IL28B in the Era of DAA Therapy:Ten Years Too Late?

Donald M. Jensen, MDProfessor of Medicine

Director, Center for Liver DiseaseUniversity of Chicago

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 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…….

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

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?

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)

Summary

• How will IL28B be utilized in the era of DAA triple therapy?– Predict shorter treatment duration– Identify patients who may benefit from dual

therapyHowever,… – True utilization may depend upon real life clinical

experience with triple therapy and retrospective analysis of IL28B

Ten years too late????