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Future Directions for Hepatitis C Therapy
Although TVR- and BOC-based regimens represent the first generation of oral DAA agents that have significantly improved SVR rates in HCV genotype 1-infected individuals, PegIFN and RBV are still required, treatment regimens are complex, adverse effects are significant, and treatment has limited efficacy in certain subgroups (e.g., nonresponders to PegIFN/RBV). Future therapies against HCV will likely yield higher SVR, lower pill burden with once or twice daily dosing, shorter treatment duration, less viral resistance, more favorable safety profiles, and broader genotype coverage (86, 87, 88, 89, 90) . Classes of agents currently in clinical trials include: second generation HCV PIs, nucleoside/nucleotides, and non-nucleoside/non-nucleotides polymerase inhibitors, nonstructural protein 5a inhibitors, novel IFNs, and cyclophilin inhibitors. Second-generation PIs with PegIFN and RBV yield similar or better SVR rates than BOC- or TVR-based triple therapy. PegIFN lambda appears to be as effective as PegIFN alfa, but with fewer side effects, including less anemia and neutropenia. IFN-free regimens, which contain two direct acting agents (e.g., a PI and a polymerase inhibitor), with or without RBV, appear to improve SVR rates in both treatment-naive and -experienced HCV-infected individuals (91, 92, 93) . Larger studies are in progress, and FDA approval of IFN-free regimens is not expected for at least 3 years. The potency, improved dosing regimens, and continually improving efficacy of new HCV combination therapies mean that the HCV treatment field will remain dynamic for many years.