1. IL28B in the Era of DAA Therapy: Ten Years Too Late? Donald M. Jensen, MD Professor of Medicine Director, Center for Liver Disease University of Chicago

2. 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?

3. 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

4. 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 – But, if government or insurance mandated…….

5. 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 – It’s on-treatment virologic responses that really matter, not pre-treatment dispositions

6. 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 Surrogate testing not perfect either – Could argue that all ‘mild’ cases be deferred given the toxicity of DAA triple therapy, not just IL28B T? – When is IFN-free therapy anticipated? 2014-2015?

7. 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, will there even be a role for -IFN responsiveness? (e.g. PROTON)

8. 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????