A4 and P-gp inhibitors contraindicated NNRTIs No expected interaction Clinical effect of rivaroxaban (case report) Potential for apixaban AUC (rifampin apixaban AUC 33%) Adapted from Egan et al. Ann Pharmacother 2014;48(6):

24 Using Warfarin with Antiretrovirals Racemic mixture (R: CYP1A2, 3A, 2C19; S: 2C9) Impact on Warfarin Concentrations Warfarin due to 2C9 induction Warfarin due to 2C9 inhibition Protease Inhibitors NNRTIs InSTIs Ritonavir: % warfarin dose to maintain INR Nevirapine Doubling/exceeding max recommended warfarin dose Efavirenz 4-fold reduction in warfarin dose Elvitegravir No impact Rilpivirine Dolutegravir Raltegravir Close monitoring recommended, especially when starting/changing antiretrovirals Fulco et al. Pharmacother 2008;28: Hughes et al. CMAJ 2007;177: Dionisio et al. AIDS 2001;15: Bonora et al. CID 2008;46:146-7.

25 Summary Increasing incidence of cardiac disease in HIV High potential for interactions between antiretrovirals and cardiac medications ARVs mostly as perpetrators; potential impact on efficacy or toxicity Management options: increased monitoring, dose adjustment, alternative agent May be possible to change HIV regimen (drug resistance may limit options)

26

27

28 A Guide to Assessing Antiretroviral Therapy in HIV Hospitalized Patients Pittman E, Foisy M.