HCV Case Study Treat Now or Wait

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HCV Case  Study Treat Now or Wait for New  Therapies HCV Case Study Treat Now or Wait for New Therapies

Program  Disclosure • This activity has been planned and implemented in  accordanceProgram Disclosure • This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. • This program is supported by educational grants from Kadmon and Merck Pharmaceuticals.

Learning  Objectives • Describe current data on approved and experimental  DAA’s usedLearning Objectives • Describe current data on approved and experimental DAA’s used in combination with Pegylated Interferon and Ribavirin • Define the benefits and risks of treating now versus delaying therapy for different patient populations

Glenn: Patient Characteristics • 55 year old  male • Shift  worker •Glenn: Patient Characteristics • 55 year old male • Shift worker • History/risk factors – BMI=34 – Hypertension and dyslipidemia – Moderate drinker/cigarette smoker • Concomitant medications – Simvastatin 20 mg/day – Lisinopril 10 mg/day

Glenn: Baseline  Labs • H e moglo b in • Neutrophils • PlateletsGlenn: Baseline Labs • H e moglo b in • Neutrophils • Platelets • AST/ALT • Albumin • Bilirubin 15. 6 g/d. L 1400 cells/mm 3 210, 000 cells/mm 3 55/75 IU/L 4. 1 g/d. L 0. 7 mg/d. L

Glenn: Disease Characteristics • Treatment  naïve • Genotype • IL 28 B •Glenn: Disease Characteristics • Treatment naïve • Genotype • IL 28 B • METAVIR • BL viral load 1 a CC F 3 1, 3 00, 00 0 IU/ m. L

Clinical Decision  1 • How would you manage this  patient? 1. ContinueClinical Decision 1 • How would you manage this patient? 1. Continue to monitor patient but do not start treatment 2. Start patient on first generation protease inhibitor/PEG-IFN/RBV

Modeling of Liver Fibrosis in Chronic Hepatitis  C n=1157  Patients 01234 0Modeling of Liver Fibrosis in Chronic Hepatitis C n=1157 Patients 01234 0 10 20 30 40 50 F M etavir Y ears. Rapid progressors Intermediate progressors Slow progressors Poynard et al, Hepatology

D ’ Amico G et al.  J Hepatol.  2006; 44: 217 -231.D ’ Amico G et al. J Hepatol. 2006; 44: 217 -231. Proportion of Patients 1. 0 0 0. 7 5 0 0. 2 5 0. 0 0 Pts at risk m on t h s 0 8 06 24 513 48 4 02 72 302 96 2 43 120 217 Cumulative Proportion of Patients Transitioning from Compensated to Decompensated Stage Over Time

020406080100 N on -res ponders  (n=1452) Relapsers  (n=464) Sustained  res ponders0%20%40%60%80%100% N on -res ponders (n=1452) Relapsers (n=464) Sustained res ponders (n=1094)36% 43% 86%43% 36% 12% 21% 2%% of patients. Impro v ed Stabilized Worsened *Necrosis and Inflammation. Poynard et al. Gastroenterology , 2002; 122: 1303 -1313. Impact According to Response of 10 Different Treatment Regimens on Evolution of Activity* in 3010 Patients with Paired Biopsies

*T 12 PR = T+PR 12 weeks,  then PR 12 or 36 weeks*T 12 PR = T+PR 12 weeks, then PR 12 or 36 weeks depending on e. RVR status **T 8 PR = T+PR 8 weeks, then PR 16 or 40 weeks depending on e. RVR status Jacobson et al. EASL 2011 In Patients Tested for IL 28 B (%) In All A D V A N C E Patients CC CT TT Total T 12 PR* 90 71 73 78 75 T 8 PR** 87 58 59 67 69 PR 64 25 23 38 44 ADVANCE: IL 28 B Genotype Effect on Telaprevir Therapy

SVR Rates in F 1/2 vs F 3/4 Naïve  Patients 100 90 80SVR Rates in F 1/2 vs F 3/4 Naïve Patients 100 90 80 70 60 50 40 30 20 10 0 Telaprevir. F 1 / 2 F 3 / 4 76% 67% 48%SVR Boceprevir Jacobson IM et al, NEJM, 2011; 364: 2405 -2416 Poordad F et al, NEJM, 2011; 364: 1195 —

OPTIMIZE Trial:  Telaprevir BID vs  TID • PR + TVR 1125 mgOPTIMIZE Trial: Telaprevir BID vs TID • PR + TVR 1125 mg BID versus 750 mg TID • Response-guided therapy • 740 patients • 29% bridging fibrosis or cirrhosis • 57% G 1 a, IL 28 B CC 29% Buti M et al, Abstract LB-8, AASL

OPTIMIZE Trial:  Results 020406080100 R VR SVRTVR 1125 mg  BID TVR 750OPTIMIZE Trial: Results 020406080100 R VR SVRTVR 1125 mg BID TVR 750 mg TID ( % ) 69% 67% 74% 73% Buti M et al, Abstract LB-8, AASL

Should Glenn Be Treated  Now?  • F 3 disease – risk ofShould Glenn Be Treated Now? • F 3 disease – risk of progression with waiting • IL 28 B CC • Potential BID option is attractive

 • Multiple issues with current  therapy – Compliance – pill  burden • Multiple issues with current therapy – Compliance – pill burden – Co-morbidities – Adverse effects – New treatments on the horizon. The Case for Waiting

Pill  Burden Food  Requirement BOC =  18/d  RBV  4Pill Burden Food Requirement BOC = 18/d RBV 4 -7/d TVR = 12/d RBV 4 -7/d. Co m pliance

 • Cardiac Risk  Factors – Hypertension,  hyperlipidemia,  smoker • Pre • Cardiac Risk Factors – Hypertension, hyperlipidemia, smoker • Pre Treatment – DDI – Statin with TVR/BOC likely just stop it • On Treatment – Anemia management consider pre-treatment cardiac testing. Co-Morbidities

Drugs with the Potential to Interact with First  Generation Protease Inhibitors are CommonlyDrugs with the Potential to Interact with First Generation Protease Inhibitors are Commonly Used by HCV Patients Mayer et al, Abstract #136, AASLD 2012 Drug Name Percent Zolpidem * 17. 4 Diazepam 7. 9 Codeine 16. 0 Bupropion * 7. 2 Prednisone 15. 4 Trazodone 7. 1 Tramadol * 14. 3 Fluconazole 6. 8 Citalopram 13. 5 Sertraline 6. 4 Fluticasone 13. 1 Clarithromycin 6. 1 Methylprednisolone 13 Sildenafil (Viagra) 5. 4 Alprazolam * 11. 8 Clonazepam 5. 3 Amlodipine * 10. 2 Simvastatin 5. 2 Escitalopram * 8. 1 Venlafaxine 5. 0 * One of the 20 most frequently filled

 • No clinically significant  interactions – Boceprevir • Prednisone (abstract  #1896) • No clinically significant interactions – Boceprevir • Prednisone (abstract #1896) • Omeprazole (abstract #1808) • Ethinyl estrodiol/norethidrone (abstract #1901) – Simeprevir (TMC-435) • Cyclosporine/tacrolimus (abstract #80) • Ethinyl estrodiol/norethidrone (abstract #773)New Drug-Drug Interaction Data at AASLD 2012: HCV Protease Inhibitors

100 90 80 70 60 50 40 30 20 10 0 BOC PR 100100 90 80 70 60 50 40 30 20 10 0 BOC PR 100 90 80 70 60 50 40 30 20 10 0 T VR PR% of patients 36% 17% 14% 5% 49% 28% 7% 3%Anemia is a Known Side Effect with First Generation Protease Inhibitor Based Therapies % of patients < 10 g/d. L < 8. 5 g/d. L < 10 g/d. L < 8. 5 g/d. L Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012. Boceprevir (VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp. , Whitehouse Station, NJ, November 2012.

Future Options for Waiting?  (Short-Term) x 12 wks + PR x  24Future Options for Waiting? (Short-Term) x 12 wks + PR x 24 -48 81 020406080100% n/ N = 62/ 77 50/ 77 65 P = 0. 0 13 SVR PILLAR (G 1 Naïve) 1 Simeprevir 150 mg OD PR x 48 Faldaprevir 240 mg OD x 24 wks + PR x 24 -48 83% n/ N = 1 18/ 142 40/ 71 56 P = 0. 0 01 SVR SILEN C 1 (G 1 Naïve) 2 PR x 48 93 57/ 6179 61/ 77 SVRMet RGT 93 53/ 5787 124/ 142 SVRMet RGT 2. Sulkowski et al. EASL 2011020406080100 1. Fried et al. AASL

Anemia  with Simeprevir +  P/R 1 Anemia  with Faldaprevir + Anemia with Simeprevir + P/R 1 Anemia with Faldaprevir + P/R 2 2. Sulkowski et al, EASL 2011 No Incremental Decline in Hemoglobin or Neutrophils with Simeprevir or Faldaprevir 1. Jacobson et al, IDSA,

Select Oral Directing Antivirals in  Development for the Treatment of Chronic Hepatitis C,Select Oral Directing Antivirals in Development for the Treatment of Chronic Hepatitis C, 2012 Compound Sponsor Activity ABT-267 Abbott NS 5 A inhibitor ABT-333 Abbott Non-nucleoside NS 5 B polymerase inhibitor ABT-450 Abbott NS 3/4 A protease inhibitor Faldaprevir (BI 2 01335) Boehringer Ingelheim NS 3/4 A protease inhibitor BI 207127 Boehringer Ingelheim Non-nucleoside NS 5 B polymerase inhibitor

Select Oral Directing Antivirals in  Development for the Treatment of Chronic Hepatitis C,Select Oral Directing Antivirals in Development for the Treatment of Chronic Hepatitis C, 2012 (cont) Compound Sponsor Activity Asunaprevir (BM S -650032) Bristol-Myers Squibb NS 3 protease inhibitor Daclatasvir (BMS-790052) Bristol-Myers Squibb NS 5 A replication complex inhibitor BMS-791325 Bristol-Myers Squibb Non-nucleoside NS 5 B polymerase inhibitor Sofosbuvir (GS-7977) Gilead Uridine nucleotide analog NS 5 B polymerase inhibitor GS-5885 Gilead NS 5 A protein inhibitor Not all-inclusive, but indicates drugs covered in this presentation

Should Glenn Delay Treatment?  • IL 28 B CC ~80 chance of shortenedShould Glenn Delay Treatment? • IL 28 B CC ~80% chance of shortened therapy — 80 -90% chance of SVR • F 3 disease – risk of progression with waiting • No clear issues with IFN • Seems anxious and willing to be treated now • I would suggest treatment

Glenn: On Treatment  Response • Glenn was started on  TVR/PEG/RBV • TWGlenn: On Treatment Response • Glenn was started on TVR/PEG/RBV • TW 4 and TW 12 – HCV RNA undetectable

Clinical Decision  2 • Which regimen should Glenn  receive? 1. 12 weeksClinical Decision 2 • Which regimen should Glenn receive? 1. 12 weeks TVR/PEG/RBV 2. 12 weeks TVR/PEG/RBV + 12 weeks PEG/RBV 3. 12 weeks TVR/PEG/RBV + 24 weeks PEG/RBV 4. 12 weeks TVR/PEG/RBV + 36 weeks PEG/RBV 5. 24 weeks TVR/PEG/RBV

Recommended Treatment  Duration Treatment-Naïve and Prior Relapse  Patients HCV-RNA Triple  TherapyRecommended Treatment Duration Treatment-Naïve and Prior Relapse Patients HCV-RNA Triple Therapy TVR/Peg-IFN/RBV Dual Therapy Peg-IFN/RBV Total T reatment Duration Undetectable at TW 4 and TW 12 First 12 weeks Additional 12 weeks 24 weeks Detectable ( < 1000 IU/m. L) at TW 4 and/or TW 12 First 12 weeks Additional 36 weeks 48 weeks Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.

HCV-RNA Levels and Lab  Assays Assay  Name LLOQ Roche COBAS ® HCV-RNA Levels and Lab Assays Assay Name LLOQ Roche COBAS ® A m p li Pre p /COBA S ® Taqman ® HCV Test 43 IU/m. L Roche COBAS ® Taqman ® HCV Test, v 2. 0 25 IU/m. L † Abbott Real. Time HCV Assay 12 IU/m. LLLOQ Values for Various Assays* • “ Undetectable” (or “target not detected”) result is required for assessing RGT eligibility • Below LLOQ but still “detectable” is not sufficient to shorten therapy—ie, patient should continue for full 48 wks *Package Inserts state the “the assay should have a lower limit of HCV-RNA quantification ≤ 25 IU/m. L and a limit of HCV-RNA detection of approximately 10 -15 IU/m. L. † Usually considered 25 IU/m. L, but 23 IU/m. L per FDA-approved label. COBAS ® Ampli. Prep/COBAS ® Taqman ® HCV Test. Roche Molecular Diagnostics. Accessed July 19, 2011. Harrington PR, et al. Hepatology. 2012; 55: 1046 -1057. United States Food and Drug Administration (FDA), FDA Division of Antiviral Products; June 30, 2011.

Co n clu s ions • Many chronic hepatitis C patients are good candidatesCo n clu s ions • Many chronic hepatitis C patients are good candidates for treatment today • The HCV pipeline is promising with potential new treatment modalities in the near future • Physicians should carefully consider individual patient characteristics when deciding whether to initiate or delay treatment