1 / 73

Interactive How to Optimize Treatment of GT1 Patients

Interactive How to Optimize Treatment of GT1 Patients. Sherif M. Abd El-Fattah Sherif FRCP, FACG Paris January 31, 2012. Our Patient. A lady, Mrs. F. R. 45 years, married and has 3 children

chavez
Download Presentation

Interactive How to Optimize Treatment of GT1 Patients

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Interactive How to Optimize Treatment of GT1 Patients Sherif M. Abd El-Fattah Sherif FRCP, FACG Paris January 31, 2012

  2. Our Patient • A lady, Mrs. F. R. 45 years, married and has 3 children • She gave no history of blood transfusion or major surgery, but she had many dental interventions over the years. She does not drink alcohol • She had some fatigue and on routine check up for insurance she was found to be anti-HCV positive • She admitted some gain in weight over the years and on contraceptive pills

  3. Presentation • Her mother had chronic hepatitis and advanced liver cirrhosis and they shared a lot together, father was diabetic and passed away few years ago • There were no manifestations of LCF, fair skin without jaundice or anemia. No skin manifestations of advanced liver disease or rash and no edema of lower limbs • She had no joint swelling but few signs of osteoarthritis of right knee. There was no lymphadenopathy

  4. Clinically • She was a well built lady BMI 31.1 kg/m2, she looked anxious but not depressed • BP 135/80 P 80/min heart and chest were clinically free • Abdomen was lax, liver was enlarged about 4 finger breadth below the costal margin in MCL, rounded edge, rather soft smooth surface. • Spleen was not palpable and no ascites

  5. Clinically • Anything else? • Thyroid was slightly enlarged and smooth with no signs of myxedema or thyrotoxicosis • The U/S report was: Bright liver with smooth contour and no masses detected. The spleen is minimally enlarged Conclusion: Fatty liver • Is any bright liver = fatty liver? • Yes • No

  6. Laboratory Results • CBC: Hb 11gm/dl, WBC 4300/cmm (granulocytes 2000/cmm) , platelet count 123,000/cmm • S. Bil 1.3mg/dl, ALT 50 IU, AST 50 IU (N 40) • S. Creatinine 0.8 mg/dl • Fasting blood sugar 115 mg/dl – Should we pursue this any further? • Yes • No

  7. Laboratory • Glycosylated Hb A 1 c and/or HOMA-IR • Glycosylated Hb A 1c was 7.0 – Is it common in GT1? • Do anything about it? Is reducing weight likely to succeed? • Diet and exercise? • Add metformin or a glitazone • Glucagon - Like –Peptide 1 receptor agonist (GLP-1R) • How about lipemia ? How important? • S. cholesterol 280, LDL 200mg/dl • Her family Dr. put her on simvastatin Khattab MA, 2010 Visboll T, 2012

  8. Laboratory Results • What do we need more other than HCV studies? • Testing for HBsAg • Testing for anti-HBs • Anti-HAV IgG • HIV • All the above • Do we need to test other systems? • Thyroid, fundus • Chest X-ray, ECG

  9. Laboratory Results • HCV- RNA 350,000 IU/ml • Is viral load important? • What other HCV viral tests? • Genotype – Important? Why? • Prognosis • Decide on length of treatment • Decide on type of treatment • 1&2 • 2&3

  10. Genotype Result • HCV GT 1b • Significance? • More difficult to treat? • Worse prognosis? • More prone to cirrhosis and HCC? • All the above? • None of the above • Luckily she was anti-HBs positive, anti-HAV positive and normal fundus examination and thyroid function

  11. Liver Biopsy • The patient asked for an alternative to liver biopsy. • Fibroscan F2 • Fibrotest? F2 A2 • How reliable in our patient in view of her BMI & IR? • Finally we had a liver biopsy

  12. THE FATTY LIVER

  13. Weighing the Options: Treat or Defer? Treat Defer • Consider treatment for all patients • Most treatment-naives and relapsers • Treatment urgent for medical well-being • Motivated patients • Adherence issues • Tolerability challenges with IFN and/or RBV • Very poor prognostic factors (ie, null and advanced disease) • Patient not motivated, poor timing with life events • Treatment not urgent • Complicated drug interaction issues may be considered

  14. Success and Failure Aspects and Factors

  15. IL28B Polymorphism (rs12979860) • Important? How about others: inosinetriphosphatase (ITPA) and LDL, rs8099917 genotype • How will these affect the prognosis? • If patient is CC or non CC will it affect my decision to treat or not to treat? • Yes • No • Will it affect my plan of treatment? • No • Yes – How? Ge et al 2009, Soriano V et al, 2011, Beinhart S et al 2012 Schaefer EA et al 2011, Takita M et al 2011

  16. IL28B Polymorphism (rs12979860) • Our patient was CT • How will this affect my plan of treatment? • Lead in with interferon/ Ribavirin (IFN+R) then add Boceprevir [Victrelis] • Start with triple therapy from the start (Telaprevir [Incivek]+ IFN+R) • Try IFN + R alone • How long will the treatment be?

  17. How to Manage • SOC for HCV GT1 • Pegylated interferon/Ribavirin + protease inhibitor (PI): telaprevir or Boceprevir • More effective to give combination? • So we gave PEG interferon a2a, ribavirin and telaprevir

  18. SVR With BOC and TVR+P/R in GT1 Treatment-Naive and -Experienced Pts 100 100 P/R P/R+ Protease Inhibitors 80 80 63-75[1-2] 59-66[3-4] 60 60 SVR (%) SVR (%) 38-44[1-2] 40 40 17-21[3-4] 20 20 0 0 Treatment-Naive Pts Treatment-Experienced Treatment-Naive Pts Treatment-Experienced 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529.

  19. Boceprevir or Telaprevir + PegIFN/RBV:The New Standard of Care for Genotype 1 • Potent inhibitors of HCV NS3/4A protease • Both approved by FDA and EMA in mid 2011 • Indicated in combination with pegIFN/RBV for treatment of genotype 1 HCV–infected patients • Previously untreated or previous treatment failures • Does this apply for GT4 or GT2 or 3? • Yes • No Telaprevir [package insert]. May 2011. Boceprevir [package insert]. May 2011.

  20. ADVANCE: Overall SVR and Relapse Rates 8-wk TVR + PR + 16/40-wk PR (n = 364) P < .0001 for both treatment arms vs control 12-wk TVR + PR + 12/36-wk PR (n = 363) 100 48-wk SOC (n = 361) 80 75 69 60 Patients (%) 44 40 28 20 9 9 n = 271 n = 28 64 250 158 27 0 SVR Relapse Jacobson IM, et al. AASLD 2010. Abstract 211.

  21. Difficulties to the New Standard of Care for Genotype 1 • Side effects? • Compliance issues? • Both? • Other causes? • Is therapy different with Telaprevir P & R from Boceprevir P & R ? • Yes • No

  22. Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts 1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.

  23. Adherence • Triple therapy presents challenges with already busy schedules[143] • TID dosing • Food requirements • Data show pegIFN/RBV adherence decreases over time[5] • Addition of PIs may exacerbate this trend 1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

  24. Current Standard-of-Care Therapy Is Complex • Triple therapy has greatly increased treatment complexity, involves multiple daily pills plus injection drug • BOC TID: 12 pills/day • TVR TID: 6 pills/day • RBV BID: 4-6 pills/day • PegIFN: QW injection • Increased risks with nonadherence to triple therapy include potential for resistance and mutations • Adherence to pegIFN/RBV therapy decreases over time Treatment Wk 100 97 95 95 100 0-12 89 86 84 13-24 76 80 25-36 37-48 60 Mean Adherence (%) 40 20 0 PegIFN Ribavirin (N = 5706) Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

  25. Do Mutations Occur ? • Would this affect the prognosis or further therapy?

  26. Treatment-Emergent Substitutions During PI-Based Therapy • Pooled analyses of subjects who had on-treatment failure or relapse during clinical trials with boceprevir or telaprevir • Patterns of treatment-emergent substitutions varied by subtype 1a vs 1b • Resistance most common among previous null responders and patients with subtype 1a 1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011.

  27. Loss of Detectable Resistance in Patients Stopping BOC or TVR + PegIFN/RBV Telaprevir[2] Boceprevir*[1] V36MT548R155KAny mutation Genotype 1a HCV Genotype 1b HCV 100 100 98 100 94 87 80 80 66 60 60 Cumulative Rate of Wild-Type Variant (%) 60 Pts With Wild-Type Virus (%) 46 40 40 32 22 20 16 20 0 0 0 6 12 18 24 0 3 6 12 16 Most After End of Therapy Most After Treatment Failure *Data from phase II studies. 1. Vierling JM, et al. EASL 2010. Abstract 2016. 2. Sullivan J, et al. EASL 2011. Abstract 8.

  28. Optimum Therapy Courses • What are the stopping rules? • Each has side effects; can therapy be shortened without compromising results of therapy? • Yes • No

  29. Telaprevir in Genotype 1 Patients • 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g, eg, 1/2-cup nuts or 2-oz cheddar cheese) • Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Wk 48) Treatment Naive and Previous Relapsers eRVR; stop at Wk 24 PR TVR + PR No eRVR; PR Previous Partial or Null Responders TVR + PR PR 0 4 12 24 48 Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.

  30. Boceprevir in Genotype 1 Patients • 800 mg (four 200-mg capsules) q8hr with meal or light snack • All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks • If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks • EMA label recommends fixed-duration therapy for all trt-expd patients: LI + 32 wks triple + 12 wks PR Treatment Naive Early response; stop at Wk 28 BOC + PR PR BOC + PR PR Previous Relapsers or Partial Responders Early response; stop at Wk 36 BOC + PR PR BOC + PR PR 36 0 4 12 24 28 48 8 Wks Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011.

  31. Drug-Drug Interactions Represent a Clinical Challenge* *Studies of drug-drug interactions incomplete. 1. Boceprevir . May 2011. 2. Telaprevir May 2011.

  32. Helpful Drug-Drug Interaction Resource

  33. Complications During Treatment • She had complied mostly to regimen of IFN, R, TVR • When she came after 4 weeks HCV RNA 90 IU/ml & Hb 9 g complaining of: • Usual aches and pains after injections • Mild itchy rash manageable by an anti-histamine and local emollient • Fatigue: caused by ? • Anemia • Depression • Thyrotoxicosis • 1&2 • 1&3

  34. Our Patient Under Treatment • At weeks 12 also virus was undetectable • Fatigue was marked: cause? • Anemia • Depression • Thyroid disease • Hb remained 9 gm/dl and she showed no sign of depression; but had some tachycardia

  35. How Would You React? • Give EPO • Reduce dose of RBV • Test thyroid functions • Test autoantibodies • Reduce dose of IFN • A combination of the above

  36. Thyroid Dysfunction after Interferon Therapy • Prediction • Thyroperoxidase (TPO) and thyroglobulin (TG) antibodies more frequent before antiviral treatment in patients with dysthyroidism (10 folds risk) • Low fibrosis found to be a predictive factor of dysthyroidism, mostly hypothyroid • S.T thyrotoxicosis

  37. Our Patient Under Treatment • T3 and T4 raised -TSH lowered – what is my next step • Treat thyrotoxicosis • Investigate further: how? • Stop anti-viral treatment • All the above

  38. Thyroid Further Investigated • Radioactive iodine uptake proved destructive thyroiditis – How? • Destructive thyroiditis:  RAIU &  TSHAb Continue treatment + propranolol • Graves’ hyperthyroidism  RAIU &  TSHAbStop treatment and treat thyroid disease

  39. Results of Therapy • Week 4 - Hb 9 g/dl, HCV-RNA 90 IU/ml • At week 8 HCV – RNA was undetectable • At week 12 – EVR (virus undetectable) • At week 24 - virus undetectable • Shall we: • Continue till week 48 – then follow up till week 72 • Stop at 24 - then follow up till week 48 • Give 72 weeks – and follow up for further 24 weeks

  40. Another Problem • At some stage her GP phoned for a Question: Platelet count is down to 60,000/cmm • How much thrombocytopenia can we allow? • If it gets lower then: • Stop therapy • Reduce interferon • Stop Interferon alone • Non of the above

  41. ENABLE 1: Eltrombopag as Adjunct Therapy for Thrombocytopenia in HCV Before HCV Antiviral Therapy Double-Blind Phase (≤ 48 wks*) Open-Label Eltrombopag Treatment Phase (2-9 wks) HCV-infected patients with platelets < 75K/μL (N = 716†) Platelets ≥ 90K/μL 25 mg Platelets < 90K/μL Eltrombopag + PegIFN alfa-2a/RBV Platelets ≥ 90K/μL 50 mg 24 wks follow-up Platelets < 90K/μL 2:1 randomization Platelets ≥ 90K/μL 75 mg Placebo + PegIFN alfa-2a/RBV Platelets < 90K/μL Platelets ≥ 90K/μL 100 mg Platelets < 90K/μL Withdrawal Growth factor support allowed for anemia and neutropenia. PegIFN alfa-2a reduced or discontinued for thrombocytopenia.Eltrombopag/matched placebo could be titrated during treatment to maintain platelets between 90-200K.*24 wks if HCV genotype 2/3; otherwise 48 wks.†Demographics balanced between eltrombopag and placebo groups. Median age: 51-52 yrs; 59% to 69% male; 72% white; 66% to 68% IFN-naive; 64% to 65% genotype 1; 94% Child-Pugh 5-6; 72% to 73% platelets ≥ 50,000. Afdhal N, et al. AASLD 2011. Abstract LB-3.

  42. ENABLE 1: Eltrombopag as Adjunct Therapy for Thrombocytopenia in HCV • 95% of patients were eligible to start antiviral therapy following open-label eltrombopag • Use of eltrombopag associated with significantly improved response rates to HCV therapy Virologic Response (ITT) PlaceboEltrombopag 100 P < .0001 80 P = .008 66 P < .0001 60 50 48 P = .0064 Patients (%) 42 37 P = .7495 40 26 23 17 20 16 14 0 RVR EVR cEVR ETR SVR Afdhal N, et al. AASLD 2011. Abstract LB-3.

  43. Eltrombopag • How safe?

  44. At the End of Therapy • We went on with treatment and platelets remained at 55000/cmm • If at week 48 HCV- RNA was not detectable by RT-PCR followed up every 3 months? or 6 months? • What shall we test for on follow up? • HCV-RNA • Mutations • Liver enzymes

  45. If The Patient Relapses • What shall we tell our patient? • Re-Treat? • We will take a rest then think about it? • Consider as non-responder and follow up? • Our action should depend on the patients physical, psychological, stage of liver disease and history of compliance during treatment – also the availability of newer drugs

  46. DAA Target HCV Life Cycle Receptor bindingand endocytosis Transportand release Fusion and uncoating ER lumen Virionassembly (+) RNA LD LD LD Translation andpolyprotein processing Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  47. Each Drug Class Has Unique Features

  48. Some Agents Under Investigation Have Broad Genotypic Coverage • Majority of protease inhibitors have targeted genotypic coverage • MK-5172, TMC435 have broad coverage[1,2] • Nonnucleoside polymerase inhibitors active against GT1 • Most nucleos(t)ide analogue polymerase inhibitors are pan-genotypic • Most NS5A inhibitors have targeted genotypic coverage • Cyclophilin inhibitors are pan-genotypic Brainard DM, et al. AASLD 2010. Abstract 807. 2. Fried M, et al. AASLD 2010. Abstract LB-5 .

  49. New Agents Generally Maintain or Improve Upon Efficacy in GT1 Treatment-NaivePhase II Studies, Drug + PegIFN/RBV Not head-to-head comparisons 100 75-86 68-85 65-85 61-84 71-83 42-83 80 53-76 63-75 60 56 38-50 SVR (%) 40 20 0 BOC or TVR [1,2] Filibuvir[8] Vaniprevir[7] Tegobuvir[9] TMC435[6] Narlaprevir[5] BI 201335[3] Alisporivir[11] Danoprevir[4] Daclatasvir[10] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.

  50. Combination Therapy for Null Responders • Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks Japan Study[2] US Study[1] Daclatasvir + Asunaprevir 100 90* 90 Daclatasvir + Asunaprevir + PR 80 60 SVR24 (%) 36 40 20 N/A 0 *all genotype 1b patients. 1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.

More Related