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 IL28B polymorphism O’Brian TR et al. Nat Genet 2009 Anatomy of the IL28B gene Ge et al. Nature 2009;461:399-401 IL28B polymorphism Global prevalence 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 Percent of patients achieving spontaneous clearance 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) 40 30 24.4 p = 5.8*10-78 20 10 RR 2.63 IC: 1.8-3.9 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) Genetic variation in IL28B (rs 12979860) Tillmann HL et al. Gastroenterology 2011 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 (rs 8099917) Rauch A et al. Gastroenterology. 2010;15:1338-1345 IL28B polymorphism and HCV spontaneous clearance 100 TG 5.6 TG 10.8 GG 3.9 80 60 40 TT 94.4 TT 89.2 20 TG 72.7 GG TG TT TT 23.4 0 Spontaneous clearance (n=107) Genetic variation in IL28B (Rs 8099917) SVR (n=185) Non response (n=128) Matsuura K. Abstract 1171. EASL 2010. 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 IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Ge D et al. Nature 2009 IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Ge D et al. Nature 2009 IL28B polymorphism and RVR IL28B CC genotype predict both RVR and SVR in Caucasians without RVR 13 % 19 % TT CT CC 56 % CT 77 % CC 4% 31 % RVR=14% Non-RVR=86% TT 100% 76% CT CC 85% 66% 24% p>0.25 SVR Genetic variation in IL28B (rs 12979860) 31% CC vs. non-CC p<0.0001 SVR Thompson AJ et al. AASLD 2009 IL28B polymorphism and SVR Odds ratio 95% Confidence interval p-value CC genotype vs. non-CC 5.2 4.1 6.7 <0.001 VL ≤600,000 IU/mL 3.1 2.3 4.1 <0.001 Caucasian vs. AA ethnicity 2.8 2.0 4.0 <0.001 Hispanic vs. AA ethnicity 2.1 1.3 3.6 0.004 METAVIR F012 2.6 1.8 4.0 <0.001 Fasting blood sugar <5.6 mmol/L 1.7 1.3 2.2 <0.001 • • 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) Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009 IL28B polymorphism and SVR Genotype 2/3 Patients SVR: 57% (TT), 75% (CT), 82% (CC); p=0.005 p=0.45 90 p=0.34 88% 79% 75 74% 72% p=0.0002 87% 84% 73% 67% SVR % 60 45 29% 30 15 0 TT CT CC TT CT CC 24 Weeks (n=68) 12 Weeks If RVR (n=122) Genetic variation in IL28B (rs 12979860) TT CT CC 24 Weeks If no RVR (n=78) Mangia A et al. Abstract 126. EASL 2010. 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 IL28B polymorphism and viral kinetics African Americans Caucasians 0 0 -2.0 -2.0 TT CT TT -4.0 CT -6.0 CC 4 2 4 12 Weeks -4.0 CC -6.0 4 2 4 12 Weeks Hispanics 0 -2.0 TT -4.0 CT CC Reduction of viral load is independently associated with IL28B genotypes and ethnicity (p<0.0001). -6.0 4 2 4 12 Weeks Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009 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 (rs 8099917) Honda M, et al. Gastroenterology 2010 IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy 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 100 80 78 82 CT 80 65 RVS (%) TT 71 55 60 40 28 59 27 20 0 PR48 BOC BOC44/ PR48 BOC BOC44/ PR48 RGT PR48 RGT PR48 BOC BOC44/ RGT PR48 n/N= 50/64 63/77 44/55 33/116 67/103 82/115 10/37 23/42 26/44 SPRINT-2 Poordad F, et al. N Engl J Med 2011;364:1195-206 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 % SVR All the patients (cohort 1 and cohort 2) SPRINT-2 Vierling JM. et al. EASL 2011. (abstract 481) IL28B polymorphism and SVR Practical Implications • Dual vs. Triple therapy • Duration of therapy 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 100 % SVR if RVR • p = 0.21 99 95 80 p < 0.001 97 24 w. 48 w. 70 60 40 20 0 IL28B rs8099917 TT ARN < 600 000 UI/ml IL28B rs8099917 TT ARN > 600 000 UI/ml Liu CH et al. AASLD 2011, Abs. 414 Impact of IL28B on SVR with DAAs Higher rate of SVR in CC vs. CT/TT CC 80 78 82 CT CC CT 90 80 71 55 60 40 100 TT 80 65 RVS (%) TT 28 59 27 60 40 25 20 73 71 64 RVS (%) 100 23 20 0 0 PR48 BOC BOC44/ PR48 BOC BOC44/ PR48 RGT PR48 RGT PR48 BOC BOC44/ RGT PR48 n/N= 50/64 63/77 44/55 33/116 67/103 82/115 10/37 23/42 26/44 PR48 T12PR PR48 T12PR PR48 T12PR n/N= 35/55 45/50 20/80 48/68 6/26 16/22 Poordad F, et al. N Engl J Med 2011;364:1195-206; Jacobson IM, et al. N Engl J Med 2011;364:240516 Impact of IL28B on SVR with DAAs Higher rate of SVR in CC vs. CT/TT PILLAR study with TMC435 97 100 100 84 % SVR 78 73 80 60 50 40 20 0 n= 31 35 12 CC TMC435 75 mg 78 72 34 CT/TT TMC435 150 mg P/R Fried MW et al. AASLD 2011, Abs. LB5 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 100 90 80 78 82 BOC TGR 80 65 70 RVS (%) BOC/PR48 71 55 60 59 50 40 30 20 10 0 50 50 64 54 63 77 CC 44 55 28 27 33 67 82 116 103 115 10 37 CT 23 42 26 44 TT (SPRINT-2: Boceprevir in naïve patients) Poordad F, et al. N Engl J Med 2011;364:1195-206 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 80 77 73 RVS (%) 70 72 61 60 50 50 46 55 40 30 17 20 10 6 13 22 28 17 22 5 29 38 62 48 66 5 10 6 11 13 18 0 CC CT TT (RESPOND-2: Boceprevir in experienced patients) Bacon BR et al. N Engl J Med 2011;364:1207-17 Impact of IL28B on SVR with DAAs SVR Rates by IL28B Genotype and Prior Response Prior partial responders Prior null responders Pooled T12/PR48 (n=209) Pooled T12/PR48 (n=79) Pooled T12/PR48 (n=134) Pbo/PR48 (n=52) Pbo/PR48 (n=20) Pbo/PR48 (n=33) Patients achieving SVR (%) Prior relapsers CC n/N= 51/58 CT 4/12 100/117 6/30 TT 29/34 3/10 CC 5/8 1/5 CT 33/57 2/10 TT 10/14 0/5 CC 4/10 0/0 CT 27/92 1/18 TT 10/32 1/15 Pol S, et al. EASL 2011 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis • Phase II, randomized controlled 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) T12/PR24 (n = 81) T12/PR12 (n = 82) T12/P12 (n = 78) Placebo + PEG-IFNα-2a + ribavirin (RBV) TVR + PEG-IFNα-2a + RBV PEG-IFNα-2a + RBV TVR + PEG-IFNα-2a + RBV TVR + PEG-IFNα-2a Hezode C et al. NEJM 2009 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis Relapse (%) Virologic Response after treatment SVR % 80 60 p = 0.01* p = 0.08* RVS 12 68 62 48 20 0 48 40 NS* 29 30 36 40 % 50 20 20 14 10 39/82 55/81 51/82 28/78 9/45 8/56 18/63 22/46 0 PR48 T12/PR24 T12/PR12T12/P12 (No RBV) PR48 T12/PR24 T12/PR12 T12/P12 (No RBV) * vs PR48 Hezode C et al. NEJM 2009 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis Virologic Response after treatment SVR % 80 60 RVS 12 p = 0.01* p = 0.08* 68 62 36 40 20 0 NS* 48 TPR 12w : 100% CC SVR < 50% CT/TT 39/82 PR48 55/81 T12/PR24 51/82 28/78 T12/PR12T12/P12 (No RBV) * vs PR48 By courtesy of J-P. Bronowicki IL28B polymorphism Practical Implications The “Pro” summary • Early treatment of acute hepatitis • Dual vs. Triple therapy: PR vs. BOC/TVR PR • Duration of therapy: 12w/24w/36 w or 48w 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? Dual versus Triple Therapy • 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. Gellad et al: AASLD 2011 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 retreatment - 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 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 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? 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 lIFN responsiveness? (e.g. PROTON) 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????
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