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Beware: Clinically Significant Drug Interactions in the Treatment of HIV Betty J. Dong, PharmD, FCCP, FASHP, FAPHA, AAHIVP Professor of Clinical Pharmacy and Family and Community Medicine, University of California Schools of Pharmacy and Medicine, San Francisco HIV and HCV Consultant, Clinicians’ Consultation Center 2 Disclosures • Betty J. Dong, PharmD declares no conflicts of interest, • Target Audience: Pharmacists real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. • ACPE#: 0202-0000-16-010-L02-P • Activity Type: Application-based The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 3 • Examine common pharmacologic mechanisms of drug-drug • • interactions with non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). Evaluate the consequences of drug interactions associated with antiretroviral drugs and determine the incidence of clinical adverse effects from interactions. Formulate a list of drugs that have a high potential to interact with antiretroviral drugs. Establish monitoring parameters and strategies that can be used to minimize the incidence of adverse drug interactions 5 © 2016 by the American Pharmacists Association. All rights reserved. • • • ARV= antiretroviral agent • • ART= antiretroviral therapy • • PI= Protease inhibitor • NNRTI= non nucleoside • Glossary Learning Objectives • 4 • • • • reverse transcriptase inhibitor INSTI= integrase inhibitor DRV/r= darunavir/ritonavir ATV/r =atazanavir/ritonavir RPV = riprivirine • • • • • /cobi= cobicistat /r = ritonavir TDF=tenofovir TAF= tenofovir alafenamide FTC= emtricitabine 3TC = lamivudine ABC= abacavir DTG= dolutegravir RAL=raltegravir EVG=elvitegravir 6 Self-Assessment Question Self-Assessment Question Proton pump inhibitors are contraindicated with which antiretroviral agent? Which of the following would pose the lowest risk of drug interactions? 1. 2. 3. 4. 5. 1. 2. 3. 4. 5. Raltegravir Dolutegravir Rilprivine Elvitegravir/cobistat Darunavir/ritonavir Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID, lorazepam 2 mg prn anxiety Raltegravir Rilpivirine Dolutegravir Atazanavir/cobicistat Darunavir/ritonavir 7 8 Self-Assessment Question Self-Assessment Question Which is the most appropriate action if dolutegravir, abacavir, and lamivudine (Triumeq) is selected as initial ART? Which of the following should be considered if elvitegravir, emtricitabine, tenofovir (Stribild) or Tenofovir alafenamide (Genvoya) is started? 1. 2. 3. 4. 5. 1. 2. 3. 4. 5. Reduce metformin dose Increase amlodipine dose Give CA+ w/DTG on empty stomach Stop esomeprazole Give Al-Mg antacids at same time Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID, lorazepam 2 mg prn anxiety 9 Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID Which of the following hepatitis agents would result in the lowest risk of ARV drug interactions? 1. Sofosbuvir/ledispasvir (Harvoni) 2. Paritaprevir/ritonavir/ombitasvir/dasabuvir What can occur if ledipasvir/sofosbuvir (Harvoni) is given with tenofovir, emtricitabine, and darunavir/r regimen? 1. 2. 3. 4. 5. (ViekiraPak or PROD) 3. Sofosbuvir/simeprevir 4. Sofosbuvir/daclastasvir 5. Grazoprevir/elbasvir © 2016 by the American Pharmacists Association. All rights reserved. 10 Self-Assessment Question Self-Assessment Question Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine Reduce metformin dose Reduce amlodipine dose Change lorazepam to triazolam Separate esomeprazole by 6 hr Give Al-Mg antacids at same time 11 HCV treatment failure HIV treatment failure Darunavir hepatic toxicity Tenofovir renal toxicity Emtricitabine lipid toxicity Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine 12 Some Pharmacokinetic Basics... Prevalence of Clinically Significant Drug Interactions • • • • • • 27-41% of HIV+ persons • Risk factors: – – – – Age >50yr (aOR 2.5) Polypharmacy: >5 non-HIV agents (OR 2.7 to 15.1) Co-morbidities: dyslipidemia (aOR 1.96), anxiety (aOR 1.78) Protease (OR 5.3) or NNRTI regimen • Low recognition of CSDI--36% – – – – Substrates CYP450 inhibition CYP450 induction AUC: area under the curve = drug exposure Cmin/trough: lowest drug concentration = ARV efficacy Lower ARV concentrations Suboptimal therapy Toxicity Death J AIDS 2006;42:52; Ann Pharmacoth 2008;42:1048; Ther Drug Monit 2007;687 HIV Med 2015;16:273. Pharmacotherapy 2007;27:1379; AIDS Care 2015; 27:1443 13 CID 2006;43:933; J Clin Pharm Ther 2004;29:121;CID 2010;50:1419. Hepatic Metabolism CYP 450 and Drug Metabolism • Substrates refers to agents metabolized via the hepatic • Majority of medications are 3A4 substrates metabolized by 3A4 hepatic enzymes CYP2C 14 enzyme (CYP 450, UGT1A1) system agents • Nonnucleosides (NNRTIs), protease inhibitors (PIs), integrase inhibitor elvitegravir, statins, warfarin are metabolized via CYP 450 3A4 and associated isoenzymes • Integrase inhibitors (INSTI) raltegravir and dolutegravir are primarily metabolized by glucuronidation via the UGT1A1 enzyme (UDP-glucuronosyltransferases) • Most NRTIs (nucleoside reverse transcriptase inhibitors) are renally eliminated and do not undergo liver metabolism. Exceptions: zidovudine, abacavir CYP3A4 CYP2D6 CYP 1A2 15 16 Slide 17 of 39 CYP450 Inhibition CYP450 • Slower onset and • Quick onset and offset of effect when stopped Drug Concentration (few days) • Reduces metabolism of CYP 450 enzyme substrates • levels of substrates ( toxicity/efficacy) • Examples of inhibitors: Inhibiting protease inhibitors, cobicistat CYP 450 Induction drug added Time 17 © 2016 by the American Pharmacists Association. All rights reserved. Slide 18 of 39 Drug offset of action Concentration when stopped ~ 7 to 14 days • levels/efficacy of CYP 450 substrate • Examples of Inducing drug added inducers: efavirenz, rifampin Time 18 Mechanism of ARV Drug Interactions • Most clinically relevant antiretroviral (ARV) drug Drug Transporters • Several medications in each ARV class are affected by interactions occur because of alterations in CYP450 metabolism (e.g. inhibition or induction) of CYP 450 substrates drug transporters present in multiple cell lines • P-glycoprotein (P-gp): – efflux pump present in the intestinal epithelium, hepatocytes, renal, and other cells – Increasing recognition as an important factor in influencing drug pharmacokinetics and efficacy – Many ARVs are P-gp substrates that can be transported across cellular membranes by this protein, with potential for clinically relevant drug interactions • May also result from the action of drug transporters involved in moving ARVs across cellular membranes • Renal elimination is not a common cause of ARV drug interactions 19 Drug Transporters P-Glycoprotein (P-gp) Interactions • Renal Transporters • Can significantly affect disposition of medications • • • 20 – Dolutegravir: • Inhibits renal transporter, organic cation transporter2 (OCT2) • Decreased tubular secretion of creatinine and nonprogressive SCr elevations (not progressive or true renal impairment) • Potentially inhibits multidrug and toxin extrusion transporter (MATE1) – absorption, elimination, entry into CNS, testes P-gp substrates: digoxin P-gp inducers: PB, phenytoin, rifampin, St John’s wort P-gp inhibitors– erythromycin, clarithromycin, diltiazem, felodipine, intraconazole, ketoconazole, nicardipine, grapefruit 21 Recognizing Potential for ARV Drug Interactions Protease Inhibitors HIGH CCR5 Inhibitors Nucleoside Reverse Transcriptase Inhibitors High potential CYP450 substrates Mixed induction and inhibition effects Efavirenz and etravirine: induction >>> inhibition – Efavirenz: 3A4, 2B6 induction; 2C9, 2C19 inhibition – Etravirine: 3A4 induction, 2C9, 2C19 inhibition MEDIUM • Rilpivirine is a CYP 3A4 substrate • Nevirapine is an inducer of CYP 3A4 and 2B6 LOW 23 © 2016 by the American Pharmacists Association. All rights reserved. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • • • • Nonnucleosides Reverse Transcriptase Inhibitors Integrase Inhibitors 22 24 Protease Inhibitors (PIs) and Cobicistat Protease Inhibitors (PIs) • High potential • CYP3A4 inducers • High potential • CYP 3A4 and p-gp substrates • CYP 3A4 inhibitors • – Ritonavir: 1A2, 2C8, 2C9 – Fosamprenavir 3A4 – Tipranavir 3A4, 1A2, 2C19 – Ritonavir (/r): 3A4, 2D6 – Cobicistat (/cobi) = ritonavir: 3A4, 2D6: pharmacoenhancer to PI – LPV/r, TPV/r>>ATV/r, DRV/r >> SQV/r Variable P-gp inhibition • Glucuronidation ( estinyl estradiol) • Mixed effects; not always possible to determine overall effects 25 Potential for ARV Drug Interactions Integrase Inhibitors (INSTI) • • • • • • 26 Protease Inhibitors Low to medium potential EVG> DTG> RAL are metabolized by UGT1A1 CYP 450 enzyme effects vary. Dolutegravir is a 3A4 substrate. Raltegravir and dolutegravir are not inducers nor inhibitors Elvitegravir – CYP 3A4, 2D6, 2C9, 2C19, 2B6, and 1A2 substrate. – modest CYP2C9 inducer – Co-formulated with cobicistat, a CYP 450 inhibitor. HIGH Nonnucleosides Reverse Transcriptase Inhibitors CCR5 Inhibitors Integrase Inhibitors Nucleoside Reverse Transcriptase Inhibitors LOW 27 ARVs and Interacting Drugs/Classes Anticoagulants/Anti-platelet Acid Reducing Agents Antifungals; azoles Antiarrhythmics Antimycobacterial/macrolides Anti-epileptics Anti-depressants/psychotics Anti-hypertensives Asthma agents Benzodiazepines Cardiac medications Chemotherapeutic agents Cisapride Corticosteroids Protease Inhibitor/Cobicistat Contraindications Ectasy/illicit drugs Ergots Erectile dysfunction Gout agents HCV Direct Acting Agents Herbals Immunosuppressives Methadone/Opiates Oral contraceptives Pimozide Pulmonary hypertension Statins 29 © 2016 by the American Pharmacists Association. All rights reserved. 28 Medication Potential Consequences Alpha-1 blocker; alfuzosin Hypotension Anticonvulsants:carbamazepine oxcarbazepine, phenytoin, Pb Loss of virologic efficacy d/t lower PI/cobi levels. Consider gabapentin or levetiracetam Rifampin, rifapentin Loss of virologic efficacy d/t lower PI/cobi levels Consider rifabutin with PI. Avoid with cobi. Ergots: ergotamine, dihydroergotamine, methylergonovine acute ergot toxicity characterized by peripheral vasospasm and tissue ischemia St. John’s wort Loss of virologic efficacy d/t lower PI/cobi levels Corticosteroids: nasal fluticasone, budesonide, injectable triamcinolone Risk of Cushings’ causing adrenal insufficiency with both systemic and nasal fluticasone/budesonide. Consider montelukast or less potent steroid (e.g. beclomethasone) Dexamethasone Avoid chronic co-administration. Loss of virologic efficacy d/t lower PI/cobi levels 30 Protease Inhibitor/Cobi Contraindications Case 1 Presentation • PJ is a 38-yr-old HIV positive woman who has never taken Medication Potential Consequences Benzodiazepines: triazolam, oral midazolam Potential for life threatening/serious risk of increased sedation and respiratory depression. Consider lorazepam, temazepam or oxazepam. Neuroleptic: pimozide, lurasidone GI motility: cisapride Potential for life threatening/serious risk of cardiac arrhythmias Statins: simvastatin, lovastatin, red rice yeast statin’s risk of myopathy and rhabdomyolysis. Use lowest dose of other statins (e.g. atorvastatin, pitavastatin, pravastatin, rosuvastatin) Inhaled -agonists: salmeterol Avoid co-administration d/t risk of CV ADR (QT, palpitations, sinus tachycardia). Consider formoterol • • • • antiretroviral therapy (ART) before (“treatment naive“) PMH: GERD, type 2 diabetes, hypertension, anxiety Social history: smokes 1 PPD, denies alcohol, illicit agents Allergy: cough on lisinopril Medications: – – – – – – PDE-5 inhibitor:sildenafil (Revatio) sildenafil ADRs (visual, hypotension, prolonged for pulmonary artery hypertension erection or priapism, syncope) Esomeprazole 20 mg daily Aluminum magnesium antacids prn gastric distress Calcium carbonate (TUMS) bid Amlodipine 10 mg daily Lorazepam 2 mg prn anxiety Metformin 1000 mg BID 31 Case 1 Presentation: 32 Questions to Consider PE: BP 130/80, HR 62 beats/min, R 12. 02 sat 95% Labs: BUN 8/Scr 1.0 A1c 6.5% Baseline HIV Genotype: Wild type, no mutations HLA-B5701 negative HBV and HCV AB negative CD4 500 cells/mm3 HIV RNA: 247,500 copies/ml • Can we honor PJ’s request for a single tablet ARV? • If so, which single dose antiretroviral co-formulation would be most appropriate? • Identify if any drug interactions are expected with the • addition of each single dose co-formulated first line recommended regimen? If so, what modifications to her DM, HTN, or GERD therapy would be necessary to incorporate antiretroviral therapy? She is ready to start but would prefer a single dose tablet once daily if possible 33 DHHS Guidelines: 2015 Recommended Firstline Antiretroviral (ART) Regimens Recommended ART Regardless of BL VL or CD4+ Count Class INSTI NNRTI #Only *Only if CrCl ≥ 70 mL/min. †Only if HLA-B*5701 negative. Considerations for Selecting The Initial Antiretroviral Regimen Lifestyle Adherence Dosing Pill Burden Preference Resistance Testing RAL + TDF/FTC EVG/COBI/TDF/FTC (Stribild)* EVG/COBI/TAF/FTC (Genvoya)# DTG/ABC/3TC (Triumeq)† DTG + TDF/FTC Boosted DRV/r + TDF/FTC PI ‡Avoid Alternative Regimens 34 Co-morbid Conditions ATV/r + TDF/FTC ATV/COBI (Evotaz)+TDF/FTC* DRV/r + ABC/3TC† DRV/COBI (Prezcobix)+ ABC/3TC† DRV/COBI (Prezcobix)+ TDF/FTC* EFV/TDF/FTC (Atripla) RPV/TDF/FTC (Complera)‡ (e.g. Hepatitis CV Disease, Mental illness) Potency Drug Interactions Initial ART Treatment Toxicity Short Term Long Term if CrCl > 30 ml/min if initial VL >100,000 c/mL and CD4+ < 200 c/mm3. © 2016 by the American Pharmacists Association. All rights reserved. 35 36 Single Dose Combinations (SDC) One Pill Once Daily ART Regimens Advantages and Disadvantages of SDC Advantages Product Components Food Requirements Drug interaction Atripla Efavirenz 600 mg Tenofovir 300 mg Emtricitabine 200 mg YES, Empty stomach 3A4 inducer> inhibition Complera Rilpivirine 25 mg Tenofovir 300 mg Emtricitabine 200 mg YES: > 400 Kcal meal 3A4 substrate Stribild YES Elvitegravir (EVG) 150 mg/cobicistat 150 mg tenofovir 300 mg Emtricitabine 200 mg YES EVG150mg/cobi 150 mg tenofovir alafenamide 10mg emtricitabine 200 mg NO Dolutegravir 50 mg Abacavir 600 mg Lamivudine 300 mg Genvoya Triumeq cobi 3A4 interactions = protease inhibitors Disadvantages Simplicity Convenience Fewer copays Reduces selective nonadherence to regimen components • Inability to adjust dosage component if needed • drug–drug interactions • tolerability • renal or hepatic insufficiency Not available for all ART regimens cobi 3A4 interactions = protease inhibitors OCT-2 interactions 37 Self-Assessment Question Which is the most appropriate recommendation if dolutegravir, abacavir, and lamivudine (Triumeq) is selected as her initial ART? 1. 2. 3. 4. 5. Reduce metformin dose Increase amlodipine dose Give CA+ w/DTG on empty stomach Stop esomeprazole Give Al-Mg antacids at same time Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID, lorazepam 2 mg prn anxiety 38 Dolutegravir Drug Interactions Medication Interaction Recommendation Polyvalent cations (e.g., Mg, Al, Fe, or Ca) Antacids, laxatives, sulcrafate, or buffered meds Concurrent Al+ Mg+ antacids DTG AUC 76% vs 26% if staggered. Administer Al++, Mg++, or Ca++-containing antacids, laxatives, iron, or sulcrafate six hours before or two hours after DTG Fasting: DTG AUC 37%-39% with CA+ 54% to 57% iron Food: normal AUC Take DTG and calcium supplements or iron together with food. Multivitamins DTG AUC 33% when co-administered with a multivitamin. Standard DTG dosage PPI and H2 blockers No interaction Standard DTG dosage 39 40 Self-Assessment Question Selected Dolutegravir Drug Interactions Medication Interaction Anticonvulsants DTG Dofelitide dofelitide Recommendation Which of the following should be considered if elvitegravir, emtricitabine, tenofovir (Stribild) or Tenofovir alafenamide (Genvoya ) is selected as her initial ART? Avoid co-administration Avoid co-administration Carbamazepine DTG AUC 49% and Cmin 73% DTG 50 mg bid in naïve pts. Consider oxcarbamazepine Rifampin DTG DTG 50 mg BID in treatmentnaïve or treatment experienced if INSTI-naïve. Consider rifabutin. Metformin Metformin AUC 79%, Cmax 66%, Cmin 9% Adjust metformin to maximum of 1000 mg daily. Adjust metformin dose when stopping/starting DTG BID DTG metformin AUC 2.4 fold, Cmax 2 fold, Cmin 14% 41 © 2016 by the American Pharmacists Association. All rights reserved. 1. 2. 3. 4. 5. Reduce metformin dose Reduce amlodipine dose Change lorazepam to triazolam Separate esomeprazole by 6 hr Give Al-Mg antacids at same time Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID 42 Cobicistat 150 mg (/cobi) • • • • • • • Stribild: CrCL >70 cc/min with tenofovir Genvoya: CrCL >30cc/min tenofovir alafenamide (TAF) Pharmacokinetic booster = ritonavir but no HIV activity Take with food to increase absorption Mean Scr 0.14 mg/dl, max 0.4 mg/dL – Interference with creatinine tubular secretion – eGFR before starting, urine prot/gluc, P04 with tenofovir ADR: HA, GI distress, nausea, lipid changes FDC: atazanavir 300 mg/cobi 150 mg (Evotaz) darunavir 800 mg/cobi 150 mg (Prezcobix) Clin Pharmacok: April 2011; 50:229; Lancet. 2012 Jun 30;379:2429 Interaction Agent Interaction Recommendations Antacids (Al and Mg hydroxide, Ca carbonate) Cmax, and 41% Cmin. CardiacAntiarrhythmics: (amiodarone,digoxindi antiarrhythmics and digoxin levels (41% Cmax; 8% AUC). Separate by >2hr. Use PPI or H2 blockers EVG AUC 45%, 47% Separate 2 hr, EVG 1020%; NS if separate by 4hr Monitor antiarrhythmic levels and adjust as necessary. sopyramide, flecainide,lidocaineme xiletine,quinidine, propafenone 43 Elvitegravir/Cobi (Genvoya, Stribild) DI Agent Elvitegravir/Cobi (Genvoya, Stribild) Drug Interactions (DI) 44 Elvitegravir/Cobi (Genvoya, Stribild) DI Recommendations Agent Antifungals (itraconazole, ketoconazole, voriconazole Antifungal levels Ketoconazole and itraconazole: NTE 200 mg/day. Voriconazole: evaluate risks vs benefits Antihypertensives -β blockers -calcium channel blockers (CCB) β blockers (2D6): (metoprolol,carvedilol timolol); 3A4 CCB (amlodpine, diltiazem, felodipine, nifedipine, verapamil) Monitor BP/HR and β-blockers and CCB toxicity; dose prn. Consider labetalol, naldolol, atenolol Antidepressants, Anxiety Neuroleptics SSRI (except sertraline), Monitor for toxicity. TCA, buspirone, trazodone, doses as warranted risperidone, perphenazine, thioridazine Interaction Recommendations Colchicine colchicine. Avoid in renal/hepatic dysfunction Acute: 0.6 mg x1, 0.3 mg po one hr later, repeat no earlier than q 3 days. Prophylaxis:0.3mg daily or QOD PDE5 inhibitors for erectile PDE5 levels Avoid co-administration with avanafil. DNE 25 mg sildenafil/48 hr, 2.5 mg vardenafil or 10mg tadalafil /72 hrs Hormonal contraceptives EE AUC 25%, 2 Consider alternative contraception or use at least 30 mcg EE contraceptive Narcotics: (buprenorphine, naloxone, methadone) Watch for sedative and cognitive opioid effects. dysfunction fold AUC/Cmax norgestimate active metabolite Monitor for opioid toxicity. Normal opioid doses, adjust as needed 45 Summary: Selected INSTI Drug Interactions Agent Elvitegravir/ cobi Dolutegravir 46 Summary: Selected INSTI Drug Interactions Potential Drug–Drug Interactions COBI increases levels of 3A4 substrate drugs Give EVG/c 2 hr before or 6 hr after AL+and/or Mg+-antacids, Fe+, CA+, Zn+ supplements Administer Al++, Mg++, Ca++antacids/laxatives, iron or sulcrafate six hours before or two hours after DTG or take DTG and Ca++ supplements or iron together with food. metformin 2 fold; maximum 1000 mg daily; monitor clinically when starting/stopping DTG 47 © 2016 by the American Pharmacists Association. All rights reserved. Agent Raltegravir Potential Drug–Drug Interactions Avoid AL+-and/or Mg-containing antacids, no interaction with CA+ Give RAL at least 2 hr before or 6 hr after polyvalent cations Rifampin decreases RAL levels; RAL 800 mg BID Raltegravir [package insert]. EVG/COBI/TDF/FTC [package insert]. Dolutegravir [package insert]. 48 Case 1 Presentation Questions to Discuss • PJ is a 38-yr-old HIV positive woman who has never taken • Which SDC would be most appropriate for PJ? antiretroviral therapy (ART) before (“treatment naive“) PMH: GERD, type 2 diabetes, hypertension, anxiety Social history: smokes 1 PPD, denies alcohol, illicit agents Allergy: cough on lisinopril Medications: • • • • – – – – – – – Stribild, Genvoya, Triumeq – Avoid Complera since baseline VL > 100,000 c/ml • What drug interactions are expected with each SDC first line regimen? • What modifications to her DM, HTN, or GERD therapy would be necessary? Esomeprazole 20 mg daily Aluminum magnesium antacids prn gastric distress Calcium carbonate (TUMS) bid Amlodipine 10 mg daily Lorazepam 2 mg prn anxiety Metformin 1000 mg BID Continue PPI and lorazepam and CA Separate Al/Mg antacids by at least 6 hr after or stop Reduce metformin to 500 mg bid with Triumeq, if A1c @goal Monitor BP/HR with amlodipine and Genvoya and Stribild 49 Case 2 Presentation: Case 2 Presentation RJ is a 55 year old HIV-infected male lawyer with multiple co-morbidities who is reluctant to start ART due to concerns about side effects affecting his ability to function and think clearly. • Allergy: NKA • PMH/Medications: – – – – – – 50 Hemophiliac: weekly Factor 7 transfusions Allergic rhinitis—nasal fluticasone BID Hypertension—lisinopril 40 mg + diltiazem 300 mg daily Dyslipidemias—simvastatin 20 mg daily Severe GERD—pantoprazole 20 mg BID Depression— sertraline 100 mg daily PE: BP 140/90, HR 62 beats/min, R 12. 02 sat 95% Labs: BUN 18/Scr 1.3, CrCL 60 cc/min AST 14 ALT 16 Tchol 294 mg/dl, LDL 130 mg/dl, HDL 45 mg/dl Baseline HIV Genotype: Wild type, no mutations HLA-B5701 positive HBV and HCV AB negative CD4 500 cells/mm3 HIV RNA: 147,500 copies/ml 51 Self-Assessment Question Efavirenz, TDF/FTC (Atripla) Which is most appropriate action to consider if efavirenz,tenofovir, emtrictabine (Atripla) is selected as RJ’s initial ART? 1. 2. 3. 4. 5. Reduce diltiazem by 50% Increase simvastatin dose Reduce sertraline dose Stop nasal fluticasone Change pantoprazole to ranitidine Factor 7 transfusions, nasal fluticasone BID lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg daily, pantoprazole 20 mg BID, sertraline 100 mg daily © 2016 by the American Pharmacists Association. All rights reserved. 52 53 • No longer recommended as first line therapy • Side effects concerns: – CNS: depression, cognitive impairment, insomnia, “weird dreams”, suicidal tendencies – Rash – Dyslipidemia: TC , LDL, HDL – Vitamin D deficiency • Potential drug interactions 3A4 induction – simvastatin, diltiazem, sertraline levels/efficacy – no interactions: lisinopril, pantoprazole, nasal fluticasone 54 Selected Efavirenz (EFV) Induction Drug Interactions Association Between EFV as Initial Therapy and Suicidality • Analysis of 4 ACTG (95% CI: 1.27-4.10; p = .006) Agent Interaction Recommendations Antidepressants sertraline AUC 39% and buproprion AUC 55% Monitor clinical response and increase dose if warranted Anticonvulsants EFV, phenytoin, Monitor anticonvulsant level. carbamazepine, phenobarb Avoid efavirenz or use other anticonvulsants 0.10 Cumulative Incidence studies in ART-naive pts randomly assigned to initial therapy with EFV vs EFV-free regimens • HR for suicidality increased with EFV vs EFV-free regimens: 2.28 Cumulative Incidence of Suicidality (ITT) EFV EFV free 0.08 0.06 Calcium channel diltiazem AUC 69% blockers (CCBs) other CCBs ?? Gray P = .004 0.04 0.02 48 96 144 Wks to Suicidality 3241 2091 2949 1917 2703 1760 1782 1107 192 522 298 55 Mollan KR, et al. Ann Intern Med. 2014;161:1-10. 56 Rilpivirine (RPV) Drug Interactions and Absolute Contraindications Self-Assessment Question Which is most appropriate action in RJ if rilpivirine, tenofovir, emtrictabine (Complera) is being considered as his initial ART? 1. 2. 3. 4. 5. • CYP3A substrate, no inhibition, slight induction • Absolute contraindications: RPV levels – Proton Pump Inhibitors: gastric pH – Potent 3A4 inducers: • St John’s wort, ginko biloba • Anticonvulsants: carbamazeprine, oxcarbazeprine, phenobarbital, phenytoin • Antimycobacterials: rifampin, rifapentine – Exception: rifabutin • More than one dose of dexamethasone Reduce diltiazem by 50% Increase simvastatin dose Reduce sertraline dose Stop nasal fluticasone Stop pantoprazole Meds: Factor 7 transfusions, nasal fluticasone BID lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg daily, pantoprazole 20 mg BID, sertraline 100 mg daily 57 58 Rilpivirine (RPV) vs Efavirenz (EFV) in Treatment-Naïve Pts Selected Ripivirine Drug Interactions Agent Interaction Recommendations Antacids RPV Administer antacids 2 hrs before or 4 hrs after RPV Administer RPV 4 hr before or 12 hrs after famotidine RPV Cmax 31%, AUC Give additional 25 mg dose 42%, Cmin 48%. of rilpivirine = 50 mg daily 50 mg=Cmax 43%, AUC 16%, Cmin 7% Azole antifungals RPV; azoles Macrolides % < 50 copies/mL at Week 96 macrolides Monitor for fungal infection breakthru. Consider azithromycin Rilpivirine 77% Wk 96 Outcome, % Efavirenz 77% 100 80 Patients (%) RPV AUC 76% if RPV H2-Receptor Antagonists(HRA) given 2 hr after HRA Rifabutin simvastatin AUC 58% Require higher statin doses atorvastatin 43%, Prefer simvastatin, pravastatin 44%, lovastatin atorvastatin, rosuvastatin, or pitavastatin Statins 0 0 Titrate CCB dose based on clinical responses 68 72 83 80 74 71 DC for ADR 5 Most Common AEs of Interest, % Dizziness 1 7 Depression 2 2 Abnormal dreams 1 3 Any psychiatric 5 7 40 Any rash 1 5 20 0 VL <100,000 VL >100,000 • • • © 2016 by the American Pharmacists Association. All rights reserved. Efavirenz (n = 546) 2 60 CD4 <200 59 Rilpivirine (n = 550) *** RPV failure if HIV VL>100K c/mL and CD4 <200 c/mm3 Cohen C, et al. Lancet 2011; 378: 229–37; Molina JM et al. Lancet 2011;378:238‐46 . 60 Self-Assessment Question Ritonavir (or Cobicistat) Boosted Darunavir Which is most appropriate action in RJ if ritonavir (or cobi) boosted darunavir, tenofovir, and emtrictabine is selected as initial ART? 1. 2. 3. 4. 5. • • • • Increase diltiazem dose Change simvastatin to pitavastatin Reduce sertraline dose Change to nasal budesonide Separate pantoprazole co-administration from ritonavir (or cobi) boosted darunavir Factor 7 transfusions, nasal fluticasone BID lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg daily, pantoprazole 20 mg BID, sertraline 100 mg daily – Contraindications: simvastatin, nasal fluticasone, and nasal budesonide – DRV/r sertraline levels – Diltiazem and CCB levels may increase – No interaction with lisinopril or pantoprazole 61 Darunavir/r Statin Drug Interactions DRUG EFFECT Recommendations Statins Simvastatin/lovastatin AUC 5003000% (myositits, rhabdomyolysis) Contraindicated with simvastatin and lovastatin (red rice yeast). DRV/r atorvastatin AUC 70-836% DRV/r + atorvastatin 10 mg = 40 mg/day, DNE 20 mg/day. Pravastatin AUC 81% (single dose) Use lowest effective dose Pravastatin AUC 26% (steady state) rosuvastatin AUC 48%, Cmax 139% Use lowest effective dose. no significant effects on pitavastatin Use normal doses Sensitive regimen since no PI or other mutations Not best option unless medication changes occur No sulfa allergy—okay to consider DRV/r Drug interactions: 62 Selected Darunavir/r Drug Interactions DRUG EFFECT CCBs: Amlodipine Diltiazem risk of CCB and diltiazem Monitor BP/HR and titrate levels—no studies except with to response (diltiazem indinavir: amlodipine AUC 90% dose 50% w/ ATV/r) and diltiazem AUC 27% COMMENTS Inhaled steroids NS AUC with beclomethasone; case reports of Cushingnoid with DRV/r and TAC injections Beclomethasone preferred, use cautiously. C/I:fluticasone, budesonide SSRI paroxetine AUC 39% sertraline AUC 49% bupropion AUC 50-60% by Higher SSRI/bupropion may be required. Monitor for antidepressant efficacy LPV/r, TPV/r 63 64 DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/ Case 2 Presentation RJ is a 55 year old HIV-infected male lawyer with multiple co-morbidities who is reluctant to start ART due to concerns about side effects affecting his ability to function and think clearly. • Allergy: NKA • PMH/Medications: – – – – – – Hemophiliac: weekly Factor 7 transfusions Allergic rhinitis—nasal fluticasone BID Hypertension—lisinopril 40 mg + diltiazem 300 mg daily Dyslipidemias—simvastatin 20 mg daily Severe GERD—pantoprazole 20 mg BID Depression— sertraline 100 mg daily 65 © 2016 by the American Pharmacists Association. All rights reserved. Self-Assessment Question In RJ, which of the following initial ART regimen is most appropriate to achieve the lowest risk of drug interactions and side effects? 1. 2. 3. 4. 5. 6. Darunavir 800 mg/ritonavir 100 mg),TDF/FTC Dolutegravir, TDF/FTC) Atripla (efavirenz, TDF/FTC) Genvoya (elvitegravir/cobi, TAF/FTC) Complera (rilpivirine, TDF/FTC) Triumeq (dolutegravir, ABC/3TC) TDF/FTC = tenofovir/emtricitabine; ABC abacavir, 3TC lamivudine; TAF= tenofovir alafenamide, 66 Case 3: Interactions Among ARVs • You receive a new prescription for an new ARV regimen prescribed for a treatment experienced HIV+ person who has failed multiple regimens. His medication profile shows the following: – Depression: bupropion 15 mg TID PO – Insomnia: trazodone 100 mg @ bedtime PO – Methadone maintenance: 30 mg daily PO New prescription: dolutegravir (Tivicay) 50 mg –take one tablet daily tenofovir/emtricitabine (Truvada) one tablet daily etravirine (Intelence) 200 mg one tablet bid Which of the following would be the most appropriate to recommend to the prescriber about the new ARV regimen? A. Bupropion dose increase may be warranted B. Watch for methadone withdrawal C. Watch for increased trazodone side effects D. HIV VL suppression may be insufficient E. Monitor for increased risk of renal toxicity from tenofovir 67 Which would be the most appropriate to add and co-administer with etravirine? Dolutegravir (DTG) and Antiretroviral Drug Interactions ARVs Interaction Recommendation ATV/r, DRV/r, LPV/r, RPV No interaction Usual DTG dosage Nevirapine DTG Avoid co-administration Etravirine DTG A. B. C. D. E. Avoid co-administration Need to co-administer with PI Efavirenz, fosamprenavir/r, tipranavir/r DTG 68 Tipranavir/ritonavir Atazanavir/cobicistat (Evotaz) Fosamprenavir/ritonavir Darunavir/cobicistat (Prezcobix) Darunavir/ritonavir DTG 50 mg bid if integrase naïve, otherwise, avoid 69 Etravirine (ETR) and PI Drug Interactions • ETR Pharmacokinetics 70 Etravirine (ETR) Administration with Protease Inhibitors (PI) • Cautious co-administration of ETR and “SALoD”: – 3A4, 2C9 and 2C19 substrate – 3A4 inducer (weak) – 2C9 . 2C19, and p-gp inhibitor • Cautious administration ETR with: – SAQ 1 gm /r 100 mg bid ETR Cmin 29% NS SAQ levels ATV 300 mg /r 100 mg daily ETR AUC/Cmin 30% ATV Cmin18% ETR AUC 76%, Cmin 82% TPV AUC 18% and Cmin 24% – Fosamprenavir/r APV AUC 69% and Cmin 77% – Atazanavir/cobicistat ATV and cobi – Darunavir/cobicistat DRV and cobi – Tipranavir/r *Kakuda TN et al. 13thth Int Workshop Clin Pharm, 2012, Abst 0_24, Barcelona © 2016 by the American Pharmacists Association. All rights reserved. 71 – LPV 400mg/r 100 mg bid ETR AUC 35% LPV AUC 13% (NS) – DRV 600 mg/r 100 mg bid 600 mg bid/ r 100 mg bid ETR AUC 37%, Cmin 49% (ok DUET trial) 72 Dolutegravir (DTG) and Antiretroviral Drug Interactions ARVs Interaction Recommendation ATV/r, DRV/r, LPV/r, RPV No interaction Usual DTG dosage Nevirapine DTG Avoid co-administration Etravirine DTG Avoid co-administration Case 4 Presentation • Mr RJ is a 63 yr old male who in interested in taking new HCV agents that can cure HCV. He is reluctant to change his HIV regimen “since it works better than his past regimens of 8 tablets daily and he notices no side effects”. PMH: • – Hep C genotype 1a, no cirrhosis –failed pegylated interferon, ribavirin – HIV infection–CD4 585 c/mm3 with undetectable HIV viral load on tenofovir/emtricitabine (Truvada) plus atazanavir 300/r 100 mg daily – Dyslipidemia—on atorvastatin 40 mg daily – Hx Afib and s/p CVA on warfarin 6 mg daily (INR stable at 2.5) – Gout—indomethacin 500 mg every 8hr prn acute flares – GERD- prn OTC ranitidine Need to co-administer with ATV/r, DRV/r or LPV/r Efavirenz, fosamprenavir/r, tipranavir/r DTG DTG 50 mg bid if integrase naïve, otherwise, avoid 73 74 Case Presentation • • • • • • • Ritonavir Boosted Atazanavir (ATV/r) • No longer recommended as initial ART therapy • Side effects concerns: PE: BMI 32; BP 140/80 Labs: Scr 1.0 mg/dL; CrCL > 60 mL/min CBC, AST, ALT and liver ultrasound are normal HLA-B*5701 negative CD4+ cell count 585 cells/mm3 (30 %) HCV RNA 5,890,670 IU/mL Immune to hepatitis A and B • 75 Self-Assessment Question Considering his ART therapy, which of the following is the most appropriate to recommend to RJ’s doctor? 1. 2. 3. 4. 5. 6. Change atorvastatin to rosuvastatin Start rivaroxaban for warfarin Substitute colchicine for indomethacin Start omeprazole 40 mg daily atazanavir 400 mg/r 100 mg daily Change ranitidine to ATC with ART Meds: Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine © 2016 by the American Pharmacists Association. All rights reserved. 77 – GI effects (n,v,d) – Jaundice (“stigma”) 43% (ACTG 5257) Adverse effects – Dyslipidemia: • lower FBS, TC, non-HDL cholesterol, TG. vs LPV/r • similar lipid changes as DRV/r but worse than RAL – Hyperglycemia • FBS 4.8 mg/dl (EFV) vs 0.4 mg/dl (ATV/r)@96 wks – Others: renal stones, 2x cholethiasis (onset 42 mo) Clin Infect Dis. (2015) 60:1842; Ann Intern Med. 2014 October 7; 161: 461 76 Atazanavir (ATV/r) and Acid Reducing Agents • Acid reducing agents – increase gastric pH – can significantly reduce atazanavir absorption • Atazanavir requires acidic PH for optimal absorption – Solubility is 1.1 mg/ml at pH <1 vs. <0.002 at pH5 • Give ATV 2 hr before or 1 hr after antacid 78 Atazanavir/ritonavir or cobi interaction with Acid Reducing Agents • H2 RA – ARV naïve: DNE famotidine 40 mg BID (ranitidine 300 mg bid, cimetidine 800 mg bid, nizatidine 300 mg bid) – ARV experienced: DNE famotidine 20 mg BID (ranitidine150 mg bid, cimetidine 400 mg bid, nizatidine 150 mg bid) Atazanavir and Proton Pump Inhibitors (PPI) • Use PPI only in ARV-naïve persons – DNE 20 mg/day of omeprazole – Administer PPI 12 hours before ATV 300/r 100 mg • Avoid PPI in treatment-experienced persons ATV dose OMP Dose Cmin ATV/r 300/100 mg daily 40 mg/day 20 mg/day ↓ 78% ↓ 46% ATV/r 400/100 mg daily 20 mg/day ↓ 31% – Give ATV/r with and/or ≥10 hours after the H2RA – ATV 400 mg/r 100 mg daily if given with tenofovir + H2RA in ART experienced persons. 79 Atazanavir/r and PI Anticoagulant Drug Interactions PK EFFECTs Recommendations Rivaroxaban (Xarelto®) rivaroxaban with bleeding risk Contraindicated Apixaban (ELIQUIS®) apixaban with bleeding risk Reduce apixaban dose by 50% or avoid use Dabigatran Dabigatran (p-gp substrate) Cautious use. Avoid if CrCl < 50 mL/min. DRUG ATV/r or warfarin possible Monitor INR and adjust DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/ 80 Atazanavir/r Statin Drug Interactions PK EFFECTs Statins Simvastatin/lovastatin AUC 500-3000% DRUG Warfarin Reyataz package insert Recommendations (myositits, rhabdomyolysis) Contraindicated with simvastatin and lovastatin (red rice yeast). Atorvastatin possible Use lowest dose rosuvastatin AUC 3 fold; Cmax 7 fold Use lowest dose, DNE 10 mg/day pitavastatin AUC 31%, Cmax 60% Use normal doses No interaction with pravastatin Use normal doses DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/ 81 Selected Atazanavir/r or PI DI DRUG EFFECT CCBs: risk of CCB and diltiazem Amlodipine levels—no studies Diltiazem Questions to Discuss COMMENTS • What drug interactions are expected with appropriate DAA Monitor BP/HR and titrate to response (diltiazem dose 50% w/ ATV/r) Colchicine RTV 100 mg BID colchicine Colchicine 0.6 mg x 1 AUC 296%, Cmax 184% dose, then 0.3 mg 1 hour later. Do not repeat dose for at least 3 days. Reduce prophylaxis to daily or every other day SSRI paroxetine AUC 39% sertraline AUC 49% bupropion AUC 50-60% 82 for his hepatitis C infection? • What modifications to his co-morbid conditions would be necessary to accommodate the HCV therapy? Higher SSRI/bupropion may be required. Monitor for antidepressant efficacy by LPV/r, TPV/r 83 © 2016 by the American Pharmacists Association. All rights reserved. 84 Genotype 1 HCV Agents Polymerase Inhibitors Protease Inhibitors Nucleotide Simeprevir Sofosbuvir Paritaprevir ritonavir Nonnucleoside Dasabuvir Self-Assessment Question NS5A Inhibitors Other Ledipasvir Ribavirin 1. Sofosbuvir/ledispasvir (Harvoni) 2. Paritaprevir/ritonavir/ombitasvir/dasabuvir Ombitasvir Daclatasvir (DCV) (ViekiraPak or PROD) 3. Sofosbuvir/simeprevir 4. Sofosbuvir/daclastasvir 5. Grazoprevir/elbasvir 85 www.hcvguidelines.org Which is the most appropriate action in RJ if ledipasvir/sofosbuvir (Harvoni) is selected as his hepatitis C therapy ? 86 • LDV/SOF are p-gp and BRCP substrates • LDV but not SOF are pgp and BRCP inhibitors • Avoid co-administration: • • • • • Change HRA to omeprazole 20 mg daily Consider using abacavir for tenofovir Change atorvastatin to rosuvastatin Stop warfarin and indomethacin Change PI to NNRTI Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine Ledipasvir/Sofosbuvir (LDV/SOF) Drug Interactions Self-Assessment Question 1. 2. 3. 4. 5. Which of the following HCV GT 1a recommendations would result in RJ’s lowest risk of drug interactions? Amiodarone St. John’s wort: ledipasvir/sofosbuvir Anticonvulsants: Pb, phenytoin, carbamazepine Anti-mycobacterials: rifampin, rifabutin, rifapentine Rosuvastatin: risk myopathy • Use atorvastatin, pravastatin, simvastatin 87 Update to sofosbuvir and ledipasvir/sofosbuvir US package inserts 88 Ledipasvir/Sofosbuvir (LDV/SOF) Drug Interactions with Acid Reducing Agents • pH ledipasvir solubility LDV/SOF. Update to simeprevir US package insert simeprevir. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205834s001lbl.pdf. 89 http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205123s008lbl.pdf. © 2016 by the American Pharmacists Association. All rights reserved. • Antacids: separate from LDV/SOF by 4 hrs • H2 RA: together or 12 hr apart, max of 40 mg famotidine bid • PPI: concurrent omeprazole 20 mg max/day • Target Study: no PPI: 3.02 OR of achieving SVR • Try to avoid all, especially PPI despite current labeling 90 Tenofovir (TDF) Drug interaction with Ledipasvir (LDV)/Sofosbuvir (SOF) No Baseline PPI Use on Ledipasvir Sofosbuvir SVR Results (HCV-TARGET) No PPI @ baseline OR 3.02 (1.516.05) PPI No PPI 0.001 100 98 93 98 93 • TDF AUC 20-30% with boosted PI • Addition of LDV TDF AUC • Mechanism: ?? LDV p-glycoprotein or BCRP inhibition SVR12 (%) 80 60 40 20 n/N = 0 122/ 124 28/ 30 8-Wk 456/ 464 TDF AUC Efavirenz 98% Rilpivirine 40% Darunavir/ritonavir 38-60% • Clinical outcome of TDF AUC with LDV/SOF is unknown • Cautious use if borderline low GFR or taking boosted PI • Consider changing to ABC/3TC or INSTI regimen if feasible 151/ 163 12-Wk 91 Slide credit: clinicaloptions.com Terrault N, et al. AASLD 2015. Abstract 94 ARV withTDF/FTC ARV Interactions: Ledispasvir/Sofosbuvir (Harvoni) German P et al, 22nd CROI 2015, Abstr 82; 15th Internat Workshop Clin Pharm HepC and HIV, 2014 ARV Interactions:Paritaprevir-Ritonavir + Ombitasvir, Dasabuvir (PROD,Viekira Pak) ARV Outcome Tenofovir (TDF) Use cautiously: TDF AUC and risk of renal dysfunction. Lowest risk with INSTI vs NNRTI and PI (highest risk) NRTI Maraviroc MVC Elvitegravir/cobicistat (Stribild) • • Source: Viekira Pak Prescribing Information. AbbVie Inc. ARV Source: Viekira Pak Prescribing Information. AbbVie Inc. NRTI, TAF (except tenofovir) NNRTI INSTI: dolutegravir, raltegravir INSTI: dolutegravir, raltegravir NNRTI:efavirenz, etravirine, rilpivirine, nevirapine No interactions, standard dosing Protease inhibitors: fosamprenavir/r, tipranavir/r, lopinavir/r, saquinavir/r Maraviroc Protease inhibitors (ATV/r, DRV/r, LPV/r) Elvitegravir/cobicistat (Stribild) Not recommended, risk TDF toxicity Tipranavir/ritonavir Contraindicated Protease Inhibitors: Atazanavir Darunavir/r Outcome No interactions Contraindicated Liver elevations with efavirenz Risk QT with rilpivirine MVC to 150 mg BID 300 mg atazanavir, no ritonavir 800 mg darunavir if no PI mutations 93 ARV Interactions: Daclatasvir (DCV,Daklinza) ARV 92 Outcome 94 Antiretroviral Interactions with Sofosbuvir NRTI ARVs Sofosbuvir Interaction Rilpivirine Protease Inhibitors DRV/r No interaction Avoid TPV/r sofosbuvir NNRTI EFV, RPV OK No interaction INSTI Raltegravir OK No data w/ dolutegravir and Elvitegravir/cobicistat Maraviroc No interactions, standard 60 mg DCV INSTI: dolutegravir, raltegravir PI: darunavir/r, lopinavir/r EVG/cobicistat (Stribild) PI: atazanavir/r, fosAPV/r, Saquinavir/r DCV 30 mg d/t 3A4 inhibition NNRTI: Efavirenz, etravirine, nevirapine DCV 90 mg d/t 3A induction Tipranavir/r Contraindicated if co-administered with DCV and sofosbuvir 95 © 2016 by the American Pharmacists Association. All rights reserved. NRTI OK No interaction CCR5: maraviroc OK No interaction 96 Antiretroviral Interactions with Simeprevir ARVs Simeprevir ARV Interactions: Grazoprevir (GZR) and Elbasvir (EBR) • GZR is 3A, p-gp, and OATP substrate, weak 3A inhibitor • EBR is 3A and p-gp substrate Interaction Protease Inhibitors Avoid or Simeprevir NNRTI (EFV, NVP, ETR) Avoid. Simeprevir INSTI Raltegravir OK ARV Outcome NRTI: Tenofovir Rilpivirine OK No interaction NNRTI: rilpivirine No data with dolutegravir No interactions, standard dosing INSTI: dolutegravir, raltegravir Cobicistat Avoid Stribild Simeprevir NRTI OK No interaction Protease inhibitors (ATV/r, DRV/r, LPV/r) Elvitegravir/cobicistat (Stribild) CCR5: maraviroc OK No interaction Efavirenz Not recommended 97 98 HIV Drug Interaction Website Strategies to Identifying and Reducing Risk of Drug Interactions • Review risk factors for DI • Review list of all medications, including herbals, OTC, • • • • • • • supplements Understand metabolism for all medications If feasible, design INSTI regimens; avoid PI and NNRTI Ultilize medication management services (e.g. pharmacists) Check drug interaction drug data bases Hold drug or adjust dose, therapeutic interchange Counsel patient about interacting agents Inform prescriber about potential interactions 99 100 Additional HIV and HCV Resources HCV Drug Interaction Websites • Clinicians’ Consultation Center: • 1-800-933-3413 http://www.nccc.ucsf.edu/ • Conference on Retrovirus and Opportunistic Infections (CROI 2016) http://retroconference.org/ • AIDS Education and Training Centers National Resource Center http://www.aids-ed.org • Clinical Care Options HIV and HCV : http://www.clinicaloptions.com • HIV Insite: http://hivinsite.ucsf.edu • HIV-Associated Resources on the Web. (http://www.iasusa.org) • El-Sherif O et al. Key drug–drug interactions with direct-acting • 101 © 2016 by the American Pharmacists Association. All rights reserved. antiviral in HIV–HCV coinfection. Curr Opin HIV AIDS 2015,10:348–54 Drug interactions-Toronto Immunodeficiency Clinic. http://www.hivclinic.ca/main/drugs_interact.html 102 Self-Assessment Question Key Points Which of the following would pose the lowest risk of drug interactions? • Drug Interactions are common with ART • Drug Interactions can lead to ART failure and/or toxicity • The CYP450 system are major reasons for ART drug interactions. • Important to review all medications, including OTC, herbal • Pharmacists can play a major role in preventing drug • interactions and improving HIV care Difficult to know all drug interactions, use drug interaction websites and drug metabolism to identify potential drug interactions. 1. 2. 3. 4. 5. Raltegravir Dolutegravir Rilprivine Elvitegravir/cobistat Darunavir/ritonavir 103 Self-Assessment Question Self-Assessment Question Proton pump inhibitors are contraindicated with which antiretroviral? 1. 2. 3. 4. 5. Raltegravir Rilpivirine Dolutegravir Atazanavir/cobicistat Darunavir/ritonavir Self-Assessment Question Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID, lorazepam 2 mg prn anxiety 106 Which of the following hepatitis agents would result in the lowest risk of ARV drug interactions? Reduce metformin dose Reduce amlodipine dose Change lorazepam to triazolam Separate esomeprazole by 6 hr Give Al-Mg antacids at same time © 2016 by the American Pharmacists Association. All rights reserved. Reduce metformin dose Increase amlodipine dose Give CA+ w/DTG on empty stomach Stop esomeprazole Give Al-Mg antacids at same time Self-Assessment Question Which of the following should be considered if elvitegravir, emtricitabine, tenofovir (Stribild) or Tenofovir alafenamide (Genvoya) is started? Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress, Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID Metformin 1000 mg BID Which is the most appropriate recommendation if dolutegravir, abacavir, and lamivudine (Triumeq) is selected as initial ART? 1. 2. 3. 4. 5. 105 1. 2. 3. 4. 5. 104 1. Sofosbuvir/ledispasvir (Harvoni) 2. Paritaprevir/ritonavir/ombitasvir/dasabuvir (ViekiraPak or PROD) 3. Sofosbuvir/simeprevir 4. Sofosbuvir/daclastasvir 5. Grazoprevir/elbasvir 107 Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine 108 Self-Assessment Question What can occur if ledipasvir/sofosbuvir (Harvoni) is given with tenofovir, emtricitabine, and darunavir/r regimen? 1. 2. 3. 4. 5. HCV treatment failure HIV treatment failure Darunavir hepatic toxicity Tenofovir renal toxicity Emtricitabine lipid toxicity Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin, warfarin, indomethacin, OTC ranitidine © 2016 by the American Pharmacists Association. All rights reserved. 109