The field of hepatitis C treatment is rapidly evolving. Given the constant changes in this field, treatment of patients with hepatitis C will become extremely challenging in 2013. Several questions remain controversial.1 Which patients should be treated promptly with the drugs already available? Which patients can wait until interferon-free therapies become available? When will interferon-free therapies become available, and will the new drugs be effective and well tolerated? What are the costs of interferon-free therapies? Are there other alternatives that could further improve the efficacy of the drugs currently used? IFN-α has been the cornerstone of antiviral therapy for chronic hepatitis C for more than two decades, with sustained virologic response (SVR) rates ranging from 30-90% depending on HCV genotype, stage of liver disease progression, and host genetic background.2 However, because IFN-α-containing therapy is associated with a range of adverse events, IFN-α is used for the treatment of only a small number of HCV-infected individuals Unlike most other persistent viral infections, HCV infection is potentially curable. HCV completes its life cycle in the cytoplasm alone (no nuclear phase exists), and therefore, effective inhibition of viral replication can cure HCV-infected cells in the absence of drug resistance. Thus, one obvious way to improve hepatitis C therapies is to use a combination of novel direct antiviral agents (DAAs) that target different stages of the HCV life cycle. Initial success with interferon-free therapies In fact, back in 2012, the results of the first proof-of-concept study were published demonstrating that SVR could indeed be achieved with interferon-free DAA combinations in patients with chronic hepatitis C.4 The drugs involved in that study were inhibitors of HCV nonstructural protein 5A – daclatasvir and asunaprevir, a protease inhibitor of HCV nonstructural protein 3. The study was conducted in patients infected with genotype 1a or 1b HCV virus and previously non-responders to IFN-α-based therapies who received PEG (polyethylene glycol)-IFN-α2a (interferon α2a)-ribavirin (ribavirin), daclatasvir and asunaprevir quadruple therapy or a combination of both daclatasvir and asunaprevir alone for 24 weeks. The quadruple therapy successfully cured all 10 patients with HCV infection. This is an excellent result given the low cure rate in non-responders receiving PEG-IFN-α, ribavirin, telaprevir (telaprevir) or boceprevir (boceprevir). In the interferon-free therapy group with daclatasvir and asunaprevir, HCV RNA was rapidly reduced in all patients, and SVR was seen in 4 of 11 patients, with 2 of the genotype 1b HCV-infected patients successfully clearing the virus. A study in Japan using daclatasvir and asunaprevir, which enrolled only patients infected with genotype 1b HCV, was also successful.5 All 10 patients who had not previously responded to PEG-IFN-α-ribavirin therapy were treated with daclatasvir and asunaprevir after the study. asunaprevir therapy to obtain SVR. Key Advances in Interferon-Free Therapy In 2012, although some interferon-free therapies were not successful,6 the first successful cure of chronic hepatitis C cases with interferon-free therapy was also reported.4 Before achieving interferon-free therapy, clinicians must consider the adverse events and cost-benefit relationships of existing therapies9 and adapt IFN therapy to increase sustained virologic response rates7