1 / 38

IL28B polymorphism and SVR Do IL28B or not do IL28B?

IL28B polymorphism and SVR Do IL28B or not do IL28B?. Donald M. Jensen, MD, FACP Professor of Medicine Director, Center for Liver Diseases University of Chicago, USA Stanislas Pol, MD, PhD Unité d’Hépatologie, Hôpital Cochin 27 Rue du Faubourg Saint-Jacques 75014 Paris France.

cameran-clark
Download Presentation

IL28B polymorphism and SVR Do IL28B or not do IL28B?

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. IL28B polymorphism and SVRDo IL28B or not do IL28B? Donald M. Jensen, MD, FACP Professor of Medicine Director, Center for Liver Diseases University of Chicago, USA Stanislas Pol, MD, PhD Unité d’Hépatologie, Hôpital Cochin 27 Rue du Faubourg Saint-Jacques 75014 Paris France

  2. IL28B polymorphism O’Brian TR et al. Nat Genet 2009

  3. Anatomy of the IL28B gene Ge et al. Nature 2009;461:399-401

  4. IL28B polymorphism Globalprevalence of C/T Alleles at SNP rs 12979860 may explain recognized geographical variation in SVR rates Thomas DL, et al. Nature. 2009;461:798-802

  5. Genetic variation in IL28B (rs 12979860) IL28B polymorphism and HCV spontaneous clearance 70 64.2 RR 2.63 (CI: 1.8-3.9) 60 50 p = 4.0*10-8; RR 10.6 (CI: 2.7 – 41.1) Percent of patients achieving spontaneous clearance 40 30 24.4 p = 5.8*10-78 20 RR 2.63 IC: 1.8-3.9 10 6.1 p = 0.021 0 T/T (n=2/33) C/T (n=22/90) C/C (n=43/67) German anti-D cohort infected with HCV genotype 1 (N=194) Tillmann HL et al. Gastroenterology 2011

  6. IL28B polymorphism and HCV spontaneous clearance Predictors of chronic vs. spontaneously cleared HCV infection 1362 individuals 1015 HCV infected 347 who cleared the virus spontaneously 448 HCV/HIV co-infected Rs 8099917 G-risk allele is associated with progression to chronicity in either HCV or HCV/HIV co-infected patients. Genetic variation in IL28B (rs8099917) Rauch A et al. Gastroenterology. 2010;15:1338-1345

  7. Genetic variation in IL28B (Rs 8099917) IL28B polymorphism and HCV spontaneous clearance GG3.9 TG5.6 TG10.8 100 80 60 TG72.7 GG TG TT94.4 TT89.2 TT 40 20 TT23.4 0 Spontaneous clearance (n=107) SVR (n=185) Non response (n=128) Matsuura K. Abstract 1171. EASL 2010.

  8. IL28B polymorphism and HCV spontaneous clearance Practical Implications • IL28B polymorphism could be used in acute hepatitis C in order to: • Select patients who needed to be treated rapidly (TT or asymptomatic CT rs 12979860 and GT or GG rs 8099917) • Follow and delay treatment in patients with expected high spontaneous clearance

  9. IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Ge D et al. Nature 2009

  10. IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Ge D et al. Nature 2009

  11. 13 % TT 56 % 19 % CT CC CT 77 % CC 4 % 31 % RVR=14% Non-RVR=86% TT CT CC 100% 85% 76% 66% CC vs. non-CCp<0.0001 31% 24% p>0.25 SVR SVR IL28B polymorphism and RVR IL28B CC genotype predict both RVR and SVR in Caucasians without RVR Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009

  12. Logistic regression, backward selection Covariates: rs 12979860 (2-level), ethnicity (4-level), age (>40), gender, BMI (>30), VL (>600,000), ALT (>ULN), fasting glucose (≥5.6), hepatic steatosis (>0%), fibrosis (METAVIR F34), RBV (≤13 mg/kg/d) IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009

  13. IL28B polymorphism and SVR Genotype 2/3 Patients SVR: 57% (TT), 75% (CT), 82% (CC); p=0.005 p=0.45 p=0.34 p=0.0002 88% 87% 90 84% 79% 74% 73% 72% 75 67% 60 SVR % 45 29% 30 15 TT CT CC TT CT CC TT CT CC 0 24 Weeks (n=68) 12 Weeks If RVR (n=122) 24 Weeks If no RVR (n=78) Genetic variation in IL28B (rs 12979860) Mangia A et al. Abstract 126. EASL 2010.

  14. IL28B polymorphism and SVR 164 HCV/HIV co-Infected patients treated by PR CC genotype is associated with SVR only in genotype 1/4 patients. Genetic variation in IL28B (rs 12979860) Rallon NI, et al. AIDS. 2010;15:F23-29

  15. Reduction of viral load is independently associated with IL28B genotypes and ethnicity (p<0.0001). Caucasians African Americans 0 0 TT -2.0 -2.0 CT TT -4.0 -4.0 CT CC -6.0 -6.0 CC 4 2 4 12 4 2 4 12 Weeks Weeks Hispanics 0 -2.0 TT -4.0 CT CC -6.0 Weeks 4 2 4 12 IL28B polymorphism and viral kinetics Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009

  16. IL28B polymorphism and hepatic ISG • 91 patients, gene expression profile in the liver • Expression of IFN stimulated gene (ISG) in relation to IL28B (Rs 8099917) • Patients with up-regulated ISGs are associated with NR. • IL28B polymorphisms are strongly associated with SVR (TT: 86% vs. GG: 65%; p<0.001) • Hepatic ISGs were strongly associated with IL28B polymorphism; its expression was higher in patients with minor genotypes (TG or GG) • The different expression of hepatic ISGs before treatment may be due to polymorphisms in IL28B Genetic variation in IL28B (rs8099917) Honda M, et al. Gastroenterology 2010

  17. IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy

  18. IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy

  19. Impact of IL28B on SVR with DAAs CC patients with non extensive fibrosis (F0-2) and RVR have the same rate of SVR with dual vs. triple therapy CC CT TT 100 82 80 78 80 71 65 59 55 60 RVS (%) 40 28 27 20 0 PR48 50/64 BOC RGT 63/77 BOC44/PR48 44/55 PR48 33/116 BOC RGT 67/103 BOC44/PR48 82/115 PR48 10/37 BOC RGT 23/42 BOC44/PR48 26/44 n/N= SPRINT-2 Poordad F, et al. N Engl J Med 2011;364:1195-206

  20. Impact of IL28B on SVR with DAAs CC patients with non extensive fibrosis (F0-2) and RVR have the same rate of SVR with dual vs. triple therapy All the patients (cohort 1 and cohort 2) % SVR Indétectable Indétectable Indétectable SPRINT-2 Vierling JM. et al. EASL 2011. (abstract 481)

  21. IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy

  22. p = 0.21 p < 0.001 99 97 95 100 24 w. 80 70 48 w. 60 % SVR if RVR 40 20 0 IL28B rs8099917 TTARN < 600 000 UI/ml IL28B rs8099917 TTARN > 600 000 UI/ml Impact of IL28B on SVR Retrospective analysis of randomized comparing PEG-IFNα-2a 180 μg/w. + RBV 1000-1200 mg/j 24 w. vs 48 w. in Taïwan 662 genotype 1-infected patients Liu CH et al. AASLD 2011, Abs. 414

  23. Impact of IL28B on SVR with DAAs Higher rate of SVR in CC vs. CT/TT CC CT TT CC CT TT 100 100 90 82 80 78 80 73 80 71 71 65 64 59 55 60 60 RVS (%) RVS (%) 40 40 28 27 25 23 20 20 0 0 PR4820/80 T12PR 48/68 PR4835/55 T12PR 45/50 PR486/26 T12PR16/22 PR48 50/64 BOC RGT 63/77 BOC44/PR48 44/55 PR48 33/116 BOC RGT 67/103 BOC44/PR48 82/115 PR48 10/37 BOC RGT 23/42 n/N= BOC44/PR48 26/44 Poordad F, et al. N Engl J Med 2011;364:1195-206; Jacobson IM, et al. N Engl J Med 2011;364:2405­16 n/N=

  24. 100 97 100 84 78 73 80 60 50 % SVR 40 20 0 n = 31 35 12 78 72 34 CC CT/TT TMC435 75 mg TMC435 150 mg P/R Impact of IL28B on SVR with DAAs PILLAR study with TMC435 Higher rate of SVR in CC vs. CT/TT Fried MW et al. AASLD 2011, Abs. LB5

  25. Impact of IL28B on SVR with DAAs Higher rate of « short » treatments in CC vs. CT/TT : ~ 80 % of CC naïve patients are eligible PR48 BOC TGR BOC/PR48 100 90 82 80 78 80 71 65 70 59 55 60 RVS (%) 50 40 28 27 30 20 50 54 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 10 0 CC CT TT (SPRINT-2: Boceprevir in naïve patients) Poordad F, et al. N Engl J Med 2011;364:1195-206

  26. Impact of IL28B on SVR with DAAs Higher rate of « short » treatments in CC vs. CT/TT : ~ 80 % of CC experienced patients are eligible 100 PR48 BOC TGR BOC/PR48 90 79 77 80 73 72 70 61 55 60 50 RVS (%) 46 50 40 30 17 20 6 13 22 28 17 22 5 29 38 62 48 66 5 10 6 11 13 18 10 0 CC CT TT (RESPOND-2: Boceprevir in experienced patients) Bacon BR et al. N Engl J Med 2011;364:1207-17

  27. Impact of IL28B on SVR withDAAs SVR Rates by IL28B Genotype and Prior Response Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Patients achieving SVR (%) TT TT TT CC CT CC CT CC CT n/N= 4/12 100/117 3/10 5/8 1/5 2/10 10/14 4/10 0/0 27/92 1/15 51/58 6/30 29/34 33/57 0/5 1/18 10/32 Pol S, et al.EASL 2011

  28. Impact of IL28B on SVR withDAAs Prove 2 sub-analysis • Phase II, randomizedcontrolled trial in genotype 1 naïve patients in 323 patients • Telaprevir (TVR) 750 mg/8 h, PEG-IFN 180 µg/w, RBV 1 000-1 200 mg/d PR48 (n = 82) Placebo + PEG-IFNα-2a + ribavirin(RBV) T12/PR24 (n = 81) TVR + PEG-IFNα-2a + RBV PEG-IFNα-2a + RBV TVR + PEG-IFNα-2a + RBV T12/PR12 (n = 82) TVR + PEG-IFNα-2a T12/P12 (n = 78) Hezode C et al. NEJM 2009

  29. Impact of IL28B on SVR withDAAs Prove 2 sub-analysis Virologic Response after treatment Relapse (%) SVR % 48 % 50 p = 0.01* p = 0.08* RVS 12 80 68 40 62 NS* 60 29 48 30 36 20 40 20 14 20 10 39/82 55/81 51/82 28/78 9/45 8/56 18/63 22/46 0 0 PR48 T12/PR24 T12/PR12 PR48 T12/PR24 T12/PR12 T12/P12(No RBV) T12/P12(No RBV) * vs PR48 Hezode C et al. NEJM 2009

  30. Impact of IL28B on SVR withDAAs Prove 2 sub-analysis Virologic Response after treatment SVR % p = 0.01* p = 0.08* TPR 12w : 100% CC SVR < 50% CT/TT RVS 12 80 68 62 NS* 60 48 36 40 20 39/82 55/81 51/82 28/78 0 PR48 T12/PR24 T12/PR12 T12/P12(No RBV) By courtesy of J-P. Bronowicki * vs PR48

  31. IL28B polymorphism Practical Implications The “Pro” summary • Earlytreatment of acute hepatitis • Dual vs. Triple therapy: PR vs. BOC/TVR PR • Duration of therapy: 12w/24w/36 w or 48w

  32. IL28B in the Era of DAA Therapy:What’s not to like? Can we avoid the toxicity of DAAs and use dual therapy in IL28B CC patients? Is knowledge of IL28B CC status helpful in encouraging patients to be treated with the hope of eRVR+ RGT? Can we use IL28B TT or CT information in patients with “mild” disease to wait for newer therapies with better outcomes?

  33. Dual versus Triple Therapy Gellad et al: AASLD 2011 • The argument: Dual therapy for IL28B CC is more cost-effective than triple therapy: • For patients with IL28B CC: SVR rates (~90%) are about the same with P/R as if T/P/R was used right from the start • It is more cost-effective to treat IL28B CC subjects initially with PEG/RBV and reserve TVR-based triple therapy to those who do not respond.

  34. Dual versus Triple Therapy • However,…. • This two step strategy means that at least 36% of patients will require a subsequent course of triple therapy • It assumes that 100% of P/R failures will undergo re-treatment - not supported by clinical experience data. • Evolution of therapy may demonstrate that these uniquely responsive patients may achieve a comparably high rate of SVR with only 12 weeks of triple therapy without the need for a PEG/RBV tail (trial in progress) • Finally, patients may refuse a non-DAA containing therapy

  35. Duration of Therapy: 24 vs 48 weeks • The argument: Those with geno-1, IL28B CC are more likely to have an eRVR and qualify for 24 weeks (RGT) therapy. • However,…. • Regardless of IL28B status, an eRVR still requires actual measurement of undetectable HCV RNA at weeks 4 and 12 • Therefore, it’s on-treatment virologic responses that really matter, not pre-treatment dispositions

  36. Selecting Candidates for Therapy • Argument: IL28B CT or TT with ‘mild disease’ may be able to wait for future therapies However,… • How do we define ‘mild’? What is the accuracy? • E.g. Liver bx: 25-30% may miss cirrhosis • Should all ‘mild’ cases be deferred given the toxicity of DAA triple therapy? • When is IFN-free therapy anticipated?

  37. Selecting Candidates for Therapy • Argument: IL28B may identify a cohort of uniquely sensitive subjects for short course IFN-free therapy However,…. • As therapies become more effective (>90% SVR), the role of IL28B will decline as a predictor (e.g. PILLAR) • In the absence of IFN, is there even a role for l-IFN responsiveness? (e.g. PROTON)

  38. Summary • How will IL28B be utilized in the era of DAA triple therapy? • Predict shorter treatment duration • Identify patients who may benefit from dual therapy However,… • True utilization may depend upon real life clinical experience with triple therapy and retrospective analysis of IL28B Ten years too late????

More Related