HIV and HCV Drug Interactions Cased Based Discussion. John J. Faragon, PharmD, BCPS, AAHIV-P. Brief background on HCV and HIV Coinfection

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1 HIV and HCV Drug Interactions Cased Based Discussion John J. Faragon, PharmD, BCPS, AAHIV-P Roadmap Brief background on HCV and HIV Coinfection Revised AASLD Guidelines Case evaluating drug interactions Future Medications and risk of drug interactions 1

2 HCV Background and AASLD Guidelines Current Medications for HCV Older Medications Pegylated Interferon PegIntron or Pegasys Ribavirin Older Direct Acting Antivirals Boceprevir (Victrelis) Telaprevir (Incivek) New Direct Acting Antivirals Simeprevir (Olysio) Sofosbuvir (Sovaldi) 2

3 Challenges with Older DAA Telaprevir (Incivek) Rash Black Box Warning Anemia Worse than Pegylated interferon + Ribavirin alone Needs interferon and ribavirin brings all ADRs with it too Anorectal adverse events challenging Only for Genotype 1 ie not pangenotypic Response guided therapy/stopping rules Drug Interactions complex, especially when treating co-infection Large pull burden (6/day), TID, now BID frequency Challenges with Older DAA Boceprevir (Victrelis) Dygeusia Anemia Worse than Pegylated interferon + Ribavirin alone Needs interferon and ribavirin brings all ADRs with it too 4 week lead in period Only for Genotype 1 ie not pangenotypic Response guided therapy/stopping rules Drug Interactions complex, especially when treating co-infection Large pull burden (12/day), TID frequency 3

4 Contraindicated medications with boceprevir and telaprevir Drug Class Contraindicated With BOC [1] Contraindicated With TVR [2,3] Alpha 1 adrenoreceptor antagonist Anticonvulsants Alfuzosin Carbamazepine, phenobarbital, phenytoin Alfuzosin Carbamazepine, phenobarbital, phenytoin Antimycobacterials Rifampin Rifampin Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products St John s wort St John s wort HMG CoA reductase inhibitors Lovastatin, simvastatin Lovastatin, simvastatin Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sedatives/hypnotics Sildenafil or tadalafil when used for tx of pulmonary arterial HTN Triazolam; orally administered midazolam Sildenafil or tadalafil when used for tx of pulmonary arterial HTN Triazolam; orally administered midazolam 1. Boceprevir [package insert] Telaprevir [package insert] , 3. druginteractions.org Concurrent Medication Boceprevir allowed Telaprevir allowed Atazanavir/ritonavir (Reyataz /Norvir ) No Yes Darunavir/ritonavir (Prezista /Norvir ) No No Fosamprenavir/ritonavir No, not studied to date No (Lexiva /Norvir ) Lopinavir/ritonavir (Kaletra ) No No Efavirenz (Sustiva ) No Yes, increase TLV dose to 1125mg Q8H Etravirine (Intelence ) Yes, reduced etravirine levels reported Rilpivirine (Edurant ) Yes Yes Tenofovir (Viread ) Yes Yes, monitor renal fx Raltegravir (Isentress ) Yes Yes Elvitegravir (in Stribild )?? Yes Dolutegravir (Tivicay ) Yes Yes Yes Maraviroc (Selzentry ) Yes, MRV 150mg BID Yes, MRV 150mg BID 4

5 HCV Lifecycle Receptor binding and endocytosis Translation NS3/4a and polyprotein protease processing inhibitors Fusion and uncoating (+) RNA Membranous web ER lumen Telaprevir Boceprevir NS5A* inhibitors Simeprevir Faldaprevir *Role in HCV lifecycle not well defined ABT 450 Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: LD LD Transport and release ER lumen Virion LD assembly Sofosbuvir ABT 333 NS5B polymerase RNA replication inhibitors Daclatasvir Ledipasvir ABT Released 1/29/14! 5

6 Case 1 Patient Case 1 48 yo male with hemophilia, HIV infection, and chronic hepatitis C, hyperlipidemia, hypertension, mild persistent asthma CD4 cell count 550, VL< 40 copies/ml, CCR5 tropic Hepatitis C genotype 1a HCV RNA 310,000 IU/mL Albumin 3.2 g/dl; bilirubin 1.7 mg/dl; ALT 210 IU/L; platelets 130,000 Previously treated with PEGIFN alfa-2a and ribavirin Deemed non-responder per chart review never suppressed, and desires retreatment for HCV 12 6

7 Patient Case 1 Medications Darunavir/ritonavir 800mg/100mg once daily Tenofovir/emtricitabine once daily Raltegravir 400mg twice daily Lisinopril 10mg daily Hydrochlorothiazide 12.5mg daily Atorvastatin 20mg at bedtime Beclomethasone MDI, 40mcg/inh 2 puffs twice daily Zolpidem 5mg at bedtime as needed Patient and provider want initiate therapy for HCV 13 HIV/HCV Co-Infection, GT1 Preferred Treatment naïve, prior PEG/RBV relapsers, IFN eligible: SOF + PEG/RBV(WB) x 12 weeks IFN ineligible: SOF + RBV(WB) x 24 weeks SOF + SMV ±RBV(WB) x 12 weeks Treatment experienced, prior PEG/RBV nonresponders, regardless of IFN eligibility: SOF + SMV ±RBV(WB) x 12 weeks Alternative Treatment naïve, prior PEG/RBV relapsers, IFN eligible: SMV x 12 weeks + PEG/RBV(WB) x 24 weeks IFN ineligible: None Treatment experienced, prior PEG/RBV nonresponders IFN eligible: SOF + PEG/RBV(WB) x 12 Weeks IFN ineligible: SOF + RBV(WB) x 24 Weeks Not Recommended: TVR + PEG/RBV x 24 or 48 weeks (RGT), BOC + PEG/RBV x 28 or 48 weeks (RGT) PEG/RBV x 48 weeks, SMV x 12 weeks + PEG/RBV x 48 wks 7

8 Provider Decision Simeprevir + Sofosbuvir + WB ribavirin for 12 weeks COSMOS Study Design Arm1 SMV+SOF+RBV Post treatment follow up Randomized 2:1:2:1 Arm2 Arm 3 SMV+SOF + RBV SMV+SOF Post treatment follow up Post treatment follow up Arm 4 SMV+SOF Post treatment follow up Cohort 1 Metavir F0 F2, prior null responders Cohort 2 Metavir F3 F4, prior null responders or naives Primary Endpoint: SVR12 Secondary Endpoints: RVR, Tx failure, relapse rate, safety Lawitz, etal. 49 th EASL, April 9 13,

9 COSMOS, Baseline Characteristics Characteristic SMV/SOF+ RBV 24 weeks n=30 Lawitz, etal. 49 th EASL, April 9 13, SMV/SOF 24 weeks n=16 SMV/SOF + RBV 12 weeks n=27 SMV/SOF 12 weeks n=14 Total n=87 Male, % White/African American 97/3 81/19 93/7 86/14 91/9 Hispanic, Latino Median Age Median BMI GT 1a GT 1a, Q80K Median HCV VL Null Responders IL28B, non CC Cirrhosis COSMOS, SVR 12 (ITT) Results 100% % 60% 40% Relapse Non VF SVR12 20% 0% 28/30 16/16 25/27 13/14 82/87 SMV/SOF/RBV SMV/SOF SMV/SOF/RBV SMV/SOF SMV/SOF +/ RBV 24 weeks 12 weeks Overall Lawitz, etal. 49 th EASL, April 9 13,

10 Drug Interactions Considerations Simeprevir Mild inhibitor of CYP1A2 activity and intestinal CYP3A4 Does not affect hepatic CYP3A4 activity Inhibits OATP1B1/3 and P-glycoprotein Multiple drug interactions expected Simeprevir and HIV Medications Concurrent Medication Recommendation HIV Protease Inhibitors All HIV PIs Significant increases or decreases in simeprevir levels expected when used with any HIV protease inhibitor, when used with or without ritonavir. Co administration 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. Coadministration not recommended. Rilpivirine (Edurant ) Concurrent use at standard doses acceptable. 10

11 Simeprevir and HIV Medications 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 of simeprevir. Drug Interactions Considerations Sofosbuvir Substrate for P-glycoprotein and breast cancer resistance protein Intracellular metabolism mediated by hydrolase and nucleotide phosphorylation pathways Minimal drug interactions expected 11

12 Sofosbuvir and HIV Medications Concurrent Medication Recommendation HIV Protease Inhibitors All HIV PIs, with or without ritonavir, except Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. tipranavir Tipranavir (Aptivus ) Co administration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors All NNRTIs Concurrent use at standard doses acceptable. Sofosbuvir and HIV Medications 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 ) Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. 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 sofosbuvir. HIV Nucleoside/Nucleotide Reverse Transcriptase Inhibitors All NRTIs Concurrent use at standard doses acceptable. Interactions not expected based upon metabolism of sofosbuvir. 12

13 Drugs to Avoid with Simeprevir Medication and or Class Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin Antibiotics clarithromycin, erythromycin, telithromycin Antifungals fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole Antimycobacterials rifampin, rifabutin, rifapentine Rationale for Avoiding with Simeprevir Co administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co administration not recommended. 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. Co administration with these medications is likely to increase concentrations of simeprevir due to CYP3A4 inhibition from the antifungals. Co administration not recommended. Co administration with these medications is likely to reduce concentrations of simeprevir and lead to reduced simeprevir efficacy. Co administration not recommended. Drugs to Avoid with Simeprevir 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. Co administration 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. 13

14 Drugs Requiring Monitoring or Dose Limits with Simeprevir Medication and or Class Rationale for Avoiding with Simeprevir Digoxin Increased digoxin levels expected, monitor levels Antiarrhythmics Potential increase in levels, monitor levels if possible Calcium channel blockers Potential increase in levels, monitor for hypotension Atorvastatin Increased atorvastatin levels, use lowest does, do not exceed 40mg daily Rosuvastatin Increased rosuvastatin levels, initiate with 5mg daily, do not exceed 10 mg daily Simvastatin, pitavastatin, Use lowest dose possible, titrate carefully pravastatin, lovastatin Oral midazolam, triazolam Increased levels expected, titrate carefully, use lowest doses Drugs to Avoid with Sofosbuvir Medication and or Class Rationale for Avoiding with Sofosbuvir Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin Co administration with these medications is likely to reduce concentrations of sofosbuvir leading to reduced sofosbuvir efficacy. Co administration not recommended. Antimycobacterials rifampin, rifabutin, rifapentin 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 from rifampin. 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. 14

15 Provider Decision Simeprevir + Sofosbuvir + WB ribavirin for 12 weeks ARV Regimen changed to Complera + Raltegravir Lipitor dose left at 20mg Investigational HCV Medications 15

16 HCV Lifecycle Receptor binding and endocytosis Translation NS3/4a and polyprotein protease processing inhibitors Fusion and uncoating (+) RNA Membranous web ER lumen Telaprevir Boceprevir NS5A* inhibitors Simeprevir Faldaprevir *Role in HCV lifecycle not well defined ABT 450 Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: LD LD Transport and release ER lumen Virion LD assembly Sofosbuvir ABT 333 NS5B polymerase RNA replication inhibitors Daclatasvir Ledipasvir ABT Select Investigational Medications 2 groups of medications likely to be approved in late 2014 include All oral, interferon free regimens Ledipasvir combined with sofosbuvir, fixed dosage combination all once daily with or without ribavirin ABT-450/ritonavir+ABT-267 (ombitasvir), fixed dosage combination all once daily, in addition to ABT-333 (dasabuvir), given twice daily with or without ribavirin Daclatasvir likley end of 2014 as well Other meds moving forward Daclatasvir + asunaprevir + BMS Faldaprevir MK-5172, MK-8742 GS-9669, GS-9451, GS Afdhal N, et al. N Engl J Med. DOI: /NEJMoa , Afdhal N, et al. N Engl J Med. DOI: /NEJMoa , Kowdley KV, et al. N Engl J Med. DOI: /NEJMoa ,. Poordad F, et al. N Engl J Med. DOI: /NEJMoal , Feld JJ, et al. N Engl J Med. DOI: /NEJMoal , Zeuzem S, et al. N Engl J Med. DOI: /NEJMoa , Accessed 5/4/14 16

17 Drug Interaction Potential Ledipasvir/Sofosbuvir (90mg/400mg) FDC studied with Raltegravir Efavirenz/tenofovir/emtricitabine Rilpivirine/tenofovir/emtricitabine Ledipasvir reduced 30% with Atripla Tenofovir exposures in Atripla and Complera increased similar to what we see with RTVboosted PIs German P, et al. 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC. May, 2014 Drug Interaction Potential ION4 in co-infection Ledipasvir/Sofosbuvir (90mg/400mg) FDC allows Raltegravir + tenofovir/emtricitabine Efavirenz/tenofovir/emtricitabine Rilpivirine/tenofovir/emtricitabine Planned and/or ongoing studies with Ritonavir boosted Pis Stribild and Stribild (with TAF) Dolutegravir German P, et al. 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC. May,

18 Sapphire I and II Select Data AbbVie Data ABT-450/ritonavir+ABT-267 (ombitasvir) (FDC) plus ABT-333 (dasabuvir) BID with ribavirin Drug interactions an issue (RTV needed) GT1, naïve and prior non-reponders Feld JJ, et al. N Engl J Med. DOI: /NEJMoal , Zeuzem S, et al. N Engl J Med. DOI: /NEJMoa Sapphire I and II SAPPHIRE I SVR 12 (n=473) SAPPHIRE II SVR 12 (n=297) All GT1 96.2% (n=455/473) 96.3% (n=286/297)* GT1a 95.3% (n=307/322) 96.0% (n=166/173) GT1b 98.0% (n=148/151) 96.7% (n=119/123) Treatment experienced (GT1a and GT1b) Prior null responders n/a 95.2% (n=139/146) Prior relapsers n/a 95.3% (n=82/86) Prior partial responders n/a 100.0% (n=65/65) Feld JJ, et al. N Engl J Med. DOI: /NEJMoal , Zeuzem S, et al. N Engl J Med. DOI: /NEJMoa

19 Drug Interaction Potential Ritonavir boosting required for ABT-450 to allow better resistance profile and once dialy administration RTV has no effect on ABT-267 or ABT-333 Pravastatin reduce by half, limit ROS to 10mg daily Minimal effect on Tenofovir 2 fold increase in ABT-450 when used with atazanavir (OATP1B1 inhibition) Menon R, et al. 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC. May, 2014 Daclatasvir Atazanavir/ritonavir and efavirenz plasma concentrations did not change when co-administered with daclatasvir. Daclatasvir AUC was 110% higher when given with atazanavir/ritonavir Daclatasvir AUC reduced by 32% when co-administered with efavirenz. Dosage Adjustments With Atazanavir/ritonavir, lower daclatasvir dose to 30 mg once-daily With efavirenz, increase daclatasvir dose to 90 mg once-daily M Bifano, C Hwang, B Oosterhuis, et al. 19th CROI Seattle, March 5 8, Abstract

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