Anti-HCV therapy is the backbone for the treatment of CHC. Since the late 1980s, IFN-α has gradually become the core of antiviral treatment[9-13]. However, IFN-α monotherapy achieved suboptimal efficacy until combined with RBV[14-22] (Figure 1). PegIFN-α has a higher plasma concentration and half-life than interferon, which results in an improved SVR rate as well as improved patient compliance as the pegylated form can be injected once weekly[23-25]. Higher SVR rates were achieved with combination therapy of pegIFN plus RBV than with pegIFN monotherapy, which has become the SOC during the past decade[26,27]. Meanwhile, the true meaning of SVR was unclear until a large cohort study demonstrated that patients who achieved SVR could be considered cured[28]. Unfortunately, not all patients, especially those infected with genotype 1 and 4 HCV could achieve SVR with the SOC. Furthermore, side effects, long-term treatment, contraindications and poor compliance all spurred the development of new agents with shorter treatment durations, fewer contraindications, oral administration, higher specificity, and fewer side effects.

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Figure 1 Brief development history of the anti-hepatitis C virus agents. HCV: Hepatitis C virus; IFN-α: Interferon-α; SVR: Sustained virologic response; pegIFN-α: Peginterferon-α.

HCV is classified in the genus hepacivirus of the family flaviviridae. Once the virus is released into the cell, the viral polyprotein is translated and cleaved by host proteases and the viral NS3-4A protease into ten mature proteins. Next, viral RNA is replicated into progeny RNA by the viral NS5B polymerase. Another viral protein, HCV NS5A, is indispensable for viral replication and assembly and could be a nonenzymatic target for therapeutics. With the structures of NS3/4A protease and NS5B polymerase solved and the rapid development of different cell culture models and biotechnology[29], HCV research has been flourishing both on the bench and in industry. In particular, intensive efforts have focused on developing direct acting antiviral agents (DAAs) that can block the activity of viral enzymes.

The serine protease inhibitors telaprevir and boceprevir, approved by the United States Food and Drug Administration in 2011, were the first and currently only DAA to make it to the clinic. Telaprevir is a linear peptidomimetic HCV NS3/4A serine protease inhibitor, and boceprevir is a protease inhibitor that binds to the HCV NS3 active site. Treatment regimens consisting of telaprevir or boceprevir plus pegIFN-α and RBV had significantly higher SVR rates in genotype 1 patients and became the SOC thereafter[30-34]. However, this new SOC has more adverse events and a similar treatment duration when compared with the former SOC[35], and monotherapy with telaprevir or boceprevir was shown to be impractical due to the rapid selection of resistant variants. In 2012, preliminary clinical data showed that combination therapy with the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir could also achieve high efficacy rates after 24 wk of treatment[36], especially in prior null responders. These results showed the potential of a pegIFN-free regimen for 24 wk treatment duration. However, some patients in this study experienced viral breakthrough due to resistant variants, which ultimately resulted in treatment failure.

In January 2013, Gane et al[37] and Poordad et al[38] published clinical data on the efficacy of sofosbuvir- (also known as GS-7977) and ABT-450-based oral treatment regimens for 12 wk treatment duration. The results showed that 100% of genotype 2/3 patients and 93%-95% of genotype 1 patients achieved SVR. The sofosbuvir and ABT-450 studies were open-label clinical studies that assessed various combination and dosages of agents in previously treated and previously untreated patients. Sofosbuvir exhibits a higher barrier to resistance than ABT-450 because its target, the NS5B polymerase is highly conserved, and viral fitness is crippled if variants occur in the polymerase active site. Sofosbuvir also exhibits pan-genotypic antiviral activity compared to genotype-specific agents, such as ABT-450, asunaprevir, telaprevir and boceprevir. Although some mild adverse events were observed, these studies validated the feasibility of achieving extremely high SVR rates with a pegIFN-free regimen and a short treatment duration of 12 wk.

We summarize representative DAAs from 2011 to January 2013 in Table 1. There have been several treatment evolutions during this timeframe. First, most of these agents were designed for genotype 1 patients, with genotypes 2 and 3 only being considered recently. Second, the treatment period has gradually decreased to 12 wk. Third, dosing frequency has generally improved from three times daily to once daily, which will undoubtedly contribute to better patient compliance. Fourth, combination therapy has gradually shifted away from exclusive combinations with pegIFN-α to trials with and without pegIFN-α to finally pegIFN-α-free regimens. Finally, we found that at least two representative agents were developed from bench to bedside every year. Compared with other DAAs, the sofosbuvir and ABT-450 regimens not only achieve extremely high SVR rates with 12 wk of treatment in treatment-naive patients but are also efficacious in genotype 2 and 3 patients without the need for pegIFN-α.

Gane et al[37] published an open-label clinical trial of 95 previously untreated HCV genotype 1/2/3 patients and genotype 1 null responders (Table 2). The patients were divided into 8 groups: sofosbuvir monotherapy and sofosbuvir plus RBV therapy with or without pegIFN-α for 8 or 12 wk. The results showed that 100% of previously untreated genotype 2/3 patients achieved SVR based on sofosbuvir plus RBV. For previously untreated genotype 1 patients, the SVR rate was 84%. Unfortunately, the SVR rate was only 10% for genotype 1 patients who had no response to previous therapy. These results indicate that genotype 2/3 untreated patients can be completely cured with 12 wk of sofosbuvir plus RBV therapy alone.

Poordad et al[38] published an open-label, phase 2a clinical trial of 50 genotype 1 patients, including untreated patients and patients with no or partial response to prior therapy (Table 3). The patients were divided into 3 groups. Patients received a combination of ABT-333 (a nonnucleoside NS5B polymerase inhibitor), RBV and ritonavir plus two different dosages of ABT-450 for 12 wk. The results showed that 93% and 95% of previously untreated genotype 1 patients achieved SVR. Furthermore, 47% prior null and partial responders achieved SVR. These results indicate that almost all untreated patients with genotype 1 can achieve SVR with ABT-450-based regimens, and null and partial responders can achieve higher SVR rates than previously possible.

Currently, the highest SVR rate observed in genotype 1 patients who have no response to prior therapy is 90%, which was achieved with daclatasvir and asunaprevir-based therapy (Table 6). SVR rates in this patient population treated with telaprevir and boceprevir regimens were only 33% and 52%, respectively, which was significantly inferior to the rates in treatment-naive patients. Sofosbuvir plus RBV has achieved an excellent SVR rate in untreated genotype 1 patients compared with genotype 1 patients who had no response to previous treatment. While the ABT-450 regimen achieved high efficacy in genotype 1 patients with no or partial response to prior treatment, the SVR rate was still less than 50%. All of the above-mentioned results suggest that genotype 1 patients with no or partial response should be the focus of further investigation. Furthermore, genotype 1a patients have more opportunities to develop resistance to the DAAs combination from Poordad et al[38]. Genotype 1a accounts for 89%, 8 out of 9 patients with virologic failure in group 3 who have been analyzed for the presence of resistance-associated variants. The genetic barrier to resistance of protease inhibitors is relatively lower for subtype 1a because this subtype only requires one nucleotide substitution to generate resistance, whereas the 1b virus requires two. Accordingly, genotype 1a patients may be more difficult to treat in new DAAs era.

Although it has not been investigated in a head-to-head study, genotype 1 patients with no or partial response to prior therapy have different SVR rates (10% vs 90%) with different DAA combinations (Table 6)[37,38], indicating that different DAA combinations might be important to successfully treating these types of patients. Various combinations of DAAs are now under investigation[47,48]. However, why a particular combination may lead to an improved SVR rate in these patients remains unclear. It is possible that adding another DAA could complement the mechanisms of action of other agents in the regimen as well as decrease the appearance of cross-resistant variants. As Table 6 shows, 90% of genotype 1 patients with no response to prior therapy can achieve SVR[33], suggesting that a potent DAA combined with pegIFN-α and RBV may be one choice for those patients who can endure the adverse events and long period of treatment.

Various DAA combinations have now been investigated, such as asunaprevir plus daclatasvir; sofosbuvir plus RBV; sofosbuvir plus daclatasvir; faldaprevir plus BI207127; ABT-450/ritonavir plus ABT-333; ABT-450, ritonavir plus ABT-072; miracitabine, danoprevir plus ritonavir; and alisporivir plus RBV[47]. DAA combinations not only have the potential to increase antiviral efficacy but also to reduce the risk of viral breakthrough. When combining DAAs, it is important to consider combinations that have a low propensity for cross-resistance. The genetic barriers to resistance of DAAs appear to be an important factor during the development of resistance. When two agents with a low genetic barrier to resistance are combined, breakthrough occurs more quickly[49]. Adding on pegIFN-α or RBV[36] as well as nucleoside analogues with a higher genetic barrier might be better tactics for overcoming resistance[37,50]. For example, 90% of difficult-to-treat patients can achieve SVR with a combination of daclatasvir, asunaprevir, pegIFN-α2a and RBV for 24 wk of treatment[36]. Furthermore, 84%-100% of patients can achieve SVR with a combination of sofosbuvir plus RBV for 12 wk of therapy[37].

Whether or not to include pegIFN-α is a key issue in the DAA era. Several years ago, many hepatologists believed that HCV treatment would be IFN free. Now, however, the ability to do away with IFN is not so clear, especially in some difficult-to-treat patients. Although not compared in a head-to-head study, the SVR rate was relatively lower in refractory patients treated with a pegIFN-free regimen, as shown in Table 6. This information indicates that IFN-free regimens may be available for easy-to-treat patients in the near future, whereas IFN might be necessary for difficult-to-treat patients.

In Tables 2 and 5, groups 4 and 6 differ with respect to treatment duration (12 and 8 wk, respectively). In group 4, 81% (9/11) of patients were genotype CC or CT. In group 6, 90% (9/10) of patients were genotype CC or CT. It will be interesting to investigate whether IL-28B polymorphisms could predict treatment duration in the DAA era, especially in patients with the potential to reduce the treatment course.

In addition to above-mentioned situations, results from group 5 patients who received sofosbuvir monotherapy suggested the crucial role of RBV in maintaining an antiviral response (Table 2). However, the exact mechanism by which RBV contributes to SVR in the DAA era remains uncertain. Another area of important research in the future will likely be treatment of patients with cirrhosis, and hepatitis B virus and human immunodeficiency virus co-infected patients. Although the sofosbuvir- and ABT-450-based therapies were well tolerated, the safety profile of other combination treatments remains to be seen.