Λυδία Λεωνίδου Παθολόγος- Λοιμωξιολόγος Μονάδα Λοιμώξεων Πατρών

55 ετών άντρας, ετεροσεξουαλικός HIV (+) > 6 έτη, σε TNF/FTC +DRV/r HCV RNA 1.200.000 IU/mL, GT1a null responder pegifn + RBV (2012) Ιστορικό : ΣΔ τύπου 2, υπερλιπιδαιμία, υπέρταση, ΓΟΠ Φάρμακα : metformin 850 mg, rosuvastatin 20 mg, omeprazole 40 mg, lisinopril 10mg Καπνιστής, κοινωνικός πότης, παχύσαρκος CD4+ count 620 cells/mm 3, HLA-B*5701 negative ALT 42 IU/mL, AST 36 IU/mL Creatinine 1.3 mg/dl, CrCl 70 ml/min HAV Ab neg, HBsAb/HBsAg neg Fibroscan 9,5 kpa

10 1. SMV + SOF 2. LDV/SOF 3. OBV/PTV/RTV + DSV 4. Όλα είναι πιθανή επιλογή 5. Κανένα από τα παραπάνω Total: 100 20.0% (20) 20.0% (20) 20.0% (20) 20.0% (20) 20.0% (20)

No 8-wk regimens recommended in HIV/HCV coinfection Other recommendations on treatment duration and inclusion of RBV same for HCV monoinfection, HIV/HCV coinfection Population SMV + SOF [1] LDV/SOF [1] DCV + SOF [1] OBV/PTV/RTV + DSV [1] EBR/GZR [2] GT1a, no cirrhosis 12 wks 12 wks 12 wks 12 wks + RBV 12 wks GT1a, cirrhosis Naive Experienced* 24 wks ± RBV 24 wks ± RBV 12 wks 12 wks + RBV or 24 wks *PegIFN/RBV experienced. If HCV PI experienced, DCV + SOF or LDV/SOF recommended. If SOF/RBV experienced, LDV/SOF recommended. Do not use if Q80K positive. If baseline NS5A RAVs, add RBV and treat for 16 wks. 1. AASLD/IDSA. HCV guidelines. March 2016. 2. EBR/GZR [package insert]. 24 wks ± RBV 24 wks ± RBV 24 wks + RBV 24 wks + RBV 12 wks 12 wks GT1b, no cirrhosis 12 wks 12 wks 12 wks 12 wks 12 wks GT1b, cirrhosis Naive Experienced* 24 wks ± RBV 24 wks ± RBV 12 wks 12 wks + RBV or 24 wks 24 wks ± RBV 24 wks ± RBV 12 wks 12 wks 12 wks 12 wks

HCV Treatment: A Journey hcv agents: Basic Principles Pharmacology Managing the Interactions SVR Bermuda Triangle Identifying Interactions with Concomitant Medications From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Identifying Interactions with Antiretroviral Agents

Ορισμός Αλληλεπίδραση φαρμάκων συμβαίνει όταν οι δράσεις (φαρμακολογικές, τοξικές) ενός φαρμάκου μεταβάλλονται από την παρουσία ενός άλλου φαρμάκου, φυτοθεραπευτικών, τροφίμων, ποτών, ή χημικών ουσιών του περιβάλλοντος

Μειωμένη γαστρεντερική απορρόφηση του φαρμάκου Αναστολή ή επαγωγή του μεταβολισμού του φαρμάκου Φαρμακευτικές αλληλεπιδράσεις συμβαίνουν συχνά χωρίς όμως κλινικά σημαντική έκβαση Κλινική συνέπεια αποκτούν όταν σχετίζονται με μειωμένη φαρμακευτική αποτελεσματικότητα ή συστηματική τοξικότητα

Ενζυμική Αναστολή Ο μεταβολισμός ενός φαρμάκου αναστέλλεται από τη συγχορήγηση ενός άλλου φαρμάκου Ενζυμική Επαγωγή Ο μεταβολισμός ενός φαρμάκου αυξάνεται από τη συγχορήγηση ενός άλλου φαρμάκου

CYP450 and Drug Metabolism Slide 9 of 39 CYP2C CYP2D6 CYP1A2 CYP2E1 Majority of marketed medications are metabolized by (or substrates for) CYP3A4* Drugs that inhibit CYP3A raise concentrations of CYP3A substrates Drugs that induce CYP3A lower concentrations of CYP3A substrates CYP3A4 *Flockhart DA, Tanus-Santos JE. Arch Intern Med 2002;162:405-412. From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

of 39 Drug Concentration Inhibiting drug added Time

Αναστολή μεταβολισμού ενός φαρμάκου => αύξηση επιπέδων ορού => συσσώρευση στην κυκλοφο ρία => αυξημένη βιοδιαθεσιμότητα => τοξικότητα φαρμάκου Παραδείγματα Συγχορήγηση αζολών + στατινών (αναστολή CYP 3A4) => ραβδομυόλυση Συγχορήγηση μακρολιδών + στατινών (αναστολή CYP 3A4) => ραβδομυόλυση Συγχορήγηση μακρολιδών + καρβαμαζεπίνης ή βενζοδιαζεπινών => ίλιγγος, αταξία, καρ.αρρυθμία, υπνηλία, καταστολή Συγχορήγηση μακρολιδών + κυκλοσπορίνης => υπέρταση, νεφρική ανεπάρκεια Συγχορήγηση ΤΜΡ-sulfa + MTX (αναστολή CYP 3A4) => μυελοτοξικότητα, κυτταροπενίες

of 39 Drug Concentration Inducing drug added Time

Επαγωγή του μεταβολισμού ενός φαρμάκου => μείωση επιπέδων ορού => μειωμένη βιοδιαθεσιμότητα => θεραπευτική αποτυχία Παραδείγματα Συγχορήγηση ριφαμπικίνης + αντισυλληπτι κών (επιτάχυνση μεταβολισμού των αντισυλληπτικών μέσω CYP 3A4) => ανεπαρκής αντισυλληπτική προστασία, ανεπιθύμητη κύηση Συγχορήγηση ριφαμπικίνης + κορτικοστεροειδών Συγχορήγηση ριφαμπικίνης + κυκλοσπορίνης Συγχορήγηση ριφαμπικίνης + αζολών

of 39 Systemic Circulation Systemic Circulation NTC P OATP1 B1 OAT2 BCRP MRP2 Bile ABCG5/G8 BSEP MRP3 MRP4 OCT1 P-gp MDR3 Sinusoidal Membrane Canalicular Membrane

Category Viral Treatment Fibrosis stage Coinfection/comorbidities HCV GT Viral load HCV treatment history PegIFN + RBV Protease inhibitor Sofosbuvir Financial Insurance approval Factors RBV eligibility Resistance Child-Pugh score If cirrhotic, any history of decompensation? Transplant evaluation if necessary HIV coinfection Cardiovascular, renal, metabolic, etc, concerns Drug drug interactions

Drug Class Contraindicated With BOC [1] Contraindicated With TVR [2,3] Alpha 1-adrenoreceptor antagonist Anticonvulsants Alfuzosin Carbamazepine, phenobarbital, phenytoin Alfuzosin Antimycobacterials Rifampin Rifampin Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents Cisapride Cisapride Carbamazepine, phenobarbital, phenytoin Dihydroergotamine, ergonovine, ergotamine, methylergonovine Herbal products St John s wort St John s wort HMG CoA reductase inhibitors Lovastatin, simvastatin Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for tx of pulmonary arterial HTN Lovastatin, simvastatin Sildenafil or tadalafil when used for tx of pulmonary arterial HTN Sedatives/hypnotics Triazolam; orally Triazolam; orally 1. Boceprevir [package insert]. 2013. administered 2. Telaprevir midazolam [package insert]. administered 2013., 3. www.hep-druginteractio midazolam

Pts With Potential Drug Interactions (%) Retrospective analysis of pts with HIV/HCV coinfection (n = 125) 81% receiving TDF, 35% RAL, 16% EFV, 40% PI/RTV 100 80 60 Drug interactions None Moderate Severe 40 20 0 SMV + SOF LDV/SOF DCV + SOF OBV/PTV/ RTV + DSV Langness J. HIV and Hep Clin Pharm Workshop 2015. Abstract 18.

55 ετών άντρας, HIV σε DRV/RTV + TDF/FTC Lisinopril,r osuvastatin,omeprazole HCV genotype 1a, null response to pegifn/rbv HLA-B*5701 negative, CrCl 70 ml/min

Concurrent Medication Recommendation HIV Protease Inhibitors All HIV PIs, with or without ritonavir, except tipranavir Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Tipranavir Co-administration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors All NNRTIs Concurrent use at standard doses acceptable.

Concurrent Medication Recommendation HIV Integrase Strand Transfer Inhibitors Dolutegravir (Tivicay ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Elvitegravir (contained in Stribild ) Raltegravir (Isentress ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. Concurrent use at standard doses acceptable. HIV Entry Inhibitors Maraviroc (Selzentry ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. HIV Nucleoside/Nucleotide Reverse Transcriptase Inhibitors All NRTIs www.nynjaetc.org Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir.

Concurrent Medication HIV Protease Inhibitors Recommendation All HIV PIs Significant increases or decreases in simeprevir levels expected when used with any HIV protease inhibitor, when used with or without ritonavir. Coadministration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors Efavirenz (Sustiva ), Etravirine (Intelence ), Nevirapine (Viramune ) Significant reductions in simeprevir levels and reduced simeprevir efficacy due to CYP3A4 induction. Co-administration not recommended. Rilpivirine (Eviplera ) Concurrent use at standard doses acceptable.

Concurrent Medication Recommendation HIV Integrase Strand Transfer Inhibitors Dolutegravir (Tivicay ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of simeprevir. Elvitegravir (contained in Stribild ) Significant increase in simeprevir levels expected when used with a cobicistat containing regimen. Co-administration not recommended. Raltegravir (Isentress ) Concurrent use at standard doses acceptable. HIV Entry Inhibitors Maraviroc (Selzentry ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of simeprevir. HIV Nucleoside/Nucelotide Reverse Transcriptase Inhibitors All NRTIs Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism

Medication and or Class Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin Antimycobacterials rifampin, rifabutin, rifapentin Rationale for Avoiding with Sofosbuvir Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy. Co-administration not recommended. Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy due to intestinal P- glycoprotein (P-gp) induction from rifampin. Herbal products St. John s Wort Co-administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy due to intestinal P- glycoprotein (P-gp) induction associated with St. John s Wort.

Medication and or Class Rationale for Avoiding with Simeprevir Anticonvulsants - carbamazepine, oxcarbazepine, phenobarbital, phenytoin Co-administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended. Antibiotics clarithromycin, erythromycin, telithromycin Co-administration with these medications is likely to increase concentrations of either simeprevir or the antibiotic due to CYP3A4 and P-glycoprotein (P-gp) inhibition. Co-administration not recommended. Antifungals fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole Co-administration with these medications is likely to increase concentrations of simeprevir due to CYP3A4 inhibition from the antifungals. Co-administration not recommended. Antimycobacterials rifampin, rifabutin, rifapentine Co-administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended.

Medication and or Class Corticosteroids dexamethasone Rationale for Avoiding with Simeprevir Co-administration with dexamethasone is likely to decrease concentrations of simeprevir and lead to reduced simeprevir efficacy. Co-administration not recommended. Propulsive cisapride Co-administration with cisapride may result in increased concentrations of cisapride leading to potential cardiac arrhythmias. Herbal products Milk Thistle, St. John s Wort Co-administration with milk thistle is likely to increase concentrations of simeprevir. Coadministration not recommended. Co-administration with St. John s Wort is likely to reduce concentrations of simeprevir leading to reduced simeprevir efficacy, due to intestinal P- glycoprotein (P-gp) induction associated with St. John s Wort.

10 1. Μπορούμε να συνεχίσουμε DRV/RTV + TDF/FTC και να τον παρακολουθήσουμε 2. Switch σε EVG/COBI/TNF/FTC, μείωση ομεπραζόλης σε 20mg 3. Switch σε RAL + ABC/3TC και συνέχιση άλλων φαρμάκων 4. Πρέπει να διακόψουμε τη rosuvastatin Total: 32 18.8% (6) 25.0% (8) 25.0% (8) 31.3% (10) 55 ετών άντρας, HIV σε DRV/RTV + TDF/FTC Lisinopril,r osuvastatin,omeprazole, metformin HCV genotype 1a, null response to pegifn/rbv HLA-B*5701 negative, CrCl 70 ml/min

No consensus on approach Monitoring centers on evaluation for TDF-related toxicity Evaluate risk factors for kidney disease DM, Hypertension, black race HCV, HIV on TDF plus Abnormal baseline Cr Wk 2: Cr, U/A, CBC (if RBV) Wk 4: chem panel, LFTs, U/A, CBC (if RBV), HCV RNA Some providers might check at Wk 1; minimum every 4 wks for rest of therapy

When LDV/SOF and TDF are coadministered with antiretrovirals, monitor for nephrotoxicity [1] Avoid combination of LDV and TDF if CrCl < 60 ml/min or if receiving TDF with RTV-boosted PIs [1] Do not coadminister LDV/SOF and tipranavir/rtv [2] In real-world HCV-TARGET database of pts receiving 8 or 12 wks LDV/SOF, PPI use associated with higher failure rate [3] 1. AASLD/IDSA. HCV guidelines. March 2016. 2. Ledipasvir/sofosbuvir [package insert]. 3. Terrault N, et al. AASLD 2015. Abstract 94.

Per protocol analysis (n = 1979) Caution with use of high dose PPIs with LDV/SOF n = 454 P =.799 P =.965 P =.030 97% PPI drug Dexlansoprazole (n = 10) Esomeprazole (n = 48) Lansoprazole (n = 26) Omeprazole (n = 288) Pantoprazole (n = 77) Rabeprazole (n = 5) PPI dose Low (n = 282) High (n = 172) PPI frequency Once daily (n = 420) Twice daily (n = 34) Afdhal N, et al. EASL 2016. Abstract LBP519. 80% 90% 100%

SVR12 (%) Real-world data from 2034 pts with GT1 HCV receiving LDV/SOF A per protocol analysis (n = 1979) showed no effect of PPIs on SVR SVR12 According to Baseline PPI Use 100 80 98 100 98 97 99 97 PPI: No PPI: Yes 60 40 20 n/n = 0 230 41/ 1024 287 243 113 /23 41 /104 /29 /24 /11 4 8 Wks 5 7 12 Wks 6 6 24 Wks Afdhal N, et al. EASL 2016. Abstract LBP519.

Aλληλεπιδράσεις DAAs με στατίνες www.hep-druginteractions.org

10 1. Μπορούμε να προσθέσουμε OBV/PTV/RTV + DSV και να διακόψουμε τη ριτοβαρίνη 34.4% (11) 2. Αντενδείκνυται η προσθήκη ριμπαβιρίνης 3. Αναμένουμε το Elbasvir/Grazoprevir για αντιμετώπιση 18.8% (6) 28.1% (9) 4. Μπορούμε να προσθέσουμε DCV + SOF χωρίς άλλη αλλαγή 18.8% (6) Total: 32 55 ετών άντρας, HIV σε DRV/RTV + TDF/FTC Lisinopril,r osuvastatin,omeprazole,metformin HCV genotype 1a, null response to pegifn/rbv HLA-B*5701 negative, CrCl 70 ml/min

Phase III study of OBV/PTV/RTV + DSV in HIV/HCV coinfection included pts with ATV- or RAL- based ART only; pts with DRV being evaluated in ongoing part 1b [1] Use caution or do not coadminister OBV/PTV/RTV with: DRV (DRV C min decreases 43% to 48%) [2] LPV (PTV AUC increases 117%) [2] ATV/COBI, DRV/COBI, FPV, SQV, TPV (no data) [2] RPV (QT prolongation) [3] Adjust/withhold RTV if receiving a boosted PI with OBV/PTV/RTV + DSV [4] 1. Sulkowski M, et al. JAMA. 2015;313:1223-1231. 2. DHHS Guidelines. November 2015. 3. OBV/PTV/RTV + DSV [package insert].4. AASLD/IDSA. HCV guidelines. March 2016.

Phase III study of DCV + SOF in HIV/HCV coinfection allowed most ARV regimens, including EFV, RPV, PI/RTV with TDF [1] DCV + SOF recommended by AASLD when ART regimen changes cannot be made to accommodate other DAAs [2] Dose adjustment needed with ATV/RTV, EFV, or ETR, [2] but DCV + SOF not coformulated, allowing adjustment of DCV dose 90 mg DCV daily with EFV 30 mg DCV daily with ATV/RTV 60 mg DCV daily with all others (including DRV/RTV and LPV/RTV) Potential difficulty with insurance approval (cost) 1. Wyles D, et al. N Engl J Med. 2015;373:714-725 2. AASLD/IDSA. HCV guidelines. March 2016.

SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV + DSV EBR/GZR Atazanavir + RTV Darunavir + RTV Lopinavir/RTV Tipranavir + RTV Efavirenz Rilpivirine Etravirine Dolutegravir or raltegravir Elvitegravir + COBI Abacavir/lamivudine * Maraviroc Tenofovir alafenamide Tenofovir DF/ emtricitabine No clinically significant interaction expected nephrotoxicity Potential interaction may require adjustment to dosage, timing of administration, or monitoring Do not coadminister

Regimen SOF/LDV [1] Warnings/Contraindications Coadmin with amiodarone not recommended due to bradycardia reports Do not administer with P-gp inducers PTV/RTV/ OBV + DSV [2] Contraindicated in pts with moderate to severe hepatic impairment Increased risk of ALT elevations Contraindicated with drugs dependent on CYP3A for clearance, inducers of CYP3A, inducers/inhibitors of CYP2C8 SIM [3] DCV [4] Bradycardia reported when SOF coadmin with a DAA and amiodarone Not recommended in pts with moderate to severe hepatic impairment Photosensitivity and rash can occur Bradycardia reported when SOF coadmin with a DAA and amiodarone Contraindicated with inducers of CYP3A GZR/EBV [5] Contraindicated in pts with moderate/severe hepatic impairment Increased risk of ALT elevations 1. SOF/LDV [package insert]. 2. PTV/RTV/OBV + DSV [package insert]. 3. SMV [package Contraindicated insert]. 4. DCV with [package OATP1B1/3 insert]. 5. inhibitors, strong CYP3A inducers GZR/EBV [package insert]. Slide credit: clinicaloptions.com

Concomitant Medication SOF SIM LDV PTV/RTV/OBV + DSV DCV GZR/EBV Acid-reducing agents* X X Amiodarone X X X X X X Anticonvulsants X X X X X X Digoxin X X X X Ethinyl estradiol containing products X Glucocorticoids X X X X PDE5 inhibitors X X X Rifamycin antimicrobials X X X X X X Sedatives X X X St John s wort X X X X X X Statins X X X X X *eg, proton pump inhibitors such as omeprazole. Inhaled, intranasal. AASLD/IDSA Guidelines. February 2016.

ACE inhibitors and diuretics ok Metabolized to some extent by CYP3A, so consider dose reductions Beta blockers: carvedilol and nebivolol ARBs: irbesartan and losartan Calcium channel blockers Amlodipine Cmax and AUC increased 1.27- and 2.79-fold by TVR, so a reduced dose should be considered

10 1. DTG/ABC/3TC 2. DTG + TDF/FTC 3. EVG/COBI/TDF/FTC 4. EVG/COBI/TAF/FTC 5. RAL + TDF/FTC 3.1% (1) Total: 32 28.1% (9) 25.0% (8) 21.9% (7) 21.9% (7)

AASLD/IDSA. HCV guidelines. December 2015. SMV + SOF SOF LDV/SOF DCV + SOF OMV/PTV/RTV + DSV Atazanavir + RTV Darunavir + RTV Lopinavir/RTV Tipranavir + RTV Efavirenz Rilpivirine Etravirine Raltegravir Elvitegravir + COBI Dolutegravir Maraviroc Tenofovir DF nephrotoxicity No clinically significant interaction expected Potential interaction may require adjustment to dosage, timing of administration, or monitoring Do not coadminister

SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV + DSV EBR/GZR Darunavir + RTV Raltegravir Dolutegravir Elvitegravir + COBI Elvitegravir/COBI+ TAF/emtricitabine * * Efavirenz Rilpivirine Abacavir/lamivudine Tenofovir DF/ emtricitabine nephrotoxicity No clinically significant interaction expected Potential interaction may require adjustment to dosage, timing of administration, or monitoring Adapted from AASLD/IDSA. HCV guidelines. March 2016. Do not coadminister

Use same regimens as in HCV-monoinfected pts, but consider drug drug interactions Avoid combination of LDV and tenofovir DF if CrCl < 60 ml/min or if receiving tenofovir DF with RTV-boosted PIs When LDV/SOF and tenofovir DF are coadministered with antiretrovirals, monitor for nephrotoxicity Tenofovir levels increased with efavirenz, rilpivirine, or dolutegravir, when administered with LDV/SOF and tenofovir DF Adjust/withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV Adjust DCV with atazanavir/rtv, efavirenz, or etravirine DCV + SOF ± RBV recommended when ART regimen changes cannot be made to accommodate other DAAs AASLD/IDSA. HCV guidelines.

Not specific to ARV University of Liverpool www.hep-druginteractions.org Toronto General Hospital http://www.hcvdruginfo.ca/ University of Buffalo ACTG Pharmacology Support Laboratory http://tdm.pharm.buffalo.edu/home/di_search/ Specific to ARV DHHS Guidelines Drug Interaction Tables www.aidsinfo.nih.gov