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Will interferon-free strategies be a reality?. David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic www.torontoliver.ca . Disclosures. Principal Investigator in multicenter studies HCV (none for IFN-free strategies)
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Will interferon-free strategies be a reality? David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic www.torontoliver.ca
Disclosures • Principal Investigator in multicenter studies • HCV (none for IFN-free strategies) • BI, BMS, Johnson & Johnson, Vertex • HBV • BMS, Gilead • NO involvement in • Advisory Boards, Consultancy roles, Stocks
Outline • IFN free strategies can work • Choosing optimal combinations • Exploring weaknesses of individual agents • Access to treatment • Need for more drugs in each class • Cost of treatment
HCV genomeCombinations for cure Protease Pol Replication Complex
First reportNaïve x 24 weeks • BMS-790052 (Daclatasvir) 60 mg OD • NS5a replication complex inhibitor • BMS-650032 (Asunaprevir) 600 mg BID • NS3 protease inhibitor • PegIFNa2a 180 ug weekly • Weakness: IL28b, cirrhosis (excluded), safety • Ribavirin 1000-1200 mg OD • Weakness: resistance? AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216
Results (SVR) *1 PCR neg 35 days later Resistance Relapse 11 10 11 10 AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216
NS5A + PI • Adding IFN helps • IFN likely small effect (prior null response) • RBV likely even less effect (resistance) AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216
INFORM-SVRTreatment naïve x 24 weeks • Mericitabine (MCB) 1000 mg BID • Polymerase inhibitor • Danoprevir (DNV) 100 mg BID/ ritonavir 100 mg BID • Macrocyclic protease inhibitor - boosted • Ribavirin 1000-1200 mg OD • Treatment naïve • Cirrhotics excluded EJ Gane et al. EASL 2012
Results after 24 weeks • High relapse if • 12 weeks treatment • RBV not included • Adding IFN helps 43 21 15 4 28 17 EJ Gane et al. EASL 2012
PI/r + PolI + RBV • Ribavirin needed • DNV/r + MCB is weak double therapy • Adding another agent (IFN) helps • G1b > 90%, G1a > 70% • Matterhorn Study EJ Gane et al. EASL 2012
Sound-C2/3PI + NNPolI +/- RBV • Faldaprevir (FDV) 120 mg OD • Protease inhibitor (all except 3) • Deleobuvir (DLV) 600 mg BID • Non-Nuc Polymerase Inhibitor • Sound-C21 • 1b >> 1a • IL28b CC and Genotype 1a might respond? • GI side effects: cannot keep pills down • Sound-C32 (learning from our mistakes) • SVR in G1b: 19/20 (95%) • SVR in G1a, IL28b CC: 2/12 (17%) V Soriano et al. EASL 2012 S Zeuzem et al. APASL 2013
PI/r + PolI + RBV • Ribavirin needed • FDV and DLV is weak double therapy • Replacing RBV with another agent will likely help EJ Gane et al. EASL 2012
ABT orals + RBV x 12 weeks in non-cirrhotics (naïve and nulls) • ABT-450/r • Protease inhibitor • ABT-267 • NS5a inhibitor • ABT-333 • Non-Nuc Polymerase Inhibitor KV Kowdley et al. A3. EASL 2013
SVR24 Naïve N=159 Null N=88 % SVR24 81 50 124 42 44 33 33 66 45 3 78 108 35 113 115 56 55 22 41 85 1b >7 log <7 log CC Male Female 1a F0-F1 Non-CC 1b >7 log <7 log F2-F3 CC Male Female 1a F0-F1 Non-CC F2-F3 KV Kowdley et al. A3. EASL 2013
Salvage for BOC/TPV failuresSOF+DCV+/-RBV x 24 weeks • Sofosbuvir (SOF) • Nuc Polymerase Inhibitor • Declatasvir (DCV) • NS5A Replication Complex Inhibitor MS Sulkowski et al. A1417. EASL 2013
SVR12 1 missed is SVR24 % SVR 21 20 21 20 21 20 21 20 21 20 MS Sulkowski et al. A1417. EASL 2013
Gilead Pipeline • Ledipasvir (LDV) • NS5A Replication Complex Inhibitor • GS-9669 • Non-Nuc Polymerase Inhibitor • Gilead plans • SOF + LDV • What about SOF + LDV + GS-9669?
SOF + RBV + (LDV or GS-9669)x 12 weeks Electron Study: EJ Gane et al. A14. EASL 2013
FISSIONG2/3 Treatment naïve x 12 weeks • Sofosbuvir (SOF) 400 mg OD • Polymerase inhibitor • Ribavirin (RBV) 1000-1200 mg OD • Treatment naïve • Cirrhotics included but Plts > 75 • Compared with PegIFN-RBV (800) x 24 weeks E Gane et al. A5. EASL 2013 E Lawitz et al. NEJM 2013;368:1878
SVR12 251 241 250 236 244 224 190 253 243 59 54 11 13 145 139 38 37 Genotype 2 Genotype 3 Fission study: E Gane et al. A5. EASL 2013
FUSIONG2/3 Difficult to treat 1FUSION: DR Nelson et al. A6. EASL 2013 2POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867 • FUSION1 x 12 or 16 weeks • IFN failures • Cirrhosis 33% (Patelets > 50) • POSITRON2 x 12 weeks • IFN intolerant, ineligible or unwilling • Cirrhosis 15% (no platelet restriction)
SVR12SOF + RBV Genotype 3 Prior treatment > 12 weeks 26 23 92 10 9 17 38 40 84 26 23 14 Genotype 2 Genotype 3 1FUSION: DR Nelson et al. A6. EASL 2013 2POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867
SummaryIFN-Free is inevitable • Challenging populations • Cirrhosis • Genotype 3? • Dream combo • Choice of agents to choose from • Ribavirin is weak • Interferon Lambda? • 3 bedroom house • PRT ~ 4 years+ rent • SVR ~ 10 years+ rent