The standard treatment regimen for patients infected with hepatitis C virus (all six genotypes) is pegylated interferon alpha-2a (Peg-interferon) in combination with ribavirin. Although sustained virologic response (SVR) is almost equivalent to virologic cure and the above treatment regimen also reduces the likelihood of patients developing progressive liver disease. Sustained virologic response is achieved in approximately 45% of hepatitis C patients infected with genotype-1. Single nucleotide polymorphisms in the human genome affect how well patients respond to interferon. However, if the patient has cirrhosis, the response rate to treatment is reduced. Many adverse effects occur during treatment, so many patients cannot tolerate Peg-interferon and ribavirin. The first-generation NS3/4A protease inhibitors, Telaprevir and Boceprevir, have been shown to improve the response rate to treatment in first-treatment and previously treated genotype-1 hepatitis C patients. However, these drugs are also more complex to administer and have additional adverse effects when combined with Peg-interferon and ribavirin. To circumvent the adverse effects of interferon, researchers have begun to develop drugs with direct antiviral effects.HCV RNA polymerase adds a single triphosphate ribonucleoprotein to the third end of the nascent RNA strand. The HCV NS5B polymerase has 65% homology across all HCV genotypes, making the polymerase a pan-genotypic target for antiviral action. Several RNA polymerase inhibitors selectively targeting HCV NS5B RNA-dependent RNA polymerase suggest potent in vitro and in vivo anti-HCV activity.Sofosbuvir is a single diastereomer derived from a 2′-deoxy-2′-fluoro-2′-C-methyluracil nucleoside precursor drug. Its aminophosphate portion improves bioavailability as well as facilitates the transport of nucleotides into hepatocytes to produce high concentrations of nucleosides of uridine triphosphate, which are active polymerase inhibitors. In The Lancet, Kris Kowdley and colleagues evaluated the efficacy and safety of the combination of sofosbuvir, Peg interferon, and ribavirin in patients with hepatitis C who had not received prior therapy. The study was an open-label, phase 2 clinical study in which subjects were randomized into three groups: group A, which had a 12-week treatment regimen of sofosbuvir in combination with Peg interferon and ribavirin, and group A, which had 52 subjects; and group B, which had a 24-week treatment regimen of sofosbuvir in combination with Peg interferon and ribavirin, and had 125 subjects; The treatment regimen for Group C (number of subjects 155) was sofosbuvir in combination with Peg interferon and ribavirin for 12 weeks; after 12 weeks of treatment, the subjects in Group C were subdivided into 2 groups, 75 in Group C1, who were treated with sofosbuvir only after 12 weeks, and 75 in Group C2, who were treated with sofosbuvir in combination with ribavirin treatment. The investigators included patients with genotypes 4 and 6 of hepatitis C in both Group B. The intention-to-treat analysis suggested the following SVR rates in each group at week 24: 89% (46) in Group A, 89% (97) in Group B, and 87% (135) in Group C. In these patients, the efficacy of the triple therapy regimen at 12 weeks was consistent with that at 24 weeks. Rapid virologic response was seen in 94-98% of patients; therefore, there was no need to adjust the duration of treatment in order to achieve a virologic response. When comparing subtypes 1a and 1b, the investigators did not find a significant difference in response rates. Adverse effects associated with treatment were primarily due to Peg-interferon and ribavirin and manifested as anemia and neutropenia. Some patients required dose reductions of ribavirin due to hemoglobin concentrations less than 100 g/L. Since there was no sofosbuvir monotherapy control group set up in the study (the treatment regimen did not include interferon), it is difficult to determine the adverse effects caused by sofosbuvir. Of the 125 patients in Group B, 18 (14%) discontinued treatment due to these adverse reactions. So what are the shortcomings of this study? First of all the patients enrolled were older on average. And the investigators excluded patients with cirrhosis and those who had previously received interferon but had not responded to treatment. Patients in both of these categories have a low response rate to interferon themselves, possibly due to a diminished response to interferon, or congenital non-response to interferon, or age, or complexity of the viral quasispecies, abnormalities in liver tissue structure, and vascular shunting. In this study, patients had a higher response rate to treatment than patients with first-generation protease inhibitors, and the treatment regimen was simpler and shorter, but unfortunately, a control group receiving Peg interferon, ribavirin, and a first-generation protease inhibitor was not established in this study. And, the researchers also did not set up a control group that applied only Sofosbuvir and ribavirin without interferon. The results of a recent study suggest that – in HCV patients with genotype 1 who have not received prior treatment – treatment with Sofosbuvir and ribavirin can also achieve a high SVR, so while interferon-free therapy may result in a prolonged duration of treatment, we still need to determine in which patients can be treated with interferon-free regimens. In this study, the investigators noted that the 24-week regimen was also effective in patients with genotypes 4 and 6 by how well they responded to treatment, but further studies are needed to confirm that conclusion. The HCV polymerase Ser282Thr mutation causes resistance to 2′-C-methylnucleoside. In this study, sequencing of the population did not reveal the development of resistance, suggesting that prevention of resistance to the complex could be ensured. Relapse occurred in 1-4% of patients. At this time we are unsure if the IL28b haplotype affects the response rate of patients to treatment, but in patients who did not have the IL28B CC haplotype, few relapses occurred. Why some patients experience relapse is unknown, but the fact that disease relapse occurs because of the presence of wild-type virus rather than drug-resistant virus suggests that the drug failed to clear the virus that was present in the liver or in some cryptic sites. The researchers also found that the concentration of triphosphate was higher in liver cells than in peripheral blood mononuclear cells. What do these results mean for hepatitis C treatment options? While there are still questions that cannot be answered, the response rates to treatment observed in the study were previously unobserved. At the same time, the study reminds us of the additional efficacy of direct antiviral drugs (so-called interferon backup regimens). Several other drugs in the same class have similarly high cure rates when combined with interferon and ribavirin. For example, Simeprevir (protease inhibitor) in combination with Peg interferon and ribavirin. Another example is the application of faldaprevir (protease inhibitor), MK5172 (protease inhibitor) and Daclatasvir (NS5A inhibitor) in patients with genotypes 1 and 4 have equally high cure rates. It has also been demonstrated that Peg interferon-λ is equally effective compared to Peg interferon-α, and that the latter has a lower hematologic toxicity response. These data support the use of Sofosbuvir and other drugs with direct antiviral effects for the treatment of genotype 1 hepatitis C patients. Meanwhile, researchers are also developing new interferon-free combination regimens to overcome the limitations inherent in interferon itself. We are at a crossroads on the road to treating hepatitis C. For many patients, interferon-free regimens will become a viable treatment option. However, given the high SVR achieved with short-term application of interferon and direct antivirals, is it possible to apply the above regimens in patients who can tolerate interferon therapy as well? Or would the inadequacy of interferon itself prevent patients from receiving interferon therapy? How effective is the above regimen in patients who have not responded to previous interferon therapy? What is the efficacy of this regimen in patients with hepatitis C who have comorbid cirrhosis? In The Lancet Infectious Diseases, Eric Lawitz and colleagues published the results of their study, in which their regimen was associated with high treatment response rates in patients with hepatitis C of genotypes 1, 2, and 3. The regimen chosen in Lawitz et al.’s study was Sofosbuvir, Peg interferon, and ribavirin over a 12-week course, and they found that 92% of 25 patients infected with genotypes 2 or 3 achieved SVR.However, we also need to compare the following issues-such as the effect of the 12-week regimen versus the 24-week regimens, or the effect of Sofosbuvir in combination with an NS5a inhibitor such as Daclatasvir on efficacy. However, when looking at the impact of interferon-free regimens on treatment response rates in hepatitis C patients with genotypes 2 and 3, it is not comparable. We need to recognize that Sofosbuvir and other direct antivirals were not developed as adjuncts to interferon. We will continue to search for new effective interferon-free regimens. Many of the Phase 3 clinical studies currently underway are for interferon-free regimens, and these studies will confirm the impact of interferon-alternate and interferon-free regimens on treatment efficacy in patients with hepatitis C at different stages of disease. Treatment for hepatitis C is part of disease control: we need to “escalate” the interferon-free regimen. Ideally, treatment should be expanded without increasing the cost of treatment.