Initial success with interferon-free therapy In fact, in 2012, the results of the first proof-of-concept study were published demonstrating that SVR could indeed be achieved with interferon-free DAA combination therapy in patients with chronic hepatitis C.4 The drugs involved in this study were daclatasvir, an inhibitor of HCV nonstructural protein 5A, and asunaprevir, a protease inhibitor of HCV nonstructural protein 3. 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 achieve 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 Figure 1 Interferon-free combinations of direct antivirals for hepatitis C currently in the investigational phase (including previously tested interferon-free combinations) Limitations of interferon-free therapies Many other interferon-free therapies consisting of combinations of DAAs are currently in clinical development (Figure 1). The data obtained over the past 12 months highlight that simply combining different classes of DAAs is not sufficient; it is the strength of the antiviral drug and its presence or absence of resistance barriers (i.e., the ability to resist resistance) that is critical to prevent treatment failure. Zeuzem et al6 studied the antiviral activity of the HCV protease inhibitor GS-9256 and the non-nucleotide polymerase inhibitor tegobuvir for 28 days. During the first 48 hours of treatment, tegobuvir-GS-9256 significantly reduced HCV RNA levels, but by day 7, most patients experienced a virological rebound. Of the 15 patients, only 1 maintained virologic suppression until day 28. Dual virologic resistance was observed in 7 of 8 patients infected with genotype 1a HCV. The combination of ribavirin was associated with delayed virologic failure, but after 4 weeks, only 5 of 13 patients still had HCV RNA levels less than 25 IU/ml. In contrast, all 14 patients who received tegobuvir, GS-9256, ribavirin and PEG-IFN-α2a-containing quadruple therapy were treated successfully. Several important conclusions can be drawn from this study that are important for the development of future interferon-free therapies. First, the combination of two DAAs with fairly low barriers to resistance and limited antiviral efficacy is not recommended, as this could lead to tolerance to both drugs within days of starting therapy. Second, ribavirin still plays an important role in all oral interferon-free therapies for chronic hepatitis C (at least for weak DAAs). Third, the addition of two DAAs to PEG-IFN-α-ribavirin therapy is a very effective approach, which may become an option for some refractory patients. Raloxifene may increase response rates to standard therapies Until interferon-free therapies become a reality, we will have to use the existing standard therapies consisting of PEG-IFN-α, ribavirin and HCV protease inhibitors. A key question in the current treatment of chronic hepatitis C is whether protease inhibitors are needed in all patients or whether the combination of PEG-IFN-α-ribavirin alone is still sufficient against HCV for some subgroups of patients?In what follows, we will find that it is important to improve the efficacy of the original standard therapy, which would reduce the need for protease inhibitors. demand. Japanese scholars explored whether raloxifene (raloxifene, a selective estrogen receptor modulator) could improve the response rate to standard PEG-IFN-α-ribavirin therapy.7 This trial was conducted based on the observation that postmenopausal women have a very low response rate to interferon-based therapy. Researchers randomly assigned 123 women to the PEG-IFN-α-ribavirin treatment group with or without raloxifene (60 mg daily). The control group had an SVR rate of 34%, compared with 61% in the raloxifene-containing group. Those who received raloxifene-containing therapy had higher treatment response rates and lower relapse rates. The authors speculate that the significant increase in cure rates may be due to the antioxidant and anti-lipid peroxidation activities of raloxifene. In addition to this, raloxifene may be able to inhibit HCV infection at multiple points in the HCV life cycle.8 However, further placebo-controlled trials in other populations and with triple therapy (and even future interferon-free therapies) are still needed to corroborate these interesting findings. Existing issues and future perspectives One very important but still unresolved question is whether treatment with the extremely expensive telaprevir or boceprevir is value for money?Cammà and colleagues9 applied a mathematical model to address this question by comparing different approaches using these two protease inhibitors – -for all patients or only for patients who do not carry the beneficial genotype “IL28B-CC”. Another scenario they studied was that patients who achieved a rapid virological response (RVR) during the first 4 weeks of PEG-IFN-α-ribavirin treatment would not start boceprevir treatment if they achieved a rapid virological response (RVR) during this introductory phase. In the model they applied, triple therapy extended survival by about 4 years at a relatively low cost. This data is important for the defense of health insurance coverage for those payers in many countries. In addition, this study provides evidence to support the application of cost-saving therapies (limited to those individuals with the greatest benefit with protease inhibitors). A wealth of new research data on interferon-free therapies was presented during the International Liver Disease Conference organized by the European Federation for Liver Research in April 2012 and the American Association for the Study of Liver Diseases conference in November. There are several studies confirming the possibility of curing HCV infection with interferon-free therapy, even in patients with cirrhosis or those infected with genotype 1a or other genotypes of HCV virus. Notably, it is expected that very high response rates can be achieved. By the end of 2014, it is likely that more than 3 different types of DAA combination regimens with or without ribavirin will be available on the market. This will not be the end of the road for the development of new HCV therapies, as there are at least 30-40 different new compounds currently in clinical trial studies. It’s time to prepare to say goodbye to IFN!