6/2/2015. Interactive Case-Based Presentations and Audience Discussion

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1 Interactive Case-Based Presentations and Audience Discussion Charles W. Flexner, MD Professor of Medicine, Pharmacology, and International Health The Johns Hopkins University Baltimore, Maryland Formatted: Washington, DC: May 12, 2015 (ADVANCED) Learning Objectives After attending this presentation, participants will be able to: Evaluate patients with HIV/HCV coinfection for drug interactions prior to starting HCV treatment Describe the current studies using direct-acting antivirals (DAAs) for the treatment of HIV/HCV coinfection Describe issues related to switching ARV regimens prior to initiating HCV treatment Slide 2 of 62 Case 1 53 y.o. AA man with HIV-1 infection and HCV infection. He complains of extreme fatigue which is debilitating. He has been on RAL/TDF/FTC for 2 years. Initial HIV genotype showed no RT or PR mutations and he has never had HIV virologic failure. He had never had a liver biopsy and is HCV treatment naïve. You obtain the following tests: Lab HIV-1 RNA CD4 absolute Result CD4 percent 34% HCV RNA HCV genotype WBC Hemoglobin <48 copies/ml 555/cmm 16,600,000 IU/mL 1a 4.58 x 10 3 /ul 14 g/dl Platelets 200,000 Fibroscan F2 Lab INR 1.1 Creatinine Total bilirubin 0.3 AST ALT Alkaline phosphatase Albumin 4.0 Result 0.9 mg/dl 26 U/L 26 U/L 111 U/L FIB-4 score 1.35 APRI 0.33 Slide 3 of 62 1

2 Slide 4 of 62 Audience Response Question: Which regimen should you choose? 1. Defer treatment 2. Sofosbuvir + simeprevir + ribavirin 3. Sofosbuvir + ledipasvir 4. Paritaprevir/ritonavir/o mbitasvir + dasabuvir + RBV % 5% 95% 0% 0% HIV/HCV Coinfection, GT1a, Tx-Naïve, F2 Disease on RAL/TDF/FTC Slide 5 of 62 When and in Whom to Initiate HCV Therapy Highest Priority for Treatment Owing to Highest Risk for Severe Complications Advanced fibrosis (MetavirF3) or compensated cirrhosis (F4) Rating: Class I, Level A Organ Transplant Type 2 or 3 essential mixed cyroglobulinemia with end-organ manifestations (e.g. vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level B High Priority for Treatment Owing to High Risk for Complications Fibrosis (Metavir F2) HIV-1 Coinfection Hepatitis B Virus (HBV) Coinfection Other coexistent liver disease (e.g. NASH) Debilitating fatigue Type II Diabetes mellitus (insulin resistant) Porphyria cutanea tarda AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 2015 Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level C Rating: Class IIa, Level C Rating: Class IIa, Level B Rating: Class IIa, Level B Rating: Class IIb, Level C Slide 6 of 62 When and in Whom to Initiate HCV Therapy Highest Priority for Treatment Owing to Highest Risk for Severe Complications Advanced fibrosis (MetavirF3) or compensated cirrhosis (F4) Rating: Class I, Level A Organ Transplant Type 2 or 3 essential mixed cyroglobulinemia with end-organ manifestations (e.g. vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level B High Priority for Treatment Owing to High Risk for Complications Fibrosis (Metavir F2) HIV-1 Coinfection Hepatitis B Virus (HBV) Coinfection Other coexistent liver disease (e.g. NASH) Debilitating fatigue Type II Diabetes mellitus (insulin resistant) Porphyria cutanea tarda AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 2015 Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level C Rating: Class IIa, Level C Rating: Class IIa, Level B Rating: Class IIa, Level B Rating: Class IIb, Level C 2

3 SVR12 (%) 6/2/2015 Slide 7 of 62 Effectiveness of Sofosbuvir/Simeprevir for HIV/HCV Patients in Clinical Practice Specific Aim: To assess sustained virologic responses and tolerability of sofosbuvir + simeprevir (sof/sim) in HIV/HCV-coinfected patients compared to those with HCV alone. Baseline characteristics of HIV/HCV-coinfected and HCV-monoinfected patients prescribed SOF/SIM Virologic Responses to SOF/SIM HIV/HCV HCV % HCV RNA BLQ Gilmore J et al, CROI 2015, slide created by J.Gilmore 0 4 weeks 12 weeks SVR4 SVR 12 Slide 8 of 62 High SVR with SOF/LDV in co-infection Wk 0 Wk 12 Wk 24 N=335 LDV/SOF SVR Overall Naïve Exper No Cirr Cirr Failures: 10 relapses 2 on-treatment 1 lost to f/u 1 death Safety and tolerability: 2% Serious AEs No discontinuations due to AEs 1 death Naggie S. #152LB CROI D (PrO D) + RBV in HIV/HCV Slide 9 of 62 Two patients in 24 week arm were re-infected causing decrease to 90.6% at SVR12 Two virologic failures - both 1a cirrhotic null responders One patient withdrew consent Wyles. EASL TURQUOISE I: 3

4 SVR12, % 6/2/2015 High SVR with 12 weeks of SOF/DCV Naive Randomize 2:1 N DCV 30/60/90 mg + SOF 400 mg QD DCV 30/60/90 mg + SOF 400 mg QD SVR12 Slide 10 of 62 Experienced 52 DCV 30/60/90 mg + SOF 400 mg QD Week 0 8 GT 1 (N = 168) Failures (12 week arms): 1 withdrawal at week 1 1 detectable HCV RNA at EOT 2 relapses Safety and tolerability: 2% Serious AEs No discontinuations due to AEs 1 death 12-Week 12-Week Naive Experienced 2 HIV VL >400 copies on study 100% SVR12 in 1b and non-gt1 with 12 weeks. Wyles D. #151LB CROI Case 2 52 y.o. man with HIV-1/HCV coinfection and hemophilia. Recently Slide 11 of 62 hospitalized for severe anemia requiring transfusion from rectal hemorrhoids. PMH sig for nephrolithiasis with renal dysfunction. He has been on DRV/r/TDF/FTC for 2 years. Heavily ARV treatment experienced with h/o of HIV virologic failure. No hx of liver biopsy and is prior null responder to PEG/RBV. You obtain the following tests: Lab Result Lab Result HIV-1 RNA CD4 absolute CD4 percent 31% HCV RNA HCV genotype WBC Hemoglobin <48 copies/ml 514/cmm 1,932,487 IU/mL 1a 5.2 x 10 3 /ul 14.1 g/dl Platelets 150,000 INR 1.1 Creatinine 1.2 mg/dl, egfr 69 Total bilirubin 0.5 AST ALT Alkaline phosphatase Albumin 4.0 Ultrasound 65 IU/L 66 U/L 161 U/L Cirrhosis, no masses Audience Response Question Case 2: What treatment regimen would you offer him? 1. Defer therapy for newer agents 2. Sofosbuvir+ simeprevir+rbv x 24 weeks 3. Sofosbuvir + ledipasvir x 24 weeks 4. Paritaprevir/ritonavir/ombitasvir + dasabuvir + RBV x 24 weeks 5. Sofosbuvir + ledipasvir +RBV x 12 weeks 4% 4% 64% 12% Slide 12 of 62 16% HIV/HCV Coinfection, GT1a, Tx-Exp, Cirrhotic, on DRV/r/TDF/FTC; hemophilia recent severe anemia, h/x renal disease 4

5 Simeprevir AE Slide 13 of 62 Potential AE related to increased SMV exposure Rash Pruritis Photosensitivity Increased bilirubin Strategies for reducing SMV exposure Avoid significant DDI Take medication on an empty stomach Adverse Reactions 3D Regimen Slide 14 of 62 Skin Reactions: - 7-9% without RBV, 10-16% with ribavirin. Higher in HIV coinfected. Anemia/decreased hemoglobin Mean change from BL in 0.5 mg/dl without RBV vs 2.4 mg/dl with RBV Effect of RBV Dose Reductions on SVR12 7% (101/1551) of subjects underwent a RBV dose reduction due to a decrease in hemoglobin; of these 98% achieved SVR12 Serum Bilirubin Elevations outs. 15% in those treated with RBV Not associated with serum ALT elevations Serum ALT Elevations Pooled analyses of clinical trials: Approximately 1% patients experienced serum ALT levels >5xULN after starting treatment Not associated with bilirubin elevations and cirrhosis was not a risk factor for elevated ALT ALT elevations in 25% among women on ethinyl estradiol or estradiol-containing medication. Slide 15 of 62 Adverse Reactions: FDC SOF/LDV Adverse Reactions (All Grades) Reported in > 5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with (ledipasvir-sofosbuvir) FDC SOF/LDV 8 weeks FDC SOF/LDV 12 weeks FDC SOF/LDV 24 weeks N=215 N=539 N=326 Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% HARVONI [package insert] 5

6 Drug-Drug Interactions Slide 16 of 62 Simeprevir Mild inhibitor of CYP1A2 and intestinal CYP3A4, inhibits OATP1B1/3 and P-gp Multiple drug interactions Sofosbuvir Substrate of P-gp and BCRP; potent P-gp inducers may decrease sofosbuvir concentrations Tipranavir, rifampin, St. John s wort induces P-gp at steady state Do not use with amiodarone Ledipasvir Inhibits P-gp and BCRP, substrate of P-gp and BCRP Solubility decreases as gastric ph increases, alkaline environment will decrease LDV concentrations (Simeprevir) Package Insert, Janssen, September 2013; (sofosbuvir) Package Insert, Gilead Sciences, December 2013; (ledipasvir-sofosbuvir) Package Insert, Gilead Sciences October 2014 Simeprevir PK Slide 17 of 62 Intake with food increases exposure by about 60% Substrate of the intestinal uptake transporter P- glycoprotein (P-gp) Distributed to liver by organic anion-transporting polypeptide (OATP) Metabolized primarily by CYP3A Inhibits OATP and P-gp Mild inhibitor of intestinal CYP3A and 1A2 (not liver) Simeprevir package insert Slide 18 of 62 Simeprevir and HIV Medications (NNRTIs, PIs) 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. Coadministration not recommended HIV Non Nucleoside Reverse Transcriptase Inhibitors Efavirenz Etravirine Nevirapine Significant reductions in simeprevir levels and reduced simeprevir efficacy due to CYP3A4 induction. Co-administration not recommended. Rilpivirine Concurrent use at standard doses acceptable. 6

7 Slide 19 of 62 Darunavir/Ritonavir Increases Simeprevir Exposures 2.6-fold even after reducing the simeprevir dose by 2/3 Ouwerkerk-Mahadaven S, et al. IDWeek 2012 Slide 20 of 62 Efavirenz Reduces Simeprevir Exposures by 71% Ouwerkerk-Mahadaven S, et al. IDWeek 2012 Concurrent Medication Slide 21 of 62 Simeprevir and HIV Medications (EIs, NRTIs, INSTIs) 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. 7

8 Sofosbuvir PK Slide 22 of 62 Pro-drug nucleotide analog that gets phosphorylated in the liver to the triphosphate form Does not undergo traditional hepatic metabolism Primary metabolite (GS ) undergoes renal elimination via glomerular filtration and active tubular secretion Substrate of P-gp and breast cancer resistance protein (BCRP) Sofosbuvir Interaction Potential Slide 23 of 62 Sofosbuvir P-gp and BCRP substrate Sofosbuvir impact on other drugs: Very low potential for altering PK of other agents In vitro not an inhibitor or inducer of CYP450, UGT1A1, P-gp, BCRP, OATP1B1, OCT1, BSEP Sofosbuvir DDI Slide 24 of 62 Decreased Sofosbuvir concentrations Anticonvulsants Antimycobacterials Others Carbamazepine Rifampin St. John s Wort Oxcarbazepine Rifapentine Tipranavir/r Phenobarbital Rifabutin Phenytoin Amiodarone + SOF : DO NOT USE EVER 8

9 Ledipasvir PK Slide 25 of 62 NS5A inhibitor Primarily eliminated in the feces as unchanged parent drug Approx. 1% of drug is eliminated in the urine Little to no effect on CYP enzymes P-gp and BCRP substrate Weak inhibitor of P-gp and BCRP Europeans Medicine Agency LDV DDI P-gp inducer/inhibitors similar DDIs to sofosbuvir Avoid co-administration with Anticonvulsants carbamazepine, phenytoin, phenobarbital, oxcarbazepine Antmycobacterials rifabutin, rifampin, rifapentine St. Johns Wort Monitor digoxin levels No significant DDI with CSA or FK P-gp substrates Colchicine, atorvastatin, simvastatin, pravastatin, lovastatin, digoxin, diltiazem, verapamil, rivaroxaban, methotrexate, anti-neoplastics, cyclosporine, tacrolimus Slide 26 of 62 BCRP substrates Methotrexate, ciprofloxacin, antineoplastics, pravastatin, rosuvastatin, rivaroxaban, AZT, 3TC Slide 27 of 62 Gilead Sciences, unpublished data 9

10 Creatinine Clearance (ml/min), mean ± SD 6/2/2015 Creatinine levels on study LDV/SOF + EFV+FTC+TDF (n=160) RAL+FTC+TDF (n=146) RPV+FTC+TDF (n=29) BL FU-4 Week 4 patients (1%) had change in creatinine 0.4 mg/dl 2 completed treatment with no ART change 1 had dose reduction of TDF, 1 discontinued TDF Slide 28 of 62 Naggie S. #152LB CROI Slide 29 of 62 SOF/LDV DDIs with antiretrovirals EFV: ~35% reduction in LDV exposure LDV: no impact of EFV LDV: 40-98% increase in TFV AUC % increase in C tau German P. 15th Inter Clin Pharm HIV and HCV Slide 30 of 62 CROI 2015, abstract 82 10

11 Slide 31 of 62 CROI 2015, abstract 82 Slide 32 of 62 CROI 2015, abstract 82 Slide 33 of 62 CROI 2015, abstract 82 11

12 Slide 34 of 62 CROI 2015, abstract 82 Slide 35 of 62 CROI 2015, abstract 82 Slide 36 of 62 CROI 2015, abstract 82 12

13 OMV/PTV/RTV + DSV Slide 37 of 62 Paritaprevir Substrate of: 3A4, P-gp, BCRP, OATP1B1 Inhibitor or inducer of: Inhibitor of UGT1A1, OATP1B1, BCRP Ombitasvir P-gp, BCRP - Dasabuvir 2C8, P-gp, BCRP Inhibitor of BCRP Combining (PrOD) with ARV s Slide 39 of 62 Khatri et al., ICAAC 2014 Slide 40 of 62 Audience Response Question: Case 2: You treat him with SOF/LDV/RBV for 12 weeks. How often should you monitor HCV VL and Creatinine? 1. Both at 12 weeks after end of treatment (EOT) 2. HCV VL at week 4 and 12 weeks after EOT, Cr at week 4 and q month thereafter 3. HCV VL at week 4 and 12 weeks after EOT, Cr q 2 weeks 4. HCV VL at Cr at week 4, 8, 12 0% 25% 35% 40% HIV/HCV Coinfection, GT1a, Tx-Exp, Cirrhotic, on DRV/r/TDF/FTC; hemophilia recent severe anemia, h/x renal disease 13

14 Monitoring Slide 41 of 62 HCV VL is recommended after 4 wks on therapy and 12 weeks after EOT If HCV VL detectable at week 4, repeat HCV VL at week 6. If week 6 HCV VL > 1 log 10 IU/ml then discontinue therapy Antiviral therapy should not be stopped if week 4 HCV VL result unavailable Monitoring Slide 42 of 62 CBC, Cr, CrCl, and hepatic function panel are recommended after 4 weeks of treatment and as clinically indicated TDF-containing/ ritonavir boosted PI regimens: Cr, CrCl, electrolytes, phosphorus, urinary protein and glucose q2-4 weeks Audience Response Question Slide 44 of 62 Which of the following drug interactions must be avoided when considering treatment with ombitasvir/paritaprevir/ritonavir + dasabuvir (OMV/PTV/RTV + DSV) + ribavirin: 1. Omeprazole 2. Rosuvastatin 3. Fluticasone/salmeterol 4. Metoprolol 39% 52% 9% 0%

15 Slide 45 of 62 Other Drug-Drug Interactions Acid-suppressing medications and SOF/LDV Decreased absorption of ledipasvir Salmeterol and paritaprevir/ritonavir/ombitasvir + dasabuvir Prolonged QT St. John s Wort and Milk Thistle St John s wort will decrease ombitasvir/paritaprevir/ritonavir + dasabuvir levels and SOF/LDV levels Slide 46 of 62 LDV and acid-reducing agents Decreased solubility with increasing ph Separate administration with antacids by 4 hours H2-receptor antagonists to be administered simultaneously with or 12 hours apart Do not exceed comparable dose of famotidine 40mg twice daily Administer PPIs simultaneously Do not exceed comparable dose of omeprazole 20mg daily Ledipasvir and statins Slide 47 of 62 15

16 Statin metabolism Slide 48 of 62 Simvastatin Lovastatin Atorvastatin Rosuvastatin Pravastatin Fluvastatin CYP3A4 CYP2C9 PgP +/- +/- +/- BCRP OATP1B1 Hochman JH, Pudvah N, Qui J, et al. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm Res 2004;21: Slide 49 of 62 Drug interaction scorecard (Kisergram) TDF SOF SOF + LDV RAL/DTG HIV PI/EFV ( TDF) EFV ( TDF) SMV RLP RAL/DTG ATV/r DRV/r TDF/FTC/E LV/Cobi ABC TDF ABC TDF SMV DCV 3D SMV SMV SMV* DCV 90mg DCV 30mg DCV 30mg* RLP DRV *not studied, based on predicted interactions. No expected issues with co-administration Caution- potentially significant interactions or interactions of unknown significance. Additional monitoring may be necessary-see text. Do not co-administer ARV Interaction Score Card Slide 50 of 62 Simeprevir Sofosbuvir Ledipasvir Daclatasvir AbbVie 3D ATV/r No data No data LDV, ATV a DCV b ATV ; ABT450 DRV/r SIM ; DRV SOF ; DRV LDV, DRV a No data DRV / ; 3D LPV/r No data No data No data No data LPV ; ABT450 TPV/r No data No data No data No data No data EFV SIM ; EFV SOF ; EFV LDV ; EFV a DCV b No PK data c RPV SIM ; RPV SOF ; RPV LDV ; RPV No data ABT450 ; RPV ETV No data No data No data No data No data RAL SIM ; RAL SOF ; RAL LDV ; RAL No data 3D ; RAL ELV/cobi No data No data No data No data No data DLG No data No data No data No data No data MVC No data No data No data No data No data TDF SIM ; TFV SOF ; TFV LDV ; TFV DCV ; TFV 3D ; TFV a Watch renal function, TFV levels increased, b Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, c 3D + EFV led to premature study discontinuation due to toxicities * Slide generated by JEN KISER, University of Colorado 16

17 Regimen Switching in the Setting of Viral Suppression Prior to Starting Hep C Treatment Cardinal principle of regimen switching Maintain viral suppression without jeopardizing future options Virologic failure with emergence of new resistance mutations Increases need for more complex, difficult-to-follow, or expensive regimens Slide 53 of 62 Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014; DHHS. Revision May 1, Slide 54 of 62 ART switches in HIV/HCV coinfection Objectives: Determine need for ART switch prior to initiation of simeprevir-containing HCV regimen Determine feasibility of ART switch to allow for use of simeprevir Key Results: Majority of our HIV-HCV patients (76%) will need a change to antiretroviral therapy in order to accommodate use of simeprevir for treatment of HCV Limitations were primarily driven by protease inhibitor (PI) regimens 40% on a boosted -PI could not be switched to a safe and effective ART regimen Most often due to use of salvage regimen where PI has become indispensable Safe Regimens SMV + RAL, RPV, T20, MVC, TDF, FTC, 3TC, ABC LDV + all regimens except EVG/cobi and TDF + EFV or PI/r PTV/r + RAL, TDF, FTC, 3TC, ATZ, T20 Prasad et al CROI 2015, slide created by R Prasad Slide 57 of 62 Monitoring After Switching Regimens Evaluate more closely for several months after a treatment switch 1 to 2 weeks post switch: a clinic visit or phone call 4 to 8 weeks post switch: viral load test (rebound viremia) Goal of the intensive monitoring Assess medication tolerance Conduct targeted laboratory testing within 3 months after the regimen switch (ie, pre-existing laboratory abnormalities or potential concerns with the new regimen) Absent any specific complaints, laboratory abnormalities, or evidence of viral rebound at this 3-month visit, clinical and laboratory monitoring of the patient may resume on a regularly scheduled basis Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014; DHHS. Revision May 1,

18 Slide 58 of 62 Take-Home Points: Similarities between HIV and HCV Drug Interactions Drug interactions are common and can be clinically significant. Nucleoside analogs have a lower potential for drug interactions. Protease inhibitors have a higher potential for drug interactions. Unexpected or unanticipated drug interactions are often due to inhibition of drug transport proteins. Slide 59 of 62 Take-Home Points: Differences between HIV and HCV Drug Interactions HIV drug interactions are for life; HCV drug interactions are for 8-12 weeks! Beneficial or deleterious effects of other drugs on the PK of anti-hiv drugs are the consequence of changes in plasma drug concentrations (usually). Beneficial or deleterious effects of other drugs on the PK of HCV DAA s are the consequence of changes in intracellular/ intrahepatic drug concentrations (probably). Slide 60 of 62 18

19 Interactive Case-Based Presentations and Audience Discussion Charles W. Flexner, MD Professor of Medicine, Pharmacology, and International Health The Johns Hopkins University Baltimore, Maryland Formatted: Washington, DC: May 12, 2015 (ADVANCED) 19