29/09/2014 Disclosures Genetic determinants of ᴧ HCV treatment outcome • Advisory board member - Gilead, Abbvie, Bristol-Myers Squibb (BMS), Janssen, Merck, and Roche • Speaker - Gilead, Janssen, Merck, BMS, Abbvie Prof. Alex Thompson St. Vincent’s Hospital Melbourne, Australia The University of Melbourne, Australia • PI - Gilead, Merck, Roche, BMS, Janssen, Achillion, Springbank • Research / grant support – Gilead, Merck, BMS, Abbvie Alice Springs, September, 2014 • My presentation includes discussion of genetic tests and drugs which are not approved for clinical use Genome-wide association studies identify an association b/w IL28B polymorphism and SVR Genome-wide association studies identify an association b/w IL28B polymorphism and SVR IDEAL study pharmacogenomics cohort, n = 1604 rs12980275 rs8099917 rs12972991 rs8109886 rs4803223 rs12980602 IL28B IL28B = IFN-lambda-3 Ge*, Fellay*, Thompson* et al, Nature, 2009 C/C genotype predicts SVR IDEAL: IL28B-type is the strongest pre-treatment predictor of SVR 95% Confidence Interval p-value CC IL28B-type vs non-CC Odds Ratio 5.2 4.1 6.7 <0.0001 VL ≤ 600,000 IU/mL 3.1 2.3 4.1 <0.0001 Caucasian vs AA ethnicity 2.8 2.0 4.0 <0.0001 Hispanic vs AA ethnicity 2.1 1.3 3.6 0.004 METAVIR F012 2.7 1.8 4.0 <0.0001 Fasting Blood Sugar < 5.6 mmol/L 1.7 1.3 2.2 <0.0001 Co-variates - rs12979860 (2-level), ethnicity (4-level), age (≤ 40), gender, BMI (< 30), VL (≤ 600,000), ALT (≤ ULN), fasting glucose (< 5.6), hepatic steatosis (N/Y[>0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d) Ge*, Fellay*, Thompson* et al, Nature, 2009 Thompson, Gastro, 2010 1 29/09/2014 IL28B genotype is associated with phase 1 viral kinetics The global prevalence of C/T alleles at rs12979860 may explain the recognized geographical variation in SVR rates Median HCV RNA Change From Baseline (Log10 IU/mL) • Genotype 1 HCV, IL28B rs12979860 0 -1 -2 TT CT -3 -4 CC -5 0 7 14 21 28 Day 1, P < 0.001 Neumann, EASL, 2010 Thomas, Thio, Martin et al. Nature, 2009 IL28B variation is associated with spontaneous clearance of HCV Summary • In genotype 1(/4) HCV patients, IL28B genotype: • Multi-national IDU cohort, n = 388 (cleared) vs 620 (chornic) • Case-control candidate gene study, SNP = rs12979860 • OR for clearance (CC vs non-CC) = 3.0, P = 10-13 – strongly associated with cure of HCV – strongest baseline predictor – explains much of the ethnic difference in response rates – profoundly influences viral kinetics • In genotype 2/3/6 HCV, the association between IL28B genotype and PR response is attenuated • IL28B polymorphism is also strongly associated with spontaneous clearance of HCV IL28B genotype Thomas, Thio, Martin et al. Nature, 2009 PIs attenuate the association between IL28B genotype and SVR Direct acting antiviral agents (DAAs) PI - Telaprevir, boceprevir, simeprevir NI - sofosbuvir SVR (%) DAA + peginterferon and ribavirin Boceprevir, treatment naive 100 90 80 70 60 50 40 30 20 10 0 82 78 65 55 Telaprevir, treatment naive 80 71 59 27 28 PR BOC/RGT Poordad, Gastroenterology, 2012 BOC/PR48 100 90 80 70 60 TT 50 CT 40 CC 30 20 10 0 90 87 64 73 71 59 58 23 25 PR T8PR T12PR Pol, J Hepatology, 2013 2 29/09/2014 PIs attenuate the association between IL28B genotype and SVR SVR (%) Boceprevir, treatment naive 100 90 80 70 60 50 40 30 20 10 0 82 78 Telaprevir, treatment naive 100 90 80 70 60 TT 50 CT 40 CC 30 20 10 0 80 71 65 59 55 27 28 PR BOC/RGT IL28B CC genotype predicts for short duration therapy 87 100 Week 8 HCV RNA Undetectable* (%) 59 58 89 60 eRVR* (%) 40 60 20 0 Non-CC PR T8PR T12PR 54 48 40 0 BOC/PR48 72 80 52 20 23 25 100 80 73 71 64 Telaprevir + PR Boceprevir + PR 90 TT CC CT CC *Decision point for short vs. long treatment duration with RGT Pol, J Hepatology, 2013 Poordad, Gastroenterology, 2012 Jacobson, EASL, 2011 Simeprevir + PR: IL28B genotype predicts SVR Clinical utility similar to the setting of TVR / BOC + PR QUEST-1 Simeprevir + PR, Phase 3, n=394 Poordad, Gastro, 2012; Jacobson, EASL, 2011 Sofosbuvir + PR: IL28B genotype is less relevant NEUTRINO (n=327) 100 100 SVR12 (%) 80 71 70 50 65 87 40 42 28 80 60 52 49 40 98 78 76 60 60 94 90 83 80 20 24 20 0 no-CC CC 0 PEG+RBV +SIMEPREVIR PEG+RBV +PLACEBO F0-F2 F3-F4 1a 1b/other TT CT CC 12 week fixed duration (no RGT) Predicts short duration therapy (note – 85% of patients overall were eligible) Jacobson, EASL, 2013 Lawitz, NEJM, 2013 Summary • PI + PR regimens: Direct acting antiviral agents (DAAs) – Naïve patients - association b/w IL28B and SVR is attenuated – CC patients: • small absolute increase in SVR • goal = short duration therapy – Non-CC patients: • 2-fold increase in SVR with DAA – PR experienced patients - IL28B less useful • Sofosbuvir + PR: IFN-free regimens – As SVR rates approach 100%, IL28B is less clinically useful 3 29/09/2014 Lessons from SOUND-C2: IL28B genotype is associated with viral kinetics during IFN-free therapy – 2nd phase more important? IL28B genotype predicted SVR for HCV-1a • IL28B genotype is important for HCV-subtype 1a • INFORM-1 : Mericitabine (NS5B NI) + danoprevir (NS3 PI), 14 days BI-201335 + BI-207127 + RBV, 28 weeks CC SVR12 (%) Non-CC Chu, Gastro , 2012 Zeuzem S, EASL, 2012: A101 2014 – IFN-free treatment for Gt 1 2014 – IFN-free treatment for Gt 2/3 SVR genotype 1 (n=1556) W0 W8 W12 SVR genotype 2 W24 W0 W12 W24 Sofosbuvir + RBV1 Sofosbuvir + ledipasvir +/- RBV1 +RBV +RBV +RBV +RBV 24w Naïve (TN) 8w Treatment experienced (TE) TN SVR genotype 3 SVR genotype 1 (n=2308) ABT-450/rb + ABT-267 + ABT-333 +/- RBV2 1Gilead press release, Dec 18, 2013 2Abbvie press release, Dec 2013 Summary: IFN-free therapy Sofosbuvir + RBV2 1Jacobson, NEJM, 2013; 2Zeuzem AASLD, 2013 Predictors of response: 2015+ • IL28B genotype was relevant to early IFN-free DAA regimens – CC patients were “easy to cure”, esp HCV-1a • As SVR rates increase with more potent combination DAA regimens, IL28B no longer predicts for SVR One Size… …Fits All? • There may not be any baseline variables that predict for outcome – Cirrhotic null responders? – Adherence may remain an issue? “Perfectovir” 4 29/09/2014 But does everyone need perfectovir? Can IL28B genotype individualize treatment: Shorter? Cheaper? • Ultra-short duration for C/C IL28B patients is possible SVR12 (%) 100 98 $$$ 80 79 Quad vRVR = 92% 60 40 20 0 6 weeks 12 weeks 1Thompson A, et al. EASL, 2013 The future of HCV therapy Beyond IL28B…? PEG R IL28B 2012 PEG R PEG R PEG R NS3 TVR/BOC IL28B NS3 PEG NS5A RBV NI NI NS5A RBV NS3 NS3 NS5A R Cost minimization NI 2014+ NS5A NNI • Peg backbone • Simpler/shorter DAA regimens • Restricted access $$$ We have the technology… • ITPA polymorphism predicts RBV-associated anemia • Fibrosis progression Conclusion Fellay, Nature, 2010; Thompson, Gastro, 2010; Holmes, Hepatology, 2014 – Cirrhosis Risk Score - 7-snp signature (AZIN1, TLR4, TRPM5, AQP2, Chr 1(rs2290351), Chr 3 (rs4290029), and Chr 5 (rs17740066)) – RNF7, MERTK polymorphisms • Huang , Hepatology. 2007; Marcolongo, Hepatology, 2009; Trepo, J Hepatol., 2011 Patin, Gastro, 2012 Hepatic steatosis • The discovery of the association between IL28B genotype and peginterferon-response was a success story for pharmacogenomics – Personalized medicine became reality for HCV – IL28B genotype informed pre-treatment counselling – PNPLA3 on 22q13.31 (rs738409 C>G encoding I148M) – Has also been associated with HCV-related fibrosis progression Trepo, Hepatology, 2011; Cai, J Hep, 2011; Valenti, Hepatology, 2011; Clark, Dig Dis Sci. 2012 • HCC – MICA on 6p21.33 (rs2596542) • Recent data suggests this signal may be due to linked variation in HCP5 • IL28B genotype predicts for short duration treatment with first generation protease inhibitors (TVR/BOC) Kumar, Nature genetics, 2011; Lange, EASL, 2013 (Late-breaker) – DEPDC5 on 22q12 (rs1012068) Miki, Nature genetics, 2011 5 29/09/2014 Conclusion • The field is now moving away from personalized therapy for HCV – Multiple “optimized” treatment regimens from 2015+ – IL28B genotype will not directly predict SVR – One size will fit all • BUT… not all patients will be able to pay for perfectovir ($$$) • IL28B genotyping will remain useful to personalize regimens: – Cheaper – Simpler (less drugs) – Shorter 6
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